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Qiang Wang, Akram A Da'dara, Patrick J Skelly
BACKGROUND: Schistosomes are blood dwelling parasitic worms that cause the debilitating disease schistosomiasis. Here we examined the influence of the parasites on their external environment by monitoring the impact of adult Schistosoma mansoni worms on the murine plasma proteome in vitro and, in particular, on how the worms affect the blood coagulation protein high molecular weight kininogen (HK). METHODS: Following the incubation of adult schistosomes in murine plasma, two-dimensional differential in-gel electrophoresis (2D-DIGE) was conducted to look for changes in the plasma proteome compared with control plasma...
March 14, 2018: Parasites & Vectors
Sonja Oehmcke-Hecht, Juliane Köhler
The name human contact system is related to its mode of action, as "contact" with artificial negatively charged surfaces triggers its activation. Today, it is generally believed that the contact system is an inflammatory response mechanism not only against artificial material but also against misfolded proteins and foreign organisms. Upon activation, the contact system is involved in at least two distinct (patho)physiologic processes: i . the trigger of the intrinsic coagulation via factor XI and ii ...
2018: Frontiers in Immunology
Daniel P Teufel, Gavin Bennett, Helen Harrison, Katerine van Rietschoten, Silvia Pavan, Catherine Stace, François Le Floch, Tine Van Bergen, Elke Vermassen, Philippe Barbeaux, Tjing-Tjing Hu, Jean H M Feyen, Marc Vanhove
Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and pico-molar potencies towards plasma kallikrein...
March 8, 2018: Journal of Medicinal Chemistry
Céléna Dubuc, Martin Savard, Veronica Bovenzi, Andrée Lessard, Audrey Fortier, Jérôme Côté, Witold Neugebauer, Flavio Rizzolio, Sameh Geha, Antonio Giordano, Sylvain Chemtob, Fernand Gobeil
G protein-coupled receptors (GPCRs) are integral cell-surface proteins having a central role in tumor growth and metastasis. However, several GPCRs retain an atypical intracellular/nuclear location in various types of cancer. The pathological significance of this is currently unknown. Here we extend this observation by showing that the bradykinin B2R (BK-B2R) is nuclearly expressed in the human triple-negative breast cancer (TNBC) cell line MDA-MB-231 and in human clinical specimens of TNBC. We posited that these "nuclearized" receptors could be involved in oncogenic signaling linked to aberrant growth and survival maintenance of TNBC...
February 9, 2018: Oncotarget
Carla Blum-Johnston, Richard B Thorpe, Chelsea Wee, Raechel Opsahl, Monica Romero, Samuel Murray, Alexander Brunelle, Quintin Blood, Rachael Wilson, Arlin B Blood, Lubo Zhang, Lawrence D Longo, William J Pearce, Sean M Wilson
Bradykinin-induced activation of the pulmonary endothelium triggers a rise in intracellular Ca2+ , which activates nitric oxide (NO)-dependent vasorelaxation. Chronic hypoxia is commonly associated with increased pulmonary vascular tone, which can cause pulmonary hypertension in responsive individuals. In the present study, we tested the hypothesis that long-term high altitude hypoxia (LTH) diminishes bradykinin-induced Ca2+ signals and inhibits eNOS, PGI2 and BKCa channels in sheep, which are moderately responsive to LTH, resulting in decreased pulmonary arterial vasorelaxation...
March 7, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
J Hogwood, A Naggi, G Torri, C Page, P Rigsby, B Mulloy, E Gray
Oversulfated chondroitin sulfate (OSCS) was identified as a contaminant in certain heparin preparations as the cause of adverse reactions in patients. OSCS was found to possess both plasma anticoagulant activity and the ability to activate prekallikrein to kallikrein. Differentially sulfated chondroitin sulfates were prepared by synthetic modification of chondroitin sulfate and were compared to the activity of OSCS purified from contaminated heparin. Whilst chondroitin sulfate was found to have minimal anticoagulant activity, increasing sulfation levels produced an anticoagulant response which we directly show for the first time is mediated through heparin cofactor II...
2018: PloS One
Coen Maas, Thomas Renné
Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII-driven-contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate provides protection from thromboembolic diseases without interfering with hemostasis...
February 26, 2018: Blood
Tracey J Flores, Vivian B Nguyen, Robert E Widdop, Megan R Sutherland, Graeme R Polglase, Helen E Abud, Mary Jane Black
Background: For infants born moderately/late preterm (32-37 weeks of gestation), immaturity of the intestine has the potential to impact both short- and long-term gastrointestinal function. The aim of this study conducted in sheep was to compare the morphology and smooth muscle contractility of the ileum in term and late preterm lambs. Materials and methods: Lambs delivered preterm (132 days gestation; n  = 7) or term (147 days gestation; n  = 9) were milk-fed after birth and euthanased at 2 days of age...
2018: Frontiers in Pediatrics
Károly Baintner
The first 60-min phase of inflammatory ascites formation was studied by intraperitoneally (i.p.) administered macromolecular inducers: yeast cell wall zymosan binds to specific macrophage receptors, polyethyleneimine (PEI) and concanavalin A (ConA), produces non-covalent cross-links on the surface of various cells, while λ-carrageenan may function as a contact activator. Depletion of peritoneal macrophages was performed by overnight pretreatment with diphtheria toxin in transgenic mice, resulting in a significant (p < 0...
February 23, 2018: Acta Microbiologica et Immunologica Hungarica
Bo Wang, Aizhen Yang, Zhenzhen Zhao, Chao He, Yuanyuan Liu, Robert W Colman, Jihong Dai, Yi Wu
The kallikrein-kinin system (KKS) consists of two serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-molecular-weight kininogen (HK). Upon activation of the KKS, HK is cleaved to release bradykinin. Although the KKS is activated in humans and animals with inflammatory bowel disease (IBD), its role in the pathogenesis of IBD has not been characterized. In the present study, we determined the role of the KKS in the pathogenesis of IBD using mice that lack proteins involved in the KKS...
2018: Frontiers in Immunology
Marion Bisha, Vu Thao-Vi Dao, Ehsan Gholamreza-Fahimi, Michael Vogt, Marc van Zandvoort, Sarah Weber, Murat Bas, Farbod Khosravani, Georg Kojda, Tatsiana Suvorava
BACKGROUND AND PURPOSE: Non-allergic angio-oedema is a life threatening disease mediated by activation of bradykinin type 2 receptors (B2). The aim of this study was to investigate whether activation of B2 by endogenous bradykinin contributes to physiologic extravasation. This may shed new light on the assumption that treatment with an ACEi results in an alteration of the vascular barrier function predisposing to non-allergic angio-edema. EXPERIMENTAL APPROACH: We generated a new transgenic mouse model characterized by endothelium-specific overexpression of B2 (B2tg ) and established a non-invasive two-photon laser microscopy approach to measure the kinetics of spontaneous extravasation in-vivo...
February 21, 2018: British Journal of Pharmacology
Alecia Seliga, Michael Hweemoon Lee, Nicole C Fernandes, Viviana Zuluaga-Ramirez, Marta Didukh, Yuri Persidsky, Raghava Potula, Stefania Gallucci, Uma Sriram
The Kallikrein-Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor)...
2018: Frontiers in Immunology
Cuiqin Shi, Siwei Liang, Xianghuai Xu, Qiang Chen, Lan Wang, Li Yu, Hanjing Lv, Zhongmin Qiu
PURPOSE: The purpose of this study was to investigate cough hypersensitivity and its potential mechanisms in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: Fifteen OSAHS patients, 12 simple snoring patients, and 15 healthy volunteers received cough sensitivity test and induced sputum cytology. Cough thresholds C2 and C5 (the minimum of capsaicin inducing ≥ 2 and ≥ 5 coughs, respectively), total cell count, cell differentials and the levels of bradykinin, histamine, prostaglandin E 2 , substance P, calcitonin gene-related peptide, pepsin, and interleukin-2 in the induced sputum detected by enzyme-linked immunosorbent assay were compared...
February 16, 2018: Sleep & Breathing, Schlaf & Atmung
Zhifang Zheng, Yishu Liu, Lulu Zhu, Jianbing Tang, Wenhua Huang, Biao Cheng
BACKGROUND: The effect of lumbar sympathectomy for the treatment of lower limb ischemia remains a matter of controversy. METHODS: Sprague-Dawley rats were subjected to lumbar sympathectomy, after which Evans blue dye was injected into the hind plantar skin. Extravasation of dye was measured and compared with rats undergoing sham operation. Hind plantar skin was processed for HE staining, immunohistochemistry, and Western blot. RESULTS: In sympathectomized rats, blue stained areas in hind plantar skin and concentrations of Evans blue were significantly less than that of sham sympathectomy (control) rats, both 2 weeks and 3 months after surgery...
2018: Clinical Hemorheology and Microcirculation
Qingquan Wei, Qingyu Liu, Chengda Ren, Junling Liu, Wenting Cai, Meijiang Zhu, Huizi Jin, Mengmei He, Jing Yu
The aim of the present study was to investigate the effects of bradykinin (BK) on an epithelial-mesenchymal transition (EMT) model in retinal pigment epithelium (RPE) cells through exposure to transforming growth factor‑β1 (TGF‑β1). The aim was to improve the effect of BK on proliferative vitreoretinopathy (PVR) progression, and to find a novel method of clinical prevention and treatment for PVR. The morphology of ARPE‑19 cells was observed using an inverted phase‑contrast microscope. A Cell Counting Kit‑8 was used to assess the effects of TGF‑β1 on the proliferation of ARPE‑19 cells...
February 2, 2018: Molecular Medicine Reports
Xiaofan Chen, Jun Wan, Bo Yu, Yarui Diao, Wei Zhang
BACKGROUND: Skeletal muscle satellite cell-derived myoblasts are mainly responsible for postnatal muscle growth and injury-induced regeneration. Many intracellular signaling pathways are essential for myogenic differentiation, while a number of kinases are involved in this modulation process. Type I phosphatidylinositol 4-phosphate 5-kinase (PIP5KI) was identified as one of the key kinases involved in myogenic differentiation, but the underlying molecular mechanism is still unclear. METHODS: PIP5K1α was quantified by quantitative reverse transcriptase PCR and western blot assay...
February 9, 2018: Stem Cell Research & Therapy
Luciana Garros Ferreira, Paulo Roberto Barbosa Evora, Verena Kise Capellini, Agnes Afrodite Albuquerque, Marco Túlio Menezes Carvalho, Roseli Aparecida da Silva Gomes, Marco Túlio Parolini, Andrea Carla Celotto
BACKGROUND: In recent years, it has been demonstrated the inhibitory effect of some plant species on the angiotensin-converting enzyme and rosmarinic acid is a prominent constituent of these species. HYPOTHESIS/PURPOSE: This study was carried out to verify the effect of rosmarinic acid on blood pressure through inhibitory activity on angiotensin-converting enzyme in rats. STUDY DESIGN: The arterial hypertension was promoted using 2-kidneys 1-clip model in rats...
January 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Oleksiy Gryshchenko, Julia V Gerasimenko, Shuang Peng, Oleg V Gerasimenko, Ole H Petersen
Physiological Ca 2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca 2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca 2+ signals in the peri-acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we have explored Ca 2+ signalling in the different cell types to be found in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization-evoked Ca 2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells...
February 9, 2018: Journal of Physiology
Alvin H Schmaier
Plasma prekallikrein (PK) has a critical role in acute attacks of hereditary angioedema (HAE). Unlike C1 inhibitor, its levels fall during HAE attacks with resultant cleaved high-molecular-weight kininogen. Cleavage of high-molecular-weight kininogen liberates bradykinin, the major biologic peptide that promotes the edema. How prekallikrein initially becomes activated in acute attacks of HAE is not known. PK itself is negatively associated with cardiovascular disease. High prekallikrein is associated with accelerated vascular disease in diabetes and polymorphisms of prekallikrein that reduce high-molecular-weight kininogen binding are associated with protection from cardiovascular events...
2018: Frontiers in Medicine
Xavier Charest-Morin, Robert Lodge, François Marceau
To support bradykinin (BK) B2 receptor (B2R) detection and therapeutic stimulation, we developed and characterized fusion proteins consisting of the BK homolog maximakinin (MK), or variants, positioned at the C-terminus of functional proteins (enhanced green fluorescent protein (EGFP), the peroxidase APEX2 or human serum albumin (HSA)). EGFP-MK loses its reactivity with anti-BK antibodies and molecular mass as it progresses in the endosomal tract of cells expressing rat B2Rs (immunoblots, epifluorescence microscopy)...
February 7, 2018: Canadian Journal of Physiology and Pharmacology
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