Biochemistry, Genetics and Molecular Biology › Cancer Research

Protease and Inhibitor Mechanisms

Works Count: 53064

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This cluster of papers explores the multifaceted roles of matrix metalloproteinases (MMPs) in cancer progression, angiogenesis, inflammation regulation, and extracellular matrix remodeling. It also delves into the potential of MMPs as therapeutic targets for cancer therapy and their involvement in various physiological processes such as cell signaling and tissue remodeling.

Keywords

Matrix Metalloproteinases; Tissue Inhibitors of Metalloproteinases; Cancer Progression; Angiogenesis; Extracellular Matrix Remodeling; Protease Inhibition; Inflammation Regulation; Cell Signaling; Metastasis; Extracellular Matrix

Tissue inhibitors of metalloproteinases: structure, regulation and biological functions.

1997-10-01

Daniel E. Gómez , Daniel F. Alonso , Hitoshi Yoshiji +1 more

Tissue inhibitors of metalloproteinases: evolution, structure and function

2000-03-01

Keith Brew , Deendayal Dinakarpandian , Hideaki Nagase

Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

2000-09-20

Gabriele Bergers , Rolf A. Brekken , Gerald McMahon +7 more

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Matrix Metalloproteinases: Role In Arthritis

2006-01-01

Silke Peter

The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of … The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of proteoglycans and type II collagen, tendon and bone are composed primarily of type I collagen. RA is an autoimmune disease afflicting numerous joints throughout the body; in contrast, OA develops in a small number of joints, usually resulting from chronic overuse or injury. In both diseases, inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) stimulate the production of matrix metalloproteinases (MMPs), enzymes that can degrade all components of the extracellular matrix. The collagenases, MMP-1 and MMP-13, have predominant roles in RA and OA because they are rate limiting in the process of collagen degradation. MMP-1 is produced primarily by the synovial cells that line the joints, and MMP-13 is a product of the chondrocytes that reside in the cartilage. In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, giving it a dual role in matrix destruction. Expression of other MMPs such as MMP-2, MMP-3 and MMP-9, is also elevated in arthritis and these enzymes degrade non-collagen matrix components of the joints. Significant effort has been expended in attempts to design effective inhibitors of MMP activity and/or synthesis with the goal of curbing connective tissues destruction within the joints. To date, however, no effective clinical inhibitors exist. Increasing our knowledge of the crystal structures of these enzymes and of the signal transduction pathways and molecular mechanisms that control MMP gene expression may provide new opportunities for the development of therapeutics to prevent the joint destruction seen in arthritis.

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Regulation of matrix metalloproteinase expression in tumor invasion

1999-05-01

Jukka Westermarck , Veli‐Matti Kähäri

Degradation of basement membranes and stromal extracellular matrix (ECM) is crucial for invasion and metastasis of malignant cells. Degradation of ECM is initiated by proteinases secreted by different cell types … Degradation of basement membranes and stromal extracellular matrix (ECM) is crucial for invasion and metastasis of malignant cells. Degradation of ECM is initiated by proteinases secreted by different cell types participating in tumor cell invasion, and increased expression or activity of every known class of proteinases (metallo-, serine-, aspartic-, and cysteine) has been linked to malignancy and invasion of tumor cells. Studies performed over the last decade have revealed that matrix metalloproteinases (MMPs) play a crucial role in tumor invasion. Expression of MMP genes is transcriptionally regulated by a variety of extracellular factors including cytokines, growth factors, and cell contact to ECM. This review will summarize the current view on the role of MMPs in tumor growth, invasion, and survival, and focus on the role of mitogen-activated protein kinases and AP-1 and ETS transcription factors in the regulation of MMP gene expression during invasion process.

Matrix Metalloproteinases: Biologic Activity and Clinical Implications

2000-03-01

Amy R. Nelson , Barbara Fingleton , Mace L. Rothenberg +1 more

ABSTRACT: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and … ABSTRACT: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.

Matrix Metalloproteinases: A Review

1993-01-01

Henning Birkedal‐Hansen , William G. I. Moore , Malena Bodden +4 more

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn ++ endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The … Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn ++ endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting

2010-10-21

Chrysostomi Gialeli , Achilleas D. Theocharis , Nikos K. Karamanos

Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal … Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs.

Remodelling the extracellular matrix in development and disease

2014-11-21

Caroline Bonnans , Jonathan Chou , Zena Werb

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Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability

2005-07-01

Derek C. Radisky , Dan D. Levy , Laurie E. Littlepage +7 more

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ECM and Cell Surface Proteolysis: Regulating Cellular Ecology

1997-11-01

Zena Werb

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A matrix metalloproteinase expressed on the surface of invasive tumour cells

1994-07-01

Hiroshi Sato , Takahisa Takino , Yasunori Okada +4 more

Metalloproteinases and their inhibitors in matrix remodeling

1990-01-01

Lynn M. Matrisian

Matrix metalloproteinases as modulators of inflammation and innate immunity

2004-07-30

William C. Parks , Carole L. Wilson , Yolanda S. López-Boado

Matrix metalloproteinases and tumor metastasis

2006-03-01

Elena I. Deryugina , James P. Quigley

Structure and function of matrix metalloproteinases and TIMPs

2006-01-06

Hiroyuki Nagase , Robert Visse , G MURPHY

Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They play central roles in morphogenesis, wound healing, tissue repair … Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They play central roles in morphogenesis, wound healing, tissue repair and remodelling in response to injury, e.g. after myocardial infarction, and in progression of diseases such as atheroma, arthritis, cancer and chronic tissue ulcers. They are multi-domain proteins and their activities are regulated by tissue inhibitors of metalloproteinases (TIMPs). This review introduces the members of the MMP family and discusses their domain structure and function, proenyme activation, the mechanism of inhibition by TIMPs and their significance in physiology and pathology.

New functions for the matrix metalloproteinases in cancer progression

2002-03-01

Mikala Egeblad , Zena Werb

The urokinase-type plasminogen activator system in cancer metastasis: A review

1997-07-03

Peter A. Andreasen , Lars Kjøller , Lise Christensen +1 more

The urokinase-type plasminogen activator (u-PA) system consists of the serine proteinases plasmin and u-PA; the serpin inhibitors alpha2-anti-plasmin, PAI-1 and PAI-2; and the u-PA receptor (u-PAR). Two lines of evidence … The urokinase-type plasminogen activator (u-PA) system consists of the serine proteinases plasmin and u-PA; the serpin inhibitors alpha2-anti-plasmin, PAI-1 and PAI-2; and the u-PA receptor (u-PAR). Two lines of evidence have strongly suggested an important and apparently causal role for the u-PA system in cancer metastasis: results from experimental model systems with animal tumor metastasis and the finding that high levels of u-PA, PAI-1 and u-PAR in many tumor types predict poor patient prognosis. We discuss here recent observations related to the molecular and cellular mechanisms underlying this role of the u-PA system. Many findings suggest that the system does not support tumor metastasis by the unrestricted enzyme activity of u-PA and plasmin. Rather, pericellular molecular and functional interactions between u-PA, u-PAR, PAI-1, extracellular matrix proteins, integrins, endocytosis receptors and growth factors appear to allow temporal and spatial re-organizations of the system during cell migration and a selective degradation of extracellular matrix proteins during invasion. Differential expression of components of the system by cancer and non-cancer cells, regulated by paracrine mechanisms, appear to determine the involvement of the system in cancer cell-directed tissue remodeling. A detailed knowledge of these processes is necessary for utilization of the therapeutic potential of interfering with the action of the system in cancers.

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Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

2010-04-01

Kai Kessenbrock , Vicki Plaks , Zena Werb

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Plasminogen: Purification from Human Plasma by Affinity Chromatography

1970-12-04

Dale G. Deutsch , Edwin T. Mertz

Plasminogen was prepared from human plasma by affinity chromatography on L-lysine-substituted Sepharose. Thirty milligrams of plasminogen, with a specific activity of 100 caseinolytic units (Committee on Thrombolytic Agents) per milligram … Plasminogen was prepared from human plasma by affinity chromatography on L-lysine-substituted Sepharose. Thirty milligrams of plasminogen, with a specific activity of 100 caseinolytic units (Committee on Thrombolytic Agents) per milligram of nitrogen, were obtained from 340 milliliters of plasma. This corresponds to over 200-fold purification from plasma. Disc-gel electrophoresis at pH 8.3 indicated seven distinct bands, all of which contained activity.

MMP-9/Gelatinase B Is a Key Regulator of Growth Plate Angiogenesis and Apoptosis of Hypertrophic Chondrocytes

1998-05-01

Thiennu H. Vu , J. Michael Shipley , Gabriele Bergers +6 more

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MT1-MMP-Deficient Mice Develop Dwarfism, Osteopenia, Arthritis, and Connective Tissue Disease due to Inadequate Collagen Turnover

1999-10-01

Kenn Holmbeck , Paolo Bianco , John J. Caterina +7 more

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Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics

2003-04-09

Matthias P. Lütolf , Janelle L. Lauer‐Fields , Hugo G. Schmoekel +4 more

Synthetic hydrogels have been molecularly engineered to mimic the invasive characteristics of native provisional extracellular matrices: a combination of integrin-binding sites and substrates for matrix metalloproteinases (MMP) was required to … Synthetic hydrogels have been molecularly engineered to mimic the invasive characteristics of native provisional extracellular matrices: a combination of integrin-binding sites and substrates for matrix metalloproteinases (MMP) was required to render the networks degradable and invasive by cells via cell-secreted MMPs. Degradation of gels was engineered starting from a characterization of the degradation kinetics (k(cat) and K(m)) of synthetic MMP substrates in the soluble form and after crosslinking into a 3D hydrogel network. Primary human fibroblasts were demonstrated to proteolytically invade these networks, a process that depended on MMP substrate activity, adhesion ligand concentration, and network crosslinking density. Gels used to deliver recombinant human bone morphogenetic protein-2 to the site of critical defects in rat cranium were completely infiltrated by cells and remodeled into bony tissue within 4 wk at a dose of 5 microg per defect. Bone regeneration was also shown to depend on the proteolytic sensitivity of the matrices. These hydrogels may be useful in tissue engineering and cell biology as alternatives for naturally occurring extracellular matrix-derived materials such as fibrin or collagen.

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Strategies for MMP inhibition in cancer: innovations for the post-trial era

2002-09-01

Christopher M. Overall , Carlos López-Otı́n

cDNA sequence of human apolipoprotein(a) is homologous to plasminogen

1987-11-01

John W. McLean , James Tomlinson , Wun-Jing Kuang +5 more

Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli

1983-01-01

Diane Pennica , William E. Holmes , William J. Kohr +7 more

Mechanism Of Cell Surface Activation Of 72-kDa Type IV Collagenase

1995-03-01

Alex Y. Strongin , Ivan E. Collier , G. A. Bannikov +3 more

Matrix metalloproteases are secreted by mammalian cells as zymogens and, upon activation, initiate tissue remodeling by proteolytic degradation of collagens and proteoglycans. Activation of the secreted proenzymes and interaction with … Matrix metalloproteases are secreted by mammalian cells as zymogens and, upon activation, initiate tissue remodeling by proteolytic degradation of collagens and proteoglycans. Activation of the secreted proenzymes and interaction with their specific inhibitors determine the net enzymatic activity in the extracellular space. We have previously demonstrated that 72T4Cl can be activated by a plasma membrane-dependent mechanism specific for this enzyme. Here, we report purification of the membrane activator of 72T4Cl, which is a new metalloprotease identical to a recently cloned membrane-type matrix metalloprotease (MT-MMP). We demonstrate that activated MT-MMP acts as a cell surface tissue inhibitor of metalloprotease 2 (TIMP-2) receptor with Kd = 2.54 × 10−9M. The activator•TlMP-2 complex in turn acts as a receptor for 72T4Cl (Kd = 0.56 × 10−9M), binding to the carboxyl-end domain of the enzyme. Activation of 72T4Cl on the cell membrane provides a basic mechanism for spatially regulated extracellular proteolysis and presents a new target for prognosis and treatment of metastatic disease. The activator, purified as a tri-molecular complex of MT-MMP•TIMP2•carboxyl-end domain of 72T4Cl, is itself an activated form of MT-MMP, posing the following question: what is the mechanism of the activator's activation? Matrix metalloproteases are secreted by mammalian cells as zymogens and, upon activation, initiate tissue remodeling by proteolytic degradation of collagens and proteoglycans. Activation of the secreted proenzymes and interaction with their specific inhibitors determine the net enzymatic activity in the extracellular space. We have previously demonstrated that 72T4Cl can be activated by a plasma membrane-dependent mechanism specific for this enzyme. Here, we report purification of the membrane activator of 72T4Cl, which is a new metalloprotease identical to a recently cloned membrane-type matrix metalloprotease (MT-MMP). We demonstrate that activated MT-MMP acts as a cell surface tissue inhibitor of metalloprotease 2 (TIMP-2) receptor with Kd = 2.54 × 10−9M. The activator•TlMP-2 complex in turn acts as a receptor for 72T4Cl (Kd = 0.56 × 10−9M), binding to the carboxyl-end domain of the enzyme. Activation of 72T4Cl on the cell membrane provides a basic mechanism for spatially regulated extracellular proteolysis and presents a new target for prognosis and treatment of metastatic disease. The activator, purified as a tri-molecular complex of MT-MMP•TIMP2•carboxyl-end domain of 72T4Cl, is itself an activated form of MT-MMP, posing the following question: what is the mechanism of the activator's activation?

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Tumor Cell Interactions with the Extracellular Matrix During Invasion and Metastasis

1993-11-01

William G. Stetler‐Stevenson , Sadie Aznavoorian , Lance A. Liotta

Recent findings have produced great strides in developing an understanding of the molecular events involved in processes necessary for tumor cell invasion and subsequent metastasis formation. This information has been … Recent findings have produced great strides in developing an understanding of the molecular events involved in processes necessary for tumor cell invasion and subsequent metastasis formation. This information has been useful in developing new targets for therapeutic intervention such as disruption of tumor cell attachment by peptide analogues of cell adhesion molecules and the use of protease inhibitors to limit extracellular matrix proteolysis required for tumor cell invasion. Future efforts must focus on how the events of cell attachment, matrix proteolysis, and cell migration are controlled and integrated. This requires a better understanding of the transcriptional controls and cell signaling mechanisms that are involved in these events. Preliminary findings suggest that cell-matrix interactions influence gene expression and that the protease inhibitor balance can greatly influence cell-matrix interactions. Therefore it appears that all three steps in the invasive process are linked and interdependent. While this complicates the study of these processes, it is our belief that understanding this interdependence is critical for further development of metastasis research.

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Matrix metalloproteinases and the regulation of tissue remodelling

2007-02-23

Andrea Page-McCaw , Andrew J. Ewald , Zena Werb

MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis

2000-10-01

Lisa M. Coussens , Christopher L. Tinkle , Douglas Hanahan +1 more

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Cysteine cathepsins: From structure, function and regulation to new frontiers

2011-10-16

Vito Türk , Veronika Stoka , Olga Vasiljeva +3 more

It is more than 50 years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these … It is more than 50 years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate "warhead". The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

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Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates

1980-02-01

Christa Heussen , Eugene B. Dowdle

The matrix‐degrading metalloproteinases

1992-07-01

Lynn M. Matrisian

The matrix-degrading metalloproteinases are an intriguing family of enzymes that have evolved to digest specific extracellular matrix components. The expression of these enzymes is very highly regulated and can be … The matrix-degrading metalloproteinases are an intriguing family of enzymes that have evolved to digest specific extracellular matrix components. The expression of these enzymes is very highly regulated and can be controlled transcriptionally by a number of growth factors, tumor promoters, oncogenes, and hormones. It is suggested that the coordinated regulation of matrix metalloproteinases and their inhibitors by these agents modify the integrity of the extracellular matrix. These modifications may, at least in part, be responsible for mediating the effects of these factors on complex physiological processes.

Changing views of the role of matrix metalloproteinases in metastasis

1997-09-03

Ann F. Chambers , L M Matrisian

Metastatic spread of cancer continues to be the greatest barrier to cancer cure. Understanding the molecular mechanisms of metastasis is crucial for the design and effective use of novel therapeutic … Metastatic spread of cancer continues to be the greatest barrier to cancer cure. Understanding the molecular mechanisms of metastasis is crucial for the design and effective use of novel therapeutic strategies to combat metastases. One class of molecules that has been repeatedly implicated in metastasis is the matrix metalloproteinases (MMPs). In this review, we re-examine the evidence that MMPs are associated with metastasis and that they make a functional contribution to the process. Initially, it was believed that the major role of MMPs in metastasis was to facilitate the breakdown of physical barriers to metastasis, thus promoting invasion and entry into and out of blood or lymphatic vessels (intravasation, extravasation). However, recent evidence suggests that MMPs may have a more complex role in metastasis and that they may make important contributions at other steps in the metastatic process. Studies using intravital videomicroscopy, as well as experiments in which levels of MMPs or their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are manipulated genetically or pharmacologically, suggest that MMPs are key regulators of growth of tumors, at both primary and metastatic sites. On the basis of this evidence, a new view of the functional role of MMPs in metastasis is presented, which suggests that MMPs are important in creating and maintaining an environment that supports the initiation and maintenance of growth of primary and metastatic tumors. Further clarification of the mechanisms by which MMPs regulate growth of primary and metastatic tumors will be important in the development of novel therapeutic strategies against metastases.

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Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.

1994-12-01

Zorina S. Galis , Galina K. Sukhova , Michael W. Lark +1 more

Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of … Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components in human atherosclerotic plaques (n = 30) and in uninvolved arterial specimens (n = 11). We studied members of all three MMP classes (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immunocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts contained activated forms of gelatinases determined zymographically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active matrix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymography revealed gelatinolytic and caseinolytic activity in frozen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvasculature of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.

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Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly.

2002-02-22

Zorina S. Galis , Jaikirshan Khatri

Vascular remodeling, defined as any enduring change in the size and/or composition of an adult blood vessel, allows adaptation and repair. On the other hand, inappropriate remodeling, including its absence, … Vascular remodeling, defined as any enduring change in the size and/or composition of an adult blood vessel, allows adaptation and repair. On the other hand, inappropriate remodeling, including its absence, underlies the pathogenesis of major cardiovascular diseases, such as atherosclerosis and restenosis. Since degradation of the extracellular matrix scaffold enables reshaping of tissue, participation of specialized enzymes called matrix metalloproteinases (MMPs) has become the object of intense recent interest in relation to physiological ("good") and pathological ("bad") vascular remodeling. Experimental evidence acquired in vitro and in vivo suggests that the major drivers of vascular remodeling, hemodynamics, injury, inflammation, and oxidative stress, regulate MMP expression and activity. Alternatively, nonspecific MMP inhibition seems to oppose remodeling, as suggested by the inhibition of intimal thickening and outward arterial remodeling. An emerging concept is that MMP-related genetic variations may contribute to heterogeneity in the presentation and natural history of atherosclerosis. The hypothesis that MMPs contribute to weakening of atherosclerotic plaques is especially attractive for the potential development of therapeutic interventions aimed at preventing plaque disruption ("the ugly"), a major cause of acute cardiovascular events. However, the current lack of appropriate experimental tools, including availability of specific MMP inhibitors and pertinent animal models, still limits our understanding of the many actions and relative contributions of specific MMPs. Our future potential ability to control vascular remodeling via regulation of MMPs will also depend on reaching a consensus of what is indeed "good" or "bad" vascular remodeling, concepts that have continued to evolve and change.

Matrix metalloproteinases and their inhibitors in connective tissue remodeling

1991-05-01

J. Frederick Woessner

Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many … Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28000 to 92000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activition. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein α2-macroglobulin and relatives are also strongly inhibitory.—Woessner, J. F., Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 5: 2145–2154; 1991.

How Matrix Metalloproteinases Regulate Cell Behavior

2001-11-01

Mark D. Sternlicht , Zena Werb

▪ Abstract The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, … ▪ Abstract The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor–binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.

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Matrix metalloproteinases: effectors of development and normal physiology

2000-09-01

Thiennu H. Vu , Zena Werb

The matrix metalloproteinase (MMP) family of extracellular proteinases regulates development and physiologic events. Genetic analyses using transgenic mice that have gain and loss of function of MMPs or of their … The matrix metalloproteinase (MMP) family of extracellular proteinases regulates development and physiologic events. Genetic analyses using transgenic mice that have gain and loss of function of MMPs or of their endogenous inhibitors, the TIMPs, and pharmacogenetic studies with chemical inhibitors have begun to elucidate the roles that they play. It is now clear that these enzymes are important for cell migration, invasion, proliferation, and apoptosis. They regulate many developmental processes, including branching morphogenesis, angiogenesis, wound healing, and extracellular matrix degradation. The matrix metalloproteinases (MMPs) are a family of extracellular matrix (ECM)-degrading enzymes that shares common functional domains and activation mechanisms (Sternlicht et al. 2000). These are Caand Zn-dependent endopeptidases that are active at neutral pH. They are synthesized as secreted or transmembrane proenzymes and processed to an active form by the removal of an amino-terminal propeptide. The propeptide is thought to keep the enzyme in latent form by the interaction of a cysteine residue in this peptide with the zinc moiety in the enzyme active site. Disruption of this interaction triggers the cysteine switch mechanism and results in activation of the enzyme. MMPs can be activated by chaotropic agents or by cleavage of the propeptide by members of the MMP family or by other proteases. They are inhibited by a family of tissue inhibitors of metalloproteinases, the TIMPs. As a family, MMPs degrade most components of the ECM. There are now >20 members of the MMP family. There are several distinct subgroups based on preferential substrates or similar structural domains: Collagenases that are active against fibrillar collagen, gelatinases that have high activity against denatured collagens, stromelysins that degrade noncollagen components of the ECM, membranetype MMPs (MT-MMPs) that are transmembrane molecules, and other less characterized members (Fig. 1; Table 1). Because MMPs can degrade ECM molecules, their main function has been presumed to be remodeling of the ECM. They are thought to play important roles during embryonic development, as ECM remodeling is a critical component of tissue growth and morphogenesis. In fact, the discovery of MMPs was based on the observation that during amphibian metamorphosis, a collagenolytic activity has to be present to digest the collagens in tadpole tails (Gross and Lapiere 1962). The activity of MMPs during embryonic development may extend to more than the removal of unwanted ECM molecules, however. It is now clear that MMPs not only remodel the ECM, but also influence many cellular functions. MMP activity may be required during development and normal physiology in several ways: (1) to degrade ECM molecules and allow cell migration; (2) to alter the ECM micro-environment and result in alteration in cellular behavior; (3) to modulate the activity of biologically active molecules by direct cleavage, release from bound stores, or the modulating of the activity of their inhibitors (Fig 2). During tissue morphogenesis any number of these activities may contribute to the role that each MMP plays in a developmental process. Although insights into the activities of MMPs have emerged from in vitro studies, genetic and pharmacogenetic studies now indicate that MMPs do have important influence on many cellular functions. Two general approaches have been employed to identify the roles of MMPs during mammalian development: (1) general or tissue-specific expression of a transgene encoding an MMP or an MMP inhibitor (TIMP), and (2) generating null mutations in an MMP gene or TIMP gene using targeted mutagenesis. These approaches have given insights into the roles of several MMPs in development and normal physiology. The range of developmental effects seen in these function perturbation studies suggests that these enzymes do indeed participate as essential effectors of developmental processes in vivo.

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Collagens—structure, function, and biosynthesis

2003-10-29

Kolja Gelse , Ernst Pöschl , Thomas Aigner

Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

2003-05-01

Robert Visse , Hideaki Nagase

Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, … Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.

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The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity

2010-01-01

Keith Brew , Hideaki Nagase

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Matrix metalloproteinases: they're not just for matrix anymore!

2001-10-01

Lisa J. McCawley , Lynn M. Matrisian

The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family.

1990-07-01

Harold E. Van Wart , Henning Birkedal‐Hansen

The general applicability of the "cysteine-switch" activation mechanism to the members of the matrix metalloproteinase (MMP) gene family is examined here. All currently known members of the MMP gene family … The general applicability of the "cysteine-switch" activation mechanism to the members of the matrix metalloproteinase (MMP) gene family is examined here. All currently known members of the MMP gene family share the characteristic that they are synthesized in a latent, inactive, form. Recent evidence suggests that this latency in human fibroblast collagenase (HFC) is the result of formation of an intramolecular complex between the single cysteine residue in its propeptide domain and the essential zinc atom in the catalytic domain, a complex that blocks the active site. Latent HFC can be activated by multiple means, all of which effect the dissociation of the cysteine residue from the complex. This is referred to as the "cysteine-switch" mechanism of activation. The propeptide domain that contains the critical cysteine residue and the catalytic domain that contains the zinc-binding site are the only two domains common to all of the MMPs. The amino acid sequences surrounding both the critical cysteine residue and a region of the protein chains containing two of the putative histidine zinc-binding ligands are highly conserved in all of the MMPs. A survey of the literature shows that many of the individual MMPs can be activated by the multiple means observed for latent HFC. These observations support the view that the cysteine-switch mechanism is applicable to all members of this gene family. This mechanism is unprecedented in enzymology as far as we know and offers the opportunity for multiple modes of physiological activation of these important enzymes. Since conditions in different cells and tissues may match those necessary to effect one of these activation modes for a given MMP, this may offer metabolic flexibility in the control of MMP activation.

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Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.

2000-01-15

Qin Yu , Ivan Stamenkovic

We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-beta in the control of tumor-associated tissue remodeling. CD44 provides … We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-beta in the control of tumor-associated tissue remodeling. CD44 provides a cell surface docking receptor for proteolytically active MMP-9 and we show here that localization of MMP-9 to cell surface is required for its ability to promote tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as well as MMP-2, proteolytically cleaves latent TGF-beta, providing a novel and potentially important mechanism for TGF-beta activation. In addition, we show that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-beta. These observations suggest that coordinated CD44, MMP-9, and TGF-beta function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion.

Plasminogen Activators, Tissue Degradation, and Cancer

1985-01-01

Keld Danø , P.A. Andreasen , J Grøndahl-Hansen +3 more

Increased Plasma Levels of a Rapid Inhibitor of Tissue Plasminogen Activator in Young Survivors of Myocardial Infarction

1985-12-19

Anders Hamsten , Björn Wiman , Ulf dé Fairé +1 more

Certain risk factors for myocardial infarction have been linked with disturbances in fibrinolytic activity. The recent development in our laboratory of new sensitive and specific methods for determination of tissue … Certain risk factors for myocardial infarction have been linked with disturbances in fibrinolytic activity. The recent development in our laboratory of new sensitive and specific methods for determination of tissue plasminogen activator (t-PA) activity and antigen, as well as the discovery of a new rapid inhibitor of this enzyme, enabled us to study fibrinolytic function in detail in a representative population of postinfarction patients. Seventy-one patients (62 men and 9 women) who had survived a myocardial infarction before the age of 45 were compared with 50 healthy subjects of similar age, three years after the infarction. Low t-PA activity after venous occlusion, mostly explained by high plasma levels of the t-PA inhibitor and to some extent by impaired release of t-PA from the vessel wall, was a frequent finding in the patients. The level of t-PA inhibitor was positively and significantly correlated with levels of serum triglycerides. Our data suggest that reduced fibrinolytic capacity due to increased plasma levels of a rapid inhibitor of t-PA may have pathogenetic importance in myocardial infarction, particularly in patients with hypertriglyceridemia.

Matrix Metalloproteinases

1999-07-01

Hideaki Nagase , J. Frederick Woessner

The timely breakdown of extracellular matrix (ECM)1 is essential for embryonic development, morphogenesis, reproduction, and tissue resorption and remodeling. The matrix metalloproteinases (MMPs), also called matrixins, are thought to play … The timely breakdown of extracellular matrix (ECM)1 is essential for embryonic development, morphogenesis, reproduction, and tissue resorption and remodeling. The matrix metalloproteinases (MMPs), also called matrixins, are thought to play a central role in these processes. The expression of most matrixins is transcriptionally regulated by growth factors, hormones, cytokines, and cellular transformation (1, 2). The proteolytic activities of MMPs are precisely controlled during activation from their precursors and inhibition by endogenous inhibitors, α-macroglobulins, and tissue inhibitors of metalloproteinases (TIMPs).

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Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis

2000-01-15

Qin Yu , Ivan Stamenkovic

We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-β in the control of tumor-associated tissue remodeling. CD44 provides … We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-β in the control of tumor-associated tissue remodeling. CD44 provides a cell surface docking receptor for proteolytically active MMP-9 and we show here that localization of MMP-9 to cell surface is required for its ability to promote tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as well as MMP-2, proteolytically cleaves latent TGF-β, providing a novel and potentially important mechanism for TGF-β activation. In addition, we show that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-β. These observations suggest that coordinated CD44, MMP-9, and TGF-β function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion.

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Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis

2002-02-22

Zorina S. Galis , Jaikirshan Khatri

Vascular remodeling, defined as any enduring change in the size and/or composition of an adult blood vessel, allows adaptation and repair. On the other hand, inappropriate remodeling, including its absence, … Vascular remodeling, defined as any enduring change in the size and/or composition of an adult blood vessel, allows adaptation and repair. On the other hand, inappropriate remodeling, including its absence, underlies the pathogenesis of major cardiovascular diseases, such as atherosclerosis and restenosis. Since degradation of the extracellular matrix scaffold enables reshaping of tissue, participation of specialized enzymes called matrix metalloproteinases (MMPs) has become the object of intense recent interest in relation to physiological (“good”) and pathological (“bad”) vascular remodeling. Experimental evidence acquired in vitro and in vivo suggests that the major drivers of vascular remodeling, hemodynamics, injury, inflammation, and oxidative stress, regulate MMP expression and activity. Alternatively, nonspecific MMP inhibition seems to oppose remodeling, as suggested by the inhibition of intimal thickening and outward arterial remodeling. An emerging concept is that MMP-related genetic variations may contribute to heterogeneity in the presentation and natural history of atherosclerosis. The hypothesis that MMPs contribute to weakening of atherosclerotic plaques is especially attractive for the potential development of therapeutic interventions aimed at preventing plaque disruption (“the ugly”), a major cause of acute cardiovascular events. However, the current lack of appropriate experimental tools, including availability of specific MMP inhibitors and pertinent animal models, still limits our understanding of the many actions and relative contributions of specific MMPs. Our future potential ability to control vascular remodeling via regulation of MMPs will also depend on reaching a consensus of what is indeed “good” or “bad” vascular remodeling, concepts that have continued to evolve and change.

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Bioresponsive Hyaluronic Acid‐Based Hydrogel Inhibits Matrix Metalloproteinase‐2 in Glioblastoma Microenvironment

2025-06-24

Federica Barbugian , Domenico Salerno , E Ballarini +7 more | ChemMedChem

Glioblastoma multiforme (GBM) is an extremely malignant cancer, resistant to standard therapies. Tumor resection is associated with better outcomes but a complete resection of GBMs is challenging for anatomical limitation … Glioblastoma multiforme (GBM) is an extremely malignant cancer, resistant to standard therapies. Tumor resection is associated with better outcomes but a complete resection of GBMs is challenging for anatomical limitation and for the high degree of invasiveness. A bioresponsive hydrogel based on hyaluronic acid (HA) cross‐linked with a branched metalloproteinase (MMP) inhibitor (MMPI) is proposed. The fully characterized hydrogel, HA‐MMPI, presents physical properties suitable for filling the surgical resection cavity and for in situ delivery of the inhibitor. The bioresponsive material selectively inhibits MMP‐2 versus MMP‐9 in glioblastoma microenvironment.

Altered co-expression patterns of synovial fluid proteins related to the immune system and extracellular matrix organization in late stage OA, compared to non-OA controls

2025-06-23

Jenny Lönsjö , Martin Rydén , Aleksandra Turkiewicz +5 more | Frontiers in Immunology

Objective Synovial fluid contains proteins that may have been released from surrounding tissues, our aim was to gain new insights into the proteomic profiles of human synovial fluid in knees … Objective Synovial fluid contains proteins that may have been released from surrounding tissues, our aim was to gain new insights into the proteomic profiles of human synovial fluid in knees with and without osteoarthritis (OA). Methods We used synovial fluid from 11 patients with end-stage medial compartment knee OA, aspirated during total knee replacement, and from 13 deceased donors who had no prior history of knee OA (healthy controls). These samples were analyzed using high-multiplex immunoassays Olink ® . The differential expression of proteins between the groups was analyzed using a linear mixed effects model. The linear associations between pairs of protein expressions were estimated with a linear regression model. Results We found that almost half of the detected proteins were differentially expressed between the OA and non-OA controls. The proteins that were most elevated in the OA group compared to controls were tartrate-resistant acid phosphatase type 5 (fold change 10.6, 95% CI [6.6-17.0]), plasminogen activator inhibitor 1 (5.0 [3.1, 8.0]), coagulation factor XI (4.3 [2.6-6.8]) and urokinase-type plasminogen activator (4.3 [2.3-6.8]). The proteins with lower levels in OA compared to controls were fatty acid-binding protein, adipocyte (0.03 [0.02-0.05]), myocilin (0.05 [0.03-0.08]) and carbonic anhydrase 3 (0.14 [0.09-0.23]). The protein-protein co-expression analysis suggests an overall lower number of protein pairs that show co-expression in OA. Conclusion There is a substantial change in protein abundance in synovial fluid in end-stage knee OA, suggesting that global joint homeostasis is severely deranged. Our findings suggest altered co-expression between the immune response and extracellular matrix organization in end-stage knee OA, in comparison to non-OA controls.

Causal Role of Endothelial Dysfunction in Ischemic Stroke and Its Subtypes: A Two-Stage Analysis

2025-06-19

Qian Wu , Jingjing Cui , Yao Jiang +2 more | SLAS TECHNOLOGY

Endothelial dysfunction is implicated in the pathogenesis of ischemic stroke (IS), but its causal role remains unclear. This study systematically investigates the causal relationship between endothelial dysfunction proteins and IS … Endothelial dysfunction is implicated in the pathogenesis of ischemic stroke (IS), but its causal role remains unclear. This study systematically investigates the causal relationship between endothelial dysfunction proteins and IS and its subtypes through integrated observational and genetic evidence. A two-stage study was conducted combining systematic meta-analysis and Mendelian randomization (MR). The meta-analysis integrated data from 29 observational studies to assess associations between endothelial dysfunction proteins (vWF, sE-selectin, sP-selectin, ICAM-1, VCAM-1, sLOX-1, VEGF, ET-1, SDF-1) and IS. This meta-analysis was registered online (PROSPERO ID: CRD42023461783). Subsequent MR was applied to discern the causal effects of the endothelial dysfunction proteins on IS and its subtypes, utilizing genetically instrumental variants. A meta-analysis demonstrated significant correlations with IS for vWF, sE-selectin, ICAM-1, sP-selectin, sLOX-1, and VEGF (all p < 0.05). Furthermore, MR analysis showed that genetically elevated vWF increased the risk for any IS and cardioembolic stroke (CES), while E-selectin was causally linked to large-artery atherosclerosis stroke (LAS). This work offers causal evidence that endothelial dysfunction significantly contributes to IS, highlighting the thrombotic activity of vWF in CES and the inflammatory function of E-selectin in LAS. These findings not only offer valuable insights into the mechanisms underlying IS and its subtypes but also help inform personalized stroke prevention strategies.

Alpha-1 Antitrypsin Deficiency - Characteristics, Diagnosis, Monitoring and Therapy of Patients in the Czech Republic

2025-06-19

Libor Nevoránek , Marek Kvarda , M Wanke +2 more | Vnitřní lékařství

Spotlight on Proteases: Roles in Ovarian Health and Disease

2025-06-18

Bhawna Kushawaha , Emanuele Pelosi | Cells

Proteases play crucial roles in ovarian folliculogenesis, regulating several processes from primordial follicle activation to ovulation and corpus luteum formation. This review synthesizes the current knowledge on the diverse functions … Proteases play crucial roles in ovarian folliculogenesis, regulating several processes from primordial follicle activation to ovulation and corpus luteum formation. This review synthesizes the current knowledge on the diverse functions of proteases in ovarian physiology and pathology. We discuss the classification and regulation of proteases, highlighting their importance in extracellular matrix remodeling, cell signaling, and apoptosis during ovarian follicular development. We explore the roles of several proteases including matrix metalloproteinases, tissue inhibitors of metalloproteinases, the plasminogen activator system, and cathepsins, and their roles in the critical functions of ovarian biology including follicle dynamics and senescence. Furthermore, we address the involvement of proteases in ovarian pathologies, including cancer, polycystic ovary syndrome, and primary ovarian insufficiency. By integrating recent findings from clinical genomics and animal models, this review provides a comprehensive overview of protease functions in the ovary, emphasizing their potential use for therapeutic interventions in reproductive medicine.

Kringle-Dependent Inhibition of Plasmin-Mediated Fibrinolysis by Native and Citrullinated Core Histones

2025-06-17

Erzsébet Komorowicz , Anna Gurabi , András Wacha +3 more | International Journal of Molecular Sciences

The fibrin matrix of thrombi is intertwined with neutrophil extracellular traps (NETs) containing histones that render resistance to fibrinolysis. During NET formation, histones are citrullinated. Our study addresses the question … The fibrin matrix of thrombi is intertwined with neutrophil extracellular traps (NETs) containing histones that render resistance to fibrinolysis. During NET formation, histones are citrullinated. Our study addresses the question of whether citrullination modifies the fibrin-stabilizing effects of histones. We studied the structure and viscoelastic properties of fibrin formed in the presence of native or citrullinated H1 and core histones by scanning electron microscopy, clot permeation, and oscillation rheometry. The kinetics of fibrin formation and its dissolution were followed by turbidimetry and thromboelastometry. Co-polymerizing H1 with fibrin enhanced the mechanical strength of the clots, thickened the fibrin fibers, and enlarged the gel pores. In contrast, the addition of core histones resulted in a reduction in the fiber diameter, and the pores were only slightly larger, whereas the mechanical stability was not modified. Plasmin-mediated fibrinogen degradation was delayed by native and citrullinated core histones, but not by H1, and the action of des-kringle1-4-plasmin was not affected. Plasmin-mediated fibrinolysis was inhibited by native and citrullinated core histones, and this effect was moderated when the kringle domains of plasmin were blocked or deleted. These findings suggest that in NET-containing thrombi that are rich in core histones, alternative fibrinolytic enzymes lacking kringle domains are more efficient lytic agents than the classic plasmin-dependent fibrinolysis.

Association Between PAI-1 4G/5G Genetic Polymorphism and Uncontrolled Allergic Asthma

2025-06-17

Harun Iskandar , Muh. Ilyas , Eliana Muis +2 more | Advance Sustainable Science Engineering and Technology

Airway remodeling is a major challenge in the management of uncontrolled allergic asthma, despite standard therapy with a combination of inhaled corticosteroids (ICS) and long-acting bronchodilators (LABA). Increased levels of … Airway remodeling is a major challenge in the management of uncontrolled allergic asthma, despite standard therapy with a combination of inhaled corticosteroids (ICS) and long-acting bronchodilators (LABA). Increased levels of Plasminogen Activator Inhibitor-1 (PAI-1) are thought to play a role in this process, and the 4G/5G polymorphism in the PAI-1 gene is one of the genetic factors that affect it. This study aimed to analyze the association between the 4G/5G PAI-1 genetic polymorphism and uncontrolled allergic asthma. A case-control study was conducted at Wahidin Sudirohusodo General Hospital between January-March 2024 on 40 patients with allergic asthma and 40 non-asthmatic subjects. Diagnosis was made through prik test (+), bronchodilator test (+), and asthma control classification according to GINA criteria. All asthmatic patients received Budesonide-Formoterol therapy for 4 weeks. PAI-1 levels were measured and 4G/5G polymorphism was analyzed by RT-PCR. Results showed that PAI-1 levels were significantly higher in uncontrolled asthma patients and in individuals with the 4G/4G genotype compared to non-4G/4G (2.38 ± 0.770 vs 1.65 ± 0.714; p=0.001). The 4G/4G genotype was more common in uncontrolled asthma (OR: 5.8) and was associated with the risk of severe obstruction (OR: 11.6). Thus, it was concluded that the 4G/4G genotype in the PAI-1 gene is associated with increased PAI-1 levels, risk of uncontrolled allergic asthma, and more severe degree of airway obstruction. The implication of the results shows that genetic testing of PAI-1 has the potential to be a predictive biomarker in personalized asthma therapy strategies. This approach can help clinicians identify high-risk patients and tailor interventions early and effectively to prevent remodeling and reduce long-term morbidity

Alpha-1 antitrypsin deficiency-associated panniculitis: a case report

2025-06-17

Špela But , Maja Jerše , Pij Bogomir Marko | Slovenian Medical Journal

Alpha-1 antitrypsin deficiency is a hereditary disorder with predominantly pulmonary but also extrapulmonary manifestations. In the skin, it is associated with panniculitis, a necrotizing neutrophilic inflammation in the subcutis. Clinically, … Alpha-1 antitrypsin deficiency is a hereditary disorder with predominantly pulmonary but also extrapulmonary manifestations. In the skin, it is associated with panniculitis, a necrotizing neutrophilic inflammation in the subcutis. Clinically, it presents with tender, erythematous, oedematous, recurrent, and potentially ulcerative nodules, most often located on the extremities or the trunk. The entity is often unrecognized, though it can greatly affect the patient’s quality of life and is potentially lethal. Clinical suspicion is supported by deep-skin biopsy, the concentration of alpha-1 antitrypsin in the serum, and electrophoresis, or, if possible, by genotype or phenotype characterization. Currently, the most widely accepted treatment options include dapsone, doxycycline, and augmentation therapy. We report a case of a young Caucasian man with alpha-1 antitrypsin deficiency that manifested with recurring and extremely painful nodules on his legs and gluteal area. The diagnosis was established based on the patient’s history, a low serum level of alpha-1 antitrypsin, and the findings of the deep-skin biopsy, which were suggestive of neutrophilic panniculitis. Total remission was achieved with dapsone, and the therapy was well-tolerated.

Plasminogen activator inhibitors orchestrate the immunosuppressive tumor microenvironment in pancreatic cancer

2025-06-17

Chiara Falcomatà , Sebastian R. Nielsen , Marion Schaefer +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that sustains an immunosuppressive tumor microenvironment (TME). While this protective niche has been described, the molecular determinants orchestrating … Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that sustains an immunosuppressive tumor microenvironment (TME). While this protective niche has been described, the molecular determinants orchestrating its formation and dictating its immune interactions are not well defined. Using Perturb-map, we determine how dozens of different gene perturbations shape the growth and cellular environments of PDAC clones through space and time. Our study reveals dynamic, gene-specific adaptations of immune neighborhoods during clonal selection. We identified Serpinb2 (PAI2) and Serpine1 (PAI1) as key cancer-derived mediators of TME remodeling and immune evasion. These factors promote the deposition of a fibrin-rich ECM that shapes immune cell composition, locally retains and polarizes immunosuppressive macrophages and excludes cytotoxic T cells. Deletion of either Serpinb2 or Serpine1 greatly enhanced tumor response to anti-PD1 immunotherapy in an aggressive PDAC model. Transcriptomic analysis further linked their expression to distinct PDAC subtypes and poor patient survival. Our findings demonstrate that Serpinb2 and Serpine1 establish a permissive niche for tumor progression and show how PDAC cells exploit components of the fibrinolysis pathway to remodel the ECM, alter macrophage composition, and protect themselves from immune editing, ultimately reinforcing the role of extracellular factors in shaping an immune-privileged tumor niche.

Matrix Metalloproteinases 1 and 3 in Ovarian Cancer: Diagnostic and Prognostic Potential of Genetic Variants and Expression Profiling

2025-06-15

Amal M.H. Mackawy , Hajed Obaid Alharbi , Ahmad Almatroudi +2 more | Diagnostics

Background: Ovarian carcinoma (OC) is one of the foremost factors in female carcinoma-related fatalities worldwide. Matrix metalloproteinases (MMPs) are key mediators of tissue remodeling and are linked to tumor aggressiveness, … Background: Ovarian carcinoma (OC) is one of the foremost factors in female carcinoma-related fatalities worldwide. Matrix metalloproteinases (MMPs) are key mediators of tissue remodeling and are linked to tumor aggressiveness, yet there is still a lack of information on the link between genetic changes in MMPs-1,3 and the onset and progression of OC in Egyptian women. This study examines the effects of immunoreactive biomolecule variations of MMPs-1,3, as well as the MMP-1 (1607 1G/2G) and MMP-3 (-1171 5A/6A) genetic variants, on OC risk and progression in Egyptian women. Methods: Tissue specimens embedded in paraffin from 100 OC patients and 60 controls were stained using immunohistochemistry to examine expression of MMPs-1,3. MMP levels were quantified using ELISA, and single-nucleotide polymorphisms (SNPs) of MMPs-1,3 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: Increased levels of MMPs-1,3 in OC patients relative to controls, with more of an increase in the late stages (III and IV) than in the early OC stages (I and II). Additionally, the MMP-1 2G/2G and MMP-3 6A/6A genotypes were more prevalent in OC patients than in controls. Ovarian MMPs-1,3 were comparatively elevated in the identified genotypes compared to the 1G/1G and 5A/5A genotypes, respectively. The transcriptional activity of MMPs-1,3 showed strong potential for distinguishing patients with epithelial ovarian carcinoma (EOC) from controls, boasting an area under the curve (AUC) of 0.956 and 0.816, respectively. Sensitivity and specificity were 94.0% and 90.0% for MMP-1 and 80.0% and 73.3% for MMP-3, respectively. Conclusions: The MMP-1 2G/2G and MMP-3 6A/6A genotypes are correlated with elevated MMP-1 and MMP-3 levels and immunohistochemical expression in carcinomatous ovarian tissues, particularly in advanced stages of OC. This indicates that genetic variations of MMPs-1,3 could be valuable diagnostic and prognostic markers for OC in Egyptian women. Our findings may carry clinical relevance for optimizing OC therapeutic effectiveness, contribute to the growing body of knowledge on the role of MMPs, and shed new light on the genetic background of OC. Future studies with larger sample sizes and comprehensive MMP genetic profiling are needed for results validation.

Abstract P1-07-23: Matrix Metalloproteinase-7 regulates the process of pulmonary metastasis in triple-negative breast cancer cells

2025-06-13

Ji Su Kim | Clinical Cancer Research

Abstract Background: Organ-specific metastasis is a phenomenon where certain types of cancer preferentially metastasize to specific organs. This process is determined by a variety of factors such as the molecular … Abstract Background: Organ-specific metastasis is a phenomenon where certain types of cancer preferentially metastasize to specific organs. This process is determined by a variety of factors such as the molecular traits of tumor cells, the microenvironment of target organs, and the interactions between tumor cells and the immune system. Understanding the molecular mechanisms regulating the organ-specific metastasis is crucial for developing targeted therapies for metastatic breast cancers. Methods: We established patient-derived xenograft (PDX) models of triple-negative breast cancer (TNBC), which exhibited the repetitive metastasis patterns either to lung or liver. Four TNBC PDX models, which repeatedly developed lung metastasis, were analyzed by performing RNA sequencing of their primary tumor and lung metastatic tumor tissues to characterize the gene expression features associated with lung metastasis. Control and MMP7 overexpression vectors were transfected into MDA-MB-231 and MDA-MB-468 cells, and transwell assay was performed to assess the role of MMP7 in cell migration and invasion in vitro. Furthermore, an in vivo orthotopic mouse model was established by injecting control and MMP7-overexpressed MDA-MB-231 cells into the fourth mammary fat pad. Experimental metastasis models were established via spleen injection to induce liver metastasis and tail vein injection to induce lung metastasis. Results: Matrix metalloprotease-7 (MMP7) is one of the genes found to be consistently upregulated in lung metastatic tumors compared to primary tumors, based on RNA sequencing data. MMP7 overexpression in TNBC cell lines increased the migration and invasion in vitro. In addition, MMP7-overexpressed MDA-MB-231 cells showed significantly increased tumor growth in vivo in terms of tumor weight and volume. Moreover, there was no statistically significant difference in an experimental liver metastasis model while MMP7 significantly increased the metastasis in an experimental lung metastasis model. Conclusion: In our TNBC PDX models, MMP7 was significantly upregulated in the lung metastasis tissues when compared to that of primary tumors. MMP7 upregulation was associated with increased cancer cell migration, invasion, and tumor growth, and MMP7 selectively promotes lung metastasis in TNBC. Further understanding of the biologic functions of MMP7 in TNBC can provide insights into the organ-specific metastasis to the lung. Citation Format: Ji Su Kim. Matrix Metalloproteinase-7 regulates the process of pulmonary metastasis in triple-negative breast cancer cells [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-23.

Dynamic regulation of the COPII interactome and collagen trafficking by site-specific glycosylation of Sec24D

2025-06-13

Tetsuya Hirata , Dharmendra Choudhary , Brittany J. Bisnett +3 more | bioRxiv (Cold Spring Harbor Laboratory)

Coat protein complex II (COPII) mediates anterograde trafficking from the endoplasmic reticulum (ER). While the core COPII machinery is well-characterized, how cells regulate COPII to accommodate large cargoes, including collagens, … Coat protein complex II (COPII) mediates anterograde trafficking from the endoplasmic reticulum (ER). While the core COPII machinery is well-characterized, how cells regulate COPII to accommodate large cargoes, including collagens, remains incompletely understood. Here, we show that the cargo-selecting COPII subunit Sec24D is modified by site-specific O-linked β-N-acetylglucosamine (O-GlcNAc) in its N-terminal intrinsically disordered region upon induction of collagen transport. These glycosylations are required for collagen trafficking in human cells and developing zebrafish. Crosslinking proteomics demonstrated that each O-GlcNAcylation influences the Sec24D interactome in a distinct way, revealing novel mediators of COPII function. In particular, Sec24D glycosylation is required for its interaction with myoferlin, which unexpectedly facilitates fusion of ER exit sites (ERES) and the ER- Golgi intermediate compartment (ERGIC) to enable collagen transport. Our results establish Sec24D O-GlcNAcylation as a dynamic regulator of COPII protein-protein interactions and collagen trafficking and identify myoferlin as a novel mediator of this process.

Dysregulation of cell migration by matrix metalloproteinases in geleophysic dysplasia

2025-06-06

Alejo A. Morales , Vladimir Camarena , LéShon Peart +7 more | Scientific Reports

Geleophysic dysplasia (GD) is characterized by short stature, brachydactyly, joint limitations, a distinctive facial appearance, as well as cardiac and respiratory dysfunction that can be life-threatening. GD is caused by … Geleophysic dysplasia (GD) is characterized by short stature, brachydactyly, joint limitations, a distinctive facial appearance, as well as cardiac and respiratory dysfunction that can be life-threatening. GD is caused by pathogenic variants in the ADAMTSL2, FBN1, or LTBP3 genes. While dermal fibroblasts derived from affected individuals have shown poor organization of the extracellular matrix (ECM), it remains elusive how the disorganized ECM contributes to GD pathogenesis. To understand the molecular mechanisms in GD, we isolated and characterized primary human dermal fibroblasts from affected individuals with ADAMTSL2 and FBN1 variants. We found that the secretion of ECM proteins including ADAMTSL2, FBN1, and Fibronectin were impaired in GD fibroblasts. Increased cell migration was observed in GD fibroblasts carrying ADAMTSL2 or FBN1 variants, which was associated with up-regulation of MMP-1 and MMP-14, two proteases related to cell mobility. The enhanced cell migration and up-regulation of MMP-1 and MMP-14 were corroborated in mouse primary dermal fibroblasts carrying pathogenic variants in Adamtsl2 and in lung and heart tissues from Adamtsl2-knockout mice. A pan MMP inhibitor, GM6001, inhibited the migration of GD fibroblasts. Overall, our results suggest that MMP-1/-14 up-regulation play a role in the development of GD and may be utilized as a treatment target.

Uncovering the Role of the Hsp40 Family Member, Cysteine String Protein-α, in Mouse Platelets

2025-06-05

A.D. Smith , Hammodah R. Alfar , Smita Joshi +7 more | Blood Advances

Bibliometric analysis of MXRA7 gene research trajectory: trends and insights (2015–2024)

2025-06-03

Huihui Zhang , Ying Shen , P. L. Bai +3 more | Discover Oncology

Abstract Background Matrix remodeling-associated 7 (MXRA7) plays a key role in physiological and pathological processes involving the extracellular matrix (ECM) and tissue remodeling. Recent studies have highlighted its functions in … Abstract Background Matrix remodeling-associated 7 (MXRA7) plays a key role in physiological and pathological processes involving the extracellular matrix (ECM) and tissue remodeling. Recent studies have highlighted its functions in tissue injury, immune response, and cellular differentiation, yet no bibliometric studies have systematically mapped MXRA7 research. This study evaluates global MXRA7 research from 2015 to 2024 to identify current trends and future directions. Methods A comprehensive bibliometric analysis was conducted using the Web of Science Core Collection. We examined publication trends, geographical contributions, influential authors, and high-impact journals, identifying research hotspots and emerging trends with advanced bibliometric tools. Results Analysis of 553 English-language publications showed that MXRA7 research has progressed significantly after 2017, showing a general upward trend accompanied by short-term fluctuations. The United States leads, followed by China and the United Kingdom. Key studies appear in high-impact journals like PLOS ONE, and influential authors such as Frangogiannis NG have propelled the field. Keywords including “inflammation”, “extracellular matrix”, “matrix metalloproteinases” and “angiogenesis” underscore MXRA7’s roles in immune responses, tissue repair, and fibrosis. Conclusion This analysis shows significant growth in MXRA7 research, especially in inflammation, ECM remodeling, and tissue regeneration. Future work should explore MXRA7’s molecular mechanisms in immune diseases, fibrosis, and cancer, advancing its potential as a therapeutic target.

Human plastins are novel cytoskeletal pH sensors with a reduced F-actin bundling capacity at basic pH

2025-06-01

Lucas A. Runyan , Elena Kudryashova , Richa Agrawal +2 more | Journal of Molecular Biology

Intracellular pH (pHi) is a fundamental component of cell homeostasis. Controlled elevations in pHi precede and accompany cell polarization, cytokinesis, and directional migration. pH dysregulation contributes to cancer, neurodegenerative diseases, … Intracellular pH (pHi) is a fundamental component of cell homeostasis. Controlled elevations in pHi precede and accompany cell polarization, cytokinesis, and directional migration. pH dysregulation contributes to cancer, neurodegenerative diseases, diabetes, and other metabolic disorders. While cytoskeletal rearrangements are crucial for these processes, only a few cytoskeletal proteins, namely CDC42, cofilin, talin, cortactin, α-actinin, and AIP1 have been documented as pH sensors. Here, we report that actin-bundling proteins plastin 2 (PLS2, aka LCP1) and plastin 3 (PLS3) respond to physiological scale pH fluctuations by a reduced F-actin bundling at alkaline pH. The inhibition of PLS2 actin-bundling activity at elevated pH stems from the reduced affinity of the N-terminal actin-binding domain (ABD1) to actin. In fibroblast cells, elevated cytosolic pH caused the dissociation of ectopically expressed PLS2 from actin structures, whereas acidic conditions promoted its tighter association with focal adhesions and stress fibers. We identified His207 as one of the pH-sensing residues whose mutation to Lys and Tyr reduces pH sensitivity by enhancing and inhibiting the bundling ability, respectively. Our results suggest that weaker actin bundling by plastin isoforms at alkaline pH favors higher dynamics of the actin cytoskeleton. Therefore, like other cytoskeleton pH sensors, plastins promote disassembly and faster dynamics of cytoskeletal components during cytokinesis and cell migration. Since both plastins are implemented in cancer, their pH sensitivity may contribute to the accelerated proliferation and enhanced invasive and metastatic potentials of cancer cells at alkaline pHi.

Exploring Flavonoids as Regulators of <scp>MMP</scp>‐2 and <scp>MMP</scp>‐9 in Cancer Pathogenesis

2025-06-01

Ha Vy Thi Vo , Geewoo Nam Patton , Song Ja Kim +2 more | Chemical Biology & Drug Design

ABSTRACT Last few decades, extensive research efforts have been dedicated to uncovering novel cancer treatments. Among the most vital targets in this pursuit are matrix metalloproteinases (MMPs), enzymes integral to … ABSTRACT Last few decades, extensive research efforts have been dedicated to uncovering novel cancer treatments. Among the most vital targets in this pursuit are matrix metalloproteinases (MMPs), enzymes integral to the progression and spread of cancer. Their role in tumor development and metastasis positions MMPs as key players in cancer pathogenesis, offering promising avenues for therapeutic intervention. Specifically, MMP‐2 and MMP‐9 have emerged as promising targets in cancer treatment based on their critical roles in cell invasion, angiogenesis, immune evasion, and metastasis. Studies indicate the potential of plant‐derived natural products as anticancer agents through the regulation of MMP activity. Among various phytochemicals, flavonoids are reported to exhibit inhibitory activities against MMPs and antioxidant properties that present them as candidates for anticancer molecules. In this study, the potential of flavonoids as anticancer agents was explored by investigating the effects of flavonoids on (i) cancer cell viability and migration, (ii) enzymatic activity and cellular expression of MMP‐2/9, and (iii) the MAPK signaling pathway. Docking simulation data regarding the interactions between MMP‐2/9 and selected flavonoids provide an in‐depth look at the potential mechanisms through which these molecules suppress the enzymatic activities of MMPs. Select flavonoids exhibited notable efficacy in suppressing cell proliferation and migration in A549 cells, which may be a consequence of their ability to attenuate MMP activity and expression through the suppression of the MAPK signaling pathway. These observations demonstrate the prospect of flavonoids as a naturally occurring molecular framework for the development of novel anticancer therapeutics.

Evaluation of Salivary Biomarkers in the Early Detection of Oral Squamous Cell Carcinoma

2025-06-01

Deepak Kumar , Hiren Hansraj Patadiya , Anshul Sawhney +5 more | Journal of Pharmacy And Bioallied Sciences

A BSTRACT Background: The most prevalent malignant tumor affecting the oral cavity is called oral squamous cell carcinoma (OSCC). Improving patient outcomes and survival rates requires early identification. Salivary biomarkers … A BSTRACT Background: The most prevalent malignant tumor affecting the oral cavity is called oral squamous cell carcinoma (OSCC). Improving patient outcomes and survival rates requires early identification. Salivary biomarkers have drawn a lot of interest as noninvasive diagnostic methods for early OSCC detection. Materials and Methods: One hundred people participated in a cross-sectional research, 50 of whom had been diagnosed with OSCC and 50 of whom were healthy controls. Samples of unstimulated saliva were taken from each participant. The enzyme-linked immunosorbent test (ELISA) was used to measure the salivary levels of three biomarkers: tissue polypeptide-specific antigen (TPSA), matrix metalloproteinase-9 (MMP-9), and interleukin-6 (IL-6). Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic accuracy of the biomarker levels and compare them across groups using statistical analysis. Results: OSCC patients had substantially higher salivary levels of TPSA (12.5 ± 2.4 ng/mL), MMP-9 (400 ± 30 ng/mL), and IL-6 (35.2 ± 7.1 pg/mL) than healthy controls (TPSA: 4.2 ± 1.1 ng/mL; P < 0.001), MMP-9: 150 ± 20 ng/mL, and IL-6: 10.1 ± 2.3 pg/mL. High diagnostic accuracy was found by ROC analysis for TPSA (AUC = 0.85), MMP-9 (AUC = 0.87), and IL-6 (AUC = 0.89). When these indicators were combined, the early identification of OSCC had a 90% sensitivity and an 88% specificity. Conclusion: Salivary biomarkers with intriguing potential for OSCC early detection include TPSA, MMP-9, and IL-6. They are useful instruments for screening high-risk people because of their noninvasiveness and excellent diagnostic precision. It is advised that further longitudinal research be done to confirm these results and investigate how they may be used in therapeutic settings.

Polarity-responsive fluorescence lifetime probe for in vivo imaging of Aβ plaque dynamics: Unveiling PBM-induced Aβ polarity reversal

2025-06-01

Zhenlong Huang , Yiqiang Wang , Fangrui Lin +7 more | Matter

Harnessing Metformin for Targeted Intervention: Addressing Cardiac Fibrosis in Plasminogen Activator Inhibitor-1 (PAI-1) Deficiency

2025-06-01

Serena M. Pulente , Claire Fong-McMaster , Natasha A. Trzaskalski +5 more | Journal of Molecular and Cellular Cardiology Plus

Alpha-1 antitrypsin promotes re-epithelialization by regulating inflammation and migration

2025-05-30

I Färber , Muhammad Wated , Ronen Schuster +7 more | Frontiers in Immunology

Regulation of inflammation and re-epithelialization are critical for efficient wound healing. This study explores the role of human α1-antitrypsin (hAAT), an immunomodulatory protein, in modulating inflammation and promoting re-epithelialization across … Regulation of inflammation and re-epithelialization are critical for efficient wound healing. This study explores the role of human α1-antitrypsin (hAAT), an immunomodulatory protein, in modulating inflammation and promoting re-epithelialization across various epithelial cell types. In-vitro, epithelial gap closure and migration assays were performed using two human epithelial cell lines-HaCaT and A549 cells with and without mitomycin C treatment. These cell lines were also used in an in-vitro gel-directed epithelial migration assay. Cells were treated with hAAT, and the gap area was measured using image analysis. Gene expression of inflammatory markers (IL-1β, IL-6, and TNFα) and adhesion molecules (desmoglein-1, plectin, and integrin α6β4) were analyzed using qPCR. In-vivo, corneal abrasions were induced in C57BL/6 mice using an Ophthalmic Burr. Mice received topical hAAT treatment immediately after injury and every 6 hours thereafter. Wound closure was assessed by applying the standard ophthalmic staining technique, fluorescein, and image analysis. Inflammatory markers and adhesion molecule expression were evaluated using qPCR and immunohistochemistry. In-vitro, hAAT accelerated epithelial gap closure and increased migration distance, independent of cell proliferation. hAAT-treated cells also exhibited earlier peak expressions of IL-1β and IL-6. In-vivo, hAAT treatment accelerated corneal wound closure and resulted in a preference for IL-1Ra over IL-1β expression. hAAT also enhanced the expression of desmoglein-1, plectin, and integrin α6β4, both in-vitro and in-vivo, and increased desmoglein-1 expression in the epithelial migration zone of mouse cornea. hAAT enhances re-epithelialization by modulating inflammation, promoting epithelial cell migration, and regulating expression of adhesion molecules.

Pathophysiological Bases and Clinical Uses of Metalloproteases in Cardiovascular Disease: A Scoping Review

2025-05-29

Laura Manuela Olarte Bermúdez , Camila Karduss Preciado , Julián Manuel Espitia Ángel +4 more | Cardiogenetics

(1) Objective: Cardiovascular diseases (CVD) are one of the main entities responsible for the progressive increase in morbidity and mortality worldwide. Some of the biomarkers involved in these processes are … (1) Objective: Cardiovascular diseases (CVD) are one of the main entities responsible for the progressive increase in morbidity and mortality worldwide. Some of the biomarkers involved in these processes are matrix metalloproteases (MMPs) and disintegrants and metalloproteases (ADAMS), produced by multiple tissues and whose main function is the excessive degradation of the extracellular matrix (ECM). The aim of this study is to describe the existing literature on the role of MMP in the pathophysiology of CVD and its usefulness in clinical practice for the diagnostic and therapeutic approach. (2) Methods: A systematic exploratory review of the literature was carried out according to the guidelines of the Joanna Briggs Institute. The information was collected from the PubMed/Medline and Embase databases, using the search strategy “cardiovascular disease” AND “Metalloprotease”. (3) Results: Thirty eight papers that mainly mention 17 types of MMPs were included. Pathologies such as atherosclerosis, coagulation diseases, atrial fibrillation, ischemic heart disease, heart failure, hypertension, dyslipidemias, congenital cyanotic heart disease and Takotsubo cardiomyopathy were identified. (4) Conclusions: The stimulation or inhibition of these biomolecules could generate positive and/or negative effects, which impact the development and prognosis of the disease. Furthermore, they can be potential biomarkers for new diagnostic and even therapeutic approaches in the future.

Fazirsiran for the treatment of alpha-1 antitrypsin deficiency-associated liver disease findings from the SEQUOIA phase 2 trial

2025-05-29

Tahira Liaquat , Bareera Tanveer Malik , Taqi Hashmi +3 more | Annals of Medicine and Surgery

Effect of EDIL3+ CAFs on lymph node metastasis through disruption of lymphatic endothelial barriers in breast cancer.

2025-05-28

Lesang Shen , Chao Ni | Journal of Clinical Oncology

e13029 Background: Axillary lymph node (LN) metastasis is the most common metastatic route in breast cancer and a critical prognostic indicator. While previous studies focused on tumor cells, the role … e13029 Background: Axillary lymph node (LN) metastasis is the most common metastatic route in breast cancer and a critical prognostic indicator. While previous studies focused on tumor cells, the role of stromal components within the tumor microenvironment (TME) in mediating LN metastasis remains unclear. This study aims to identify key functional stromal cell subsets and molecular mechanisms driving breast cancer LN metastasis. Methods: We analyzed high-LN-metastasis cases from our cohort, TCGA, and METABRIC databases. Immunohistochemistry and transcriptomic deconvolution were used to compare stromal cell abundance, including lymphatic endothelial cells (LECs) and cancer-associated fibroblasts (CAFs). Single-nucleus RNA sequencing (snRNA-seq) was employed to identify metastasis-associated CAF subsets. Functional assays, including siRNA knockdown, lentiviral overexpression, CCK-8, tube formation, wound healing, endothelial permeability, and trans-endothelial migration assays, were conducted to assess the role of EGF-like repeat and discoidin domain-containing protein 3 (EDIL3) on LEC function. In vivo effects were validated using immunofluorescence, H&E staining, and intravital imaging in murine models. Transcriptomic sequencing, western blot, and small-molecule inhibitors were employed to elucidate the molecular mechanisms by which EDIL3 regulates LEC permeability. Results: snRNA-seq of our cohort (n = 9) revealed significant enrichment of EDIL3+ CAFs in primary tumors with high LN metastasis, correlating with axillary LN burden and poor survival. EDIL3 was predominantly expressed by a specific CAF subset within TME. Using immortalized 4T1 breast cancer CAF cell lines, we demonstrated that EDIL3+ CAFs enhance LEC permeability via EDIL3. In vitro, EDIL3 disrupted LEC tight junction integrity without affecting proliferation, migration, or lymphangiogenesis. In murine models, EDIL3 promoted lymphatic metastasis by increasing LEC permeability. Mechanistically, EDIL3 activated the integrin αvβ3/Src/ERK signaling axis to drive LEC barrier dysfunction. Conclusions: This study identifies EDIL3+ CAFs as a novel stromal subset driving breast cancer LN metastasis. EDIL3 enhances lymphatic dissemination by activating integrin αvβ3/Src/ERK signaling to compromise LEC integrity. These findings highlight CAFs as pivotal mediators of lymphatic metastasis and propose EDIL3 as a potential therapeutic target to mitigate LN metastasis in breast cancer.

A matters arising: discussion on urokinase dosing and individualized treatment strategies in the TRUST trial

2025-05-28

Yue Qiao , Xunming Ji , Wenbo Zhao | BMC Medicine

This matters arising addresses the recently published article in BMC Medicine by Tao Y et al., entitled "Effect of intravenous urokinase vs best medicine treatment on functional outcome for patients … This matters arising addresses the recently published article in BMC Medicine by Tao Y et al., entitled "Effect of intravenous urokinase vs best medicine treatment on functional outcome for patients with acute minor stroke (TRUST): a randomized controlled trial." While appreciating the rigorous methodology and important findings of the TRUST trial, we raise several points regarding optimizing urokinase dosing and treatment strategies. Specifically, we discuss the potential for optimizing urokinase dosing based on emerging evidence. Given China's extensive clinical experience with urokinase and associated cost considerations, we advocate for further research, including trials evaluating weight-based dosing strategies, to optimize urokinase thrombolytic therapy for patients with acute ischemic stroke. Such research is crucial for optimizing urokinase thrombolysis and establishing its role as a cost-effective treatment option, especially in resource-limited settings.

Novel Insights Into the Dynamic Conformational Transitions and Active Site Plasticity of Human Immunoregulatory <scp>Cathepsin S</scp>

2025-05-26

D. Evangelin Geetha , Bee Hameeda , Deepthi Jose +2 more

ABSTRACT Cathepsin S (CatS), a cysteine protease, catalyzes the cleavage of immunoregulatory peptides and mediates tissue destruction in autoimmune and inflammatory diseases. Plasticity of its ligand binding site and mechanisms … ABSTRACT Cathepsin S (CatS), a cysteine protease, catalyzes the cleavage of immunoregulatory peptides and mediates tissue destruction in autoimmune and inflammatory diseases. Plasticity of its ligand binding site and mechanisms of dynamic transitions between different conformational states are critical in drug discovery; however, knowledge of its entire conformational landscape and transition mechanisms remains incomplete. Therefore, we investigated the atomic‐level interactions between active site cleft residues that contribute to its structural and functional plasticity. Here, we show that the hinge movement of side chains of Phe211, Phe70, and Tyr118, followed by side chain reorientation of active site residues and inter‐residue interactions, results in open or closed conformations, contributing to the plasticity of the S2 binding affinity hotspot pocket of CatS. Hinge movements of Phe211, Phe70, and Tyr118 regulate the space available in the S2 pocket, with Phe70 acting as a key regulator, thereby affecting small molecule binding in the active site cleft. Further, the non‐covalent interactions between active site residues during transitions between open and closed states lead to the formation of three distinct, dynamic, semi‐closed substates. The transition to the closed state can be blocked by a ligand that sterically hinders the hinge movement of Phe70 or Phe211. The cooperative, organized side chain rotation of Phe211, Phe70, and Tyr118, and subsequent emergence of non‐covalent interactions between the active site residues can influence the accommodation of ligands and their specificity. These novel findings might further aid the design of selective small molecule drugs targeting specific conformational states of the immunoregulatory and inflammatory/autoimmune disease target human CatS.

Can Proteomics Play a Significant Role in the Identification of Biomarkers for Alpha1-Antitrypsin Deficiency?

2025-05-26

Maria Antonietta Grignano , Maura D’Amato , Marilena Gregorini +3 more

Alpha-1 antitrypsin deficiency (AATD) is a common genetic disorder that can manifest in a broad spectrum of clinical symptoms, ranging from asymptomatic cases to severe, progressive systemic diseases, primarily affecting … Alpha-1 antitrypsin deficiency (AATD) is a common genetic disorder that can manifest in a broad spectrum of clinical symptoms, ranging from asymptomatic cases to severe, progressive systemic diseases, primarily affecting the lungs and liver. Despite its prevalence, AATD is often perceived as a rare condition, which can lead to a lack of awareness among primary care physicians and even some respiratory specialists. This misconception may result in missed opportunities for diagnosis, particularly in mild or asymptomatic patients. Consequently, it is vital for healthcare providers to familiarize themselves with the various presentations, diagnostic techniques, and management strategies for AATD. This review explores the current understanding of AATD, emphasizing the valuable role of liquid chromatography-mass spectrometry in identifying biomarkers that could enhance early diagnosis and help predict disease outcomes. As knowledge about the complexities of AATD continues to grow, physicians may begin to view the disorder not as a fatal pathology, but as a treatable inherited condition with the potential for improved management.

Circulating protein biomarkers and their association with vulnerable plaque characteristics – a PROSPECT II substudy

2025-05-24

Tania Sharma , Akiko Maehara , Michael Mæng +7 more

Streptokinase

2025-05-24

Designing nonlinear sweep signal to improve the resolution of vibroseis acquisition

2025-05-22

Yang Liu , Xiaotao Wen , Bo Li +2 more

The widespread usage of vibroseis in seismic acquisition offers several advantages, including environmental sustainability and precisely controllable excitation. However, challenges persist, such as low acquisition efficiency and suboptimal data quality. … The widespread usage of vibroseis in seismic acquisition offers several advantages, including environmental sustainability and precisely controllable excitation. However, challenges persist, such as low acquisition efficiency and suboptimal data quality. Expanding the frequency bandwidth of linear sweep signals can potentially enhance the resolution of seismic exploration. However, its effectiveness is limited by subsurface absorption and attenuation effects. Recent advancements have introduced nonlinear sweep signals, providing broader frequency bandwidth and improved resolution. Nevertheless, the combination of waveform and frequency range in these methods remains suboptimal, which indicates that there is room for further improvement in data quality. To address these limitations, we propose a nonlinear sweep signal design method based on a derived equation. Unlike traditional approaches, this method eliminates the need for inverse transformation processes, thereby reducing uncertainty in signal design. The nonlinear function is guided by reflection characteristics, enabling the creation of a tailored encoding window for each time sampling interval. This tailored design ensures a better match with seismic data, leading to improved resolution. Additionally, time window segmentation yields more refined frequency domain information, enhancing the adaptability of the sweep signal to field conditions. Overall, this method broadens the frequency bandwidth of acquired seismic data, mitigates subsurface absorption and attenuation effects, and improves resolution, thereby providing a theoretical framework for designing nonlinear sweep signals.