Curcumin Regulates Expression and Activity of Matrix Metalloproteinases 9 and 2 during Prevention and Healing of Indomethacin-induced Gastric Ulcer

Matrix metalloproteinases (MMPs) are suggested to play a critical role in extracellular matrix degradation and remodeling during inflammation and wound healing processes. However, the role of MMPs in indomethacin-induced gastric ulcer and its healing process are not clearly understood. This study is aimed at determining the regulation of MMP-9 and -2 activities in indomethacin-induced acute gastric ulceration and healing. Indomethacin-ulcerated stomach extracts exhibit significant up-regulation of pro-MMP-9 (92 kDa) activity and moderate reduction of MMP-2 activity, which strongly correlate with indomethacin dose and severity of ulcer. The anti-inflammatory and antioxidant properties of curcumin, an active component of turmeric, suggest that curcumin may exert antiulcer activity through scavenging reactive oxygen species, by regulating MMP activity, or both. To test these possibilities, the effect of curcumin in indomethacin-induced gastric ulcer is examined by biochemical and histological methods. The results show that curcumin exhibits potent antiulcer activity in acute ulcer in rat model by preventing glutathione depletion, lipid peroxidation, and protein oxidation. Denudation of epithelial cells during damage of gastric lumen is reversed by curcumin through re-epithelialization. Furthermore, both oral and intraperitoneal administration of curcumin blocks gastric ulceration in a dose-dependent manner. It accelerates the healing process and protects gastric ulcer through attenuation of MMP-9 activity and amelioration of MMP-2 activity. Omeprazole, an established antiulcer drug does not inhibit MMP-9 while protecting indomethacin-induced gastric ulcer. We conclude that antiulcer activity of curcumin is primarily attributed to MMP-9 inhibition, one of the major path-ways of ulcer healing. Matrix metalloproteinases (MMPs) are suggested to play a critical role in extracellular matrix degradation and remodeling during inflammation and wound healing processes. However, the role of MMPs in indomethacin-induced gastric ulcer and its healing process are not clearly understood. This study is aimed at determining the regulation of MMP-9 and -2 activities in indomethacin-induced acute gastric ulceration and healing. Indomethacin-ulcerated stomach extracts exhibit significant up-regulation of pro-MMP-9 (92 kDa) activity and moderate reduction of MMP-2 activity, which strongly correlate with indomethacin dose and severity of ulcer. The anti-inflammatory and antioxidant properties of curcumin, an active component of turmeric, suggest that curcumin may exert antiulcer activity through scavenging reactive oxygen species, by regulating MMP activity, or both. To test these possibilities, the effect of curcumin in indomethacin-induced gastric ulcer is examined by biochemical and histological methods. The results show that curcumin exhibits potent antiulcer activity in acute ulcer in rat model by preventing glutathione depletion, lipid peroxidation, and protein oxidation. Denudation of epithelial cells during damage of gastric lumen is reversed by curcumin through re-epithelialization. Furthermore, both oral and intraperitoneal administration of curcumin blocks gastric ulceration in a dose-dependent manner. It accelerates the healing process and protects gastric ulcer through attenuation of MMP-9 activity and amelioration of MMP-2 activity. Omeprazole, an established antiulcer drug does not inhibit MMP-9 while protecting indomethacin-induced gastric ulcer. We conclude that antiulcer activity of curcumin is primarily attributed to MMP-9 inhibition, one of the major path-ways of ulcer healing. Curcumin regulates expression and activity of matrix metalloproteinases 9 and 2 during prevention and healing of indomethacin-induced gastric ulcer. Vol. 280 (2005) 9409-9415Journal of Biological ChemistryVol. 280Issue 33PreviewPage 9412, Table I: In the original submission, the data presented in Table I had been prepared by Dr. Ranajit K. Banerjee and Dr. Ishita Chattopadhyay and was based on previous work performed in Dr. Banerjee's laboratory. Full-Text PDF Open Access Nonsteroidal anti-inflammatory drugs (NSAIDs), 1The abbreviations used are: NSAID, nonsteroidal anti-inflammatory drug; MMP, matrix metalloproteinase; ECM, extracellular matrix; ROS, reactive oxygen species; TIMP, tissue inhibitors of metalloproteinase; IL, interleukin; TX, Triton X-100. stress, and Helicobacter pylori are the major causative factors for gastric ulcer where extracellular matrix (ECM) degradation plays a very important role in the development of the ulcer wound. Healing of ulcer encompasses a complex series of cell/matrix interaction involving cellular proliferation, migration, and differentiation. Wound formation and the healing thereof are dynamic processes of ECM remodeling that are mainly influenced by MMPs and tissue inhibitors of metalloproteinases (TIMPs). MMPs are a growing family of zinc-dependent endopeptidases that selectively degrade components of ECM (1Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5244) Google Scholar). The catalytic activities of MMPs are highly regulated at multiple levels, including gene expression, spatial localization, zymogen activation, and inhibition by TIMPs (2Parks W.C. Mecham R.P. Matrix Metalloproteinases. Academic Press, New York1998Google Scholar). MMPs especially pro-MMP-2 (72-kDa gelatinase A) and pro-MMP-9 (92-kDa gelatinase B) as well as their active forms are responsible for regulating most of the turnover of matrix proteins because they together are capable of degrading basement membrane proteins like gelatin, collagen IV, collagen V, elastin, and fibronectin (2Parks W.C. Mecham R.P. Matrix Metalloproteinases. Academic Press, New York1998Google Scholar). Interestingly, MMP-9 remains as zymogen under identical cellular conditions where a majority of co-expressed pro-MMP-2 is activated via the cell surface mechanism (1Egeblad M. Werb Z. Nat. Rev. Cancer. 2002; 2: 161-174Crossref PubMed Scopus (5244) Google Scholar, 2Parks W.C. Mecham R.P. Matrix Metalloproteinases. Academic Press, New York1998Google Scholar, 3Piedagnel R. Murphy G. Ronco P.M. Lelongt B. J. Biol. Chem. 1999; 274: 1614-1620Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Although MMP-2 appears to be constitutively expressed by many cell types in culture, MMP-9 expression is induced by cytokines (4Magid R. Murphy T.J. Galis Z.S. J. Biol. Chem. 2003; 278: 32994-32999Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar), growth factors, and cell/stroma interactions (5Kondapaka S.B. Fridman R. Reddy K.B. Int. J. Cancer. 1997; 70: 722-726Crossref PubMed Scopus (198) Google Scholar, 6Xie B. Laouar A. Huberman E. J. Biol. Chem. 1998; 273: 11576-11582Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Indomethacin, a NSAID, causes gastric lesions through a number of mechanisms including inhibition of prostaglandin synthesis, increased expression of interleukin-1 (IL-1), generation of reactive oxygen species (ROS), and induction of apoptosis (7Miller T.A. Am. J. Physiol. 1983; 245: G601-G623PubMed Google Scholar, 8Yoshikawa T. Naito Y. Kishi A. Tomii T. Kaneko T. Iinuma S. Ichikawa H. Yasuda M. Takahashi S. Kondo M. Gut. 1993; 34: 732-737Crossref PubMed Scopus (332) Google Scholar, 9Slomiany B.L. Piotrowski J. Slomiany A. Scand. J. Gastroenterol. 1997; 32: 638-642Crossref PubMed Scopus (80) Google Scholar, 10Fujii Y. Matsura T. Kai M. Matsui H. Kawasaki H. Yamada K. Proc. Soc. Exp. Biol. Med. 2000; 224: 102-108Crossref PubMed Scopus (62) Google Scholar). Increased lipid peroxidation, protein oxidation, and depletion of glutathione are the major indications of the oxidative damage of the gastric mucosal cells by indomethacin (8Yoshikawa T. Naito Y. Kishi A. Tomii T. Kaneko T. Iinuma S. Ichikawa H. Yasuda M. Takahashi S. Kondo M. Gut. 1993; 34: 732-737Crossref PubMed Scopus (332) Google Scholar, 11Miura T. Muraoka S. Fujimoto Y. Biochem. Pharmacol. 2002; 63: 2069-2074Crossref PubMed Scopus (47) Google Scholar). However, very little is known about the involvement of MMP and TIMP expression in NSAID-induced gastric ulcer (12Menges M. Chan C.C. Zeitz M. Stallmach A. Z. Gastroenterol. 2000; 38: 887-891Crossref PubMed Scopus (23) Google Scholar, 13Lempinen M. Inkinen K. Wolff H. Ahonen J. Eur. Surg. Res. 2000; 32: 169-176Crossref PubMed Scopus (44) Google Scholar, 14Saarialho-Kere U. Vaalamo M. Puolakkainen P. Airola K. Parks W.C. Karjalainen-Lindsberg M.L. Am. J. Pathol. 1996; 148: 519-526PubMed Google Scholar, 15Shahin M. Konturek J.W. Pohle T. Schuppan D. Herbst H. Domschke W. Microsc. Res. Tech. 2001; 53: 396-408Crossref PubMed Scopus (46) Google Scholar). MMP-1 concentration is found to be significantly higher in H. pylori-induced ulcer compared with that of NSAIDs ulcer (12Menges M. Chan C.C. Zeitz M. Stallmach A. Z. Gastroenterol. 2000; 38: 887-891Crossref PubMed Scopus (23) Google Scholar). The roles for ECM proteins and ECM degrading enzymes (i.e. MMPs) in gastric ulceration have been implicated in few reports during the last few years (15Shahin M. Konturek J.W. Pohle T. Schuppan D. Herbst H. Domschke W. Microsc. Res. Tech. 2001; 53: 396-408Crossref PubMed Scopus (46) Google Scholar, 16Ernst H. Grunert S. Schneider H.T. Beck W.S. Brune K. Hahn E.G. Scand. J. Gastroenterol. 1995; 30: 847-853Crossref PubMed Scopus (11) Google Scholar), but the mechanistic basis is not very clear today. MMP-2 has been suggested to participate in the physiological turnover of the gastric ECM, whereas MMP-9 may be important in the early phase of indomethacin-induced chronic gastric ulcers (13Lempinen M. Inkinen K. Wolff H. Ahonen J. Eur. Surg. Res. 2000; 32: 169-176Crossref PubMed Scopus (44) Google Scholar). Very recently, Mori et al. (17Mori N. Sato H. Hayashibara T. Senba M. Geleziunas R. Wada A. Hirayama T. Yamamoto N. Gastroenterology. 2003; 124: 983-992Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar) reported MMP-9 induction through activation of NF-κB in H. pylori-infected cultured gastric mucosal cells. Literature is very the role of MMPs and TIMPs during the healing process of the gastric ulcer Z. A. Scand. J. Gastroenterol. 1997; 32: PubMed Scopus Google Scholar). The roles of MMPs in ulcer development and healing have been in the gastric ulcer model Z. A. Scand. J. Gastroenterol. 1997; 32: PubMed Scopus Google Scholar). The of the study is to in the expression and activities of MMP-9 and -2 during indomethacin-induced gastric ulceration and its healing by Although the and of used for the healing of ulcers by NSAIDs are well established 1998; PubMed Scopus Google Scholar). have been reported Eur. J. Gastroenterol. 2001; Scholar, J. P. B. P. D. N. J. A. Gastroenterology. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The of healing remains for preventing Am. J. Med. 2001; Full Text Full Text PDF PubMed Google Scholar) because ulcer with antiulcer as are these a for an antiulcer is Curcumin a and properties G. R. 1995; PubMed Scopus Google Scholar, Chem. 2002; PubMed Scopus Google Scholar). This has been to inhibit the expression of a of cytokines as or Chem. 2002; PubMed Scopus Google Scholar). Curcumin is a of and the of glutathione during apoptosis E. S. J. S. E. A. G. 1998; PubMed Scopus Google Scholar). and are to ulcer a like curcumin potent anti-inflammatory and antioxidant activities is to exert an antiulcer on its and in Chem. 2002; PubMed Scopus Google Scholar), the study is to the and ulcer healing effect of curcumin in indomethacin-induced gastric ulcer and its healing process with on the regulation of MMP-9 and -2 has been presented to show that curcumin not protects gastric mucosal cell damage and oxidative but regulates expression and activities of MMPs during and healing of indomethacin-induced gastric have for the the antiulcer activity of curcumin and its mechanism of that blocks gastric damage by the up-regulation of MMP-9 and of Furthermore, of ulcer prevention by its properties to be curcumin and to the This the in to the for curcumin, Triton inhibitors and MMP-9 and MMP-2 was was with to and used for of the of the in and at of the to and to the number with The by by for The in to the of the of the of and ulcer induction of both and in conditions for with to gastric ulcers induced by oral administration of indomethacin at a dose of and of indomethacin The the whereas the indomethacin for gastric the and gastric lesions in the stomach and expressed as ulcer K. U. Chattopadhyay A. E. Banerjee J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar) as a ulcer and a of K. U. Chattopadhyay A. E. Banerjee J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). The of the by the number of is expressed as the ulcer Curcumin was or to indomethacin to the and at a dose of and the ulcer the stomach was for histological The tissue in and in The with and Z. S. J.W. M. Am. J. Physiol. 1998; 274: Google Scholar), and under an and of stomach was in and of of was with and The was to of J. Biochem. PubMed Scopus Google Scholar) and with of The of was at a was prepared of glutathione with under identical of membrane the stomach was used for of lipid as reactive species H. N. K. Biochem. PubMed Scopus Google Scholar). of the membrane was to with 2 of in a for and The of the was at and the number of of reactive species was a as of was as in the of the stomach K. U. Chattopadhyay A. E. Banerjee J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). The stomach and in in a for 2 to at for the proteins of the with and to with of for with the protein was with a of in of a in to with and and the was for at and of the gastric was in and for at at for the was The was in the Triton and at for to extracts at and used in MMP activity was significantly a of the was in the of of MMP-2 and MMP-9 activity, mucosal extracts in under The in and in for at and with by Z. A. Scand. J. Gastroenterol. 1997; 32: PubMed Scopus Google Scholar). The of activity as activity was by a to a to to the by by and to S. J. S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The membrane was for 2 at in by at in of MMP-9 in The membrane was with and with and the The in study are at Healing of gastric ulcer was in a of under the conditions as for whereas the with curcumin or of administration of Healing was at and the ulcer was as The activity of MMP-9 and -2 during ulcer healing was as ulcer data a The data presented as the was of during and the of indomethacin administration lesions the of the lesions and expressed as ulcer that at administration of indomethacin at a dose of gastric lesions in the stomach not found in of the tissue that indomethacin of the gastric epithelial cells with of mucosal of stomach compared with that of and and of ulcer was in tissue with an of mucosal was in tissue of Curcumin on in is one of the major causative factors for gastric ulceration by indomethacin that oxidative damage by membrane lipid peroxidation, protein oxidation, and glutathione the effect of curcumin on oxidative damage of the gastric by indomethacin was Table I the antioxidant activity of curcumin in protecting gastric lesions through of indomethacin-induced in lipid and protein oxidation. The glutathione which was significantly in was to the by of curcumin on indomethacin-induced oxidative damage of gastric Curcumin was to indomethacin administration The lipid peroxidation, and protein as in the reactive The results are expressed as the curcumin a test to the a test to the a test to the a test to the Open in a of MMP-9 and -2 in during MMP-9 and MMP-2 activities in gastric tissue extracts and the extracts to at was to ulcer at of The as in that of indomethacin in the ulcer at The activity of pro-MMP-9 (92 kDa) was significantly increased with of indomethacin the at and MMP-9 expression was with of indomethacin as in In under the the activities of both pro-MMP-2 and active MMP-2 the dose of indomethacin the ulcer was the as as to as as To in the activity of MMPs at of severity of was with gastric tissue extracts of ulcer and The in the activity of both MMPs found well with the in the severity of ulcer as by ulcer the of activity of MMP-9 and MMP-2 in of ulcer. higher of MMP-9 activity was in compared with of activity of MMP-2 and active to be in compared with of as well as MMP-9 activity was at indomethacin We found that the ulcer was increased at in with the and MMP-9 activity in the gastric tissue increased at indomethacin administration with to the of ulcer with MMP-9 and -2 induced in by and the ulcer as under and as in the of was performed extracts gastric ulcer of ulcer activity of pro-MMP-9 and MMP-2 activity as by the and ulcer induction and MMP-9 and -2 induced in by oral administration of and the ulcer was under and of ulcer as well as pro-MMP-9 activity as a of for indomethacin MMP-9 activity was the activity of MMP-9 and -2 by as in the of extracts gastric at used for and of of MMP-9 and -2 that intraperitoneal administration of curcumin was highly in indomethacin-induced gastric ulcer. of ulcer with an intraperitoneal dose of curcumin Curcumin indomethacin-induced gastric lesions through reduction of MMP-9 activity and of MMP-2 and active activity This of MMP-9 activity was to attenuation of MMP-9 at protein as by with on data curcumin be for in oral administration of curcumin was highly in protecting ulcer through reduction of MMP-9 activity and of MMP-2 and active activity. an oral dose of curcumin inhibition of ulcer It is to that a higher dose of curcumin was to ulcer compared with that In oral administration of curcumin indomethacin-induced gastric lesions and a significant role on MMP-9 activity The up-regulation of MMP-9 activity by (i.e. dose of at the oral dose of where ulcer was by of oral of curcumin on the of gastric ulcer and with MMP of curcumin to of to indomethacin The and the ulcer of ulcer as well as pro-MMP-9 activity as a of oral dose of activity was the and as in the to was performed extracts gastric tissue of of Healing of by Curcumin and MMP-9 and -2 test the effect of curcumin on ulcer healing and on MMP-9 activity, with or curcumin induction of ulcer. The of that curcumin not gastric but the healing of ulcer by on the of ulcer that ulcers healing and healing was by of curcumin ulcer healing because the ulcer to at and healing was at by curcumin, whereas for the by an established was used in healing to the healing of curcumin, which was found to be with It is that healing of indomethacin-induced ulcer well with the inhibition of MMP-9 and the of MMP-2 activity for both and curcumin healing. Curcumin significantly MMP-9 activity and MMP-2 activity during and the activities at during the process at of and on MMP-9 during of The effect of on MMP-9 activity during of ulcer was curcumin, gastric ulcer through reduction of MMP-9 activity, whereas not have role on MMP-9 activity and curcumin of the ulcers that induced by indomethacin and a for the had an antiulcer effect inhibition by curcumin and with attenuation of pro-MMP-9 activity. In ulcers MMP-9 activity with the of a through a number of mechanisms including of prostaglandin and increased expression of cytokines like and (7Miller T.A. Am. J. Physiol. 1983; 245: G601-G623PubMed Google Scholar, 8Yoshikawa T. Naito Y. Kishi A. Tomii T. Kaneko T. Iinuma S. Ichikawa H. Yasuda M. Takahashi S. Kondo M. Gut. 1993; 34: 732-737Crossref PubMed Scopus (332) Google Scholar, 9Slomiany B.L. Piotrowski J. Slomiany A. Scand. J. Gastroenterol. 1997; 32: 638-642Crossref PubMed Scopus (80) Google Scholar, T. Konturek Konturek Z. R. D. A. Hahn E.G. Microsc. Res. Tech. 2001; Scopus Google Scholar). The mechanisms of of prostaglandin and the of expression are through generation of (8Yoshikawa T. Naito Y. Kishi A. Tomii T. Kaneko T. Iinuma S. Ichikawa H. Yasuda M. Takahashi S. Kondo M. Gut. 1993; 34: 732-737Crossref PubMed Scopus (332) Google Scholar). In indomethacin-induced of prostaglandin is with the inhibition of pro-MMP-9 and the of MMP-9 activity T. Konturek Konturek Z. R. D. A. Hahn E.G. Microsc. Res. Tech. 2001; Scopus Google Scholar, M. W. R. J. Surg. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). has been to show that pro-MMP-9 is by indomethacin and that the expression of MMP-9 via the A. T. Takahashi S. Mori Y. 1995; PubMed Scopus Google Scholar, A. Y. T. Y. M. Am. J. Physiol. Physiol. 2001; PubMed Google Scholar). is clear that MMP-9 activity by or M. W. R. J. Surg. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. T. Takahashi S. Mori Y. 1995; PubMed Scopus Google Scholar, A. Y. T. Y. M. Am. J. Physiol. Physiol. 2001; PubMed Google Scholar, J. 2000; PubMed Scopus Google Scholar, W. M. E. J. 2002; PubMed Scopus (114) Google Scholar). of cytokines at as well as their during of inflammation may the for induction of MMP-9 activity. The and of MMPs at the gene and protein are to be of the mechanisms for damage and of ECM during ulceration and healing that gastric mucosal tissue of rat stomach significant of MMP-9 activity and MMP-2 activity that of In gastric lesions by indomethacin are to of MMP-9 protein in et al. (13Lempinen M. Inkinen K. Wolff H. Ahonen J. Eur. Surg. Res. 2000; 32: 169-176Crossref PubMed Scopus (44) Google Scholar) that indomethacin causes of MMP-9 as well as MMP-2 activity in chronic gastric ulcers in the rat In have MMP-2 activity and increased MMP-9 activity by indomethacin in a and dose-dependent in the acute ulcer data are by the of and W.C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) that NSAIDs the activity of MMP-2 gene expression by its is clear the that of MMP-2 and activity involvement of MMP-2 in the ulceration of of these expression of MMP-2 and MMP-9 is that they are regulated by In with is reported that MMP-2 and MMP-9 MMP-9 but not MMP-2 and NF-κB W. M. E. J. 2002; PubMed Scopus (114) Google Scholar, W.C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, P. A. J. J. K. J. Biol. Chem. Full Text PDF PubMed Google Scholar). is used to gastric damage by and NSAIDs and is to its antiulcer activity through scavenging of and cell K. U. Chattopadhyay A. E. Banerjee J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). Although is has like and of ulcers Am. J. Med. 2001; Full Text Full Text PDF PubMed Google Scholar). the of well established an antiulcer is at It is that oxidative damage of the by reactive oxygen species and by cell are the major causative factors for gastric ulceration Y. Matsura T. Kai M. Matsui H. Kawasaki H. Yamada K. Proc. Soc. Exp. Biol. Med. 2000; 224: 102-108Crossref PubMed Scopus (62) Google Scholar, 11Miura T. Muraoka S. Fujimoto Y. Biochem. Pharmacol. 2002; 63: 2069-2074Crossref PubMed Scopus (47) Google Scholar). Increased lipid and protein with the depletion of are the major indications of generation in gastric (8Yoshikawa T. Naito Y. Kishi A. Tomii T. Kaneko T. Iinuma S. Ichikawa H. Yasuda M. Takahashi S. Kondo M. Gut. 1993; 34: 732-737Crossref PubMed Scopus (332) Google Scholar). generation plays a major role in types of gastric the role of in the regulation of MMPs and the effect of curcumin is an for are in the formation of indomethacin-induced gastric like curcumin potent anti-inflammatory antioxidant properties are to exert on ulceration (8Yoshikawa T. Naito Y. Kishi A. Tomii T. Kaneko T. Iinuma S. Ichikawa H. Yasuda M. Takahashi S. Kondo M. Gut. 1993; 34: 732-737Crossref PubMed Scopus (332) Google Scholar, G. R. 1995; PubMed Scopus Google Scholar, Chem. 2002; PubMed Scopus Google Scholar). Interestingly, data that curcumin by preventing oxidative damage by glutathione depletion, lipid peroxidation, and protein oxidation. It is histological that curcumin the damage of the surface epithelial cells and the mucosal of gastric lumen by However, the biochemical mechanism the regulation of MMP activity and the in which ECM remodeling by curcumin during healing process are The study the antiulcer activity of curcumin in indomethacin-induced gastric ulcer and its with of MMP-9 activity and up-regulation of MMP-2 activity. of MMP-9 activity is to the of of In the study have found the of curcumin to gastric ulcer in a dose-dependent The that oral dose of curcumin blocks of gastric damage by may be a for and healing of gastric ulcer. for is by the that curcumin is to to for W. C.C. Res. 2001; Google Scholar). The important is that healing of indomethacin-induced ulcer is by curcumin through an of indomethacin-induced ulcer was with and well with the attenuation of MMP-9 activity and of MMP-2 activity. curcumin not MMP-9 but MMP-2 activity while the healing It is that curcumin MMP-9 via because the of rat MMP-9 gene for like and NF-κB W. M. E. J. 2002; PubMed Scopus (114) Google Scholar). We are to NF-κB is a role in the induction of MMP-9 gene during gastric ulceration or of MMP-9 gene during or healing by the curcumin may MMP-2 expression in a process during healing of gastric be to test these the effect of indomethacin on via of MMP-2 has been reported H. E. Nat. Med. 1999; PubMed Scopus Google Scholar, J. 1999; PubMed Scopus Google Scholar), is to the role of curcumin in the and healing of gastric lesions by regulating through the results the important of MMP-9 inhibition ulcer healing. in is MMP-9 for ulcer To the used and an established for indomethacin-induced ulcer and for the MMP-9 protects gastric ulcers MMP-9 activity. the as well as curcumin significant MMP-9 inhibition during of of these data is that ulcer healing is with as well as data that the for ulcer healing is the and curcumin healing with like in a The of of ulcer may be by the during the healing In the results of study that up-regulation of MMP-9 in indomethacin-induced gastric ulcer is to of The antiulcer activity of curcumin causes of indomethacin-induced epithelial cell damage and the oxidative of the gastric lumen by preventing lipid and protein oxidation. Furthermore, curcumin protects ulcer and the healing process by MMP-9 activity and by MMP-2 activity. ulcer healing is a processes and of curcumin in the in ulcer wound healing may to healing are that curcumin is of for the healing of ulcer