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International Journal of Molecular... Aug 2021In the late 1980s, Paul Primakoff and colleagues showed that fertilization could be blocked in an in vitro sperm-egg fusion assay by inoculating them in the presence of...
In the late 1980s, Paul Primakoff and colleagues showed that fertilization could be blocked in an in vitro sperm-egg fusion assay by inoculating them in the presence of a disintegrin and metalloprotease (ADAM)-specific antibody [...].
Topics: ADAM Proteins; Animals; Humans; Inflammation; Neoplasms
PubMed: 34445468
DOI: 10.3390/ijms22168762 -
International Journal of Molecular... Nov 2021Endometrial cancer is one of the most common gynecological malignancies, yet the molecular mechanisms that lead to tumor development and progression are still not fully... (Review)
Review
Endometrial cancer is one of the most common gynecological malignancies, yet the molecular mechanisms that lead to tumor development and progression are still not fully established. Matrix metalloproteinases (MMPs) are a group of enzymes that play an important role in carcinogenesis. They are proteases involved in the degradation of the extracellular matrix (ECM) that surrounds the tumor and the affected tissue allows cell detachment from the primary tumor causing local invasion and metastasis formation. Recent investigations demonstrate significantly increased metalloproteinase and metalloproteinase inhibitor levels in patients with endometrial cancer compared to those with normal endometrium. In this review, we aim to show their clinical significance and possible use in the diagnosis and treatment of patients with endometrial cancer. We have critically summarized and reviewed the research on the role of MMPs in endometrial cancer.
Topics: Endometrial Neoplasms; Endometrium; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Metalloproteases
PubMed: 34830354
DOI: 10.3390/ijms222212472 -
Science Advances Jan 2023Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While the role of the host...
Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While the role of the host transmembrane protease serine 2 in SARS-CoV-2 infection is widely recognized, the involvement of other proteases capable of facilitating SARS-CoV-2 entry remains incompletely explored. Here, we show that multiple members from the membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin and metalloproteinase families can mediate SARS-CoV-2 entry. Inhibition of MT-MMPs significantly reduces SARS-CoV-2 replication in vitro and in vivo. Mechanistically, we show that MT-MMPs can cleave SARS-CoV-2 spike and angiotensin-converting enzyme 2 and facilitate spike-mediated fusion. We further demonstrate that Omicron BA.1 has an increased efficiency on MT-MMP usage, while an altered efficiency on transmembrane serine protease usage for virus entry compared with that of ancestral SARS-CoV-2. These results reveal additional protease determinants for SARS-CoV-2 infection and enhance our understanding on the biology of coronavirus entry.
Topics: Humans; SARS-CoV-2; Peptide Hydrolases; COVID-19; Proteolysis; Metalloproteases; Virus Internalization
PubMed: 36662861
DOI: 10.1126/sciadv.add3867 -
Frontiers in Immunology 2022ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and... (Review)
Review
ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.
Topics: Humans; Immunomodulation; Metalloproteases; Neoplasms; Antineoplastic Agents, Immunological; Antibodies, Monoclonal; ADAM17 Protein
PubMed: 36466812
DOI: 10.3389/fimmu.2022.1059376 -
Advanced Science (Weinheim,... Sep 2023High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing...
High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing oxygen and nutrition supply to the brain. RNA N6-methyladenosine (m6A) is susceptible to modification and regulates gene expression in response to environmental changes, including hypoxia. However, the biological significance of m6A in endothelial cell performance under hypoxic conditions is unknown. Using m6A-seq, RNA immunoprcipitation-seq, and transcriptomic co-analysis, the molecular mechanism of vascular system remodeling under acute hypoxia is investigated. A novel m6A reader protein, proline-rich coiled-coil 2B (PRRC2B), exists in endothelial cells. PRRC2B knockdown promoted hypoxia-induced endothelial cell migration by regulating alternative splicing of the alpha 1 chain of collagen type XII in an m6A-dependent manner and the decay of matrix metallopeptidase domain 14 and ADAM metallopeptidase domain 19 mRNA in an m6A-independent manner. In addition, conditional knockout of PRRC2B in endothelial cells promotes hypoxia-induced vascular remodeling and cerebral blood flow redistribution, thus alleviating hypoxia-induced cognitive decline. Therefore, PRRC2B is integral in the hypoxia-induced vascular remodeling process as a novel RNA-binding protein. These findings provide a new potential therapeutic target for hypoxia-induced cognitive decline.
Topics: Mice; Animals; Endothelial Cells; Vascular Remodeling; RNA; Hypoxia; Metalloproteases
PubMed: 37395402
DOI: 10.1002/advs.202300892 -
Enzyme and Microbial Technology Jan 2023The rational design of enzymes with enhanced thermostability is efficient. Solvent-tolerant metalloprotease from Pseudomonas aeruginosa PT121 presents high Z-aspartame...
The rational design of enzymes with enhanced thermostability is efficient. Solvent-tolerant metalloprotease from Pseudomonas aeruginosa PT121 presents high Z-aspartame (Z-APM) synthesis activity, but insufficient thermostability. In this study, we enhanced enzyme thermostability using a rational strategy. Molecular dynamics (MD) simulation was applied to rapidly identify that the D28 and D116 mutations are likely to exhibit increased thermostability, and experimentation verified that the D28N and D116N mutants were more stable than the wild-type (WT) enzyme. In particular, the T of the D28N and D116N mutants increased by 6.1 °C and 9.2 °C, respectively, compared with that of the WT enzyme. The half-lives of D28N and D116N at 60 °C were 1.07- and 1.8-fold higher than that of the WT, respectively. Z-APM synthetic activities of the mutants were also improved. The potential mechanism of thermostability enhancement rationalized using MD simulation indicated that increased hydrogen bond interactions and a regional hydration shell were mostly responsible for the thermostability enhancement. Our strategy could be a reference for enzyme engineering, and our mutants offer considerable value in industrial applications.
Topics: Enzyme Stability; Temperature; Metalloproteases; Molecular Dynamics Simulation; Pseudomonas aeruginosa; Protein Engineering
PubMed: 36115275
DOI: 10.1016/j.enzmictec.2022.110123 -
Frontiers in Immunology 2023Chronic inflammation participates in the progression of multiple chronic diseases, including obesity, diabetes mellitus (DM), and DM related complications. Diabetic... (Review)
Review
Chronic inflammation participates in the progression of multiple chronic diseases, including obesity, diabetes mellitus (DM), and DM related complications. Diabetic ulcer, characterized by chronic wounds that are recalcitrant to healing, is a serious complication of DM tremendously affecting the quality of life of patients and imposing a costly medical burden on society. Matrix metalloproteases (MMPs) are a family of zinc endopeptidases with the capacity of degrading all the components of the extracellular matrix, which play a pivotal part in healing process under various conditions including DM. During diabetic wound healing, the dynamic changes of MMPs in the serum, skin tissues, and wound fluid of patients are in connection with the degree of wound recovery, suggesting that MMPs can function as essential biomarkers for the diagnosis of diabetic ulcer. MMPs participate in various biological processes relevant to diabetic ulcer, such as ECM secretion, granulation tissue configuration, angiogenesis, collagen growth, re-epithelization, inflammatory response, as well as oxidative stress, thus, seeking and developing agents targeting MMPs has emerged as a potential way to treat diabetic ulcer. Natural products especially flavonoids, polysaccharides, alkaloids, polypeptides, and estrogens extracted from herbs, vegetables, as well as animals that have been extensively illustrated to treat diabetic ulcer through targeting MMPs-mediated signaling pathways, are discussed in this review and may contribute to the development of functional foods or drug candidates for diabetic ulcer therapy. This review highlights the regulation of MMPs in diabetic wound healing, and the potential therapeutic ability of natural products for diabetic wound healing by targeting MMPs.
Topics: Animals; Quality of Life; Ulcer; Diabetes Mellitus; Wound Healing; Biological Products; Metalloproteases
PubMed: 36875064
DOI: 10.3389/fimmu.2023.1089001 -
FEBS Letters Mar 2022Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead... (Review)
Review
Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead to organ failure and death, and their increasing incidence represents a major issue for the healthcare system. Protease-mediated ectodomain shedding of cytokines and their receptors represents a central mechanism in the regulation of inflammatory responses. The metalloprotease A disintegrin and metalloproteinase (ADAM) 17 is the best-characterized ectodomain sheddase capable of releasing TNF-α and soluble IL-6 receptor, which are decisive factors of systemic inflammation. Recently, meprin metalloproteases were also identified as IL-6 receptor sheddases and activators of the pro-inflammatory cytokines IL-1β and IL-18. In different mouse models of SID, particularly those mimicking a sepsis-like phenotype, ADAM17 and meprins have been found to promote disease progression. In this review, we summarize the role of ADAM10, ADAM17, and meprins in the onset and progression of sepsis and discuss their potential as therapeutic targets.
Topics: Animals; Mice; ADAM10 Protein; ADAM17 Protein; Amyloid Precursor Protein Secretases; Cytokines; Inflammation; Metalloproteases; Receptors, Interleukin-6; Sepsis; Tiopronin
PubMed: 34762736
DOI: 10.1002/1873-3468.14225 -
ELife Sep 2023The amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been...
The amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic strain that expresses and secretes human Aβ. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.
Topics: Animals; Humans; Amyloid beta-Peptides; Caenorhabditis elegans; Peptide Hydrolases; Disintegrins; Alzheimer Disease; Endopeptidases; Plaque, Amyloid; Metalloproteases; Membrane Proteins; ADAM Proteins
PubMed: 37728486
DOI: 10.7554/eLife.83465 -
Cardiovascular Research Aug 2023Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such...
AIMS
Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis.
METHODS AND RESULTS
The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload. Disease mechanisms affected by the treatment were identified based on changes in the myocardial transcriptome. Following aortic banding, rats receiving an ADAMTS inhibitor, with high inhibitory capacity for ADAMTS4, showed substantially better cardiac function than vehicle-treated rats, including ∼30% reduction in E/e' and left atrial diameter, indicating an improvement in diastolic function. ADAMTS inhibition also resulted in a marked reduction in myocardial collagen content and a down-regulation of transforming growth factor (TGF)-β target genes. The mechanism for the beneficial effects of ADAMTS inhibition was further studied in cultured human cardiac fibroblasts producing mature ECM. ADAMTS4 caused a 50% increase in the TGF-β levels in the medium. Simultaneously, ADAMTS4 elicited a not previously known cleavage of TGF-β-binding proteins, i.e. latent-binding protein of TGF-β and extra domain A-fibronectin. These effects were abolished by the ADAMTS inhibitor. In failing human hearts, we observed a marked increase in ADAMTS4 expression and cleavage activity.
CONCLUSION
Inhibition of ADAMTS4 improves cardiac function and reduces collagen accumulation in rats with cardiac pressure overload, possibly through a not previously known cleavage of molecules that control TGF-β availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular, in heart failure with fibrosis and diastolic dysfunction.
Topics: Rats; Humans; Animals; Disintegrins; Myocardium; Heart Failure; Cardiomyopathies; Collagen; Fibroblasts; Transforming Growth Factor beta; Thrombospondins; Metalloproteases; Fibrosis
PubMed: 37216909
DOI: 10.1093/cvr/cvad078