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Human Cell Nov 2022Endothelial dysfunction is one of the key cornerstone complications of emerging and re-emerging viruses which lead to vascular leakage and a high mortality rate. The... (Review)
Review
Endothelial dysfunction is one of the key cornerstone complications of emerging and re-emerging viruses which lead to vascular leakage and a high mortality rate. The mechanism that regulates the origin of endothelial dysregulation is not completely elucidated. Currently, there are no potential pharmacological treatments and curable management for such diseases. In this sense, mesenchymal stromal/stem cells (MSCs) has been emerging to be a promising therapeutic strategy in restoring endothelial barrier function in various lung disease, including ALI and ARDS. The mechanism of the role of MSCs in restoring endothelial integrity among single-strand RNA (ssRNA) viruses that target endothelial cells remains elusive. Thus, we have discussed the therapeutic role of MSCs in restoring vascular integrity by (i) inhibiting the metalloprotease activity thereby preventing the cleavage of tight junction proteins, which are essential for maintaining membrane integrity (ii) possessing antioxidant properties which neutralize the excessive ROS production due to virus infection and its associated hyper host immune response (iii) modulating micro RNAs that regulate the endothelial activation and its integrity by downregulating the inflammatory response during ssRNA infection.
Topics: Antioxidants; Endothelial Cells; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Metalloproteases; RNA; Reactive Oxygen Species; Tight Junction Proteins; Virus Diseases
PubMed: 36068397
DOI: 10.1007/s13577-022-00785-3 -
Science Advances Mar 2023The metalloproteases meprin α and meprin β are highly expressed in the healthy gut but significantly decreased in inflammatory bowel disease, implicating a protective...
The metalloproteases meprin α and meprin β are highly expressed in the healthy gut but significantly decreased in inflammatory bowel disease, implicating a protective role in mucosal homeostasis. In the colon, meprin α and meprin β form covalently linked heterodimers tethering meprin α to the plasma membrane, therefore presenting dual proteolytic activity in a unique enzyme complex. To unravel its function, we applied N-terminomics and identified galectin-3 as the major intestinal substrate for meprin α/β heterodimers. Galectin-3-deficient and meprin α/β double knockout mice show similar alterations in their microbiome in comparison to wild-type mice. We further demonstrate that meprin α/β heterodimers differentially process galectin-3 upon bacterial infection, in germ-free, conventionally housed (specific pathogen-free), or wildling mice, which in turn regulates the bacterial agglutination properties of galectin-3. Thus, the constitutive cleavage of galectin-3 by meprin α/β heterodimers may play a key role in colon host-microbiome homeostasis.
Topics: Mice; Animals; Metalloendopeptidases; Galectin 3; Metalloproteases; Proteolysis; Mice, Knockout; Homeostasis
PubMed: 37000885
DOI: 10.1126/sciadv.adf4055 -
Current Topics in Medicinal Chemistry 2015Botulinum Neurotoxins are the most poisonous of all toxins with lethal dose in nanogram quantities. They are potential biological warfare and bioterrorism agents due to... (Review)
Review
Botulinum Neurotoxins are the most poisonous of all toxins with lethal dose in nanogram quantities. They are potential biological warfare and bioterrorism agents due to their high toxicity and ease of preparation. On the other hand BoNTs are also being increasingly used for therapeutic and cosmetic purposes, and with that the chances of accidental overdose are increasing. And despite the potential damage they could cause to human health, there are no post-intoxication drugs available so far. But progress is being made in this direction. The crystal structures in native form and bound with substrate peptides have been determined, and these are enabling structure-based drug discovery possible. High throughput assays have also been designed to speed up the screening progress. Substrate-based and small molecule inhibitors have been identified. But turning high affinity inhibitors into clinically viable drug candidates has remained a challenge. We discuss here the latest developments and the future challenges in drug discovery for Botulinum neurotoxins.
Topics: Animals; Botulinum Antitoxin; Botulinum Toxins; Drug Discovery; Endopeptidases; High-Throughput Screening Assays; Humans; Metalloproteases; Models, Molecular; Neurotoxins; Peptides; Peptidomimetics; Protease Inhibitors; Small Molecule Libraries
PubMed: 25751268
DOI: 10.2174/1568026615666150309150338 -
Journal of Molecular Biology Aug 2020Intramembrane proteolysis, although once a controversial concept, is a widely studied field. Four classes of intramembrane proteases have been identified and are... (Review)
Review
Intramembrane proteolysis, although once a controversial concept, is a widely studied field. Four classes of intramembrane proteases have been identified and are classified by their catalytic mechanism of peptide bond hydrolysis: metallo, glutamyl, aspartyl, and serine proteases. One of the most studied of these classes is the rhomboid superfamily of serine intramembrane proteases. Rhomboids consist of six or seven transmembrane segments that form a helical bundle within the membrane and are involved in a multitude of cellular processes. These proteases are characterized by a catalytic dyad composed of a serine and a histidine residue, which distinguishes them from classical serine proteases wherein a catalytic triad is utilized. Of all currently identified rhomboid proteases, one that is of great interest is the mammalian mitochondrial rhomboid protease PARL. Most well known for its processing of the kinase PINK1 and potential link to Parkinson's disease, PARL has been shown to cleave a variety of substrates within the cell including PGAM5, Smac, TTC19, and others. While recent proteomic studies have provided insight on new potential substrates of PARL, its regulation, activity, and role in maintaining mitochondrial homeostasis remain largely unknown.
Topics: Gene Expression Regulation; Homeostasis; Humans; Metalloproteases; Mitochondrial Membranes; Mitochondrial Proteins; Parkinson Disease; Protein Conformation; Proteolysis
PubMed: 32320686
DOI: 10.1016/j.jmb.2020.04.006 -
Cell Adhesion & Migration Dec 2020The ADAMs family belongs to the transmembrane protein superfamily of zinc-dependent metalloproteases, which consists of multiple domains. These domains have independent... (Review)
Review
The ADAMs family belongs to the transmembrane protein superfamily of zinc-dependent metalloproteases, which consists of multiple domains. These domains have independent but complementary functions that enable them to participate in multiple biological processes. Among them, ADAM9 can not only participate in the degradation of extracellular matrix as a metalloprotease, but also mediate tumor cell adhesion through its deintegrin domain, which is closely related to tumor invasion and metastasis. It is widely expressed in a variety of tumor cells and can affect the proliferation, invasion and metastasis of related cancer cells. We provide our views on current progress, its increasing importance as a strategic treatment goal, and our vision for the future of ADAM9.
Topics: ADAM Proteins; Evolution, Molecular; Gene Expression Regulation, Neoplastic; Humans; Neoplasms
PubMed: 32875951
DOI: 10.1080/19336918.2020.1817251 -
Mass Spectrometry Reviews Sep 2020Zinc metalloproteases (ZnMPs) participate in diverse biological reactions, encompassing the synthesis and degradation of all the major metabolites in living organisms.... (Review)
Review
Zinc metalloproteases (ZnMPs) participate in diverse biological reactions, encompassing the synthesis and degradation of all the major metabolites in living organisms. In particular, ZnMPs have been recognized to play a very important role in controlling the concentration level of several peptides and/or proteins whose homeostasis has to be finely regulated for the correct physiology of cells. Dyshomeostasis of aggregation-prone proteins causes pathological conditions and the development of several different diseases. For this reason, in recent years, many analytical approaches have been applied for studying the interaction between ZnMPs and their substrates and how environmental factors can affect enzyme activities. In this scenario, mass spectrometric methods occupy a very important role in elucidating different aspects of ZnMPs-substrates interaction. These range from identification of cleavage sites to quantitation of kinetic parameters. In this work, an overview of all the main achievements regarding the application of mass spectrometric methods to investigating ZnMPs-substrates interactions is presented. A general experimental protocol is also described which may prove useful to the study of similar interactions. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.
Topics: Allosteric Regulation; Animals; Humans; Mass Spectrometry; Metalloproteases; Zinc
PubMed: 31898821
DOI: 10.1002/mas.21621 -
Chemistry (Weinheim An Der Bergstrasse,... Nov 2018Metallopeptides that show efficiency and selectivity in peptide bond cleavage in water at room temperature and neutral conditions are presented. These small and...
Metallopeptides that show efficiency and selectivity in peptide bond cleavage in water at room temperature and neutral conditions are presented. These small and versatile organozymes take advantage of metal-coordinating building blocks that are strategically positioned centrally in a peptide backbone or in a peptide macrocycle. This approach provided peptide-metal complexes with scaffolds capable of utilizing the peptide functionality for productive binding of fluorogenic FRET peptide substrates, subsequently leading to highly selective peptide bond cleavage. The ligand chemistry has been optimized to provide an easy access to new metallo-peptides with the ability to cleave previously inaccessible peptide bonds. Evolutionary principles of stepwise selection and variation offered by combinatorial methods were used and were guided by molecular modeling to develop catalytic metallo-peptides that mimic metalloproteases.
Topics: 2,2'-Dipyridyl; Catalysis; Coordination Complexes; Hydrolysis; Metalloproteases; Models, Molecular; Peptides; Peptidomimetics; Phenanthrolines; Substrate Specificity
PubMed: 30146681
DOI: 10.1002/chem.201803666 -
Critical Reviews in Food Science and... Apr 2018The diet polyphenols are a secondary metabolites of plants able to act on inflammation process. Their anti-inflammatory activity is articulated through several... (Review)
Review
The diet polyphenols are a secondary metabolites of plants able to act on inflammation process. Their anti-inflammatory activity is articulated through several mechanisms that are related to their antioxidative and radical scavengers properties. Our work is focused on a novel approach to inflammatory disease management, based on anti-glycative and matrix metalloproteinases (MMPs) inhibition effects, as a connected phenomena. To better understand these correlation, polyphenols Structure-Activity Relationship (SAR) studies were also reported. The antioxidant polyphenols inhibit the AGEs at different levels of the glycation process in the following ways: (1) prevention of Amadori adduct oxidation; (2) trapping reactive dycarbonyl compounds; (3) attenuation of receptor for AGEs (RAGE) expression. Moreover, several flavonoids with radical scavenging property showed also MMPs inhibition interact directly with MMPs or indirectly via radical scavengers and AGEs reduction. The essential polyphenols features involved in these mechanisms are C2-C3 double bond and number and position of hydroxyl, glycosyl and O-methyl groups. These factors induce a change in molecular planarity interfering with the hydrogen bond formation, electron delocalization and metal ion chelation. In particular, C2-C3 double bond improve the antioxidant and MMPs inhibition, while the hydroxylation, glycosylation and methylation induce a positive and negative correlation, respectively.
Topics: Antioxidants; Flavonoids; Glycation End Products, Advanced; Glycosylation; Humans; Inflammation; Matrix Metalloproteinase Inhibitors; Metalloproteases; Polyphenols; Structure-Activity Relationship
PubMed: 27646710
DOI: 10.1080/10408398.2016.1229657 -
Chemical Reviews Feb 2018Proteases enzymatically hydrolyze peptide bonds in substrate proteins, resulting in a widespread, irreversible posttranslational modification of the protein's structure... (Review)
Review
Proteases enzymatically hydrolyze peptide bonds in substrate proteins, resulting in a widespread, irreversible posttranslational modification of the protein's structure and biological function. Often regarded as a mere degradative mechanism in destruction of proteins or turnover in maintaining physiological homeostasis, recent research in the field of degradomics has led to the recognition of two main yet unexpected concepts. First, that targeted, limited proteolytic cleavage events by a wide repertoire of proteases are pivotal regulators of most, if not all, physiological and pathological processes. Second, an unexpected in vivo abundance of stable cleaved proteins revealed pervasive, functionally relevant protein processing in normal and diseased tissue-from 40 to 70% of proteins also occur in vivo as distinct stable proteoforms with undocumented N- or C-termini, meaning these proteoforms are stable functional cleavage products, most with unknown functional implications. In this Review, we discuss the structural biology aspects and mechanisms of catalysis by different protease classes. We also provide an overview of biological pathways that utilize specific proteolytic cleavage as a precision control mechanism in protein quality control, stability, localization, and maturation, as well as proteolytic cleavage as a mediator in signaling pathways. Lastly, we provide a comprehensive overview of analytical methods and approaches to study activity and substrates of proteolytic enzymes in relevant biological models, both historical and focusing on state of the art proteomics techniques in the field of degradomics research.
Topics: Humans; Metalloproteases; Peptide Hydrolases; Protein Processing, Post-Translational; Proteolysis; Proteomics; Serine Proteases; Substrate Specificity
PubMed: 29265812
DOI: 10.1021/acs.chemrev.7b00120 -
Endocrine, Metabolic & Immune Disorders... 2015In different inflammatory diseases, many metalloproteinases are over expressed and thought to promote progression of the disease. Understanding roles of these enzymes in... (Review)
Review
In different inflammatory diseases, many metalloproteinases are over expressed and thought to promote progression of the disease. Understanding roles of these enzymes in disease progression as well as in normal homeostasis is crucial to identify target enzymes for the disease. Rheumatoid arthritis (RA) is one of the autoimmune inflammatory diseases in which around 1-2 % of the world populations are suffered from. Roles of metalloproteinases are well documented in RA, but so far none of them is proposed to be a target enzyme. However, there are at least three enzymes that can potentially be molecular targets to inhibit progression of RA. Understanding roles of these enzymes in more detail and developing highly selective inhibitors to these enzymes would be essential for novel antimetalloproteinase therapies in future.
Topics: Animals; Arthritis, Rheumatoid; Drug Delivery Systems; Humans; Matrix Metalloproteinase Inhibitors; Metalloproteases
PubMed: 25772173
DOI: 10.2174/1871530315666150316122335