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Archives of Toxicology Jun 2022Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons,... (Review)
Review
Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons, metalloproteases specifically cleaving the SNARE proteins that are essential for the release of neurotransmitters. Research on their mechanism of action is intensively carried out in order to devise improved therapies based on antibodies and chemical drugs. Recently, major results have been obtained with human monoclonal antibodies and with single chain antibodies that have allowed one to neutralize the metalloprotease activity of botulinum neurotoxin type A1 inside neurons. In addition, a method has been devised to induce a rapid molecular evolution of the metalloprotease domain of botulinum neurotoxin followed by selection driven to re-target the metalloprotease activity versus novel targets with respect to the SNARE proteins. At the same time, an intense and wide spectrum clinical research on novel therapeutics based on botulinum neurotoxins is carried out, which are also reviewed here.
Topics: Botulinum Toxins, Type A; Clostridium botulinum; Humans; Neurotoxins; SNARE Proteins; Tetanus
PubMed: 35333944
DOI: 10.1007/s00204-022-03271-9 -
General and Comparative Endocrinology Dec 2021Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and... (Review)
Review
Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and metalloprotease with thrombospondin motif (Adamts), and their endogenous inhibitors (tissue inhibitors of metalloproteases, Timp), have been shown to be critical for ovulation in various species from studies in past decades. Some of these metalloproteases such as Adamts1, Adamts9, Mmp2, and Mmp9 have also been shown to be regulated by luteinizing hormone (LH) and/or progestin, which are essential triggers for ovulation in all vertebrate species. Most of these metalloproteases also express broadly in various tissues and cells including germ cells and somatic gonad cells. Thus, metalloproteases likely play roles in gonad formation processes comprising primordial germ cell (PGC) migration, development of germ and somatic cells, and sex determination. However, our knowledge on the functions and mechanisms of metalloproteases in these processes in vertebrates is still lacking. This review will summarize our current knowledge on the metalloproteases in ovulation and gonad formation with emphasis on PGC migration and germ cell development.
Topics: Animals; Female; Germ Cells; Gonads; Luteinizing Hormone; Matrix Metalloproteinases; Ovulation
PubMed: 34606745
DOI: 10.1016/j.ygcen.2021.113924 -
Matrix Biology : Journal of the... 2015ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are complex extracellular proteases that have been related to both oncogenic and... (Review)
Review
ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are complex extracellular proteases that have been related to both oncogenic and tumor-protective functions. These enzymes can be secreted by cancer and stromal cells and may contribute to modify the tumor microenvironment by multiple mechanisms. Thus, ADAMTSs can cleave or interact with a wide range of extracellular matrix components or regulatory factors, and therefore affect cell adhesion, migration, proliferation and angiogenesis. The balance of protumor versus antitumor effects of ADAMTSs may depend on the nature of their substrates or interacting-partners upon secretion from the cell. Moreover, different ADAMTS genes have been found overexpressed, mutated or epigenetically silenced in tumors from different origins, suggesting the direct impact of these metalloproteases in cancer development. However, despite the important advances on the tumor biology of ADAMTSs in recent years, more mechanistic and functional studies are necessary to fully understand how these proteases can influence tumor microenvironment to potentiate cancer growth or to induce tumor regression. This review outlines current and emerging connections between ADAMTSs and cancer.
Topics: ADAM Proteins; Animals; Extracellular Matrix Proteins; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasms; Tumor Microenvironment
PubMed: 25636539
DOI: 10.1016/j.matbio.2015.01.013 -
American Journal of Physiology. Cell... Sep 2020Vascular remodeling is the adaptive response to various physiological and pathophysiological alterations that are closely related to aging and vascular diseases.... (Review)
Review
Vascular remodeling is the adaptive response to various physiological and pathophysiological alterations that are closely related to aging and vascular diseases. Understanding the mechanistic regulation of vascular remodeling may be favorable for discovering potential therapeutic targets and strategies. The extracellular matrix (ECM), including matrix proteins and their degradative metalloproteases, serves as the main component of the microenvironment and exhibits dynamic changes during vascular remodeling. This process involves mainly the altered composition of matrix proteins, metalloprotease-mediated degradation, posttranslational modification of ECM proteins, and altered topographical features of the ECM. To date, adequate studies have demonstrated that ECM dynamics also play a critical role in vascular remodeling in various diseases. Here, we review these related studies, summarize how ECM dynamics control vascular remodeling, and further indicate potential diagnostic biomarkers and therapeutic targets in the ECM for corresponding vascular diseases.
Topics: Animals; Biomarkers; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Matrix Metalloproteinases; Vascular Diseases; Vascular Remodeling
PubMed: 32579472
DOI: 10.1152/ajpcell.00147.2020 -
Cellular and Molecular Life Sciences :... Aug 2019'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active... (Review)
Review
'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.
Topics: ADAM Proteins; Animals; Biological Transport; Epilepsy; Humans; Inflammation; Myelin Sheath; Nervous System; Potassium Channels; Proteolysis
PubMed: 31236626
DOI: 10.1007/s00018-019-03173-7 -
International Journal of Molecular... Apr 2023Chronic kidney disease (CKD) is a major health problem, affecting millions of people worldwide, in particular hypertensive and diabetic patients. CKD patients suffer... (Review)
Review
Chronic kidney disease (CKD) is a major health problem, affecting millions of people worldwide, in particular hypertensive and diabetic patients. CKD patients suffer from significantly increased cardiovascular disease (CVD) morbidity and mortality, mainly due to accelerated atherosclerosis development. Indeed, CKD not only affects the kidneys, in which injury and maladaptive repair processes lead to local inflammation and fibrosis, but also causes systemic inflammation and altered mineral bone metabolism leading to vascular dysfunction, calcification, and thus, accelerated atherosclerosis. Although CKD and CVD individually have been extensively studied, relatively little research has studied the link between both diseases. This narrative review focuses on the role of a disintegrin and metalloproteases (ADAM) 10 and ADAM17 in CKD and CVD and will for the first time shed light on their role in CKD-induced CVD. By cleaving cell surface molecules, these enzymes regulate not only cellular sensitivity to their micro-environment (in case of receptor cleavage), but also release soluble ectodomains that can exert agonistic or antagonistic functions, both locally and systemically. Although the cell-specific roles of ADAM10 and ADAM17 in CVD, and to a lesser extent in CKD, have been explored, their impact on CKD-induced CVD is likely, yet remains to be elucidated.
Topics: Humans; Renal Insufficiency, Chronic; ADAM17 Protein; Kidney; ADAM10 Protein; Cardiovascular Diseases; Inflammation; Atherosclerosis; Membrane Proteins; Amyloid Precursor Protein Secretases
PubMed: 37108478
DOI: 10.3390/ijms24087309 -
Trends in Immunology Nov 2019Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble... (Review)
Review
Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble factors in the niche respond to stress and enable progenitor activity. Metalloproteases (MMPs, ADAMs, ADAMTSs) and their inhibitors (TIMPs) control certain physical and biochemical features of the niche by altering protease-dependent bioavailability of local niche factors (e.g., CXCL12, SCF, TGFβ, VEGF), matrix turnover, and cellular interactions. With over 40 examples of diverse metalloprotease substrates known to trigger fate-changing decisions, the spatially confined activity of this multi-member protease family is ideally positioned to constitute a higher order control over hematopoiesis. Comprehension of regulated proteolysis in the bone marrow may fuel innovative strategies to harness HSC fate and function.
Topics: Animals; Cell Differentiation; Cell Self Renewal; Extracellular Matrix; Hematopoiesis; Hematopoietic Stem Cells; Humans; Metalloproteases; Proteolysis; Stem Cell Niche
PubMed: 31645297
DOI: 10.1016/j.it.2019.09.006 -
Biochimica Et Biophysica Acta.... Jan 2022Mucus is covering the entire epithelium of the gastrointestinal tract (GIT), building the interface for the symbiosis between microorganisms and their host. Hence, a... (Review)
Review
Mucus is covering the entire epithelium of the gastrointestinal tract (GIT), building the interface for the symbiosis between microorganisms and their host. Hence, a disrupted mucosal barrier or alterations of proper mucus composition, including the gut microbiota, can cause severe infection and inflammation. Meprin metalloproteases are well-known to cleave various pro-inflammatory molecules, contributing to the onset and progression of pathological conditions including sepsis, pulmonary hypertension or inflammatory bowel disease (IBD). Moreover, meprins have an impact on migration and infiltration of immune cells like monocytes or leukocytes during intestinal inflammation by cleaving tight junction proteins or cell adhesion molecules, thereby disrupting epithelial cell barrier and promoting transendothelial cell migration. Interestingly, both meprin α and meprin β are susceptibility genes for IBD. However, both genes are significantly downregulated in inflamed intestinal tissue in contrast to healthy donors. Therefore, a detailed understanding of the underlying molecular mechanisms is the basis for developing new and effective therapies against manifold pathologies like IBD. This review focuses on the regulation of meprin metalloproteases and its impact on physiological and pathological conditions related to mucosal homeostasis.
Topics: Animals; Homeostasis; Humans; Intestinal Mucosa; Metalloendopeptidases; Protein Multimerization
PubMed: 34626680
DOI: 10.1016/j.bbamcr.2021.119158 -
Journal of Neuroscience Research Apr 2018The brain extracellular matrix (ECM) plays a crucial role in both the developing and adult brain by providing structural support and mediating cell-cell interactions. In... (Review)
Review
The brain extracellular matrix (ECM) plays a crucial role in both the developing and adult brain by providing structural support and mediating cell-cell interactions. In this review, we focus on the major constituents of the ECM and how they function in both normal and injured brain, and summarize the changes in the composition of the ECM as well as how these changes either promote or inhibit recovery of function following traumatic brain injury (TBI). Modulation of ECM composition to facilitates neuronal survival, regeneration and axonal outgrowth is a potential therapeutic target for TBI treatment.
Topics: Brain Injuries, Traumatic; Extracellular Matrix; Extracellular Matrix Proteins; Metalloproteases; Proteoglycans; Tenascin
PubMed: 29344975
DOI: 10.1002/jnr.24151 -
Toxins Apr 2016Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin... (Review)
Review
Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs' function that have underscored the importance of these proteins in physiological and pathological processes over the years.
Topics: ADAM Proteins; Animals; Biomedical Research; History, 20th Century; History, 21st Century; Humans
PubMed: 27120619
DOI: 10.3390/toxins8040122