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Toxins Jul 2018Botulinum neurotoxins (BoNT) are produced by several species of clostridium. There are seven immunologically unique BoNT serotypes (A⁻G). The Centers for Disease... (Review)
Review
Botulinum neurotoxins (BoNT) are produced by several species of clostridium. There are seven immunologically unique BoNT serotypes (A⁻G). The Centers for Disease Control classifies BoNTs as 'Category A' select agents and are the most lethal protein toxins for humans. Recently, BoNT-like proteins have also been identified in several non-clostridia. BoNTs are di-chain proteins comprised of an -terminal zinc metalloprotease Light Chain (LC) and a C-terminal Heavy Chain (HC) which includes the translocation and receptor binding domains. The two chains are held together by a disulfide bond. The LC cleaves Soluble -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). The cleavage of SNAREs inhibits the fusion of synaptic vesicles to the cell membrane and the subsequent release of acetylcholine, which results in flaccid paralysis. The LC controls the catalytic properties and the duration of BoNT action. This review discusses the mechanism for LC catalysis, LC translocation, and the basis for the duration of LC action. Understanding these properties of the LC may expand the applications of BoNT as human therapies.
Topics: Animals; Botulinum Toxins; Humans; Neurotoxins; SNARE Proteins
PubMed: 30004421
DOI: 10.3390/toxins10070268 -
Biochemistry Sep 2017The inner mitochondrial membrane (IM) is among the most protein-rich cellular compartments. The metastable IM subproteome where the concentration of proteins is... (Review)
Review
The inner mitochondrial membrane (IM) is among the most protein-rich cellular compartments. The metastable IM subproteome where the concentration of proteins is approaching oversaturation creates a challenging protein folding environment with a high probability of protein malfunction or aggregation. Failure to maintain protein homeostasis in such a setting can impair the functional integrity of the mitochondria and drive clinical manifestations. The IM is equipped with a series of highly conserved, proteolytic complexes dedicated to the maintenance of normal protein homeostasis within this mitochondrial subcompartment. Particularly important is a group of membrane-anchored metallopeptidases commonly known as m-AAA and i-AAA proteases, and the ATP-independent Oma1 protease. Herein, we will summarize the current biochemical knowledge of these proteolytic machines and discuss recent advances in our understanding of mechanistic aspects of their functioning.
Topics: Animals; Gene Expression Regulation, Enzymologic; Homeostasis; Metalloproteases; Mitochondrial Membranes; Protein Conformation
PubMed: 28806058
DOI: 10.1021/acs.biochem.7b00663 -
Scientific Reports Mar 2022Exudate production is a natural part of the wound healing process, however levels of exudate need to be appropriately managed to maintain a moist wound environment which...
Exudate production is a natural part of the wound healing process, however levels of exudate need to be appropriately managed to maintain a moist wound environment which supports healing. An overly-exuding wound creates an environment favourable to bacterial growth. In recent years, a significant increase in commercially available superabsorbent dressings have become available which claim to absorb and retain excess exudate and its components. However, the effectiveness of these dressings in sequestering and retaining bacteria and host-derived proteins has not been compared. We have therefore investigated several superabsorbent dressings for their ability to absorb and retain bacteria (Staphylococcus aureus and Pseudomonas aeruginosa), their impact on bacterial viability, and their ability to sequester matrix metalloproteinases (MMP)-2 and 9 over 7 days. Whilst all dressings could sequester bacteria, some dressings internalised bacteria more effectively. There was considerable variation in bacterial viability within the dressings' core, as well as differences in bacterial retention. Some dressings effectively internalised and retained bacteria over time, whereas other dressings retained significantly less. These differences were reflected visually using scanning electron microscopy. Most dressings fully sequestered MMP-2 and 9. These data illustrate differences in the ability of superabsorbent dressings to absorb and retain exudate and its components.
Topics: Bandages; Exudates and Transudates; Metalloproteases; Pseudomonas aeruginosa; Wound Healing
PubMed: 35306513
DOI: 10.1038/s41598-022-08361-3 -
Microbiology Spectrum Apr 2016Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix turnover. To accomplish these tasks, myeloid cells carry an arsenal of... (Review)
Review
Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix turnover. To accomplish these tasks, myeloid cells carry an arsenal of metalloproteinases, which include the matrix metalloproteinases and the adamalysins. These enzymes have diverse substrate repertoires, and are thus involved in mediating proteolytic cascades, cell migration, and cell signaling. Dysregulation of metalloproteinases contributes to pathogenic processes, including inflammation, fibrosis, and cancer. Metalloproteinases also have important nonproteolytic functions in controlling cytoskeletal dynamics during macrophage fusion and enhancing transcription to promote antiviral immunity. This review highlights the diverse contributions of metalloproteinases to myeloid cell functions.
Topics: Animals; Humans; Metalloproteases; Myeloid Cells
PubMed: 27227311
DOI: 10.1128/microbiolspec.MCHD-0002-2015 -
Cellular and Molecular Life Sciences :... Aug 2019This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of... (Review)
Review
This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of the central nervous system. The collection covers a wide range of situations in which matrix metalloproteinases, adamalysins and meprins are regulated and in turn regulate substrates or signalling pathways involved in: nervous system development, learning and memory, neuroinflammation, degeneration and repair after traumatic and ischemic injury or neurodegenerative mechanisms underlying retinopathies, psychiatric and neurodegenerative disorders. The authors also argue that these proteinases can be considered in some cases as biomarkers or potential therapeutic targets for diseases of the nervous system. Overall, metalloproteinases are placed among the key factors that can help us better understand the cellular and molecular processes that govern neuropathophysiology and implement the strategies that result from this knowledge to open up much-needed treatment opportunities.
Topics: Central Nervous System; Humans; Matrix Metalloproteinases; Metalloproteases; Neurodegenerative Diseases; Tissue Inhibitor of Metalloproteinases
PubMed: 31175371
DOI: 10.1007/s00018-019-03172-8 -
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 -
Drug Design, Development and Therapy 2016Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid...
BACKGROUND
Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance.
METHODS
The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed.
RESULTS
UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect.
CONCLUSION
UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent.
Topics: Administration, Oral; Animals; Benzhydryl Compounds; Brain Ischemia; Disease Models, Animal; Epoxy Compounds; Male; Metalloproteases; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Triterpenes; Ursolic Acid
PubMed: 27274199
DOI: 10.2147/DDDT.S103829 -
Toxins Jan 2020The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic... (Review)
Review
The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLAs and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA-induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA activation, arachidonic acid, increases in intracellular Ca and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLAs and hyaluronidases enhance venom spread, accentuating venom-induced neurotoxicity, inflammation, coagulopathy and tissue injury. Improving snakebite treatment requires new tools to understand direct and indirect effects of envenoming. Homologous PLA and MP activities in both venoms and prey/snakebite victim provide molecular targets for non-antibody, small molecule agents for dissecting mechanisms of venom toxicity. Importantly, these tools enable the separation of venom-specific and prey-specific pathological responses to venom.
Topics: Animals; Blood Coagulation; Humans; Inflammation; Metalloproteases; Phospholipases A2, Secretory; Reptilian Proteins; Signal Transduction; Snake Venoms
PubMed: 31979014
DOI: 10.3390/toxins12020068 -
Cytokine Feb 2019Meprin metalloendopeptidases, comprising α and β isoforms, are widely expressed in mammalian cells and organs including kidney, intestines, lungs, skin, and bladder,... (Review)
Review
Meprin metalloendopeptidases, comprising α and β isoforms, are widely expressed in mammalian cells and organs including kidney, intestines, lungs, skin, and bladder, and in a variety of immune cells and cancer cells. Meprins proteolytically process many inflammatory mediators, including cytokines, chemokines, and other bioactive proteins and peptides that control the function of immune cells. The knowledge of meprin-mediated processing of inflammatory mediators and other target substrates provides a pathophysiologic link for the involvement of meprins in the pathogenesis of many inflammatory disorders. Meprins are now known to play important roles in inflammatory diseases including acute kidney injury, sepsis, urinary tract infections, bladder inflammation, and inflammatory bowel disease. The proteolysis of epithelial and endothelial barriers including cell junctional proteins by meprins promotes leukocyte influx into areas of tissue damage to result in inflammation. Meprins degrade extracellular matrix proteins; this ability of meprins is implicated in the cell migration of leukocytes and the invasion of tumor cells that express meprins. Proteolytic processing and maturation of procollagens provides evidence that meprins are involved in collagen maturation and deposition in the fibrotic processes involved in the formation of keloids and hypertrophic scars and lung fibrosis. This review highlights recent progress in understanding the role of meprins in inflammatory disorders in both human and mouse models.
Topics: Amino Acid Sequence; Animals; Cytokines; Extracellular Matrix Proteins; Humans; Inflammation; Metalloproteases; Proteolysis
PubMed: 30580156
DOI: 10.1016/j.cyto.2018.11.032 -
Frontiers in Immunology 2022CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent... (Review)
Review
CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent apoptotic inducer in CD95 (Fas)-expressing cells, more recent studies pointed out its role in the implementation of non-apoptotic signals. Accordingly, this ligand has been associated with the aggravation of inflammation in different auto-immune disorders and in the metastatic occurrence in different cancers. Although it remains to decipher all key factors involved in the ambivalent role of this ligand, accumulating clues suggest that while the membrane bound CD95L triggers apoptosis, its soluble counterpart generated by metalloprotease-driven cleavage is responsible for its non-apoptotic functions. Nonetheless, the metalloproteases (MMPs and ADAMs) involved in the CD95L shedding, the cleavage sites and the different stoichiometries and functions of the soluble CD95L remain to be elucidated. To better understand how soluble CD95L triggers signaling pathways from apoptosis to inflammation or cell migration, we propose herein to summarize the different metalloproteases that have been described to be able to shed CD95L, their cleavage sites and the biological functions associated with the released ligands. Based on these new findings, the development of CD95/CD95L-targeting therapeutics is also discussed.
Topics: Humans; Fas Ligand Protein; Ligands; fas Receptor; Metalloproteases; Signal Transduction; Neoplasms; Inflammation
PubMed: 36544756
DOI: 10.3389/fimmu.2022.1074099