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Journal of Extracellular Vesicles Jul 2023Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and...
Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and cancer cell-derived extracellular vesicles (EV). The mechanisms of how chemoresistance is sustained by EV remained elusive. One potentially contributing factor is A Disintegrin and Metalloprotease 17 (ADAM17)-itself being able to promote chemoresistance and inducing tumour cell proliferation and survival via the Epidermal Growth Factor Receptor (EGFR) pathway by shedding several of its ligands including Amphiregulin (AREG). We now demonstrate that upon chemotherapeutic treatment, proteolytically active ADAM17 is released in association with EV from OvCa cells. In terms of function, we show that patient-derived EV induce AREG shedding and restore chemoresistance in ADAM17-deficient cells. Confirming that ADAM17-containing EV transmit chemoresistance in OvCa, we propose that ADAM17 levels (also on EV) might serve as an indicator for tumour progression and the chemosensitivity status of a given patient.
Topics: Humans; Female; ADAM Proteins; ErbB Receptors; Extracellular Vesicles; Ovarian Neoplasms; Antineoplastic Agents; ADAM17 Protein
PubMed: 37408115
DOI: 10.1002/jev2.12338 -
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 -
Biomolecules Jul 2022Osteoarthritis (OA) is a principal cause of aches and disability worldwide. It is characterized by the inflammation of the bone leading to degeneration and loss of... (Review)
Review
Osteoarthritis (OA) is a principal cause of aches and disability worldwide. It is characterized by the inflammation of the bone leading to degeneration and loss of cartilage function. Factors, including diet, age, and obesity, impact and/or lead to osteoarthritis. In the past few years, OA has received considerable scholarly attention owing to its increasing prevalence, resulting in a cumbersome burden. At present, most of the interventions only relieve short-term symptoms, and some treatments and drugs can aggravate the disease in the long run. There is a pressing need to address the safety problems due to osteoarthritis. A disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats (ADAMTS) metalloproteinase is a kind of secretory zinc endopeptidase, comprising 19 kinds of zinc endopeptidases. ADAMTS has been implicated in several human diseases, including OA. For example, aggrecanases, ADAMTS-4 and ADAMTS-5, participate in the cleavage of aggrecan in the extracellular matrix (ECM); ADAMTS-7 and ADAMTS-12 participate in the fission of Cartilage Oligomeric Matrix Protein (COMP) into COMP lyase, and ADAMTS-2, ADAMTS-3, and ADAMTS-14 promote the formation of collagen fibers. In this article, we principally review the role of ADAMTS metalloproteinases in osteoarthritis. From three different dimensions, we explain how ADAMTS participates in all the following aspects of osteoarthritis: ECM, cartilage degeneration, and synovial inflammation. Thus, ADAMTS may be a potential therapeutic target in osteoarthritis, and this article may render a theoretical basis for the study of new therapeutic methods for osteoarthritis.
Topics: ADAMTS Proteins; Humans; Inflammation; Metalloendopeptidases; Osteoarthritis; Zinc
PubMed: 35883515
DOI: 10.3390/biom12070959 -
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 -
International Journal of Molecular... Feb 2024Rosavin, a phenylpropanoid in 's rhizome, and an adaptogen, is known for enhancing the body's response to environmental stress. It significantly affects cellular... (Review)
Review
Rosavin, a phenylpropanoid in 's rhizome, and an adaptogen, is known for enhancing the body's response to environmental stress. It significantly affects cellular metabolism in health and many diseases, particularly influencing bone tissue metabolism. In vitro, rosavin inhibits osteoclastogenesis, disrupts F-actin ring formation, and reduces the expression of osteoclastogenesis-related genes such as cathepsin K, calcitonin receptor (CTR), tumor necrosis factor receptor-associated factor 6 (TRAF6), tartrate-resistant acid phosphatase (TRAP), and matrix metallopeptidase 9 (MMP-9). It also impedes the nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), c-Fos, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways and blocks phosphorylation processes crucial for bone resorption. Moreover, rosavin promotes osteogenesis and osteoblast differentiation and increases mouse runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) expression. In vivo studies show its effectiveness in enhancing bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) mice, restraining osteoclast maturation, and increasing the active osteoblast percentage in bone tissue. It modulates mRNA expressions by increasing eukaryotic translation elongation factor 2 (EEF2) and decreasing histone deacetylase 1 (HDAC1), thereby activating osteoprotective epigenetic mechanisms, and alters many serum markers, including decreasing cross-linked C-telopeptide of type I collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator for nuclear factor κ B ligand (RANKL), macrophage-colony-stimulating factor (M-CSF), and TRAP, while increasing alkaline phosphatase (ALP) and OCN. Additionally, when combined with zinc and probiotics, it reduces pro-osteoporotic matrix metallopeptidase 3 (MMP-3), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), and enhances anti-osteoporotic interleukin 10 (IL-10) and tissue inhibitor of metalloproteinase 3 (TIMP3) expressions. This paper aims to systematically review rosavin's impact on bone tissue metabolism, exploring its potential in osteoporosis prevention and treatment, and suggesting future research directions.
Topics: Animals; Mice; Osteoclasts; Tartrate-Resistant Acid Phosphatase; Osteogenesis; Bone Resorption; Cell Differentiation; NF-kappa B; Metalloproteases; RANK Ligand; NFATC Transcription Factors; Disaccharides
PubMed: 38396794
DOI: 10.3390/ijms25042117 -
Biomolecules Jan 2021Metalloproteinases (MPs) are proteolytic enzymes involved in extracellular matrix deposition, regulation of cellular signals of inflammation, proliferation, and... (Review)
Review
Metalloproteinases (MPs) are proteolytic enzymes involved in extracellular matrix deposition, regulation of cellular signals of inflammation, proliferation, and apoptosis. Metalloproteinases are classified into three families: Matrix-MPs (MMPs), A-Disintegrin-and-Metalloprotease (ADAMs), and the A-Disintegrin-and-Metalloproteinase-with-Thrombospondin-1-like-Domains (ADAMTS). Previous studies showed that MPs are involved in the development of aortic aneurysms (AA) and, concomitantly, in the onset of chronic kidney disease (CKD). CKD has been, per se, associated with an increased risk for AA. The aim of this review is to examine the pathways that may associate MPs with CKD and AA. Several MMPs, such as MMP-2, -8, -9, and TIMP-1 have been shown to damage the AA wall and to have a toxic effect on renal tubular cells, leading to fibrosis. Similarly, ADAM10 and 17 have been shown to degrade collagen in the AA wall and to worsen kidney function via pro-inflammatory stimuli, the impairment of the Renin-Angiotensin-Aldosterone System, and the degradation of structural proteins. Moreover, MMP-2 and -9 inhibitors reduced aneurysm growth and albuminuria in experimental and human studies. It would be important, in the future, to expand research on MPs from both a prognostic, namely, to refine risk stratification in CKD patients, and a predictive perspective, likely to improve prognosis in response to targeted treatments.
Topics: Aneurysm; Animals; Aortic Aneurysm; Apoptosis; Cell Proliferation; Disease Progression; Epithelial-Mesenchymal Transition; Extracellular Matrix; Fibrosis; Glomerular Filtration Rate; Humans; Inflammation; Kidney Failure, Chronic; Matrix Metalloproteinase 2; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Metalloproteases; Prognosis; Renal Insufficiency, Chronic; Renin-Angiotensin System; Risk; Tissue Inhibitor of Metalloproteinase-1
PubMed: 33573220
DOI: 10.3390/biom11020194 -
International Journal of Molecular... Feb 2022Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I... (Review)
Review
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen . The development of gastric cancer follows a cascade of transformative tissue events in an inflammatory environment. Proteases of host origin as well as -derived proteases contribute to disease progression at every stage, from chronic gastritis to gastric cancer. In the present article, we discuss the importance of (metallo-)proteases in colonization, epithelial inflammation, and barrier disruption in tissue transformation, deregulation of cell proliferation and cell death, as well as tumor metastasis and neoangiogenesis. Proteases of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase domain-containing protein (ADAM) families, caspases, calpain, and the proteases HtrA, Hp1012, and Hp0169 cleave substrates including extracellular matrix molecules, chemokines, and cytokines, as well as their cognate receptors, and thus shape the pathogenic microenvironment. This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment.
Topics: Bacterial Proteins; Disease Progression; Gene Expression Regulation; Helicobacter Infections; Helicobacter pylori; Humans; Metalloproteases; Peptide Hydrolases; Proteolysis; Serine Proteases; Stomach Neoplasms
PubMed: 35269560
DOI: 10.3390/ijms23052419 -
Science Advances Mar 2022Axonal fusion is an efficient means of repair following axonal transection, whereby the regenerating axon fuses with its own separated axonal fragment to restore...
Axonal fusion is an efficient means of repair following axonal transection, whereby the regenerating axon fuses with its own separated axonal fragment to restore neuronal function. Despite being described over 50 years ago, its molecular mechanisms remain poorly understood. Here, we demonstrate that the metalloprotease ADM-4, an ortholog of human ADAM17, is essential for axonal fusion. We reveal that animals lacking ADM-4 cannot repair their axons by fusion, and that ADM-4 has a cell-autonomous function within injured neurons, localizing at the tip of regrowing axon and fusion sites. We demonstrate that ADM-4 overexpression enhances fusion to levels higher than wild type, and that the metalloprotease and phosphatidylserine-binding domains are essential for its function. Last, we show that ADM-4 interacts with and stabilizes the fusogen EFF-1 to allow membranes to merge. Our results uncover a key role for ADM-4 in axonal fusion, exposing a molecular target for axonal repair.
Topics: Animals; ADAM17 Protein; Axons; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Membrane Glycoproteins; Metalloproteases
PubMed: 35294233
DOI: 10.1126/sciadv.abm2882