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Frontiers in Immunology 2019Angiogenesis is facilitated by the proteolytic activities of members of the matrix metalloproteinase (MMP) family. More specifically, MMP-9 and MT1-MMP directly regulate... (Review)
Review
Angiogenesis is facilitated by the proteolytic activities of members of the matrix metalloproteinase (MMP) family. More specifically, MMP-9 and MT1-MMP directly regulate angiogenesis, while several studies indicate a role for MMP-2 as well. The correlation of MMP activity to tumor angiogenesis has instigated numerous drug development programs. However, broad-based and Zn-chelating MMP inhibitors have fared poorly in the clinic. Selective MMP inhibition by antibodies, biologicals, and small molecules has utilized unique modes of action, such as (a) binding to protease secondary binding sites (exosites), (b) allosterically blocking the protease active site, or (c) preventing proMMP activation. Clinical trials have been undertaken with several of these inhibitors, while others are in advanced pre-clinical stages. The mechanistically non-traditional MMP inhibitors offer treatment strategies for tumor angiogenesis that avoid the off-target toxicities and lack of specificity that plagued Zn-chelating inhibitors.
Topics: Animals; Antineoplastic Agents; Drug Development; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Protein Interaction Domains and Motifs; Structure-Activity Relationship
PubMed: 31214203
DOI: 10.3389/fimmu.2019.01278 -
Periodontology 2000 Feb 2016Matrix metalloproteinase-8 is a promising candidate biomarker for oral fluid (gingival crevicular fluid, peri-implant sulcular fluid and saliva) and mouthrinse... (Review)
Review
Matrix metalloproteinase-8 is a promising candidate biomarker for oral fluid (gingival crevicular fluid, peri-implant sulcular fluid and saliva) and mouthrinse chair-side/point-of-care diagnostics to predict, diagnose and determine the progressive phases of episodic periodontitis and peri-implantitis, as well as to monitor the treatments and medications. Matrix metalloproteinase-8 can be used alone or together with interleukin-1beta and Porphyromonas gingivalis to calculate cumulative risk score at the subject level as a successful diagnostic tool, especially in large-scale public health surveys, in which a thorough periodontal examination is not feasible.
Topics: Biomarkers; Diagnosis, Oral; Female; Gingival Crevicular Fluid; Humans; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinases; Periodontal Diseases; Pregnancy; Saliva
PubMed: 26662488
DOI: 10.1111/prd.12101 -
The Journal of Clinical Pediatric... 2014Matrix metalloproteinases (MMPs) seem to play a dual role in dentistry. While several MMPs have an important role to play in developmental defects of teeth and in... (Review)
Review
Matrix metalloproteinases (MMPs) seem to play a dual role in dentistry. While several MMPs have an important role to play in developmental defects of teeth and in caries, some MMPs also seem to have a defensive role. The main organic component of tooth structure is collagen and MMPs that degrade collagen and the extra cellular matrix have been implicated in progression of dental caries. MMPs have also been shown to be active in pulpitis and studies have shown that they can be used as diagnostic markers of pulpal inflammation. This paper reviews the role of MMPs in restorative dentistry and endodontics.
Topics: Biomarkers; Dental Caries; Dental Pulp Diseases; Humans; Matrix Metalloproteinases; Tooth; Tooth Diseases
PubMed: 25631728
DOI: 10.17796/jcpd.39.1.x452446251r1q428 -
Molecular Medicine Reports Jul 2016Mammalian diaphanous‑related formin 1 (mDia1) was initially identified as a Rho GTPase effector involved in the progression of various diseases, including types of...
Mammalian diaphanous‑related formin 1 (mDia1) was initially identified as a Rho GTPase effector involved in the progression of various diseases, including types of cancer. However, the precise underlying molecular mechanism of mDia1‑mediated cancer cell invasion remains to be elucidated. In the present study, mDia1 expression was demonstrated to be upregulated in tissues from a number of cancer types, including kidney, prostate, and breast cancer using immunohistochemical analysis. Forced expression of a constitutively active (CA) form of mDia1 induces invasion, as measured by Transwell invasion assay, of MDA‑MB‑231 cells, which is a highly invasive breast cancer cell line, and this effect was markedly impaired by matrix metalloproteinase (MMP)‑2 silencing. Furthermore, the present study demonstrated that overexpression of the CA form of mDia1 leads to the induction of invasive ability in MCF‑7 cells, which is a non‑invasive breast cancer cell line, as a result of increased MMP‑2 activity. Thus, the results of the current study suggest that mDia1 is an important regulator of breast cancer cell invasion and that this effect may be mediated by MMP‑2 activity.
Topics: Adaptor Proteins, Signal Transducing; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Enzyme Activation; Female; Formins; Humans; Immunohistochemistry; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases
PubMed: 27177153
DOI: 10.3892/mmr.2016.5282 -
Drug and Chemical Toxicology Sep 2022In the present study, we assessed the therapeutic potential of Biochanin-A (BCA) (10 mg/kg BW/day) pretreatment for 30 days on lipid metabolic abnormalities,...
Attenuation of lipid metabolic abnormalities, proinflammatory cytokines, and matrix metalloproteinase expression by biochanin-A in isoproterenol-induced myocardial infarction in rats.
In the present study, we assessed the therapeutic potential of Biochanin-A (BCA) (10 mg/kg BW/day) pretreatment for 30 days on lipid metabolic abnormalities, proinflammatory cytokines and matrix metalloproteinase expression in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. We measured the potential role of BCA on tissue and circulatory lipid profiles as well as on lipid metabolic enzymes: serum inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6 and MCP1) and serum Matrix Metalloproteinases (particularly, MMP-2 and MMP-9) together with mRNA expressions of TNF-α, IL-6, MMP-2 and MMP-9 by RT-PCR analysis. Administration of ISO to rats significantly distorted their lipid metabolism and augmented inflammatory process, MMP expression and proteolytic activity. In addition, pretreatment with BCA of ISO-induced MI rats significantly reestablished the altered lipid metabolism and concealed the inflammation of cytokines. BCA suppressed the expressions of proinflammatory cytokines and MMPs in ISO-induced MI in rats when compared to normal untreated MI rats. Hence, these results established that BCA could improve the pathological processes of myocardial remodeling which was confirmed by histopathology of heart in MI rats and might be an effective beneficial ingredient for the management of heart failure disorders.
Topics: Animals; Cytokines; Inflammation; Interleukin-6; Isoproterenol; Lipids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Myocardial Infarction; Rats; Tumor Necrosis Factor-alpha
PubMed: 33719799
DOI: 10.1080/01480545.2021.1894707 -
Journal of Medicinal Chemistry Oct 2020Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidence of their pathological roles have also been... (Review)
Review
Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidence of their pathological roles have also been obtained in the last decades, making MMPs attractive therapeutic targets for several diseases. Recent discoveries of their involvement in central nervous system (CNS) disorders, and in particular in Alzheimer's disease (AD), have paved the way to consider MMP modulators as promising therapeutic strategies. Over the past few decades, diverse approaches have been undertaken in the design of therapeutic agents targeting MMPs for various purposes, leading, more recently, to encouraging developments. In this article, we will present recent examples of inhibitors ranging from small molecules and peptidomimetics to biologics. We will also discuss the scientific knowledge that has led to the development of emerging tools and techniques to overcome the challenges of selective MMP inhibition.
Topics: Alzheimer Disease; Central Nervous System; Drug Delivery Systems; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Peptidomimetics
PubMed: 32459966
DOI: 10.1021/acs.jmedchem.0c00352 -
Gynecological Endocrinology : the... Aug 2005It is becoming more and more evident that different types of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in the pathogenesis of...
OBJECTIVE
It is becoming more and more evident that different types of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in the pathogenesis of endometriosis. The aim of the present study was to measure levels of the active forms of MMP-13 and membrane type-1 matrix metalloproteinase (MT1-MMP)/MMP-14 as well as TIMP-2 in the peritoneal fluid of women with endometriosis.
STUDY DESIGN
We determined the levels of the active forms MMP-13 and MT1-MMP/MMP-14 as well as TIMP-2 in the peritoneal fluid of 20 women with endometriosis and 18 controls by different types of enzyme-linked immunosorbent assay.
RESULTS
We found that the concentrations (mean +/- standard deviation) of total active MMP-13 and endogenous active MT1-MMP/MMP-14 in the peritoneal fluid of patients with endometriosis were 1.69 +/- 0.67 and 3.12 +/- 1.07 ng/ml, respectively. In control women the corresponding values were 3.02 +/- 0.43 and 4.45 +/- 1.03 ng/ml. The differences were statistically significant (p < 0.0001 and p < 0.0004 for MMP-13 and MMP-14, respectively). Levels of TIMP-2 did not differ significantly.
CONCLUSIONS
Decreased concentrations of active MMP-13 and MT1-MMP/MMP-14 may imply that the proteolytic activity of the peritoneal milieu of women with endometriosis is disturbed, which may have implications in the pathogenesis of the disease.
Topics: Adult; Ascitic Fluid; Collagenases; Endometriosis; Female; Humans; Infertility; Matrix Metalloproteinase 13; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Tissue Inhibitor of Metalloproteinase-2
PubMed: 16109597
DOI: 10.1080/09513590500154043 -
Molecular Neurobiology Nov 2016Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Studies revealed that the pathogenesis of TBI involves upregulation of MMPs. MMPs... (Review)
Review
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Studies revealed that the pathogenesis of TBI involves upregulation of MMPs. MMPs form a large family of closely related zinc-dependent endopeptidases, which are primarily responsible for the dynamic remodulation of the extracellular matrix (ECM). Thus, they are involved in several normal physiological processes like growth, development, and wound healing. During pathophysiological conditions, MMPs proteolytically degrade various components of ECM and tight junction (TJ) proteins of BBB and cause BBB disruption. Impairment of BBB causes leakiness of the blood from circulation to brain parenchyma that leads to microhemorrhage and edema. Further, MMPs dysregulate various normal physiological processes like angiogenesis and neurogenesis, and also they participate in the inflammatory and apoptotic cascades by inducing or regulating the specific mediators and their receptors. In this review, we explore the roles of MMPs in various physiological/pathophysiological processes associated with neurological complications, with special emphasis on TBI.
Topics: Animals; Blood-Brain Barrier; Brain Injuries, Traumatic; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy
PubMed: 26541883
DOI: 10.1007/s12035-015-9520-8 -
FEBS Letters Jul 2022Tiki proteins represent a new family of Wnt-specific proteases that inhibit Wnt signalling by cleaving and inactivating Wnt proteins. Tiki proteins are...
Tiki proteins represent a new family of Wnt-specific proteases that inhibit Wnt signalling by cleaving and inactivating Wnt proteins. Tiki proteins are glycosylphosphatidylinositol (GPI)-anchored proteases and function in both Wnt-producing and Wnt-responsive cells. However, how Tiki proteins are regulated remains elusive. In this study, we demonstrate that matrix metalloproteinase 15 (MMP15) interacts with TIKI2 and degrades TIKI2 on the cell surface. Functionally, MMP15 relieves the inhibitory effect of TIKI2 on Wnt signalling in Wnt-responsive cells. We further show that Tiki proteins are substrates of MMP14, MMP15 and MMP16 but not MMP3 or MMP13. Our study provides insights into the potential regulation of Tiki family proteins by other proteases.
Topics: Matrix Metalloproteinase 14; Matrix Metalloproteinase 15; Matrix Metalloproteinases, Membrane-Associated; Wnt Proteins; Wnt Signaling Pathway
PubMed: 35689492
DOI: 10.1002/1873-3468.14423 -
Current Pharmaceutical Design 2014Degradation of the extracellular matrix is an important feature of embryonic development, morphogenesis, angiogenesis, tissue repair and remodeling. It is precisely... (Review)
Review
Degradation of the extracellular matrix is an important feature of embryonic development, morphogenesis, angiogenesis, tissue repair and remodeling. It is precisely regulated under physiological conditions, but when dysregulated it becomes a cause of many diseases, including atherosclerosis, osteoarthritis, diabetic vascular complications, and neurodegeneration. Various types of proteinases are implicated in extracellular matrix degradation, but the major enzymes are considered to be metalloproteinases such as matrix metalloproteinases (MMPs) and disintegrin and metalloproteinase domain (ADAMs) that include ADAMs with a thrombospondin domain (ADAMTS). This review discusses involvement of the major metalloproteinases in some age-related chronic diseases, and examines what is currently known about the beneficial effects of their inhibitors, used as new therapeutic strategies for treating or preventing the development and progression of these diseases.
Topics: Age Factors; Animals; Disease Progression; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Metalloproteases
PubMed: 24079771
DOI: 10.2174/13816128113196660701