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Dorjay Tamang JS, Banerjee S, Baidya SK, Das S, Ghosh B, Jha T, Adhikari N. An overview of matrix metalloproteinase-12 in multiple disease conditions, potential selective inhibitors, and drug designing strategies. Eur J Med Chem 2025; 283:117154. [PMID: 39709794 DOI: 10.1016/j.ejmech.2024.117154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/08/2024] [Accepted: 12/06/2024] [Indexed: 12/24/2024]
Abstract
Matrix metalloproteases (MMPs) are the proteolytic enzymes accountable for extracellular matrix (ECM) modification through their Zn2+-dependent catalytic activity. Among these, MMP-12 is one of the crucial MMPs that contributes to various disease states including different types of cancers and other major pathophysiological conditions including COPD, asthma, emphysema, skin diseases, arthritis, vascular diseases, and neurological disorders. The majority of the MMP-12 inhibitors should have three constitutional pharmacophoric features (i.e., a hydrophobic group to occupy the S1' pocket, a zinc-binding motif for chelating to the catalytic Zn2+ ion present at the catalytic site, and a flexible and hydrogen bond forming linker region between the S1' pocket substituent and the zinc chelating group for interacting with the catalytic and Ω-loop amino acid residues). This review mainly focuses on the various roles of MMP-12 in different diseases along with the structural comparison with other MMPs as well as promising and MMP-12-selective inhibitors and molecular modeling studies performed on MMP-12 inhibitors. Therefore, this review will provide comprehensive information to the researchers for designing effective and MMP-12-selective inhibitors for therapeutic advancement in the future.
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Affiliation(s)
- Jigme Sangay Dorjay Tamang
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Suvankar Banerjee
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Sandip Kumar Baidya
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Sanjib Das
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
| | - Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
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Minyaylo ON, Ponomarenko IV, Churnosov MI. Gender-Specific Features of Associations of Polymorphism of Matrix Metalloproteinase Genes with the Development of Peptic Ulcer Disease in the Population of the Central Chernozem Region of Russia. RUSS J GENET+ 2021. [DOI: 10.1134/s1022795421100082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Shaymardanova EK, Nurgalieva AK, Khidiyatova IM, Gabbasova LV, Kuramshina OA, Kryukova AY, Sagitov RB, Munasipov FR, Khusnutdinova EK. Role of allelic genes of matrix metalloproteinases and their tissue inhibitors in the risk of peptic ulcer disease development. RUSS J GENET+ 2016. [DOI: 10.1134/s1022795416020113] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Lee HH, Park JM, Lee SW, Kang SH, Lim CH, Cho YK, Lee BI, Lee IS, Kim SW, Choi MG. C-reactive protein as a prognostic indicator for rebleeding in patients with nonvariceal upper gastrointestinal bleeding. Dig Liver Dis 2015; 47:378-83. [PMID: 25769503 DOI: 10.1016/j.dld.2015.02.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 02/11/2015] [Accepted: 02/15/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND In patients with acute nonvariceal upper gastrointestinal bleeding, rebleeding after an initial treatment is observed in 10-20% and is associated with mortality. AIM To investigate whether the initial serum C-reactive protein level could predict the risk of rebleeding in patients with acute nonvariceal upper gastrointestinal bleeding. METHODS This was a retrospective study using prospectively collected data for upper gastrointestinal bleeding. Initial clinical characteristics, endoscopic features, and C-reactive protein levels were compared between those with and without 30-day rebleeding. RESULTS A total of 453 patients were included (mean age, 62 years; male, 70.9%). The incidence of 30-day rebleeding was 15.9%. The mean serum C-reactive protein level was significantly higher in these patients than in those without rebleeding (P<0.001). The area under the receiver operating characteristics curve with a cutoff value of 0.5mg/dL was 0.689 (P<0.001). High serum C-reactive protein level (odds ratio, 2.98; confidence interval, 1.65-5.40) was independently associated with the 30-day rebleeding risk after adjustment for the main confounding risk factors, including age, blood pressure, and initial haemoglobin level. CONCLUSIONS The serum C-reactive protein was an independent risk factor for 30-day rebleeding in patients with acute nonvariceal upper gastrointestinal bleeding, indicating a possible role as a useful screening indicator for predicting the risk of rebleeding.
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Affiliation(s)
- Han Hee Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Myung Park
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Soon-Wook Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Hun Kang
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chul-Hyun Lim
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yu Kyung Cho
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bo-In Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - In Seok Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Woo Kim
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Myung-Gyu Choi
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Abstract
Key Points
CRP enhances IgG-mediated respiratory burst and phagocytosis of platelets in vitro and their clearance in vivo. CRP levels are increased in ITP patients and correlate with platelet counts and bleeding severity and predict time to recovery.
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Tomizawa M, Shinozaki F, Hasegawa R, Togawa A, Shirai Y, Ichiki N, Motoyoshi Y, Sugiyama T, Yamamoto S, Sueishi M. Reduced hemoglobin and increased C-reactive protein are associated with upper gastrointestinal bleeding. World J Gastroenterol 2014; 20:1311-1317. [PMID: 24574805 PMCID: PMC3921513 DOI: 10.3748/wjg.v20.i5.1311] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 09/01/2013] [Accepted: 09/15/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the early upper gastrointestinal endoscopy (endoscopy) significantly reduces mortality resulting from upper gastrointestinal (GI) bleeding. METHODS Upper GI bleeding was defined as 1a, 1b, 2a, and 2b according to the Forrest classification. The hemoglobin (Hb), and C-reactive protein (CRP) were examined at around the day of endoscopy and 3 mo prior to endoscopy. The rate of change was calculated as follows: (the result of blood examination on the day of endoscopy - the results of blood examination 3 mo prior to endoscopy)/(results of blood examination 3 mo prior to endoscopy). Receiver operating characteristic curves were created to determine threshold values. RESULTS Seventy-nine men and 77 women were enrolled. There were 17 patients with upper GI bleeding: 12 with a gastric ulcer, 3 with a duodenal ulcer, 1 with an acute gastric mucosal lesion, and 1 with gastric cancer. The area under the curve (AUC), threshold, sensitivity, and specificity of Hb around the day of endoscopy were 0.902, 11.7 g/dL, 94.1%, and 77.1%, respectively, while those of CRP were 0.722, 0.5 mg/dL, 70.5%, and 73%, respectively. The AUC, threshold, sensitivity, and specificity of the rate of change of Hb were 0.851, -21.3%, 76.4%, and 82.6%, respectively, while those of CRP were 0.901, 100%, 100%, and 82.5%, respectively. CONCLUSION Predictors for upper GI bleeding were Hb < 11.7 g/dL, reduction rate in the Hb > 21.3% and an increase in the CRP > 100%, 3 mo before endoscopy.
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Cheng HC, Yang HB, Chang WL, Chen WY, Yeh YC, Sheu BS. Expressions of MMPs and TIMP-1 in gastric ulcers may differentiate H. pylori-infected from NSAID-related ulcers. ScientificWorldJournal 2012; 2012:539316. [PMID: 22645431 PMCID: PMC3353510 DOI: 10.1100/2012/539316] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 01/03/2012] [Indexed: 01/12/2023] Open
Abstract
Background. Two major causes of gastric ulcers are Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) use. Aims. This study aimed to determine if there were different expressions of matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) between H. pylori-infected and NSAID-related ulcers. Methods. The 126 gastric ulcer patients (H. pylori infected n = 46; NSAID related n = 30; combined with two factors n = 50) provided ulcer and nonulcer tissues for assessment of MMP-3, -7, and -9 and TIMP-1 expression by immunohistochemical staining. Results. Gastric ulcer tissues had significantly higher MMP-3, -7, and -9 and TIMP-1 expressions than nonulcer tissues (P < 0.05). H. pylori-infected gastric ulcers had even higher MMP-7, MMP-9, and TIMP-1 expressions in epithelial cells than NSAID-related gastric ulcers (P < 0.05). In patients with the two combined factors, gastric ulcers expressed similar proportions of antral ulcers and MMP-7 and MMP-9 intensities to NSAID-related gastric ulcers, but lower MMP-9 and TIMP-1 than H. pylori-infected gastric ulcers (P < 0.05). Conclusions. H. pylori-infected gastric ulcers express higher MMP-7, MMP-9, and TIMP-1 than NSAID-related ulcers. In patients with the two combined factors, ulcer location and MMP-7 and MMP-9 intensities are similar to NSAID use.
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Affiliation(s)
- Hsiu-Chi Cheng
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan 70403, Taiwan
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Ham M, Akiba Y, Takeuchi K, Montrose MH, Kaunitz JD. Gastroduodenal Mucosal Defense. PHYSIOLOGY OF THE GASTROINTESTINAL TRACT 2012:1169-1208. [DOI: 10.1016/b978-0-12-382026-6.00043-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Marathe SA, Dasgupta I, Gnanadhas DP, Chakravortty D. Multifaceted roles of curcumin: two sides of a coin! Expert Opin Biol Ther 2011; 11:1485-1499. [PMID: 21942554 DOI: 10.1517/14712598.2011.623124] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Curcumin has been a front-line topic of mainstream scientific research for a variety of diseases from cancer to Alzheimer's to infectious diseases. Curcumin suppresses the type 1 immune response, which might lead to alleviation of type 1 immune response disorders. However, the inhibition of type 1 immune response might invite infections with opportunistic pathogens. Considering its low bioavailability, several curcumin derivatives have been designed to improve its functionality. AREAS COVERED This is a consolidated review which aims to compare and contrast diverse aspects of curcumin in variety of diseases. The intricate underlying mechanisms and the functional determinants of curcumin are discussed. EXPERT OPINION Curcumin being considered as a spicy panacea, is not a remedy for all diseases. However, its ability to act differentially as an anti-oxidant or pro-oxidant akin to that of a double-edged sword/friend turning foe can be either beneficial or harmful for the host. It exhibits anti-oxidant properties at concentrations achievable in the body, making the host vulnerable to infections due to the suppression of innate immune responses. With the increase in knowledge of its functional groups, production of analogues of curcumin is underway to enhance its bioavailability and hence its therapeutic potency.
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Affiliation(s)
- Sandhya A Marathe
- Indian Institute of Science, Centre for Infectious Disease Research and Biosafety Laboratories, Department of Microbiology and Cell Biology, Bangalore 560012, India
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Singh LP, Mishra A, Saha D, Swarnakar S. Doxycycline blocks gastric ulcer by regulating matrix metalloproteinase-2 activity and oxidative stress. World J Gastroenterol 2011; 17:3310-21. [PMID: 21876619 PMCID: PMC3160535 DOI: 10.3748/wjg.v17.i28.3310] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Revised: 12/19/2010] [Accepted: 12/26/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the effect of doxycycline on the activity of matrix metalloproteinases (MMPs) and oxidative stress in gastric tissues of rats following gastric injury.
METHODS: Gastric ulcers were generated in rats by administration of 70% ethanol, and activity of doxycycline was tested by administration 30 min prior to ethanol. Similarly, the effect of doxycycline was tested in an indomethacin-induced gastric ulcer model. The activities and expression of MMPs were examined by zymography and Western blot analysis.
RESULTS: Gastric injury in rats as judged by elevated ulcer indices following exposure to ulcerogen, either indomethacin or ethanol, was reversed significantly by doxycycline. Indomethacin-induced ulcerated gastric tissues exhibited about 12-fold higher proMMP-9 activity and about 5-fold higher proMMP-3 activity as compared to control tissues. Similarly, ethanol induced about 22-fold and about 6-fold higher proMMP-9 and proMMP-3 activities, respectively, in rat gastric tissues. Both proMMP-9 and MMP-3 activities were markedly decreased by doxycycline in ulcerogen treated rat gastric tissues. In contrast, the reduced MMP-2 activity in ulcerated tissues was increased by doxycycline during ulcer prevention. On the other hand, doxycycline inhibited significantly proMMP-9, -2 and -3 activities in vitro. In addition, doxycycline reduced oxidative load in gastric tissues and scavenged H2O2in vitro. Our 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 ulcers.
CONCLUSION: 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.
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Yeh YC, Cheng HC, Chang WL, Yang HB, Sheu BS. Matrix metalloproteinase-3 promoter polymorphisms but not dupA-H. pylori correlate to duodenal ulcers in H. pylori-infected females. BMC Microbiol 2010; 10:218. [PMID: 20707923 PMCID: PMC2928200 DOI: 10.1186/1471-2180-10-218] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Accepted: 08/13/2010] [Indexed: 02/06/2023] Open
Abstract
Background This study investigated if the H. pylori dupA genotype and certain host single nucleotide polymorphisms (SNPs) of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), including MMP-3, MMP-7, MMP-9, TIMP-1 and TIMP-2, might correlate with ulcer risk of H. pylori-infected Taiwanese patients. Results Of the 549 H. pylori-infected patients enrolled, 470 patients (265 with gastritis, 118 with duodenal ulcer, and 87 with gastric ulcer) received SNPs analysis of MMP-3-1612 6A > 5A, MMP-7-181 A > G, MMP-9exon 6 A > G, TIMP-1372 T > C and TIMP-2-418 G > C by PCR-RFLP. The 181 collected H. pylori isolates were detected for the dupA genotype by PCR. The rates of dupA-positive H. pylori infection were similar among patients with duodenal ulcer (22.8%), gastric ulcer (20.0%), and gastritis (25.5%) (p > 0.05). Males had higher rates of duodenal ulcer and gastric ulcer than females (p < 0.01). Of H. pylori-infected patients, the MMP-3 6A6A genotype were more common in patients with duodenal ulcers than in those with gastritis (87.7% vs. 74.9%, p < 0.05) in females. This genotype had a 2.4-fold (95% CI: 1.02-5.66) increased risk of duodenal ulcer, compared to those with the 5A carrier. Combining the MMP-3/TIMP-1 genotype as 6A6A/CC, the risk of duodenal ulcer increased up to 3.6 fold (p < 0.05) in H. pylori-infected females. Conclusions The MMP-3 promoter polymorphism, but not the dupA-status, may correlate with susceptibility to duodenal ulcer after H. pylori infection in Taiwanese females.
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Affiliation(s)
- Yi-Chun Yeh
- Institute of Clinical Medicine, National Cheng Kung University Hospital, Medical College, Tainan, Taiwan
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Metaloproteasas de la matriz extracelular como marcadores moleculares en cáncer gástrico. Med Clin (Barc) 2010; 134:123-6. [DOI: 10.1016/j.medcli.2009.09.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Accepted: 09/10/2009] [Indexed: 01/27/2023]
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Musumba C, Pritchard DM, Pirmohamed M. Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther 2009; 30:517-31. [PMID: 19575764 DOI: 10.1111/j.1365-2036.2009.04086.x] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most prescribed drugs worldwide and have now probably overtaken Helicobacter pylori as the most common cause of gastrointestinal injury in Western countries. Further understanding of the pathogenesis of NSAID-induced ulcers is important to enable the development of novel and effective preventive strategies. AIMS To provide an update on recent advances in our understanding of the cellular and molecular mechanisms involved in the development of NSAID-induced ulcers. METHODS A Medline search was performed to identify relevant literature using search terms including 'nonsteroidal anti-inflammatory drugs, aspirin, gastric ulcer, duodenal ulcer, pathogenesis, pharmacogenetics'. RESULTS The mechanisms of NSAID-induced ulcers can be divided into topical and systemic effects and the latter may be prostaglandin-dependent (through COX inhibition) or prostaglandin-independent. Genetic factors may play an important role in determining individual predisposition. CONCLUSIONS The pathogenesis of NSAID-induced peptic ulcers is complex and multifactorial. Recent advances in cellular and molecular biology have highlighted the importance of various prostaglandin-independent mechanisms. Pharmacogenetic studies may provide further insights into the pathogenetic mechanisms of NSAID-induced ulcers and help identify patients at increased risk.
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Affiliation(s)
- C Musumba
- Department of Pharmacology and Therapeutics, School of Biomedical Sciences, University of Liverpool, Liverpool, UK
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