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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
Farwa Sajadi, Carmela Curcuruto, Afra Al Dhaheri, Jean-Paul V Paluzzi
The mosquito, Aedes aegypti , is a vector responsible for transmitting various pathogens to humans, and their prominence as chief vectors of human disease is largely due to their anthropophilic blood feeding behaviour. Larval stage mosquitoes must deal with the potential dilution of their haemolymph in fresh water, whereas the haematophagus A. aegypti female faces the challenge of excess ion and water intake after a blood meal. The excretory system, comprised of the Malpighian tubules (MTs) and hindgut, is strictly controlled by neuroendocrine factors, responsible for the control of diuresis across all developmental stages...
March 1, 2018: Journal of Experimental Biology
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
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
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
Yanpeng Tian, Feng Jiang, Yunlun Li, Haiqiang Jiang, Yanjun Chu, Lijuan Zhu, Weixing Guo
OBJECTIVE: Tengfu Jiangya tablet (TJT) is a traditional Chinese medicine formulation composed of Uncaria rhynchophylla and Semen raphani. It is a hospital preparation that is widely used in clinics for treating hypertension. A previous metabolomics study reported that TJT exerted a protective effect on hypertension by restoring impaired NO production, ameliorating the inflammatory state, and vascular remodeling. A clinical proteomics study also revealed five key target proteins during TJT intervention...
February 13, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Gennaro Bruno, Francesca Cencetti, Caterina Bernacchioni, Chiara Donati, Kira Vanessa Blankenbach, Dominique Thomas, Dagmar Meyer Zu Heringdorf, Paola Bruni
Skeletal muscle tissue retains a remarkable regenerative capacity due to the activation of resident stem cells that in pathological conditions or after tissue damage proliferate and commit themselves into myoblasts. These immature myogenic cells undergo differentiation to generate new myofibers or repair the injured ones, giving a strong contribution to muscle regeneration. Cytokines and growth factors, potently released after tissue injury by leukocytes and macrophages, are not only responsible of the induction of the initial inflammatory response, but can also affect skeletal muscle regeneration...
February 2, 2018: Cellular Signalling
John Owoicho Orgah, Miao Wang, Xiaohu Yang, Zhilong Wang, Dandan Wang, Qi Zhang, Guanwei Fan, Jihong Han, Gangjian Qin, Xiumei Gao, Yan Zhu
BACKGROUND/AIMS: High blood pressure is a major risk factor for chronic kidney disease. Currently, single-target anti-hypertensive drugs are not designed for high blood pressure-related organ damages. Danhong injection (DHI), made from the aqueous extracts of Radix Salviae miltiorrhizae and Flos Carthamus tinctorius, has various pharmacological effects, including BP lowering in SHR, mediated by the reduction of vascular remodeling and the up-regulation of Kallikrein-kinin system published recently by our team, yet if it renders renal protection remains unknown...
January 23, 2018: Kidney & Blood Pressure Research
Do-Hyoung Kim, Young-Joon Kim, Michael E Adams
Fluid clearance from the respiratory system during developmental transitions is critically important for achieving optimal gas exchange in animals. During insect development from embryo to adult, airway clearance occurs episodically each time the molt is completed by performance of the ecdysis sequence, coordinated by a peptide-signaling cascade initiated by ecdysis-triggering hormone (ETH). We find that the neuropeptide Kinin (also known as Drosokinin or Leukokinin) is required for normal respiratory fluid clearance or "tracheal air-filling" in Drosophila larvae...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Erika Terzuoli, Lucia Morbidelli, Ginevra Nannelli, Antonio Giachetti, Sandra Donnini, Marina Ziche
The identification of components of the kallikrein-kinin system in the vitreous from patients with microvascular retinal diseases suggests that bradykinin (BK) signaling may contribute to pathogenesis of retinal vascular complications. BK receptor 2 (B2R) signaling has been implicated in both pro-inflammatory and pro-angiogenic effects promoted by BK. Here, we investigated the role of BK/B2R signaling in the retinal neovascularization in the oxygen-induced retinopathy (OIR) model. Blockade of B2R signaling by the antagonist fasitibant delayed retinal vascularization in mouse pups, indicating that the retinal endothelium is a target of the BK/B2R system...
January 23, 2018: International Journal of Molecular Sciences
Mona N Oliveira, Micheli M Pillat, Helena Motaln, Henning Ulrich, Tamara T Lah
Glioblastoma multiforme (GBM) represents the most lethal brain tumour, and these tumours have very limited treatment options. Mesenchymal stem cells (MSC) are considered as candidates for advanced cell therapies, due to their tropism towards GBM, possibly affecting their malignancy, thus also representing a potential therapeutic vector. Therefore, we aimed to compare the effects of bone-marrow-derived versus adipose-tissue-derived MSC (BM-/AT-MSC) on heterogeneous populations of tumour cells. This cells' interplay was addressed by the in-vitro two-dimensional (monolayer) and three-dimensional (spheroid) co-culture models, using U87 and U373 GBM cell lines, expressing genotypically different mesenchymal transcriptome profiles...
January 22, 2018: Scientific Reports
Nathan M Johnson, Mariana A Phillips
Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications...
January 2018: Skin Therapy Letter
Amaly Nokkari, Hadi Abou-El-Hassan, Yehia Mechref, Stefania Mondello, Mark S Kindy, Ayad A Jaffa, Firas Kobeissy
Neurological disorders represent major health concerns in terms of comorbidity and mortality worldwide. Despite a tremendous increase in our understanding of the pathophysiological processes involved in disease progression and prevention, the accumulated knowledge so far resulted in relatively moderate translational benefits in terms of therapeutic interventions and enhanced clinical outcomes. Aiming at specific neural molecular pathways, different strategies have been geared to target the development and progression of such disorders...
January 16, 2018: Progress in Neurobiology
Hui-Chuan Chang, Camy C-H Kung, Tzu-Ting Chang, Shu-Chuan Jao, Yu-Ting Hsu, Wen-Shan Li
Aminopeptidase P, a metalloprotease, targets Xaa-Proline peptides for cleavage [1-4]. There are two forms of human AMPP, a membrane-bound form (hmAMPP) and a soluble cytosolic form (hcAMPP)[5]. Similar to the angiotensin-I-converting enzyme, AMPP plays an important role in the catabolism of inflammatory and vasoactive peptides, known as kinins. The plasma kinin, bradykinin, was used as the substrate to conduct enzymatic activity analyses and to determine the Michaelis constant (Km) of 174 μM and the catalytic rate constant (kcat) of 10...
2018: PloS One
Maria E Marketou, George Kochiadakis, Joanna Kontaraki, Evangelos Zacharis, Emmanouel Kanoupakis, Emmanouel Kallergis, Hercules Mavrakis, Panagiotis Tsiverdis, Dimitris Lempidakis, John Konstantinou, Konstantinos Fragkiadakis, Gregory Chlouverakis, Panos Vardas, Fragiskos Parthenakis
OBJECTIVES: Adipose tissue plays a key role in cardiovascular physiology. Kinin receptors are important determinant of the effect of adiposity on endothelial function and cardiovascular function. We examined the gene expression levels of kinin receptors in the subcutaneous white adipose tissue (sWAT) of nondiabetic patients with and without coronary artery disease (CAD). PATIENTS AND METHODS: We evaluated 21 patients with CAD (13 men, age: 68±8 years) and 23 patients without CAD (15 men, age: 66±5 years) who underwent catheterization through the femoral route...
January 12, 2018: Coronary Artery Disease
Lisa Joedicke, Jiafei Mao, Georg Kuenze, Christoph Reinhart, Tejaswi Kalavacherla, Hendrik R A Jonker, Christian Richter, Harald Schwalbe, Jens Meiler, Julia Preu, Hartmut Michel, Clemens Glaubitz
G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors...
January 15, 2018: Nature Chemical Biology
Marina Devetzi, Maria Goulielmaki, Nicolas Khoury, Demetrios A Spandidos, Georgia Sotiropoulou, Ioannis Christodoulou, Vassilis Zoumpourlis
The tissue kallikrein‑kinin system (KKS) is an endogenous multiprotein metabolic cascade which is implicated in the homeostasis of the cardiovascular, renal and central nervous system. Human tissue kallikrein (KLK1) is a serine protease, component of the KKS that has been demonstrated to exert pleiotropic beneficial effects in protection from tissue injury through its anti‑inflammatory, anti‑apoptotic, anti‑fibrotic and anti‑oxidative actions. Mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs) constitute populations of well‑characterized, readily obtainable multipotent cells with special immunomodulatory, migratory and paracrine properties rendering them appealing potential therapeutics in experimental animal models of various diseases...
January 3, 2018: International Journal of Molecular Medicine
Jie Zhu, Hui Wang, Jingyu Chen, Wei Wei
BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Impairment of kidney functions in RA was observed. However, the mechanism of kidney injury of RA has not been clear. Plasma kallikrein-kinin system (KKS) was involved in inflammatory processes in kidney disease. AIM: This study aimed to explore the role of plasma KKS in immune reactions and kidney injury of RA. RESULTS: The paw of AA rats appeared to be swelling and redness, the arthritis index was significantly increased on the 18, 21 and 24 d after injection and secondary inflammation in multi-sites was observed...
January 5, 2018: Immunopharmacology and Immunotoxicology
Soumaya Hachana, Menakshi Bhat, Jacques Sénécal, Frédéric Huppé-Gourgues, Réjean Couture, Elvire Vaucher
BACKGROUND AND PURPOSE: Kinin B1 receptor (B1R) contributes to vascular inflammation and blood-retinal barrier breakdown in diabetic retinopathy (DR). This study aims at investigating further the changes of expression, the cellular localization and the vascular inflammatory effect of B1R in the retina of streptozotocin diabetic rats. EXPERIMENTAL APPROACH: The distribution of B1R on retinal cell types was investigated by immunocytochemistry. Impact of intravitreal B1R agonist R-838 and eye-drops application of the B1R antagonist R-954 was measured on retinal leukocytes adhesion, gene expression of the kinin and VEGF systems, B1R immunodetection, microgliosis and capillary leakage...
December 29, 2017: British Journal of Pharmacology
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