1.COX-2 Inhibitors in Inflammatory Bowel Disease: Friends or Foes?.
The Korean Journal of Gastroenterology 2007;50(6):350-355
The cyclooxygenase (COX) is a key enzyme in the coversion of arachidonic acid to prostaglandins. COX-1 is constitutively expressed and is a critical housekeeping gene, whereas COX-2 is rapidly upregulated by growth factors and cytokines and thus responsible for inflammation. COX-2 is frequently overexpressed in colonic adenoma and carcinoma. Specific inhibitors of COX-2 have been shown to induce apoptosis in tumor cells and to inhibit tumor growth in animal models and in humans. Long-standing IBD patients have increased risk of developing colorectal cancer compared to general population. IBD-associated colorectal carcinogenesis is probably promoted by chronic inflammation and closely related to COX-2. In a recent study, powerful chemopreventive ability of selective COX-2 inhibitor was observed in colitis-related colon carcinogenesis in mouse model. But it was reported that even selective COX inhibitors aggravated the DSS-induced colonic inflammation. It is assumed that endogenous PGs are involved in the mucosal defense against DSS-induced colonic ulcerations which are produced by COX-1 at early phase and by COX-2 at late phase. Long-term use of COX-2 inhibitors for the chemoprevention of colitic cancer is needed to define their mechanism of action, that reduce side effects and have specific tumor target.
Animals
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Colitis, Ulcerative/*drug therapy
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Colonic Neoplasms/diagnosis
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Cyclooxygenase 1/metabolism
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Cyclooxygenase 2/metabolism
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Cyclooxygenase 2 Inhibitors/pharmacology/*therapeutic use
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Humans
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Mice
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Models, Animal
2.Garden rue inhibits the arachidonic acid pathway, scavenges free radicals, and elevates FRAP: role in inflammation.
Manjir Sarma KATAKI ; Bibhuti B KAKOTI ; Biman BHUYAN ; Ananya RAJKUMARI ; Prakash RAJAK
Chinese Journal of Natural Medicines (English Ed.) 2014;12(3):172-179
AIM:
In the present study, the anti-inflammatory and antioxidant activities of the methanol extract of Ruta graveolens leaves (RG-M) were evaluated using various in vivo and in vitro models.
METHOD:
For anti-inflammatory activity, RG-M was administered by the oral route (p.o.) in a carrageenan-induced paw edema model, and by the intraperitoneal route (i.p.) in an exudative inflammation model. In vitro inhibition of cyclooxygenase and lipoxygenase enzymes was evaluated. In vitro antioxidant activity was also examined. Endogenous antioxidant status was further evaluated by ferric reducing ability of plasma model.
RESULTS:
RG-M showed maximum inhibition of carrageenan-induced edema (100 mg·kg⁻¹ - 33.36%; 200 mg·kg⁻¹ - 45.32% and 400 mg·kg⁻¹ - 56.28%). In the exudative inflammation model, a significant reduction in leukocyte migration (200 mg·kg⁻¹ - 54.75% and 400 mg·kg⁻¹ - 77.97%) and protein exudation (200 mg·kg⁻¹ - 31.14% and 400 mg·kg⁻¹ - 49.91%) were observed. RG-M also exhibited inhibition of COX-1 (IC50 182.27 μg·mL⁻¹) and COX-2 (IC50 190.16 μg·mL⁻¹) as well as 5-LOX (IC50 215.71 μg·mL⁻¹). Antioxidant activity was significant with improved endogenous antioxidant status.
CONCLUSION
The results demonstrated the anti-inflammatory and antioxidant activity of RG-M with potent inhibitory effects on the arachidonic acid pathways.
Animals
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Anti-Inflammatory Agents
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pharmacology
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therapeutic use
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Antioxidants
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pharmacology
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therapeutic use
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Arachidonic Acid
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metabolism
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Carrageenan
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Cyclooxygenase 1
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metabolism
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Cyclooxygenase 2
;
metabolism
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Cyclooxygenase Inhibitors
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pharmacology
;
therapeutic use
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Disease Models, Animal
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Edema
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drug therapy
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Exudates and Transudates
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Ferric Compounds
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metabolism
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Inflammation
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drug therapy
;
metabolism
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Leukocytes
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metabolism
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Lipoxygenase Inhibitors
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pharmacology
;
therapeutic use
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Lipoxygenases
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metabolism
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Male
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Phytotherapy
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Plant Extracts
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pharmacology
;
therapeutic use
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Plant Leaves
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Rats, Wistar
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Ruta
3.Role of Prostaglandins in Colon Cancer.
The Korean Journal of Gastroenterology 2008;51(5):274-279
Colon cancer is one of the major leading causes of cancer-related deaths in the Western countries. In Korea, the incidence of colon cancer is increasing due to changes in environment and lifestyle such as diet. Chemoprevention strategy using non-steroidal anti-inflammatory drugs (NSAIDs) has been under intensive clinical and epidemiological research as these drugs suppress colorectal cancer. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. Among these PGs, prostaglandin E2 (PGE2) can promote tumor growth by binding its receptors and activating signal pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Therefore, COX inhibition is promising approach for chemoprevention of colorectal cancer. However, the prolonged use of COX-2 inhibitors is associated with unacceptable cardiovascular side effects. Thus, new targets involved in PGs metabolism are under investigation. 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key metabolic enzyme of PGE2, was up-regulated in normal colonic epithelium, but decreased in colon cancer. Recent findings suggest that 15-PGDH is involved in the neoplastic progression of initiated colonic epithelial cells. Also, new players related with PGs metabolism including prostaglandin transporter (PGT) and microsomal prostaglandin E synthase (mPGES) were reported to play a role in colorectal cancer development. This review presents current knowledge about the role of prostaglandins and associated proteins in colorectal cancer development and progression.
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
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Colonic Neoplasms/drug therapy/*etiology/prevention & control
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Cyclooxygenase 2/metabolism
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Cyclooxygenase Inhibitors/pharmacology/therapeutic use
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Humans
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Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors/metabolism
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Prostaglandins/metabolism/*physiology
4.Inhibitory effects of cyclooxygenase-2 inhibitor celecoxib on the proliferation of hepatocellular carcinoma cells.
Bao-Dong TANG ; Qi ZHOU ; Qin-Hua LIN ; Si-Chun LIU
Journal of Southern Medical University 2007;27(10):1511-1513
OBJECTIVETo study the inhibitory effects of celecoxib, a cyclooxygenase-2 inhibitor, on the proliferation of hepatocellular carcinoma cells.
METHODSThe in vitro inhibitory effects of celecoxib at different concentrations and for different treatment time lengths on human liver cancer cell line SMMC-7,721 were observed with MTT assay, and flow cytometry was performed to detect the cell cycle changes. The in vivo tumor inhibition effect of celecoxib was evaluated in Kunming mice bearing transplanted tumor derived from liver cancer cell line H22 transplantation.
RESULTCelecoxib significantly inhibited the in vitro growth of human liver cancer cell line SMMC-7721 in a time- and dose-dependent manner. A 36-hour celecoxib treatment (40 micromol/L) resulted in decreased SMMC-7721 cell proliferation and an increase of the cell percentage in G1 phase from 44.7% to 49.9% with decreased cell percentage in S and G(2)/M phases from 55.4% to 50.1%. In the mice bearing H22 transplanted tumor, celecoxib showed significant inhibitory effect on the growth and local metastasis of the transplanted tumor.
CONCLUSIONCelecoxib can inhibit the proliferation of different liver cancer cell lines both in vitro and in vivo, and therefore may serve as an important candidate drug for prevention and treatment of hepatocellular carcinoma.
Animals ; Carcinoma, Hepatocellular ; drug therapy ; physiopathology ; Celecoxib ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cyclooxygenase 2 Inhibitors ; pharmacology ; therapeutic use ; Female ; Humans ; Liver Neoplasms ; drug therapy ; physiopathology ; Mice ; Neoplasm Transplantation ; Pyrazoles ; pharmacology ; therapeutic use ; Sulfonamides ; pharmacology ; therapeutic use
5.Effects of cyclooxygenase-2 selective inhibitor celecoxib on the expression of major vault protein in rats with status epilepticus.
Ting-Ting SONG ; Dan LI ; Shao-Ping HUANG ; Lin YANG ; Xue-Ying WANG ; Yong-Sheng JIANG ; Yu LIU
Chinese Journal of Contemporary Pediatrics 2016;18(5):440-445
OBJECTIVETo study the effect of cyclooxygenase -2 selective inhibitor celecoxib on the expression of major vault protein ( MVP) in the brain of rats with status epilepticus and its possible roles in the treatment of refractory epilepsy.
METHODSSixty adult male Sprague-Dawley rats were randomly assigned to blank control (n=16), epilepsy model (n=22) and celecoxib treatment groups (n=22). After the status epilepticus was induced in rats by injecting lithium and pilocarpine, each group had 16 rats enrolled as subjects. Immunohistochemical method and Western blot method were used to detect the expression of MVP in the frontal cortex and hippocampus.
RESULTSThe expression of MVP was significantly higher in the epilepsy model group than in the control group (P<0.01). The expression of MVP in the celecoxib treatment group was significantly decreased compared with the epilepsy model group, but it was still higher than in the control group (P<0.01).
CONCLUSIONSCelecoxib could decrease the expression of MVP in brain tissue of rats with status epilepticus, suggesting that it is promising for the treatment of intractable epilepsy.
Animals ; Blotting, Western ; Brain ; metabolism ; Celecoxib ; pharmacology ; therapeutic use ; Cyclooxygenase 2 Inhibitors ; pharmacology ; Immunohistochemistry ; Male ; Rats ; Rats, Sprague-Dawley ; Status Epilepticus ; drug therapy ; metabolism ; Vault Ribonucleoprotein Particles ; analysis
6.Cyclooxygenases, lipoxygenases, their targeted drugs and the prevention of Alzheimer's disease.
Jiao-Ning SHEN ; Liu-Xin XU ; Rui WANG
Acta Pharmaceutica Sinica 2013;48(12):1743-1754
Many studies have shown that chronic inflammation occurs in the brain of patients with Alzheimer's disease (AD). It is well known that long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) can alleviate the cognitive decline of AD patient and elderly. Several inflammatory cytokines produced in the metabolism of arachidonic acid (AA) are closely related to inflammatory diseases. Lipoxygenases (LOXs) and cyclooxygenases (COXs) play a crucial role in the AA network, the products eicosanoids have an important impact on the progression of AD. Although there are many arguments and conflicting evidence, currently LOXs and COXs are still the hot topics in the research on AD pathogenesis and drug development. Here, we review the progress in research on COXs and LOXs, including their actions on CNS and their association with AD, and explore the feasibility of LOXs and COXs as targets for the drugs to prevent and/or treat AD.
Alzheimer Disease
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drug therapy
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enzymology
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prevention & control
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Amyloid beta-Peptides
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metabolism
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Animals
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Anti-Inflammatory Agents, Non-Steroidal
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pharmacology
;
therapeutic use
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Arachidonic Acid
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metabolism
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Brain
;
metabolism
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Cyclooxygenase 1
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metabolism
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Cyclooxygenase 2
;
metabolism
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Cyclooxygenase Inhibitors
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therapeutic use
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Humans
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Lipoxygenase Inhibitors
;
therapeutic use
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Lipoxygenases
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metabolism
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Prostaglandin H2
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metabolism
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Prostaglandin-Endoperoxide Synthases
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metabolism
7.Celecoxib induces apoptosis and inhibits angiogenesis in gastric cancer.
Jun-tao RAN ; Yong-ning ZHOU ; Cheng-wei TANG ; Jian-rong LU ; Jing WU ; Hong LU ; Guo-dong YANG
Chinese Journal of Oncology 2008;30(6):448-451
OBJECTIVEThe aim of this study was to explore the effect of celecoxib, a cyclooxygenase-2 inhibitor, on induction of apoptosis and inhibition of angiogenesis in gastric cancer.
METHODSFifty nine gastric cancer patients were randomly divided into 2 groups: celecoxib group (n = 37) and control group (n = 22). The patients in the celecoxib group were treated orally with celecoxib 200 mg twice daily for 7 days before resection. The patients in the control group received surgical resection alone. Another group of 20 healthy subjects were recruited as normal control. The number of apoptotic tumor cells was measured by terminal deoxynucleotidyl transferse-mediated dUTP nick end labeling (TUNEL). The expression of COX-2, VEGF and the microvessel density (MVD) were evaluated by immunohistochemistry.
RESULTSThe TUNEL results showed an increase of apoptosis in the tumor cells after celecoxib treatment in comparison with that in the control group (7.1% +/- 1.0% vs. 6.2% +/- 0.9%, P < 0.05). The expression level of COX-2 and VEGF in the gastric cancer tissues was significantly decreased in the celecoxib group compared with those in the control group (P < 0.05). Furthermore, MVD was also significantly lower in the celecoxib group when compared with that in the control group (30.48 +/- 5.02 vs. 38.98 +/- 4.58, P < 0.05).
CONCLUSIONOral intake of celecoxib can induce apoptosis and suppress angiogenesis in gastric cancer. It may become an effective agent in the treatment of gastric cancer.
Adenocarcinoma ; metabolism ; pathology ; Adult ; Aged ; Apoptosis ; drug effects ; Celecoxib ; Cyclooxygenase 2 ; metabolism ; Cyclooxygenase 2 Inhibitors ; pharmacology ; therapeutic use ; Female ; Humans ; Male ; Microvessels ; pathology ; ultrastructure ; Middle Aged ; Neovascularization, Pathologic ; prevention & control ; Pyrazoles ; pharmacology ; therapeutic use ; Stomach Neoplasms ; metabolism ; pathology ; Sulfonamides ; pharmacology ; therapeutic use ; Vascular Endothelial Growth Factor A ; metabolism
8.Biochemical pathways in the antiatherosclerotic effect of berberine.
Yi GUO ; Qi-zhang WANG ; Fang-ming LI ; Xin JIANG ; Yan-fang ZUO ; Ling WANG
Chinese Medical Journal 2008;121(13):1197-1203
BACKGROUNDThis study investigated the inhibitory effect of berberine (BBR) on lipopolysaccharide (LPS) induced cyclooxygenase-2 (COX-2) expression via the mitogen activated protein kinase (MAPK) signalling cascade pathways in human peripheral blood monocytes (PBMC).
METHODSPBMC from whole blood were isolated and cultured for up to 24 hours after division into 5 groups treated with LPS, LPS + BBR 25 micromol/L, LPS + BBR 50 micromol/L or LPS + BBR 100 micromol/L and untreated. Monocytes were extracted for RT-PCR and Western blot analyses to examine COX-2 mRNA and protein activated expression of p38 mitogen activated protein kinase (p38MAPK), Jun N-terminal kinase (JNK) and extracellular regulated kinases 1/2 (ERK1/2) signalling pathways.
RESULTSCOX-2 mRNA and protein expression decreased to a minimum at 12 hours after BBR treatment (P < 0.05). With the increasing concentration of BBR treatment, the COX-2 expression decreased progressively (P < 0.01). With BBR treatment for 6, 12 or 24 hours at three doses, ERK1/2 protein expression was significantly inhibited. For the JNK pathway, only with the treatment of BBR at the concentration of 100 micromol/L was JNK protein expression inhibited compared with the LPS stimulation group (P < 0.01). Irrespective of the BBR concentration, no difference was shown between the BBR group and the LPS group for p38MAPK protein expression. Human monocytes COX-2 mRNA, by RT-PCR, and protein expression, by Western blot analysis, were inhibited when incubated with PD98059, SP600125 and SB203580 (P < 0.05).
CONCLUSIONSBerberine inhibits COX-2 expression via the ERK1/2 signalling pathway and, possibly, at a high dosage via the JNK pathway. P38MAPK may have no relationship with the effect of BBR in PBMC. Berberine inhibited COX-2 mRNA and protein expression in a dose dependent manner and suppressed COX-2 expression to a minimal level after 12 hours of berberine treatment.
Atherosclerosis ; drug therapy ; Berberine ; pharmacology ; therapeutic use ; Cells, Cultured ; Cyclooxygenase 2 ; genetics ; Cyclooxygenase 2 Inhibitors ; pharmacology ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases ; antagonists & inhibitors ; Humans ; JNK Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; Lipopolysaccharides ; pharmacology ; MAP Kinase Signaling System ; Time Factors
9.Study on the mechanism of preventing alcholic liver disease by selective cyclooxygenase 2 inhibitor.
Jun-ying ZHOU ; Dong-fang ZHOU ; Ying-hui LIU ; Wei WANG ; Feng WEI
Chinese Journal of Hepatology 2009;17(7):559-560
Animals
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Celecoxib
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Cyclooxygenase 1
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genetics
;
metabolism
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Cyclooxygenase 2
;
genetics
;
metabolism
;
Cyclooxygenase 2 Inhibitors
;
pharmacology
;
therapeutic use
;
Cytokines
;
metabolism
;
Disease Models, Animal
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Ethanol
;
adverse effects
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Fatty Liver, Alcoholic
;
pathology
;
prevention & control
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Immunohistochemistry
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Liver
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drug effects
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metabolism
;
pathology
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Liver Cirrhosis, Alcoholic
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pathology
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prevention & control
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Liver Diseases, Alcoholic
;
pathology
;
prevention & control
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Pyrazoles
;
pharmacology
;
therapeutic use
;
RNA, Messenger
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genetics
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metabolism
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Rats
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfonamides
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pharmacology
;
therapeutic use
10.Selective COX-2 inhibitor delays experimental gastric ulcer healing by stimulating gastric acid secretion in rats.
Mei-rong HE ; Jin-qiu LIN ; Yu-gang SONG
Journal of Southern Medical University 2007;27(7):1015-1017
OBJECTIVETo observe the effect of selective cyclooxygenase-2 (COX-2) inhibitor on the healing of experimental gastric ulcer in rats and explore its mechanisms in light of gastric acid secretion.
METHODSGastric ulcers were induced in rats by an application of acetic acid to the serosal surface of the anterior gastric body. The effects of selective COX-2 inhibitor, celecoxib, on the healing of gastric ulcer, the total acidity of gastric juice, the expressions of H+, K+-ATPase mRNA and protein, and the ultrastructure of the parietal cell were observed in comparison with the effects of normal saline.
RESULTSNine days after ulcer induction, the ulcer area was 11.9-/+3.1 mm square and 19.7-/+3.8 mm square in rats with normal saline and celecoxib treatments, respectively (P<0.01). The total acidity of gastric juice and the expressions of H+, K+-ATPase mRNA and protein in celecoxib group were significantly higher than that in normal saline group at both 6 and 9 days after ulcer induction, but no significant difference was found between the two groups in the amount of secretary canaliculus and microvillus.
CONCLUSIONSelective COX-2 inhibitor can significantly delay the healing of experimental gastric ulcer in rats, the mechanism of which might be associated with enhanced digestive action of gastric acid on the new granulation tissue at the ulcer base as a result of celecoxib-stimulated gastric acid secretion of the parietal cells.
Animals ; Celecoxib ; Cyclooxygenase 2 Inhibitors ; pharmacology ; therapeutic use ; Gastric Acid ; secretion ; Gene Expression Regulation, Enzymologic ; drug effects ; H(+)-K(+)-Exchanging ATPase ; genetics ; metabolism ; Hydrogen-Ion Concentration ; Male ; Microvilli ; drug effects ; pathology ; Parietal Cells, Gastric ; drug effects ; ultrastructure ; Pyrazoles ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Wistar ; Stomach Ulcer ; drug therapy ; metabolism ; pathology ; Sulfonamides ; pharmacology ; therapeutic use