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Bassem M Mohammed, Anton Matafonov, Ivan Ivanov, Mao-Fu Sun, Qiufang Cheng, S Kent Dickeson, Chan Li, David Sun, Ingrid M Verhamme, Jonas Emsley, David Gailani
Factor XI (FXI) is the zymogen of a plasma protease, factor XIa (FXIa), that contributes to thrombin generation during blood coagulation by proteolytic activation of several coagulation factors, most notably factor IX (FIX). FXI is a homolog of prekallikrein (PK), a component of the plasma kallikrein-kinin system. While sharing structural and functional features with PK, FXI has undergone adaptive changes that allow it to contribute to blood coagulation. Here we review current understanding of the biology and enzymology of FXI, with an emphasis on structural features of the protein as they relate to protease function...
October 10, 2017: Thrombosis Research
Janet C Reid, Admire Matsika, Claire M Davies, Yaowu He, Amy Broomfield, Nigel C Bennett, Viktor Magdolen, Bhuvana Srinivasan, Judith A Clements, John D Hooper
We provide evidence of a pericellular network of proteases that are elevated and co-expressed in prostate cancer. The network involves the membrane bound serine proteases hepsin and TMPRSS2, the secreted kallikrein-related peptidases KLK4 and KLK14, and the secreted matrix metalloproteinases MMP-3 and MMP-9. Western blot analysis of cell lysates, conditioned cell culture media, immunoprecipitates and cell surface proteins, demonstrates a network of interactions centred largely at the plasma membrane, with the Arg/Lys specific proteases hepsin and TMPRSS2 key regulators of the network...
2017: American Journal of Cancer Research
Henriette Farkas
Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a form of bradykinin-mediated angioedema. It is a rare disorder with an onset during childhood in most instances. Therefore, familiarity with the options for the management of pediatric cases is indispensable. The recurrent angioedematous episodes do not respond to conventional treatments and may evolve into a life-threatening condition. In view of the recommendations adopted by international consensus in 2016, patient management and follow-up should be guided by an individualized strategy...
December 7, 2017: Paediatric Drugs
Allen P Kaplan, Coen Maas
The unpredictable nature of attacks of tissue swelling in hereditary angioedema requires the identification of reliable biomarkers to monitor disease activity as well as response to therapy. At present, one can assess a C4 level (by ELISA) to assist in diagnosis but neither C4 nor C1 inhibitor levels reflect clinical course or prognosis. We will here review a collection of plasma proteins involved in blood coagulation, fibrinolysis, and innate immunity (Figure 1). A main focus is those proteins that are key to the formation of bradykinin (BK); namely, factor XII, plasma prekallikrein/kallikrein, high-molecular weight kininogen, and BK itself since overproduction of BK is key to the disease...
2017: Frontiers in Medicine
Ursula Kahler, Julian E Fuchs, Peter Goettig, Klaus R Liedl
A ten microsecond molecular dynamics simulation of a kallikrein-related peptidase 7 peptide complex revealed an unexpected change in binding mode. After more than two microseconds unrestrained sampling we observe a spontaneous transition of the binding pose including a 180 degree rotation around the P1 residue. Subsequently, the substrate peptide occupies the prime side region rather than the cognate non-prime side in a stable conformation. We characterize the unexpected binding mode in terms of contacts, solvent-accessible surface area, molecular interactions and energetic properties...
December 6, 2017: Journal of Biomolecular Structure & Dynamics
Jing-Wen Xu, Yun-Lun Li, Shi-Jun Zhang, Wen-Qing Yang, Wen-Ting Nie, Hai-Qiang Jiang
Essential hypertension (EH) is a risk factor for some severe diseases. This study aimed to screen out serum special proteins and seek interaction between them, which would provide new therapeutic targets and elucidate the comprehensive pathophysiological mechanism for EH. Patients with EH (Group A, n = 47) and healthy controls (HC) (Group B, n = 47) were recruited in this study. Serums from the two groups were analyzed with isobaric tags for relative and absolute quantitation coupled two-dimensional liquid chromatography followed by electrospray ionization-tandem mass spectrometry technique, while the candidate special proteins were verified with ELISA and western blot...
2017: BioMed Research International
Marten Michaelis, Alexander Sobczak, Dirk Koczan, Martina Langhammer, Norbert Reinsch, Jennifer Schoen, Joachim M Weitzel
BACKGROUND: Many genes important for reproductive performance are shared by both sexes. However, fecundity indices are primarily based on female parameters such as litter size. We examined a fertility mouse line (FL2), which has a considerably increased number of offspring and a total litter weight of 180% compared to a randomly bred control line (Ctrl) after more than 170 generations of breeding. In the present study, we investigated whether there might be a parallel evolution in males after more than 40 years of breeding in this outbred mouse model...
November 21, 2017: BMC Genomics
Maria Rapala-Kozik, Oliwia Bochenska, Dorota Zajac, Justyna Karkowska-Kuleta, Mariusz Gogol, Marcin Zawrotniak, Andrzej Kozik
The increased incidence of severe disseminated infections caused by opportunistic yeast-like fungi Candida spp. highlights the urgent need for research into the major virulence factors of these pathogens - extracellular aspartic proteinases of the candidapepsin and yapsin families. Classically, these enzymes were considered to be generally destructive factors that damage host tissues and provide nutrients for pathogen propagation. However, in recent decades, novel and more specific functions have been suggested for extracellular candidal proteinases...
November 15, 2017: Molecular Oral Microbiology
Melissa Assel, Liisa Sjöblom, Teemu J Murtola, Kirsi Talala, Paula Kujala, Ulf-Håkan Stenman, Kimmo Taari, Anssi Auvinen, Andrew Vickers, Tapio Visakorpi, Teuvo L Tammela, Hans Lilja
BACKGROUND: A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™...
November 11, 2017: European Urology Focus
Panagiota Gianni, Gedeon Loules, Maria Zamanakou, Maria Kompoti, Dorottya Csuka, Fotis Psarros, Markus Magerl, Dimitru Moldovan, Marcus Maurer, Matthaios G Speletas, Henriette Farkas, Anastasios E Germenis
BACKGROUND: In view of the large heterogeneity in the clinical presentation of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), great efforts are being made towards detecting measurable biological determinants of disease severity that can help to improve the management of the disease. Considering the central role that plasma kallikrein plays in bradykinin production, we investigated the contribution of the functional polymorphism KLKB1-428G/A to the disease phenotype...
November 9, 2017: International Archives of Allergy and Immunology
Magdalena Krochmal, Georgia Kontostathi, Pedro Magalhães, Manousos Makridakis, Julie Klein, Holger Husi, Johannes Leierer, Gert Mayer, Jean-Loup Bascands, Colette Denis, Jerome Zoidakis, Petra Zürbig, Christian Delles, Joost P Schanstra, Harald Mischak, Antonia Vlahou
Mechanisms underlying the onset and progression of nephropathy in diabetic patients are not fully elucidated. Deregulation of proteolytic systems is a known path leading to disease manifestation, therefore we hypothesized that proteases aberrantly expressed in diabetic nephropathy (DN) may be involved in the generation of DN-associated peptides in urine. We compared urinary peptide profiles of DN patients (macroalbuminuric, n = 121) to diabetic patients with no evidence of DN (normoalbuminuric, n = 118)...
November 9, 2017: Scientific Reports
Claire M Lawlor, Ashwin Ananth, Blair M Barton, Thomas C Flowers, Edward D McCoul
Objective Angioedema is a potentially life-threatening complication of angiotensin-converting enzyme inhibitor (ACEI) use, occurring in up to 0.5% of users. Although the pathophysiology of ACEI-induced angioedema is attributable to elevated serum bradykinin, standard management typically includes corticosteroids and antihistamines. We sought to summarize the evidence supporting pharmacotherapy for ACEI-induced angioedema. Data Sources PubMed, MEDLINE, and Embase portals. Methods A systematic literature review was conducted according to the PRISMA guidelines...
November 1, 2017: Otolaryngology—Head and Neck Surgery
M Madrigal, A Alape-Girón, E Barboza-Arguedas, W Aguilar-Ulloa, M Flores-Díaz
Snake venom serine proteinases are toxins that perturb hemostasis acting on proteins from the blood coagulation cascade, the fibrinolytic or the kallikrein-kinin system. Despite the relevance of these enzymes in envenomations by viper bites, the characterization of the antibody response to these toxins at the molecular level has not been previously addressed. In this work surface-located B cell recognized linear epitopes from a Lachesis stenophrys venom serine proteinase (UniProt accession number Q072L7) were predicted using an artificial neuronal network at the ABCpred server, the corresponding peptides were synthesized and their immunoreactivity was analyzed against a panel of experimental and therapeutic antivenoms...
October 27, 2017: Toxicon: Official Journal of the International Society on Toxinology
Titli Nargis, Krishna Kumar, Amrit Raj Ghosh, Amit Sharma, Dipayan Rudra, Debrup Sen, Saikat Chakrabarti, Satinath Mukhopadhyay, Dipyaman Ganguly, Partha Chakrabarti
OBJECTIVE: Increasing plasma levels and activity of dipeptidyl peptidase-4 (DPP4 or CD26) are associated with rapid progression of metabolic syndrome to overt type 2 diabetes mellitus (T2DM). While DPP4 inhibitors are increasingly used as anti-hyperglycemic agents, the reason for the increase in plasma DPP4 activity in T2DM patients remains elusive. METHODS: We looked into the source of plasma DPP4 activity in a cohort of 135 treatment naive nonobese (BMI < 30) T2DM patients...
November 2017: Molecular Metabolism
Peng Xu, Peter A Andreasen, Mingdong Huang
This review summarizes our studies in the development of small cyclic peptides for specifically modulating enzyme activity. Serine proteases share highly similar active sites but perform diverse physiological and pathological functions. From a phage-display peptide library, we isolated two mono-cyclic peptides, upain-1 (CSWRGLENHRMC) and mupain-1 (CPAYSRYLDC), which inhibit the activity of human and murine urokinase-type plasminogen activators (huPA and muPA) with Ki values in the micromolar or sub-micromolar range, respectively...
2017: International Journal of Biological Sciences
Stefan Belicky, Pavel Damborsky, Julia Zapatero-Rodríguez, Richard O'Kennedy, Jan Tkac
The main aim of the research was to design a functional impedimetric biosensor able to glycoprofile prostate specific antigen (PSA), a biomarker for prostate cancer (PCa), with high specificity using lectins as glycan recognising proteins. Traditionally, full-length antibody is immobilised on the biosensor interface for specific capture of PSA with subsequent glycoprofiling of PSA by addition of lectins. Since full-length antibodies contain glycans in the Fc domain, particular attention has to be paid to suppress direct binding of lectins to immobilised full-length antibodies, which would compromise accurate glycoprofiling...
August 20, 2017: Electrochimica Acta
Hidenobu Murafuji, Hiroki Sakai, Megumi Goto, Seiichi Imajo, Hajime Sugawara, Tsuyoshi Muto
Compound 1, composed of a 1,3,6-trisubstituted 1,4-diazepane-7-one, was discovered as a novel human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme, SCCE) inhibitor, and its derivatives were synthesized and evaluated. Structure-activity relationship studies of the amidoxime unit and benzoic acid part of this new scaffold led to the identification of 25 and 34, which were more potent than the hit compound, 1. The X-ray co-crystal structure of compound 25 and human KLK7 revealed the characteristic interactions and enabled explanations of the structure-activity relationship...
October 17, 2017: Bioorganic & Medicinal Chemistry Letters
Xiaocong Geng, Yueyang Liu, Sandra Diersch, Matthias Kotzsch, Sabine Grill, Wilko Weichert, Marion Kiechle, Viktor Magdolen, Julia Dorn
KLK9, 10, 11, and 15 may represent potential cancer biomarkers for evaluating ovarian cancer prognosis. In the present study, we selected a homogeneous cohort including 139 patients of advanced high-grade serous ovarian cancer (FIGO stage III/IV) and assessed the mRNA levels of KLK9, 10, 11, and 15 in tumor tissue by quantitative PCR. No significant associations of KLK9, 10, 11, and 15 mRNA with established clinical parameters (residual tumor mass, ascitic fluid volume) were found. Pronounced correlations between KLK10/KLK11 (rs = 0...
2017: PloS One
Lee-Ann Tjon-Kon-Fat, Marie Lundholm, Mona Schröder, Thomas Wurdinger, Camilla Thellenberg-Karlsson, Anders Widmark, Pernilla Wikström, Rolf Jonas Andreas Nilsson
BACKGROUND: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance. METHOD: The isolated platelet population of blood samples and digital-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis inhibiting therapy...
November 2, 2017: Prostate
Yoshio Bando, Yoshiaki Hagiwara, Yasuhiro Suzuki, Kosuke Yoshida, Yoko Aburakawa, Takashi Kimura, Chisato Murakami, Miyuki Ono, Tatsuhide Tanaka, Ying-Ping Jiang, Branka Mitrovi, Hiroki Bochimoto, Osamu Yahara, Shigetaka Yoshida
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6-/-) mice. Compared with Klk6+/+ (wild-type) mice, Klk6-/- mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease-9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood-brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors...
October 31, 2017: Glia
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