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Panagiota S Filippou, Annie H Ren, Sudarshan Bala, Michail-Dimitrios Papaioannou, Davor Brinc, Ioannis Prassas, Theano Karakosta, Eleftherios P Diamandis
OBJECTIVE: Human tissue kallikrein 15 (KLK15) is the last cloned member of the KLK-related gene family. Despite being implicated in multiple cancers, its pathophysiological role remains unknown. We aimed to biochemically characterize KLK15 and preliminarily study its role in cancer. DESIGN & METHODS: Recombinant KLK15 protein was produced, purified to homogeneity and quantified by mass spectrometry (parallel reaction monitoring analysis). We profiled the enzymatic activity of KLK15 using fluorogenic peptide substrates, and performed kinetic analysis to discover the cleavage sites...
June 18, 2018: Clinical Biochemistry
Rahil Eftekhari, Stacy G de Lima, Yu Liu, Koichiro Mihara, Mahmoud Saifeddine, Farshid Noorbakhsh, Isobel A Scarisbrick, Morley D Hollenberg
We propose that in the microenvironment of inflammatory tissues, including tumours, extracellular proteinases can modulate cell signalling in part by regulating proteinaseactivated receptors (PARs). We have been exploring this mechanism in a variety of inflammation and tumour-related settings that include tumour-derived cultured cells from prostate and bladder cancer, as well as immune inflammatory cells that are involved in the pathology of inflammatory diseases including multiple sclerosis. Our work shows that proteinase signalling via the PARs affects prostate and bladder cancer-derived tumour cell behaviour and can regulate calcium signalling in human T-cell and macrophage-related inflammatory cells as well as in murine splenocytes...
June 1, 2018: Biological Chemistry
Zhenyu Wei, Yi Lyu, XiaoLi Yang, Xin Chen, Ping Zhong, Danhong Wu
The term "tissue kallikrein" is used to describe a group of serine proteases shared considerable sequence homology and colocalize in the same chromosomal locus 19q13. 2-q13.4. It has been widely discovered in various tissues and has been proved to be involved in kinds of pathophysiological processes, such as inhibiting oxidative stress, inflammation, apoptosis, fibrosis and promoting angiogenesis, and neurogenesis. Human Urinary Kallidinogenase (HUK) extracted from human urine is a member of tissue kallikrein which could convert kininogen to kinin and hence improve the plasma kinin level...
2018: Frontiers in Neurology
Zahava Vadasz, Elias Toubi
The involvement of the hemostatic system in immune-mediated inflammation is widely reported. Many coagulation factors play a role in the pathogenesis of autoimmune diseases, such as systemic vasculitis and systemic lupus erythematosus. Hemostatic disorders are also involved in asthma and chronic spontaneous urticaria (CSU). Factor XIIa (FXIIa) was one of the first coagulation factors implicated in inducing both humoral and cellular responses and is therefore considered a prime new therapeutic target in immune-mediated inflammation...
June 19, 2018: Seminars in Thrombosis and Hemostasis
Tomas Zimmermann, Søren Brøgger Christensen, Henrik Franzyk
Since cells in solid tumors divide less rapidly than cells in the bone marrow or cells of the immune system, mitotic inhibitors often cause severe side effects when used for treatment of diseases like prostate cancer and breast cancer. One approach to overcome this problem involves attempts at developing drugs based on general cytotoxins, like calicheamicin and thapsigargin, which kill cells at all phases of the cell cycle. However, such toxins can only be used when efficient targeting to the malignant tissue is possible...
June 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Shigeyuki Tsutsui, Yuya Suzuki, Ko Shibuya, Osamu Nakamura
Kalliklectin is a novel lectin identified in the skin mucus and blood plasma of teleosts, including fugu (Takifugu rubripes). It has been found to exhibit sequence similarity to mammalian plasma kallikrein and coagulation factor XI. The objective of the present study was to clarify the cellular localization of kalliklectin using an antiserum specific to fugu kalliklectin. Immunohistochemical analysis showed that positive reactions were observed in the skin and liver, but not in other tested tissues. Several types of epidermal cells were stained by the antiserum; sacciform cells were one of the types of cells most densely stained by the antiserum in adult fugu skin, whereas mucous cells showed negative staining results...
June 11, 2018: Fish & Shellfish Immunology
Pedro F Malacarne, Thiago N Menezes, Cleciane W Martins, Gustavo B Naumann, Helena L Gomes, Rita G W Pires, Suely G Figueiredo, Fabiana V Campos
Proteins that account for the hemolytic activity found in scorpaeniform fish venoms are responsible for the majority of the effects observed upon envenomation, for instance, neurotoxic, cardiotoxic and inflammatory effects. These multifunctional toxins, described as protein lethal factors and referred to as cytolysins, are known to be extremely labile molecules. In the present work, we endeavored to overcome this constraint by determining optimal storage conditions for Sp-CTx, the major bioactive component from the scorpionfish Scorpaena plumieri venom...
June 11, 2018: Toxicon: Official Journal of the International Society on Toxinology
Anthoula Chatzikyriakidou, Paraskevi V Voulgari, Alexandros A Drosos
Objectives: This study aims to examine the following functional polymorphisms in rheumatoid arthritis (RA) susceptibility: (i) the 587C>T of kininogen gene, (ii) the 287 bp Alu repeat insertion of angiotensin converting enzyme gene, (iii) the 9 bp insertion of bradykinin receptor 2 gene, (iv) the -58T>C of bradykinin receptor 2 gene, and (v) the -699G>C of bradykinin receptor 1 gene. Patients and methods: The study included 136 RA patients (27 males; 109 females; mean age 60...
March 2018: Archives of Rheumatology
Xuegu Xu, Yonghao Cai, Yinfei Yu
The aim of the present study was to investigate the therapeutic effects of carbamyl erythropoietin (CEPO) and safflor yellow (SY) in the treatment of rats with diabetic retinopathy (DR) as well as exploring the mechanism of action. Male SD rats were used to establish a diabetes model and streptozotocin-induced retinopathy was also performed in rats. A total of 126 rats with DR were obtained, and model rats were randomly divided into the model (n=42), experimental (n=42) and control (n=42) groups. The rats in the model group were injected with saline, the rats in the experimental group were treated with CEPO, and the rats in the control group were treated with SY...
July 2018: Experimental and Therapeutic Medicine
Martin Horn, Olga Zbodakova, Petr Kasparek, Jaroslav Srp, Radka Haneckova, Martin Hradilek, Michael Mares, Radislav Sedlacek
Kallikrein-related proteases (KLKs) play a critical role in epidermis physiology and have been implicated in skin pathologies such as Netherton syndrome. Contribution of individual KLKs to skin proteolysis is poorly understood. Monitoring of their activities in skin proteome is hampered by overlapping substrate specificities, and there is a need for novel assays. Here we present a platform of selective and sensitive fluorogenic substrates and inhibitors for profiling KLK5, KLK7, and KLK14. These chemical tools were evaluated using recombinant KLKs and tissue from a unique set of mice deficient in eight combinations of KLKs and their natural regulator LEKTI...
June 1, 2018: Biological Chemistry
Carlos D Figueroa, Luis Molina, Kanti D Bhoola, Pamela Ehrenfeld
The kallikrein family comprises tissue kallikrein and 14 kallikrein-related peptidases (KLKs) recognized as a subgroup of secreted trypsin- or chymotrypsin-like serine proteases. KLKs are expressed in many cellular types where they regulate important physiological activities such as semen liquefaction, immune response, neural development, blood pressure, skin desquamation and tooth enamel formation. Tissue kallikrein, the oldest member and kininreleasing enzyme, and KLK3/PSA, a tumor biomarker for prostate cancer are the most prominent components of the family...
June 1, 2018: Biological Chemistry
Hidenobu Murafuji, Hajime Sugawara, Megumi Goto, Yoshiaki Oyama, Hiroki Sakai, Seiichi Imajo, Toshiyuki Tomoo, Tsuyoshi Muto
A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1-3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (-)-22g, exhibited potent inhibitory activity...
May 26, 2018: Bioorganic & Medicinal Chemistry
Panagiotis G Adamopoulos, Panagiotis Tsiakanikas, Andreas Scorilas
Gastrointestinal malignancies represent a wide spectrum of diseases of the gastrointestinal tract and its accessory digestive organs, including esophageal, gastric, hepatocellular, pancreatic, and colorectal cancers. Malignancies of the gastrointestinal system are responsible for nearly 30% of cancer-related morbidity and approximately 40% of cancer-related mortality, worldwide. For this reason, the discovery of novel prognostic biomarkers that can efficiently provide a better prognosis, risk assessment, and prediction of treatment response is an imperative need...
December 20, 2017: Biological Chemistry
Mélia Magnen, Brigitta Margit Elsässer, Olga Zbodakova, Petr Kasparek, Fabien Gueugnon, Agnès Petit-Courty, Radislav Sedlacek, Peter Goettig, Yves Courty
Every year, influenza A virus (IAV) affects and kills many humans worldwide. The viral hemagglutinin (HA) is a critical actor of influenza virus infectivity which needs to be cleaved by host serine proteases to exert its activity. KLK5 has been identified as an activating protease in humans with a preference for the H3N2 IAV subtype. We investigated the origin of this preference using influenza A/Puerto Rico/8/34 (PR8, H1N1) and A/Scotland/20/74 (Scotland, H3N2) viruses. Pretreatment of noninfectious virions with human KLK5 increased infectivity of Scotland IAV in MDCK cells and triggered influenza pneumonia in mice...
December 20, 2017: Biological Chemistry
Pamela Ehrenfeld, Kanti D Bhoola, Carola E Matus, Carlos D Figueroa
In the human neutrophil, kallikrein-related peptidases (KLKs) have a significant functional relationship with the classical kinin system since a kinin B1 receptor agonist induces secretion of KLK1, KLK6, KLK10, KLK13 and KLK14 into the medium. Secretion of KLK1, the kinin-forming enzyme, may perpetuate formation of kinin in the inflammatory milieu by hydrolyzing extravasated kininogens present in tissue edema. Secretion of KLKs into the inflammatory milieu, induced by kinins or other proinflammatory mediators, provides the human neutrophil with a wide range of molecular interactions to hydrolyze different cellular and extracellular matrix components, which may be of critical relevance in different mechanisms involving inflammation...
December 20, 2017: Biological Chemistry
Panagiotis G Adamopoulos, Christos K Kontos, Andreas Scorilas
Tissue kallikrein, kallikrein-related peptidases (KLKs), and plasma kallikrein form the largest group of serine proteases in the human genome, sharing many structural and functional characteristics. In this study, we describe the molecular cloning of four novel splice variants of the human KLK11 and KLK12 genes, discovered by combining 3' rapid amplification of cDNA ends (3' RACE), NGS technology, advanced bioinformatic analysis, and Sanger sequencing. Expression analysis of these new transcripts in cell lines originating from seventeen cancerous and two normal tissues revealed the expression pattern of each transcript...
December 20, 2017: Biological Chemistry
Xavier Filella, Esther Fernández-Galan, Rosa Fernández Bonifacio, Laura Foj
Prostate cancer (PCa) is the second most common cancer in men worldwide. A large proportion of PCa are latent, never destined to progress or affect the patients' life. It is of utmost importance to identify which PCa are destined to progress and which would benefit from an early radical treatment. Prostate-specific antigen (PSA) remains the most used test to detect PCa. Its limited specificity and an elevated rate of overdiagnosis are the main problems associated with PSA testing. New PCa biomarkers have been proposed to improve the accuracy of PSA in the management of early PCa...
2018: Pharmacogenomics and Personalized Medicine
Georgia Papachristopoulou, Nikolaos Tsapralis, Kleita Michaelidou, Gerasimos Ardavanis-Loukeris, Ioannis Griniatsos, Andreas Scorilas, Maroulio Talieri
OBJECTIVES: As kallikrein-related peptidase 12 (KLK12) has been implicated in the cancer progression and alternative splicing plays significant role in this disease, the aim of this study was to examine the expression profile and the clinical impact of the KLK12 splice variants in breast cancer. DESIGN AND METHODS: Total RNA was isolated and reverse transcripted from 141 tissues. Afterwards, quantitative real-time PCR were conducted, followed by the performance of the comparative CT (2-ΔΔCT) method for relative quantification, whilst their correlation with the clinicopathological features of breast malignancies were assessed by statistical analysis...
May 25, 2018: Clinical Biochemistry
Li-Juan Xu, Yu Duan, Peng Wang, Hui-Qing Yin
MiR-199 b-5p and kallikrein-related peptidase 10 (KLK10) are related to various disease processes and pathogenesis. However, little is known about the molecular mechanisms of miR-199 b-5p and KLK10 in human cervical cancer. In the present study, we found that miR-199 b-5p was highly expressed in cervical cancer tissues and cell lines, and was positively correlated with overall survival (OS) and progression-free survival (PFS), higher incidences of larger tumor sizes, late International Federation of Gynecology and Obstetrics (FIGO) stages and preoperative metastasis...
May 25, 2018: Biochemical and Biophysical Research Communications
François Marceau, Marie-Thérèse Bawolak, Jean-Philippe Fortin, Guillaume Morissette, Caroline Roy, Hélène Bachelard, Lajos Gera, Xavier Charest-Morin
Kinins are the small and fragile hydrophilic peptides related to bradykinin (BK) and derived from circulating kininogens via the action of kallikreins. Kinins bind to the preformed and widely distributed B2 receptor (B2 R) and to the inducible B1 receptor (B1 R). B2 Rs and B1 Rs are related G protein coupled receptors that possess natural agonist ligands of nanomolar affinity (BK and Lys BK for B2 Rs, Lys-des-Arg9 -BK for B1 R). Decades of structure-activity exploration have resulted in the production of peptide analogs that are antagonists, one of which is clinically used (the B2 R antagonist icatibant), and also non-peptide ligands for both receptor subtypes...
May 23, 2018: Peptides
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