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Doxycycline blocks gastric ulcer by regulating matrix metalloproteinase-2 activity and oxidative stress

World Journal of Gastroenterology 2011年第28期17卷 3310-3321页

作者： Laishram Pradeepkumar Singh Amartya Mishra Debjit Saha snehasikta swarnakar Department of Physiology Drug Development Diagnostics and Biotechnology DivisionIndian Institute of Chemical Biology

AIM: To examine the effect of doxycycline on the activity of matrix metalloproteinases (MMPs) and oxidative stress in gastric tissues of rats following gastric ***: Gastric ulcers were generated in rats by administration of 70% ethanol,and activity of doxycycline was tested by administration 30 min prior to ***,the effect of doxycycline was tested in an indomethacin-induced gastric ulcer *** activities and expression of MMPs were examined by zymography and Western blot ***: Gastric injury in rats as judged by elevated ulcer indices following exposure to ulcerogen,either indomethacin or ethanol,was reversed significantly by ***-induced ulcerated gastric tissues exhibited about 12-fold higher proMMP-9 activity and about 5-fold higher proMMP-3 activity as compared to control ***,ethanol induced about 22-fold and about 6-fold higher proMMP-9 and proMMP-3 activities,respectively,in rat gastric *** proMMP-9 and MMP-3 activities were markedly decreased by doxycycline in ulcerogen treated rat gastric *** contrast,the reduced MMP-2 activity in ulcerated tissues was increased by doxycycline during ulcer *** the other hand,doxycycline inhibited significantly proMMP-9,-2 and -3 activities in *** addition,doxycycline reduced oxidative load in gastric tissues and scavenged H2O2 in *** results suggest a novel regulatory role of doxycycline on MMP-2 activity in addition to inhibitory action on MMP-9 and MMP-3 during prevention of gastric ***: This is the first demonstration of dual action of doxycycline,that is,regulation of MMP activity and reduction of oxidative stress in arresting gastric injury.

关键词： Doxycycline Extracellular matrix Matrix metalloproteinases Reactive oxygen species Tissue inhibitor of metalloproteinase

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Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

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World Journal of Biological Chemistry 2014年第3期5卷 355-376页

作者： Sugreev Verma Kousik Kesh Nilanjan Ganguly Sayantan Jana snehasikta swarnakar Drug Development Diagnostic and Biotechnology Division CSIR-Indian Institute of Chemical Biology

The process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases(MMPs). Degradation of extracellular matrix(ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metallopro-teinase(TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK(reversion including cysteinerich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2,-9 and-14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species(ROS) through mitochondrial dysfunction leading to altered protease/anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated

关键词： Gastrointestinal cancer Matrix metalloproteinase Tissue inhibitor of matrix metalloproteinases Reactive oxygen species Antioxidants

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