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Journal of Molecular Cell Biology 2024年第4期16卷 45-56页

作者： Miao Wang Xiao-Wei Li Sen-Chao Yuan Jie Pan Zeng-Lin Guo Li-Ming Sun Shao-Zhen Jiang Ming Zhao Wen Xue Hong Cai Lin Gu Dan Luo Ling Chen Xue-Qing Zhou Qiu-Ying Han Jin Li Tao Zhou Tian Xia Tao Li Nanhu Laboratory National Center of Biomedical AnalysisBeĳing 100850China School of Basic Medical Sciences Fudan UniversityShanghai 200032China School of Medicine Tsinghua UniversityBeĳing 100084China

The recognition of cytosolic nucleic acid triggers the DNA/RNA sensor–IRF3 axis-mediated production of type I interferons(IFNs),which are essential for antiviral immune ***,the inappropriate activation of these signaling pathways is implicated in autoimmune ***,we report that indomethacin,a widely used nonsteroidal anti-inflammatory drug,inhibits nucleic acid-triggered IFN *** found that both DNA-and RNA-stimulated IFN expression can be effectively blocked by ***,indomethacin also prohibits the nuclear translocation of IRF3 following cytosolic nucleic acid ***,in cell lines and a mouse model of Aicardi–Goutières syndrome,indomethacin administration blunts self-DNA-induced autoimmune ***,our study reveals a previously unknown function of indomethacin and provides a potential treatment for cytosolic nucleic acid-stimulated autoimmunity.

关键词： indomethacin IRF3 nuclear translocation autoimmune diseases

indomethacin but not a selective cyclooxygenase-2 inhibitor inhibits esophageal adenocarcinogenesis in rats

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World Journal of Gastroenterology 2012年第35期18卷 4866-4874页

作者： Paula Esquivias Antonio Morandeira Alfredo Escartín Carmelo Cebrián Sonia Santander Francisco Esteva María Asunción García-González Javier Ortego Angel Lanas Elena Piazuelo CIBER Digestive and Hepatic Deseases Service of Surgery University Hospital "Lozano Blesa" Service of Pathology University Hospital "Lozano Blesa" Department of Medicine University of Zaragoza Service of Clinical Biochemistry University Hospital "Lozano Blesa" Aragon Health Science Institute Service of Gastroenterology University Hospital "Lozano Blesa"

AIM： To evaluate the effects of indomethacin [dual cyclooxygenase （COX）-I/COX-2 inhibitor] and 3-（3,4-difluorophenyl）-4-（4-（methylsulfonyl） phenyl）- 2-（5H）-furanone （MF-tricyclic）（COX-2 selective inhibi- tor） in a rat experimental model of Barrett＇s esophagus and esophageal ***： A total of 112 surviving post-surgery rats were randomly divided into three groups： the control group （n = 48）, which did not receive any treatment; the indomethacin group （n = 32）, which were given 2 mg/kg per day of the COX-I/COX-2 inhibitor; and the MF-tricyclic group （n = 32）, which received 10 mg/kg per day of the selective COX-2 inhibitor. Randomly se- lected rats were killed either 8 wk or 16 wk after sur- gery. The timing of the deaths was in accordance with a previous study performed in our group. Only rats that were killed at the times designated by the protocol were included in the study. We then assessed the histology and prostaglandin E2 （PGE2） expression levels in the rat esophagi. An additional group of eight animals that did not undergo esophagojejunostomy were included in order to obtain normal esophageal tissue as a control. RESULTS： Compared to a control group with no treat- ment （vehicle-treated rats）, indomethacin treatment was associated with decreases in ulcerated esophageal mucosa （16% vs 35% and 14% vs 17%, 2 mo and 4 mo after surgery, respectively; P = 0.021）, length of intestinal metaplasia in continuity with anastomosis （2 4- 1.17 mm vs 2.29 ＋ 0.75 mm and 1.25 4- 0.42 mm vs 3.5 4- 1.54 mm, 2 mo and 4 mo after surgery, respec- tively; P = 0.007）, presence of intestinal metaplasia beyond anastomosis （20% vs 71.4% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P = 0.009）, severity of dysplasia （0% vs 71.4% and 20% vs 85.7% high-grade dysplasia, 2 mo and 4 mo after surgery, re- spectively; P = 0.002）, and adenocarcinoma incidence （0% vs 57.1% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P 〈 0.0001）. Treatment with the select

关键词： Intestinal metaplasia Esophageal adeno-carcinoma indomethacin MF-tricyclic

indomethacin suppresses growth of colon cancer via inhibition of angiogenesis in vivo

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World Journal of Gastroenterology 2005年第3期11卷 340-343页

作者： Hong-MeiWang Gui-YingZhang DepartmentofGastroenterology XiangyaHospitalofCentralSouthUniversityChangsha410078HunanProvinceChina

AIM: It has been reported that regular consumption of nonsteroidal anti-inflammatory drugs like indomethacin decreases the incidence and mortality rate of a number of gastrointestinal cancers. We aimed to explore the efficacy and possible mechanisms of indomethacin on tumor growth and tumor angiogenesis of human colon cancer xenografts in nude mice. METHODS: MTT (thiazolyl blue) assay was used to assess the effect of indomethacin on cultured human colorectal cancer cell line HCT116. HCT116 cells were inoculated subcutaneously into BALB/c-nu/nu mice. After oral administration of indomethacin, 3 mg/kg·d for 4 wk, animals were sacrificed by cervical dislocation. Immunohistochemical staining was employed to determine the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in tumor tissues. RESULTS: indomethacin, a non-selective COX inhibitor, significantly decreased the viability of HCT116 cells in a dose-dependent manner (Pindomethacin. The tumor volume was significantly decreased in the treated group (458.89±32.07 mm3) compared to the control group (828.21±31.59 mm3) (Pindomethacin can significantly decrease the viability of cultured HCT116 cells and retard human colorectal HCT116 cell tumor growth via inhibiting tumor angiogenesis, which might be through reduction of VEGF expressio

关键词： Colon Cancer indomethacin Angiogenesis Microvessel density VEGF

indomethacin INHIBITS hCG AND GnRH AGONIST-INDUCED SECRETION OF PLASMINOGEN ACTIVATOR BY GRANULOSA AND THECA INTERSTITIAL CELLS OF HYPOPHYSECTOMIZED RATS

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Science China Chemistry 1988年第7期31卷 807-817页

作者：刘以训,CAJANDER STEPHEN Laboratory of Reproductive Biology Institute of Zoology Academia Sinica Beijing Department of Reproductive Medicine M-025 University of California San Diego La Jolla CA 92093 USA

Considerable data have shown that plasminogen activator (PA) may play an important role in the mechanism of ovulation. A recent report argued that PA is not a primary proteoIytic enzyme for follicular rupture because a dose of indomethacin that blocked ovulation did not inhibit ovarian PA content. To further clarify the specific role of PA in the ovulation, we have carefully examined the effect of indomethacin on the secretion of PA in granulosa and theca-interstitial (TI) cells following hCG or GnRH agonist administration in PMSG-primed hypophysectomized immature rats. We have also studies in vitro action of this compound on PA secretion in granulosa cells. The results indicate that indomethacin can only suppress hCG- and GnRH agonist-induced PA secretion, but not suppress the ovarian content of these enzymes.

关键词： indomethacin hCG GnRH agonist plasminogen activator ovulation.

Irsogladine maleate suppresses indomethacin-induced elevation of proinflammatory cytokines and gastric injury in rats

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World Journal of Gastroenterology 2008年第30期14卷 4784-4790页

作者： Koyuki Tajima Kiyoto Kageyama Takashi Kyoi Department of Pharmacology Discovery Research LaboratoriesNippon Shinyaku Co. Ltd.

AIM： To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug irsogladine maleate in gastric injury induced by indomethacin in rats. METHODS： Gastric mucosal injury was induced in male Hos：Donryu rats by oral administration of indomethacin at a dose of 48 mg/kg. One hour before indomethacin treatment, animals were orally pretreated with irsogladine maleate at doses of 1 mg/kg, 3 mg/kg or 10 mg/kg. Four hours after indomethacin administration, the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of tumor necrosis factor-α （TNF-α）, interleukin-1β （IL-1β）, IL-8 and myeloperoxidase （MPO） in mucosal tissues. RESULTS： Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h alter oral administration of indomethacin. Pretreatment with irsogladine maleate markedly reduced the number and severity of these lesions in a dose-dependent manner. The mucosal concentrations of proinflammatory cytokines （TNF-α, IL-1β, and IL-8） and MPO, which indicates the degree of mucosal infiltration by neutrophils, increased concomitantly with the occurrence of gastric injury in the indomethacintreated rats. Pretreatment with irsogladine maleate significantly decreased the levels of these inflammatory factors in gastric tissue elicited by ***： The mucosal protective effects afforded by irsogladine maleate on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration, leading to suppression of mucosal inflammation and subsequent tissue destruction.

关键词： Irsogladine Gastric injury indomethacin Cytokine Myeloperoxidase

Prophylaxis of posterior capsule opacification through autophagy activation with indomethacin-eluting intraocular lens

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Bioactive Materials 2023年第5期23卷 539-550页

作者： Xiaobo Zhang Jing Wang Jingwei Xu Wen Xu Yin Zhang Chenqi Luo Shuang Ni Haijie Han Xingchao Shentu Juan Ye Jian Ji Ke Yao Eye Center The Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009PR China Zhejiang Provincial Key Lab of Ophthalmology The Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009PR China MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education Department of Polymer Science and EngineeringZhejiang UniversityHangzhou310027PR China

Posterior capsule opacification(PCO)is the most common long-term postoperative complication of cataract surgery,leading to secondary vision *** intraocular lens(IOL)structure and appropriate pharmacological intervention,which provides physical barriers and biological inhibition,respectively,can block the migration,proliferation,and epithelial-mesenchymal transition(EMT)of lens epithelial cells(LECs)for PCO ***,a novel indomethacin-eluting IOL(INDOM-IOL)with an optimized sharper edge and a sustained drug release behavior was developed for PCO ***(INDOM),an ophthalmic non-steroidal anti-inflammatory drug(NSAID)used for postoperative ocular inflammation,was demonstrated to not only be able to suppress cell migration and down-regulate the expression of cyclooxygenase-2(COX-2)and EMT markers,including alpha-smooth muscle actin(α-SMA)and cyclin D1,but also promote the autophagy activation in ***,autophagy was also verified to be a potential therapeutic target for the down-regulation of EMT in *** novel IOL,serving as a drug delivery platform,could carry an adjustable dose of hydrophobic indomethacin with sustained drug release ability for more than 28 *** the rabbit PCO model,the indomethacin-eluting IOL showed excellent anti-inflammatory and anti-PCO *** summary,indomethacin is an effective pharmacological intervention in PCO prophylaxis,and the novel IOL we developed prevented PCO in vivo under its sustained indomethacin release property,which provided a promising approach for PCO prophylaxis in clinical application.

关键词： Posterior capsule opacification indomethacin Autophagy Drug-eluting IOLs Epithelial-mesenchymal transition

Design, Synthesis and Biological Evaluation of 2-（2-Aryl- morpholino-4-yl）ethyl Esters of indomethacin as Potential Cyclooxygenase-2 （COX-2） Inhibitors

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Chinese Journal of Chemistry 2012年第6期30卷 1339-1344页

作者：石磊胡艾希徐江平蒋毅萍 College of Chemistry and Chemical Engineering Hunan UniversityChangshaHunan 410082China Department of Pharmacology School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouGuangdong 510515China

A number of novel 2-（2-arylmorpholino-4-yl）ethyl 1-（4-chlorobenzoyl）-5-methoxy-2-methyl-lH-indol-3- acetate hydrochlorides were synthesized and tested for their cyclooxygenase （COX-1 and COX-2） inhibition prop- erties in vitro. Many of these compounds exhibited moderate to good selective COX-2 inhibition, and subtle struc- tural changes in the substituents on the side chain of the ester moiety altered the inhibitory properties significantly. 2-[2-（4-Butoxyphenyl）morpholino-4-yl]ethyl 1-（4-chlorobenzoyl）-5-methoxy-2-methyl-IH-indol-3-acetate hydro- chloride （If）, showed good selective COX-2 inhibitory activity （Selective index （SI） 182）, which is comparative with celecoxib （SI 214）, a COX-2 inhibitor of diarylpyrazoles. While 2-[2-（2,4-dichloro-5-fluorophenyl）mor- pholino-4-yl]ethyl 1-（4-chlorobenzoyl）-5-methoxy-2-methyl-IH-indol-3-acetate hydrochloride （lg）, showed greater selective COX-2 inhibitory activity （SI 358） than celecoxib. Both compounds were identified as compromising de- rivatives in this class to reduce the side effects generated by nonsteroidal anti-inflammatory drugs （NSAIDs） indo- methacin.

关键词： indomethacin 2-(2-arylmorpholino-4-yl)ethanol synthesis COX-2 selective inhibition antioxidant

Evidence against the participation of a pharmacokinetic interaction in the protective effect of single-dose curcumin against gastrointestinal damage induced by indomethacin in rats

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Journal of Integrative Medicine 2017年第2期15卷 151-157页

作者： Liliana Zazueta-Beltran Lorena Medina-Aymerich Nadia Estela Diaz-Triste Aracely Evangelina Chavez-Pina GUberto Castaneda-Hernandez Leticia Cruz-Antonio Department of Pharmacology Center for Research and Advanced Studies of the National Polytechnic Institute 07360 Mexico City Mexico Laboratory of Pharmacology Institutional Program in Molecular Biomedicine National School of Medicine and Homeopathy of the National Polytechnic Institute Academic Area of Medicine of the Institute of Health Sciences 07320 Mexico City Mexico Superior Studies Faculty of Zaragoza Universidad National Autonomous of Mexico 09230 Mexico City Mexico

OBJECTIVE： To determine the role of a pharmacokinetic interaction in the protective effect of curcumin against the gastric damage induced by indomethacin administration as such or as its prodrug acemetacin. METHODS： Wistar rats orally received single dose of indomethacin （30 mg/kg） with and without curcumin （30 mg/kg）; gastric injury was evaluated by determining the total damaged area. Additional groups of rats received an oral single dose of indomethacin （30 mg/kg） or its prodrug acemetacin （34.86 mg/kg） in the presence or absence of curcumin （30 mg/kg）. indomethacin and acemetacin concentrations in plasma from blood draws were determined by high-performance liquid chromatography Plasma concentration-against-time curves were constructed, and bioavailability parameters, maximal concentration （Cmax） and area under the curve to the last sampling time （AUC0_t） were estimated. RESULTS： Concomitant administration of indomethacin and curcumin resulted in a significantly reduced gastric damage compared to indomethacin alone. However, co-administration of curcumin did not produce any significant alteration in the bioavailability parameters of indomethacin and acemetacin after administration of either the active compound or the prodrug. CONCLUSION： Curcumin exhibits a protective effect against indomethacin-induced gastric damage, but does not produce a reduction of the bioavailability of this nonsteroidal anti-inflammatory drug, indomethacin. Data thus suggest that a pharmacokinetic mechanism of action is not involved in curcumin gastroprotection.

关键词： indomethacin curcumin acemetacin bioavailability damage, ggastrointestinal side effect drugs, Chinese herbal

Protective Effect of Holothurian Intestine Against indomethacin Induced Gastric Mucosal Damage in Rats

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Journal of Ocean University of China 2017年第3期16卷 547-554页

作者： LI Xiaoyu QIAO Xuejing ZHANG Cuiping GAO Hua NIU Qinghui WU Tong ZHANG Qi TIAN Zibin Department of Gastroenterology the Affiliated Hospital of Qingdao University Department of Pharmacy College of Medicine of Qingdao University

Our study aimed to investigate the protective effects of Holothurian intestines(HI) on NSAIDs-induced gastric mucosal damage and the possible mechanism. At first, 60 male Wistar rats were induced of gastric lesions with indomethacin(IDM, 30 mg kg^(-1)). The rats were pretreated for 15 consecutive days with saline, sucralfate, or HI(0.4g kg^(-1) d-1, 0.8 g kg^(-1) d^(-1) and 1.6 g kg^(-1) d^(-1)) prior to IDM treatment, followed by evaluations of macroscopic damage and microscopic features; and investigation of the levels of inflammatory cytokines, oxidative stress parameters, gastric mucosal prostaglandin E2(PGE2) and total hexosamine in tissues. The expression of COX-1 and COX-2 m RNA in the gastric tissue were determined by quantitative polymerase chain reaction(q PCR). Pathological gastric ulcer indexes, levels of pro-inflammatory cytokines(IL-1β, IL-17, TNF-α) and lipid peroxidation were significantly decreased in HI-treated groups, whereas the levels of protective factors(TGF-β, GSH, SOD activity and PGE2) were significantly elevated especially in the group with HI 1.61 g kg^(-1) d^(-1)(P < 0.05). Furthermore, the expression of COX-2 mRNA decreased significantly in HI groups(P < 0.05). The study investigates that holothurian intestines may act as a kind of marine medicine which have protective effect on IDM-induced gastric ulcer, which could be a dietary preventive agent for the prevention of gastric damage.

关键词： holothurian intestine NSAID indomethacin gastric ulcer sucralfate

Synthesis and Pharmacological Evaluation of Novel Conjugates of indomethacin with Antioxidant Activity

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Chinese Journal of Chemistry 2005年第11期23卷 1523-1529页

作者： ZHANG, Yi-Chun CHEN, Ping-Tao GUAN, Hua-Shi LI, Ying-Xia Key Laboratory of Marine Drugs The Ministry of Education of China Marine Drug and Food Institute Ocean University of China Qingdao Shandong 266003 China

A series of new conjugates of indomethacin with phenolic anfioxidants were synthesized for enhanced antiinflammatory activity as well as reduced ulcerogenic potency. It was found that all conjugates were very potent antioxidants in vitro. They could inhibit lipid peroxidafion significantly, while 11b-11e and 13b-13e could also interact with DPPH. However these conjugates showed little inhibition against croton oil induced mouse ear swelling.

关键词： antioxidant indomethacin antiinflammation conjugate nonsteroidal antiinflammatory drugs (NSAID)