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Susana Conde Diez, Ricardo de Las Cuevas Allende, Eulogio Conde García
Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases...
January 7, 2017: Medicina Clínica
Min Liu, Cai Yuan, Yunbin Jiang, Longguang Jiang, Mingdong Huang
Hepatocyte growth factor activator inhibitor 1 (HAI-1) is a multi-domain membrane-associated protease inhibitor that potently inhibits a variety of serine proteases such as hepatocyte growth factor activator and matriptase. Different truncates of HAI-1 show varying potencies for inhibition of target proteases, suggesting that the domain organization of HAI-1 plays a critical role in its function. Here, the soluble full-length extracellular part of HAI-1 (sHAI-1) was expressed using the Drosophila S2 insect-cell expression system...
January 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
Yuan-Bin Chen, Xiao-Yu Liao, Jiang-Bo Zhang, Fang Wang, Hai-De Qin, Lanjun Zhang, Yin Yao Shugart, Yi-Xin Zeng, Wei-Hua Jia
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is characterized by heterogeneous genetic and epigenetic changes. Recently, A-to-I RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), was found to be aberrantly regulated during tumorigenesis. We previously reported that ADAR2 was downregulated in ESCC but its role was unclear. Thus, we report here that overexpression of ADAR2 can induce apoptosis in ESCC cell lines and inhibit tumor growth in vitro and in vivo...
December 29, 2016: International Journal of Oncology
Ana R Bento, Pedro Quelhas, Maria J Oliveira, Ana P Pêgo, Isabel F Amaral
In an attempt to improve the efficacy of neural stem/progenitor cell (NSPC) based therapies, fibrin hydrogels are being explored to provide a favourable microenvironment for cell survival and differentiation following transplantation. In the present work, the ability of fibrin to support the survival, proliferation, and neuronal differentiation of NSPCs derived from embryonic stem (ES) cells under monolayer culture was explored. Single mouse ES-NSPCs were cultured within fibrin (fibrinogen concentration: 6 mg/ml) under neuronal differentiation conditions up to 14 days...
December 29, 2016: Journal of Tissue Engineering and Regenerative Medicine
Hui Chen Su, Yan A Liang, Ying-Jung J Lai, Yi-Lin Chiu, Robert B Barndt, Frank Shiao, Hsiang-Hua D Chang, Dajun D Lu, Nanxi Huang, Chun-Che Tseng, Jehng-Kang Wang, Ming-Shyue Lee, Michael D Johnson, Shih-Ming Huang, Chen-Yong Lin
The membrane-associated serine proteases matriptase and prostasin are believed to function in close partnership. Their zymogen activation has been reported to be tightly coupled, either as a matriptase-initiated proteolytic cascade or through a mutually dependent mechanism involving the formation of a reciprocal zymogen activation complex. Here we show that this putative relationship may not apply in the context of human matriptase and prostasin. First, the tightly coupled proteolytic cascade between matriptase and prostasin might not occur when modest matriptase activation is induced by sphingosine 1-phospahte in human mammary epithelial cells...
2016: PloS One
Albertine E Donker, Charlotte C M Schaap, Vera M J Novotny, Roel Smeets, Tessa M A Peters, Bert L P van den Heuvel, Martine F Raphael, Anita W Rijneveld, Inge M Appel, Andre J Vlot, A Birgitta Versluijs, Michel van Gelder, Bernd Granzen, Mirian C H Janssen, Alexander J M Rennings, Frank L van de Veerdonk, Paul P T Brons, Dirk L Bakkeren, Marten R Nijziel, L Thom Vlasveld, Dorine W Swinkels
TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female...
December 2016: American Journal of Hematology
Judit Pomothy, Gergely Szombath, Patrik Rokonál, Gábor Mátis, Zsuzsanna Neogrády, Torsten Steinmetzer, Erzsébet Pászti-Gere
Purpose. Dysfunction of matriptase-2 can be involved in iron regulatory disorder via downregulation of hepcidin expression. In the present study, we investigated the effects of 3-amidinophenylalanine-derived matriptase inhibitors on porcine hepatic inflammatory cell models. Methods. Hepatocyte-Kupffer cell cocultures (ratio of 2 : 1 and 6 : 1) were treated with four structurally related matriptase inhibitors at 50 μM. Cell cytotoxicity and relative expressions of IL-6 and IL-8 and the levels of hepcidin were determined by MTS and porcine-specific ELISA...
2016: BioMed Research International
Ai Kanemaru, Koji Yamamoto, Makiko Kawaguchi, Tsuyoshi Fukushima, Chen-Yong Lin, Michael D Johnson, Eric Camerer, Hiroaki Kataoka
Cancer-associated fibroblasts (CAFs) are known to contribute to cancer progression. We have reported that cell surface expression of hepatocyte growth factor activator inhibitor 1 (HAI-1) is decreased in invasive oral squamous cell carcinoma (OSCC) cells. This study examined if HAI-1-insufficiency contributes to CAF recruitment in OSCC. Serum-free conditioned medium (SFCM) from a human OSCC line (SAS) stimulated the migration of 3 human fibroblast cell lines, NB1RGB, MRC5 and KD. SFCM from HAI-1-knockdown SAS showed an additive effect on the migration of NB1RGB and MRC5, but not KD...
January 1, 2017: International Journal of Cancer. Journal International du Cancer
Chih-Hsin Lai, Shun-Cheng Chang, Yen-Ju Chen, Yi-Jie J Wang, Ying-Jun J Lai, Hsiang-Hua D Chang, Eric B Berens, Michael D Johnson, Jehng-Kang Wang, Chen-Yong Lin
Matriptase and prostasin, acting as a tightly coupled proteolytic cascade, were reported to be required for epidermal barrier formation in mouse skin. Here we show that, in human skin, matriptase and prostasin are expressed with an inverse pattern over the course of differentiation. Matriptase was detected primarily in epidermal basal keratinocytes and the basaloid cells in the outer root sheath of hair follicles and the sebaceous gland, where prostasin was not detected. In contrast, prostasin was detected primarily in differentiated cells in the epidermal granular layer, the inner root sheath of hair follicles, and the sebaceous gland, where matriptase expression is negligible...
October 15, 2016: Biology Open
Gina L Zoratti, Lauren M Tanabe, Thomas E Hyland, Michael J Duhaime, Éloïc Colombo, Richard Leduc, Eric Marsault, Michael D Johnson, Chen-Yong Lin, Julie Boerner, Julie E Lang, Karin List
The poor prognosis for patients with inflammatory breast cancer (IBC) compared to patients with other types of breast cancers emphasizes the need to better understand the molecular underpinnings of this disease with the goal of developing effective targeted therapeutics. Dysregulation of matriptase expression, an epithelial-specific member of the type II transmembrane serine protease family, has been demonstrated in many different cancer types. To date, no studies have assessed the expression and potential pro-oncogenic role of matriptase in IBC...
September 6, 2016: Oncotarget
Natalie J Ronaghan, Judie Shang, Vadim Iablokov, Raza Zaheer, Pina Colarusso, Sébastien Dion, Antoine Désilets, Richard Leduc, Jerrold R Turner, Wallace K MacNaughton
Barrier dysfunction is a characteristic of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Understanding how the tight junction is modified to maintain barrier function may provide avenues for treatment of IBD. We have previously shown that the apical addition of serine proteases to intestinal epithelial cell lines causes a rapid and sustained increase in transepithelial electrical resistance (TER), but the mechanisms are unknown. We hypothesized that serine proteases increase barrier function through trafficking and insertion of tight junction proteins into the membrane, and this could enhance recovery of a disrupted monolayer after calcium switch or cytokine treatment...
1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Timothy E G Ferguson, James A Reihill, Brian Walker, Robert A Hamilton, S Lorraine Martin
Many bacterial and viral pathogens (or their toxins), including Pseudomonas aeruginosa exotoxin A, require processing by host pro-protein convertases such as furin to cause disease. We report the development of a novel irreversible inhibitor of furin (QUB-F1) consisting of a diphenyl phosphonate electrophilic warhead coupled with a substrate-like peptide (RVKR), that also includes a biotin tag, to facilitate activity-based profiling/visualisation. QUB-F1 displays greater selectivity for furin, in comparison to a widely used exemplar compound (furin I) which has a chloromethylketone warhead coupled to RVKR, when tested against the serine trypsin-like proteases (trypsin, prostasin and matriptase), factor Xa and the cysteine protease cathepsin B...
2016: PloS One
Roman Szabo, Taliya Lantsman, Diane E Peters, Thomas H Bugge
The membrane-anchored serine proteases prostasin (PRSS8) and matriptase (ST14) initiate a cell surface proteolytic pathway essential for epithelial function. Mice expressing only catalytically inactive prostasin are viable, unlike prostasin null mice, indicating that at least some prostasin functions are non-proteolytic. Here we used knock-in mice expressing catalytically inactive prostasin (Prss8(Ki/Ki)) to show that the physiological and pathological functions of prostasin vary in their dependence on its catalytic activity...
August 1, 2016: Development
Pengming Sun, Zhongqing Jiang, Xiaofang Chen, Lifang Xue, Xiaodan Mao, Guanyu Ruan, Yiyi Song, Alexander Mustea
Tumor invasion and metastasis are complex biological processes. Matriptase and its endogenous inhibitor, hepatocyte growth factor activator inhibitor‑1 (HAI‑1) are involved in invasion and metastasis. To evaluate the ratio of matriptase/HAI‑1 and their potential therapeutic value in ovarian cancer, HO‑8910 human ovarian cancer cells and the homologous high‑metastatic HO‑8910PM cells were used as in vitro cellular models ovarian cancer. The invasive and metastatic abilities, and the expression of matriptase and HAI‑1 in these cells were detected using scratch assays, Transwell chamber assays, reverse transcription‑quantitative polymerase chain reaction, western blotting and fluorescent immunocytochemistry...
August 2016: Molecular Medicine Reports
Sandra Ribeiro, Patrícia Garrido, João Fernandes, Susana Rocha, Petronila Rocha-Pereira, Elísio Costa, Luís Belo, Flávio Reis, Alice Santos-Silva
The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600IU/kgbody weight/week), 3 times per week, during 3weeks. Hematological and iron data were evaluated...
July 2016: Blood Cells, Molecules & Diseases
Daniela Häußler, Martin Mangold, Norbert Furtmann, Annett Braune, Michael Blaut, Jürgen Bajorath, Marit Stirnberg, Michael Gütschow
Matriptase-2, a type II transmembrane serine protease, plays a key role in human iron homeostasis. Inhibition of matriptase-2 is considered as an attractive strategy for the treatment of iron-overload diseases, such as hemochromatosis and β-thalassemia. In the present study, synthetic routes to nine dipeptidomimetic inactivators were developed. Five active compounds (41-45) were identified and characterized kinetically as irreversible inhibitors of matriptase-2. In addition to a phosphonate warhead, these dipeptides possess two benzguanidine moieties as arginine mimetics to provide affinity for matriptase-2 by binding to the S1 and S3/S4 subpockets, respectively...
June 13, 2016: Chemistry: a European Journal
Thomas Benedict Bartnikas
No abstract text is available yet for this article.
May 12, 2016: Blood
Zebin Hong, Laura De Meulemeester, Annemarie Jacobi, Jan Skov Pedersen, J Preben Morth, Peter A Andreasen, Jan K Jensen
Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knock-out mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz...
July 1, 2016: Journal of Biological Chemistry
Gautam Rishi, Eriza S Secondes, Daniel F Wallace, V Nathan Subramaniam
Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood...
August 2016: American Journal of Hematology
Alexander Maiwald, Maya Hammami, Sebastian Wagner, Andreas Heine, Gerhard Klebe, Torsten Steinmetzer
The type II transmembrane serine protease matriptase is a potential target for anticancer therapy and might be involved in cartilage degradation in osteoarthritis or inflammatory skin disorders. Starting from previously described nonspecific thrombin and factor Xa inhibitors we have prepared new noncovalent substrate-analogs with superior potency against matriptase. The most suitable compound 35 (H-d-hTyr-Ala-4-amidinobenzylamide) binds to matriptase with an inhibition constant of 26 nM and has more than 10-fold reduced activity against thrombin and factor Xa...
2016: Journal of Enzyme Inhibition and Medicinal Chemistry
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