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https://www.readbyqxmd.com/read/29136618/hepcidin-in-iron-homeostasis-diagnostic-and-therapeutic-implications-in-type-2-diabetes-mellitus-patients
#1
Sintayehu Ambachew, Belete Biadgo
The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin...
November 15, 2017: Acta Haematologica
https://www.readbyqxmd.com/read/29125730/development-of-a-protease-biosensor-based-on-a-dimerization-dependent-red-fluorescent-protein
#2
Aaron C Mitchell, Spencer C Alford, Sean A Hunter, Deepti Kannan, R Andres Parra Sperberg, Cheryl H Chang, Jennifer R Cochran
Dysregulated activity of the protease matriptase is a key contributor to aggressive tumor growth, cancer metastasis, osteoarthritis, and iron overload disease. Methods for the detection and quantification of matriptase activity and inhibition would be useful tools. To address this need, we developed a matriptase-sensitive protein biosensor based on a dimerization-dependent red fluorescent protein (ddRFP) reporter system. In this platform, two adjoining protein domains, connected by a protease-labile linker, produce fluorescence when assembled and are non-fluorescent when the linker is cleaved by matriptase...
November 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29118397/the-kunitz-domain-i-of-hepatocyte-growth-factor-activator-inhibitor-2-inhibits-matriptase-activity-and-invasive-ability-of-human-prostate-cancer-cells
#3
Shang-Ru Wu, Chen-Hsin Teng, Ya-Ting Tu, Chun-Jung Ko, Tai-Shan Cheng, Shao-Wei Lan, Hsin-Ying Lin, Hsin-Hsien Lin, Hsin-Fang Tu, Pei-Wen Hsiao, Hsiang-Po Huang, Chung-Hsin Chen, Ming-Shyue Lee
Dysregulation of pericellular proteolysis is often required for tumor invasion and cancer progression. It has been shown that down-regulation of hepatocyte growth factor activator inhibitor-2 (HAI-2) results in activation of matriptase (a membrane-anchored serine protease), human prostate cancer cell motility and tumor growth. In this study, we further characterized if HAI-2 was a cognate inhibitor for matriptase and identified which Kunitz domain of HAI-2 was required for inhibiting matriptase and human prostate cancer cell motility...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29054928/the-type-ii-transmembrane-serine-protease-matriptase-cleaves-the-amyloid-precursor-protein-and-reduces-its-processing-to-%C3%AE-amyloid
#4
Erwan Lanchec, Antoine Désilets, François Béliveau, Anthony Flamier, Shaimaa Mahmoud, Gilbert Bernier, Denis Gris, Richard Leduc, Christine Lavoie
Recent studies have reported that many proteases, besides the canonical α-, β- and γ-secretases, cleave the amyloid precursor protein (APP) and modulate β amyloid (Aβ) peptide production. Moreover, specific APP isoforms contain Kunitz protease inhibitor (KPI) domains, which regulate the proteolytic activity of serine proteases. This prompted us to investigate the role of matriptase, a member of the type II transmembrane serine protease family, in APP processing. Using qRTPCR, we detected matriptase mRNA in several regions of the human brain, with an enrichment in neurons...
October 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28978826/progress-in-iron-metabolism-research
#5
Hiroshi Kawabata
Iron is essential for various cellular processes, but an excess of iron may cause organ damage through the production of reactive oxygen species. Therefore, the amount of iron in the body must be strictly controlled. The central regulator of systemic iron homeostasis is hepcidin, which is primarily produced in the liver. Various molecules, including HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV), are involved in sensing systemic iron status. Hepatocytes produce hepcidin in response to excess iron and inflammatory stimuli (e...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28968967/targeting-the-tumor-promoting-microenvironment-in-met-amplified-nsclc-cells-with-a-novel-inhibitor-of-pro-hgf-activation
#6
Benjamin Y Owusu, Shantasia Thomas, Phanindra Venukadasula, Zhenfu Han, James W Janetka, Robert A Galemmo, Lidija Klampfer
Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment. The tumor microenvironment plays a major role in resistance to anticancer therapy...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28926939/kempopeptin-c-a-novel-marine-derived-serine-protease-inhibitor-targeting-invasive-breast-cancer
#7
Fatma H Al-Awadhi, Lilibeth A Salvador, Brian K Law, Valerie J Paul, Hendrik Luesch
Kempopeptin C, a novel chlorinated analogue of kempopeptin B, was discovered from a marine cyanobacterium collected from Kemp Channel in Florida. The structure was elucidated using NMR spectroscopy and mass spectrometry (MS). The presence of the basic Lys residue adjacent to the N-terminus of the 3-amino-6-hydroxy-2-piperidone (Ahp) moiety contributed to its selectivity towards trypsin and related proteases. The antiproteolytic activity of kempopeptin C was evaluated against trypsin, plasmin and matriptase and found to inhibit these enzymes with IC50 values of 0...
September 16, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28924039/matriptase-2-suppresses-hepcidin-expression-by-cleaving-multiple-components-of-the-hepcidin-induction-pathway
#8
Mastura Wahedi, Aaron M Wortham, Mark D Kleven, Ningning Zhao, Shall Jue, Caroline A Enns, An-Sheng Zhang
Systemic iron homeostasis is maintained by regulation of iron absorption in the duodenum, iron recycling from erythrocytes, and iron mobilization from the liver and is controlled by the hepatic hormone hepcidin. Hepcidin expression is induced via the bone morphogenetic protein (BMP) signaling pathway that preferentially uses two type I (ALK2 and ALK3) and two type II (ActRIIA and BMPR2) BMP receptors. Hemojuvelin (HJV), HFE, and transferrin receptor-2 (TfR2) facilitate this process presumably by forming a plasma membrane complex with BMP receptors...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28915606/proteolytic-cleavages-in-the-extracellular-domain-of-receptor-tyrosine-kinases-by-membrane-associated-serine-proteases
#9
Li-Mei Chen, Karl X Chai
The epithelial extracellular membrane-associated serine proteases matriptase, hepsin, and prostasin are proteolytic modifying enzymes of the extracellular domain (ECD) of the epidermal growth factor receptor (EGFR). Matriptase also cleaves the ECD of the vascular endothelial growth factor receptor 2 (VEGFR2) and the angiopoietin receptor Tie2. In this study we tested the hypothesis that these serine proteases may cleave the ECD of additional receptor tyrosine kinases (RTKs). We co-expressed the proteases in an epithelial cell line with Her2, Her3, Her4, insulin receptor (INSR), insulin-like growth factor I receptor (IGF-1R), the platelet-derived growth factor receptors (PDGFRs) α and β, or nerve growth factor receptor A (TrkA)...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28829816/matriptase-shedding-is-closely-coupled-with-matriptase-zymogen-activation-and-requires-de-novo-proteolytic-cleavage-likely-involving-its-own-activity
#10
Chun-Che Tseng, Bailing Jia, Robert Barndt, Yayun Gu, Chien-Yu Chen, I-Chu Tseng, Sheng-Fang Su, Jehng-Kang Wang, Michael D Johnson, Chen-Yong Lin
The type 2 transmembrane serine protease matriptase is involved in many pathophysiological processes probably via its enzymatic activity, which depends on the dynamic relationship between zymogen activation and protease inhibition. Matriptase shedding can prolong the life of enzymatically active matriptase and increase accessibility to substrates. We show here that matriptase shedding occurs via a de novo proteolytic cleavage at sites located between the SEA domain and the CUB domain. Point or combined mutations at the four positively charged amino acid residues in the region following the SEA domain allowed Arg-186 to be identified as the primary cleavage site responsible for matriptase shedding...
2017: PloS One
https://www.readbyqxmd.com/read/28762604/tmeff2-shedding-is-regulated-by-oxidative-stress-and-mediated-by-adams-and-transmembrane-serine-proteases-implicated-in-prostate-cancer
#11
Katarzyna Gaweł-Bęben, Nazim Ali, Vincent Ellis, Gloria Velasco, Zaruhi Poghosyan, Ann Ager, Vera Knäuper
TMEFF2 is a type I transmembrane protein with two follistatin (FS) and one EGF-like domain over-expressed in prostate cancer; however its biological role in prostate cancer development and progression remains unclear, which may, at least in part, be explained by its proteolytic processing. The extracellular part of TMEFF2 (TMEFF2-ECD) is cleaved by ADAM17 and the membrane-retained fragment is further processed by the gamma-secretase complex. TMEFF2 shedding is increased with cell crowding, a condition associated with the tumour microenvironment, which was mediated by oxidative stress signalling, requiring jun-kinase (JNK) activation...
August 1, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28694515/physical-binding-of-endothelial-mcam-and-neural-transmembrane-protease-matriptase-novel-cell-adhesion-in-neural-stem-cell-vascular-niche
#12
Hsiu-Hui Tung, Sheau-Ling Lee
Brain neural stem cells and transit amplifying cells in the subventricular zone (SVZ) of the lateral ventricles are in direct contact with the microvascular endothelium. The mechanisms/molecules of direct cell contact in the SVZ neurovascular niche are not fully understood. We previously showed that neural stem/progenitor (NS/P) cells induce brain endothelial signaling in direct cell contact through matriptase (MTP) on NS/P cell surface. In the present study, using pull-down and LC-MS/MS, we identified melanoma cell adhesion molecule (MCAM) the brain endothelial molecule that interacts with MTP...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28691803/development-of-an-activatable-fluorescent-probe-for-prostate-cancer-imaging
#13
Takao Yogo, Keitaro Umezawa, Mako Kamiya, Rumi Hino, Yasuteru Urano
Technology to visualize small prostate cancers is urgently needed because of the difficulty of discriminating prostate cancer from normal tissue with the naked eye, and a fluorescence imaging method would be advantageous. Here, we describe the design and synthesis of a fluorogenic probe (Ac-KQLR-HMRG) that is activated by hepsin and matriptase (proteases over-expressed in prostate cancer). Ac-KQLR-HMRG exhibited significant turn-on fluorogenicity in the presence of hepsin (180-fold) and matriptase (80-fold) and allowed specific fluorescence imaging of various prostate cancer cell line in vitro...
August 16, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28671992/signaling-pathways-induced-by-serine-proteases-to-increase-intestinal-epithelial-barrier-function
#14
Kelcie A Lahey, Natalie J Ronaghan, Judie Shang, Sébastien P Dion, Antoine Désilets, Richard Leduc, Wallace K MacNaughton
Changes in barrier function of the gastrointestinal tract are thought to contribute to the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Previous work in our lab demonstrated that apical exposure of intestinal epithelial cell lines to serine proteases results in an increase in transepithelial electrical resistance (TER). However, the underlying mechanisms governing this response are unclear. We aimed to determine the requirement for proteolytic activity, epidermal growth factor receptor (EGFR) activation, and downstream intracellular signaling in initiating and maintaining enhanced barrier function following protease treatment using a canine intestinal epithelial cell line (SCBN)...
2017: PloS One
https://www.readbyqxmd.com/read/28624806/targeting-the-tumor-promoting-microenvironment-in-met-amplified-nsclc-cells-with-a-novel-inhibitor-of-pro-hgf-activation
#15
Benjamin Y Owusu, Shantasia Thomas, Phanindra Venukadasula, Zhenfu Han, James W Janetka, Robert A Galemmo, Lidija Klampfer
Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment.The tumor microenvironment plays a major role in resistance to anticancer therapy...
May 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28571576/matriptase-zymogen-supports-epithelial-development-homeostasis-and-regeneration
#16
Stine Friis, Daniel Tadeo, Sylvain M Le-Gall, Henrik Jessen Jürgensen, Katiuchia Uzzun Sales, Eric Camerer, Thomas H Bugge
BACKGROUND: Matriptase is a membrane serine protease essential for epithelial development, homeostasis, and regeneration, as well as a central orchestrator of pathogenic pericellular signaling in the context of inflammatory and proliferative diseases. Matriptase is an unusual protease in that its zymogen displays measurable enzymatic activity. RESULTS: Here, we used gain and loss of function genetics to investigate the possible biological functions of zymogen matriptase...
June 1, 2017: BMC Biology
https://www.readbyqxmd.com/read/28555756/design-and-chemical-syntheses-of-potent-matriptase-2-inhibitors-based-on-trypsin-inhibitor-sfti-1-isolated-from-sunflower-seeds
#17
Agata Gitlin-Domagalska, Dawid Dębowski, Anna Łęgowska, Marit Stirnberg, Joanna Okońska, Michael Gütschow, Krzysztof Rolka
Matriptase-2 plays a pivotal role in keeping iron concentrations within a narrow physiological range in humans. The opportunity to reduce matriptase-2 proteolytic activity may open a novel possibility to treat iron overload diseases, such as hereditary hemochromatosis and thalassemia. Here, we present 23 new analogues of trypsin inhibitor SFTI-1 designed to inhibit human matriptase-2. Influence of the modifications Gly1Lys, Ile10Arg and Phe12His, as well as the introduction of Narg in P1 or P1 and P4 positions were examined...
May 27, 2017: Biopolymers
https://www.readbyqxmd.com/read/28491880/iron-refractory-iron-deficiency-anemia-in-dizygotic-twins-due-to-a-novel-tmprss6-gene-mutation-in-addition-to-polymorphisms-associated-with-high-susceptibility-to-develop-ferropenic-anemia
#18
Joana Pinto, Gustavo Nobre de Jesus, Mónica Palma Anselmo, Lúcia Gonçalves, Daniela Brás, João Madeira Lopes, João Meneses, Rui Victorino, Paula Faustino
Iron refractory iron deficiency anemia (IRIDA) is an autosomal recessive ferropenic anemia. Its hypochromic microcytic pattern is associated with low transferrin saturation, normal-high ferritin, and inappropriately high hepcidin level. This entity is caused by mutants of the TMPRSS6 gene that encodes the protein matriptase II, which influences hepcidin expression, an iron metabolism counterregulatory protein. We report two 29-year-old dizygotic female twins with ferropenic, hypochromic microcytic anemia with 20 years of evolution, refractory to oral iron therapy...
April 2017: Journal of Investigative Medicine High Impact Case Reports
https://www.readbyqxmd.com/read/28490634/inflammatory-cytokines-down-regulate-the-barrier-protective-prostasin-matriptase-proteolytic-cascade-early-in-experimental-colitis
#19
Marguerite S Buzza, Tierra A Johnson, Gregory D Conway, Erik W Martin, Subhradip Mukhopadhyay, Terez Shea-Donohue, Toni M Antalis
Compromised gastrointestinal barrier function is strongly associated with the progressive and destructive pathologies of the two main forms of irritable bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Matriptase is a membrane-anchored serine protease encoded by suppression of tumorigenicity-14 (ST14) gene, which is critical for epithelial barrier development and homeostasis. Matriptase barrier-protective activity is linked with the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin, which is a co-factor for matriptase zymogen activation...
June 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28464560/matriptase-induction-of-metalloproteinase-dependent-aggrecanolysis-in-vitro-and-in-vivo-promotion-of-osteoarthritic-cartilage-damage-by-multiple-mechanisms
#20
David J Wilkinson, Angela Habgood, Heather K Lamb, Paul Thompson, Alastair R Hawkins, Antoine Désilets, Richard Leduc, Torsten Steinmetzer, Maya Hammami, Melody S Lee, Charles S Craik, Sharon Watson, Hua Lin, Jennifer M Milner, Andrew D Rowan
OBJECTIVE: To assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA. METHODS: Aggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction...
August 2017: Arthritis & Rheumatology
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