{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTIMP‐1 is a multifunctional protein that serves primarily as an inhibitor of matrix metalloproteinases (MMPs), thereby regulating extracellular matrix (ECM) turnover and tissue remodeling. It plays a critical role in processes such as embryonic development, angiogenesis, and wound repair by both blocking MMP‐mediated proteolysis and activating intracellular survival and growth signaling pathways. In several cell types—from hepatic stellate to breast epithelial cells—TIMP‐1 directly inhibits apoptosis, and its activity may be altered by post‐translational modifications in inflammatory conditions, highlighting its importance in maintaining tissue integrity and modulating cellular responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, TIMP‐1 exhibits context‐dependent activities that extend beyond MMP inhibition. Although its classical function would predict tumor‐suppressive effects (by curbing ECM degradation), elevated TIMP‐1 expression in the tumor microenvironment has been associated with enhanced cell survival, proliferation, and metastatic potential. It can modulate pro‐survival signaling cascades—including those involving microRNAs—and is implicated in the progression and poor prognosis of a variety of cancers (colon, esophageal, gastric, breast, pancreatic, and melanoma), often by influencing angiogenesis and stromal interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cardiovascular diseases and fibrotic disorders, an imbalance between MMP activity and its inhibition by TIMP‐1 contributes to deleterious ECM accumulation and adverse remodeling. Elevated circulating or tissue levels of TIMP‐1 have been correlated with conditions such as left ventricular hypertrophy, aortic aneurysms, hypertension, and preeclampsia, where sustained ECM deposition and vascular stiffening exacerbate disease progression. Such perturbations in the MMP/TIMP axis serve not only as markers of underlying pathology but may also actively drive structural alterations that predispose to cardiovascular events."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system, TIMP‐1 is implicated in mediating responses to injury and neuroinflammation. Its differential expression by astrocytes contributes to both homeostatic repair mechanisms and the pathogenesis of neurodegenerative conditions. Altered levels in cerebrospinal fluid and brain tissue have been associated with Alzheimer’s disease, vascular dementia, and other inflammatory neurological disorders, suggesting that TIMP‐1 might serve as a biomarker for neural injury as well as a modulator of blood–brain barrier integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTIMP‐1 also exerts nuanced control over angiogenesis, cellular migration, and ECM reorganization in varied physiological and pathological settings. In wound repair, fibroblast‐derived TIMP‐1 can promote endothelial tube formation by modulating the availability of anti‐angiogenic collagen fragments, while in conditions such as endometriosis, vasculitis, adipogenesis, and pathologic scar formation, its regulation of protease activity is central to tissue restructuring. Detailed structural studies of TIMP‐1 interactions with specific MMPs shed light on its binding specificity and provide avenues for designing targeted therapeutics. Moreover, in diseases like cystic fibrosis and melanoma, aberrations in TIMP‐1 expression or activity underscore its potential as a diagnostic or prognostic indicator."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "39", "end_ref": "50"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Griselda A Cabral-Pacheco, Idalia Garza-Veloz, Claudia Castruita-De la Rosa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms21249739"}], "href": "https://doi.org/10.3390/ijms21249739"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33419373"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33419373"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Frank R Murphy, Razao Issa, Xiaoying Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111490200"}], "href": "https://doi.org/10.1074/jbc.M111490200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11796725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11796725"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Brian C McKaig, Daniel McWilliams, Sue A Watson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)63931-4"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "63931-4) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12651627"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12651627"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xu-Wen Liu, M Margarida Bernardo, Rafael Fridman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M302999200"}], "href": "https://doi.org/10.1074/jbc.M302999200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12904305"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12904305"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Masayoshi Yamanaka, Daniel Shegogue, Heuping Pei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine kinase 1 (SPHK1) is induced by transforming growth factor-beta and mediates TIMP-1 up-regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M410144200"}], "href": "https://doi.org/10.1074/jbc.M410144200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15485866"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15485866"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Virginia Egea, Stefan Zahler, Nicole Rieth, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1115083109"}], "href": "https://doi.org/10.1073/pnas.1115083109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22223664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22223664"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yi Wang, Henry Rosen, David K Madtes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue: an oxidative mechanism for regulating proteolysis during inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704894200"}], "href": "https://doi.org/10.1074/jbc.M704894200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17726014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17726014"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Barbara Grünwald, Benjamin Schoeps, Achim Krüger "}, {"type": "b", "children": [{"type": "t", "text": "Recognizing the Molecular Multifunctionality and Interactome of TIMP-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Cell Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tcb.2018.08.006"}], "href": "https://doi.org/10.1016/j.tcb.2018.08.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30243515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30243515"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Radhika Suryadevara, Spring Holter, Kathleen Borgmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of tissue inhibitor of metalloproteinase-1 by astrocytes: links to HIV-1 dementia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glia (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/glia.10266"}], "href": "https://doi.org/10.1002/glia.10266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12951656"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12951656"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Guohe Song, Shifeng Xu, Hong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13046-016-0427-7"}], "href": "https://doi.org/10.1186/s13046-016-0427-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27644693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27644693"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ewa Zajac, Bernhard Schweighofer, Tatyana A Kupriyanova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2013-05-501494"}], "href": "https://doi.org/10.1182/blood-2013-05-501494"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24174628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24174628"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "H Cui, B Seubert, E Stahl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2014.300"}], "href": "https://doi.org/10.1038/onc.2014.300"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25263437"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25263437"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Veli-Matti Wasenius, Samuli Hemmer, Eeva Kettunen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatocyte growth factor receptor, matrix metalloproteinase-11, tissue inhibitor of metalloproteinase-1, and fibronectin are up-regulated in papillary thyroid carcinoma: a cDNA and tissue microarray study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12538453"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12538453"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Magdalena Groblewska, Maria Siewko, Barbara Mroczko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Folia Histochem Cytobiol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2478/18691"}], "href": "https://doi.org/10.2478/18691"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22532131"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22532131"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Anne-Sofie Schrohl, Mads N Holten-Andersen, Harry A Peters, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.ccr-03-0360"}], "href": "https://doi.org/10.1158/1078-0432.ccr-03-0360"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15073104"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15073104"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Mariana Toricelli, Fabiana H M Melo, Giovani B Peres, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-K signaling pathway independently of Akt phosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1476-4598-12-22"}], "href": "https://doi.org/10.1186/1476-4598-12-22"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23522389"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23522389"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Barbara Grünwald, Veronika Harant, Susanne Schaten, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pancreatic Premalignant Lesions Secrete Tissue Inhibitor of Metalloproteinases-1, Which Activates Hepatic Stellate Cells Via CD63 Signaling to Create a Premetastatic Niche in the Liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2016.07.043"}], "href": "https://doi.org/10.1053/j.gastro.2016.07.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27506299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27506299"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Berit Bernert, Helena Porsch, Paraskevi Heldin "}, {"type": "b", "children": [{"type": "t", "text": "Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.278598"}], "href": "https://doi.org/10.1074/jbc.M111.278598"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22016393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22016393"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Yixuan Gong, Evita Scott, Rong Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0077366"}], "href": "https://doi.org/10.1371/journal.pone.0077366"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24143225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24143225"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Yasuhide Ikenaka, Hitoshi Yoshiji, Shigeki Kuriyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits tumor growth and angiogenesis in the TIMP-1 transgenic mouse model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.11094"}], "href": "https://doi.org/10.1002/ijc.11094"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12704667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12704667"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Katherine E Poruk, Matthew A Firpo, Courtney L Scaife, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum osteopontin and tissue inhibitor of metalloproteinase 1 as diagnostic and prognostic biomarkers for pancreatic adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pancreas (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MPA.0b013e31825e354d"}], "href": "https://doi.org/10.1097/MPA.0b013e31825e354d"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23407481"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23407481"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Sheng Zhang, Li Li, Jian-Yin Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Imbalance between expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in invasiveness and metastasis of human gastric carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Gastroenterol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3748/wjg.v9.i5.899"}], "href": "https://doi.org/10.3748/wjg.v9.i5.899"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12717827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12717827"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Harriet M Kluger, Kathleen Hoyt, Antonella Bacchiocchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plasma markers for identifying patients with metastatic melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-10-2402"}], "href": "https://doi.org/10.1158/1078-0432.CCR-10-2402"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21487066"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21487066"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Karin Söderlund Leifler, Susanne Svensson, Annelie Abrahamsson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1202610"}], "href": "https://doi.org/10.4049/jimmunol.1202610"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23509357"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23509357"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Ilaria Guccini, Ajinkya Revandkar, Mariantonietta D'Ambrosio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2020.10.012"}], "href": "https://doi.org/10.1016/j.ccell.2020.10.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33186519"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33186519"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Stephane Heymans, Blanche Schroen, Pieter Vermeersch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.104.516963"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.104.516963"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16103240"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16103240"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "P F Mercer, J K Shute, A Bhowmik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Respir Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1465-9921-6-151"}], "href": "https://doi.org/10.1186/1465-9921-6-151"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16372907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16372907"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Muzahir H Tayebjee, Sunil Nadar, Andrew D Blann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hypertens (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.amjhyper.2004.05.019"}], "href": "https://doi.org/10.1016/j.amjhyper.2004.05.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15363817"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15363817"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Giuseppe Derosa, Angela D'Angelo, Leonardina Ciccarelli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endothelium (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/10623320600780942"}], "href": "https://doi.org/10.1080/10623320600780942"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16840178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16840178"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Toru Ogata, Hidenori Shibamura, Gerard Tromp, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Vasc Surg (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jvs.2005.02.020"}], "href": "https://doi.org/10.1016/j.jvs.2005.02.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15944607"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15944607"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Ana C T Palei, Valeria C Sandrim, Ricardo C Cavalli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative assessment of matrix metalloproteinase (MMP)-2 and MMP-9, and their inhibitors, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in preeclampsia and gestational hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Biochem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.clinbiochem.2008.04.015"}], "href": "https://doi.org/10.1016/j.clinbiochem.2008.04.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18477480"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18477480"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Ursula Hoffmann, Thomas Bertsch, Eszter Dvortsak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Scand J Infect Dis (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/00365540600702058"}], "href": "https://doi.org/10.1080/00365540600702058"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17008230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17008230"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Jonas Hansson, Ramachandran S Vasan, Johan Ärnlöv, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biomarkers of extracellular matrix metabolism (MMP-9 and TIMP-1) and risk of stroke, myocardial infarction, and cause-specific mortality: cohort study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0016185"}], "href": "https://doi.org/10.1371/journal.pone.0016185"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21283828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21283828"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Dariusz Lachowski, Ernesto Cortes, Alistair Rice, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix stiffness modulates the activity of MMP-9 and TIMP-1 in hepatic stellate cells to perpetuate fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-019-43759-6"}], "href": "https://doi.org/10.1038/s41598-019-43759-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31086224"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31086224"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Martina Montagnana, Giuseppe Lippi, Alessandro Albiero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evaluation of metalloproteinases 2 and 9 and their inhibitors in physiologic and pre-eclamptic pregnancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Lab Anal (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcla.20295"}], "href": "https://doi.org/10.1002/jcla.20295"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19288452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19288452"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Jessica Gardner, Anuja Ghorpade "}, {"type": "b", "children": [{"type": "t", "text": "Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci Res (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jnr.10835"}], "href": "https://doi.org/10.1002/jnr.10835"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14648584"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14648584"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Maria Bjerke, Henrik Zetterberg, Åke Edman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cerebrospinal fluid matrix metalloproteinases and tissue inhibitor of metalloproteinases in combination with subcortical and cortical biomarkers in vascular dementia and Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-2011-110566"}], "href": "https://doi.org/10.3233/JAD-2011-110566"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21860087"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21860087"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "S Lorenzl, D S Albers, P A LeWitt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal fluid of neurodegenerative diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurol Sci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0022-510x(02)00398-2"}], "href": "https://doi.org/10.1016/s0022-510x(02"}, {"type": "t", "text": "00398-2) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12614934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12614934"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Robert Ramer, Burkhard Hinz "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Natl Cancer Inst (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jnci/djm268"}], "href": "https://doi.org/10.1093/jnci/djm268"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18159069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18159069"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Veronica C Ardi, Philippe E Van den Steen, Ghislain Opdenakker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neutrophil MMP-9 proenzyme, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via a basic fibroblast growth factor (FGF-2)/FGFR-2 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.033472"}], "href": "https://doi.org/10.1074/jbc.M109.033472"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19608737"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19608737"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "F J G M Kubben, C F M Sier, M J W Meijer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6603307"}], "href": "https://doi.org/10.1038/sj.bjc.6603307"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16940985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16940985"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "T Collette, R Maheux, J Mailloux, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased expression of matrix metalloproteinase-9 in the eutopic endometrial tissue of women with endometriosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Reprod (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/humrep/del297"}], "href": "https://doi.org/10.1093/humrep/del297"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16880228"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16880228"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Paul A Monach, Roscoe L Warner, Gunnar Tomasson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Rheum Dis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/annrheumdis-2012-201981"}], "href": "https://doi.org/10.1136/annrheumdis-2012-201981"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22975753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22975753"}]}, {"type": "r", "ref": 44, "children": [{"type": "t", "text": "Takemi Akahane, Manabu Akahane, Amy Shah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2004.08.002"}], "href": "https://doi.org/10.1016/j.yexcr.2004.08.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15530852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15530852"}]}, {"type": "r", "ref": 45, "children": [{"type": "t", "text": "Hua Liu, Bo Chen, Brenda Lilly "}, {"type": "b", "children": [{"type": "t", "text": "Fibroblasts potentiate blood vessel formation partially through secreted factor TIMP-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Angiogenesis (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10456-008-9102-8"}], "href": "https://doi.org/10.1007/s10456-008-9102-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18273688"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18273688"}]}, {"type": "r", "ref": 46, "children": [{"type": "t", "text": "B Meissburger, L Stachorski, E Röder, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-011-2093-9"}], "href": "https://doi.org/10.1007/s00125-011-2093-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21437772"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21437772"}]}, {"type": "r", "ref": 47, "children": [{"type": "t", "text": "Dietmar Ulrich, Franziska Ulrich, Frank Unglaub, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with different types of scars and keloids."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Plast Reconstr Aesthet Surg (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bjps.2009.04.021"}], "href": "https://doi.org/10.1016/j.bjps.2009.04.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19464975"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19464975"}]}, {"type": "r", "ref": 48, "children": [{"type": "t", "text": "Jyotica Batra, Jessica Robinson, Alexei S Soares, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: binding studies and crystal structure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.341156"}], "href": "https://doi.org/10.1074/jbc.M112.341156"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22427646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22427646"}]}, {"type": "r", "ref": 49, "children": [{"type": "t", "text": "A R Thompson, F Drenos, H Hafez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Candidate gene association studies in abdominal aortic aneurysm disease: a review and meta-analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Vasc Endovasc Surg (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejvs.2007.07.022"}], "href": "https://doi.org/10.1016/j.ejvs.2007.07.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17920311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17920311"}]}, {"type": "r", "ref": 50, "children": [{"type": "t", "text": "Patricia L Jackson, Xin Xu, Landon Wilson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human neutrophil elastase-mediated cleavage sites of MMP-9 and TIMP-1: implications to cystic fibrosis proteolytic dysfunction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2119/molmed.2009.00109"}], "href": "https://doi.org/10.2119/molmed.2009.00109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20111696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20111696"}]}]}]}