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https://www.readbyqxmd.com/read/29743547/the-protease-activated-receptor2-promotes-rab5a-mediated-generation-of-pro-metastatic-microvesicles
#1
Kaushik Das, Ramesh Prasad, Sreetama Roy, Ashis Mukherjee, Prosenjit Sen
Metastasis, the hallmark of cancer propagation is attributed by the modification of phenotypic/functional behavior of cells to break attachment and migrate to distant body parts. Cancer cell-secreted microvesicles (MVs) contribute immensely in disease propagation. These nano-vesicles, generated from plasma membrane outward budding are taken up by nearby healthy cells thereby inducing phenotypic alterations in those recipient cells. Protease activated receptor 2 (PAR2), activated by trypsin, also contributes to cancer progression by increasing metastasis, angiogenesis etc...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29723131/insulin-acts-as-a-repressive-factor-to-inhibit-the-ability-of-par2-to-induce-islet-cell-transdifferentiation
#2
Seung-Hee Lee, Ergeng Hao, David Scharp, Fred Levine
Recently, we showed that pancreatitis in the context of profound β-cell deficiency was sufficient to induce islet cell transdifferentiation. In some circumstances, this effect was sufficient to result in recovery from severe diabetes. More recently, we showed that the molecular mechanism by which pancreatitis induced β-cell neogenesis by transdifferentiation was activation of an atypical GPCR called Protease-Activated Receptor 2 (PAR2). However, the ability of PAR2 to induce transdifferentiation occurred only in the setting of profound β-cell deficiency, implying the existence of a repressive factor from those cells...
May 3, 2018: Islets
https://www.readbyqxmd.com/read/29713744/skin-neurogenic-inflammation
#3
REVIEW
Jae Eun Choi, Anna Di Nardo
The epidermis closely interacts with nerve endings, and both epidermis and nerves produce substances for mutual sustenance. Neuropeptides, like substance P (SP) and calcitonin gene-related protein (CGRP), are produced by sensory nerves in the dermis; they induce mast cells to release vasoactive amines that facilitate infiltration of neutrophils and T cells. Some receptors are more important than others in the generation of itch. The Mas-related G protein-coupled receptors (Mrgpr) family as well as transient receptor potential ankyrin 1 (TRPA1) and protease activated receptor 2(Par2) have important roles in itch and inflammation...
April 30, 2018: Seminars in Immunopathology
https://www.readbyqxmd.com/read/29709920/impairment-of-protease-activated-receptor-2-induced-relaxation-of-aortas-of-aged-spontaneously-hypertensive-rat
#4
Makoto Ando, Takayuki Matsumoto, Shota Kobayashi, Maika Iguchi, Kumiko Taguchi, Tsuneo Kobayashi
Hypertension is one of the most prevalent diseases worldwide and can cause harmful complications within the vascular system. Further research on vascular responsiveness to different ligands and diverse receptors in various arteries is required to understand the mechanisms underlying the development of these vascular complications. Here, we investigated the vasorelaxant effect of the protease-activated receptor 2 (PAR2) agonist 2-furoyl-LIGRLO-amide (2-Fly) and two commonest agents, namely endothelium-dependent dilator acetylcholine (ACh) and endothelium-independent dilator sodium nitroprusside (SNP), on the thoracic aorta isolated from aged spontaneously hypertensive rats (SHR) (age, 52±1 weeks)...
2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29700120/protease-activated-receptor-2-plays-a-critical-role-in-vascular-inflammation-and-atherosclerosis-in-apolipoprotein-e-deficient-mice
#5
Tomoya Hara, Pham Tran Phuong, Daiju Fukuda, Koji Yamaguchi, Chie Murata, Sachiko Nishimoto, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Issei Imoto, Michio Shimabukuro, Masataka Sata
Background -The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X (FXa), are expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. Methods -We generated apolipoprotein E-deficient ( ApoE-/- ) mice lacking systemic PAR-2 expression ( ApoE-/- PAR-2-/- )...
April 26, 2018: Circulation
https://www.readbyqxmd.com/read/29685684/characterization-of-protease-activated-receptor-par-ligands-parmodulins-are-reversible-allosteric-inhibitors-of-par1-driven-calcium-mobilization-in-endothelial-cells
#6
Disha M Gandhi, Mark W Majewski, Ricardo Rosas, Kaitlin Kentala, Trevor J Foster, Eric Greve, Chris Dockendorff
Several classes of ligands for Protease-Activated Receptors (PARs) have shown impressive anti-inflammatory and cytoprotective activities, including PAR2 antagonists and the PAR1-targeting parmodulins. In order to support medicinal chemistry studies with hundreds of compounds and to perform detailed mode-of-action studies, it became important to develop a reliable PAR assay that is operational with endothelial cells, which mediate the cytoprotective effects of interest. We report a detailed protocol for an intracellular calcium mobilization assay with adherent endothelial cells in multiwell plates that was used to study a number of known and new PAR1 and PAR2 ligands, including an alkynylated version of the PAR1 antagonist RWJ-58259 that is suitable for the preparation of tagged or conjugate compounds...
April 6, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29677491/the-allergen-der-p3-from-house-dust-mite-stimulates-store-operated-ca-2-channels-and-mast-cell-migration-through-par4-receptors
#7
Yu-Ping Lin, Charmaine Nelson, Holger Kramer, Anant B Parekh
The house dust mite is the principal source of perennial aeroallergens in man. How these allergens activate innate and adaptive immunity is unclear, and therefore, there are no therapies targeting mite allergens. Here, we show that house dust mite extract activates store-operated Ca2+ channels, a common signaling module in numerous cell types in the lung. Activation of channel pore-forming Orai1 subunits by mite extract requires gating by STIM1 proteins. Although mite extract stimulates both protease-activated receptor type 2 (PAR2) and PAR4 receptors, Ca2+ influx is more tightly coupled to the PAR4 pathway...
April 19, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29672302/mucosal-two-step-pathogenesis-in-gastroesophageal-reflux-disease-repeated-weakly-acidic-stimulation-and-activation-of-protease-activated-receptor-2-on-mucosal-interleukin-8-secretion
#8
Lukas Winkelsett, Peter Malfertheiner, Thomas Wex, Arne Kandulski
BACKGROUND: Activation of protease-activated receptor-2 (PAR2) is involved in the mucosal immune pathogenesis of gastroesophageal reflux disease (GERD) that is characterized by proinflammatory cytokines such as interleukin-8 (IL-8). PAR2 activation on epithelial cells induces epithelial IL-8 secretion and initiates mucosal inflammation. METHODS: A human primary esophageal epithelial cell model was established to investigate the effects of repeated stimulation with weakly acidic solutions and subsequent PAR2 activation...
April 19, 2018: Digestion
https://www.readbyqxmd.com/read/29604205/kallikrein-related-peptidase-6-orchestrates-astrocyte-form-and-function-through-proteinase-activated-receptor-dependent-mechanisms
#9
Hyesook Yoon, Maja Radulovic, Isobel A Scarisbrick
Kallikrein-related peptidase 6 (Klk6) is the most abundant serine proteinase in the adult central nervous system (CNS), yet we know little regarding its physiological roles or mechanisms of action. Levels of Klk6 in the extracellular environment are dynamically regulated in CNS injury and disease positioning this secreted enzyme to affect cell behavior by potential receptor dependent and independent mechanisms. Here we show that recombinant Klk6 evokes increases in intracellular Ca2+ in primary astrocyte monolayer cultures through activation of proteinase activated receptor 1 (PAR1)...
March 1, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/29599135/par2-protease-activated-receptor-2-deficiency-attenuates-atherosclerosis-in-mice
#10
Shannon M Jones, Adrien Mann, Kelsey Conrad, Keith Saum, David E Hall, Lisa M McKinney, Nathan Robbins, Joel Thompson, Abigail D Peairs, Eric Camerer, Katey J Rayner, Michael Tranter, Nigel Mackman, A Phillip Owens
OBJECTIVE: PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. APPROACH AND RESULTS: PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively...
March 29, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29563756/proteinase-activated-receptor-2-promotes-tumor-cell-proliferation-and-metastasis-by-inducing-epithelial-mesenchymal-transition-and-predicts-poor-prognosis-in-hepatocellular-carcinoma
#11
Liang Sun, Pi-Bao Li, Yan-Fen Yao, Ai-Yuan Xiu, Zhi Peng, Yu-Huan Bai, Yan-Jing Gao
AIM: To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis. METHODS: PAR2 expression levels were assessed by qRT-PCR and immunohistochemistry (IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and HepG2. Cell proliferation and metastasis were assessed both in vitro and in vitro . Immunoblotting was carried out to monitor the levels of mitogen-activated protein kinase (MAPK) and epithelial-mesenchymal transition markers...
March 14, 2018: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29562231/hepatocyte-secreted-dpp4-in-obesity-promotes-adipose-inflammation-and-insulin-resistance
#12
Devram S Ghorpade, Lale Ozcan, Ze Zheng, Sarah M Nicoloro, Yuefei Shen, Emily Chen, Matthias Blüher, Michael P Czech, Ira Tabas
Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT). In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood...
March 29, 2018: Nature
https://www.readbyqxmd.com/read/29554016/protease-activated-receptor-1-is-implicated-in-irritable-bowel-syndrome-mediators-induced-signalling-to-thoracic-human-sensory-neurons
#13
Cleo Desormeaux, Tereza Bautzova, Sonia Garcia-Caraballo, Corinne Rolland, Maria Raffaella Barbaro, Stuart M Brierley, Giovanni Barbara, Nathalie Vergnolle, Nicolas Cenac
Proteases and Protease-Activated Receptors (PARs) are major mediators involved in irritable bowel syndrome (IBS). Our objectives were to decipher the expression and functionality (calcium signaling) of PARs in human dorsal root ganglia (DRG) neurons, and to define mechanisms involved in human sensory neuron signaling by IBS patient mediators.Human thoracic DRG were obtained from the national disease resource interchange. Expression of PAR1, PAR2 and PAR4 was assessed by immunohistochemistry and RT-qPCR in whole DRG or in primary cultures of isolated neurons...
March 15, 2018: Pain
https://www.readbyqxmd.com/read/29532457/heat-shock-protein-27-and-sex-selective-regulation-of-muscarinic-and-proteinase-activated-receptor-2-mediated-vasodilatation-differential-sensitivity-to-endothelial-nos-inhibition
#14
Vivek Krishna Pulakazhi Venu, Mahmoud Saifeddine, Koichiro Mihara, Mahmoud El-Daly, Darrell Belke, Jonathan L E Dean, Edward R O'Brien, Simon A Hirota, Morley D Hollenberg
BACKGROUND AND PURPOSE: Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on endothelial NOS (eNOS)/NO-dependent relaxation induced by ACh and the coagulation pathway-activated receptor, proteinase-activated receptor 2 (PAR2)...
March 12, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29470711/mast-cell-nerve-interaction-in-the-colon-of-trypanosoma-cruzi-infected-individuals-with-chagasic-megacolon
#15
Patrícia Rocha Martins, Rodolfo Duarte Nascimento, Aline Tomaz Dos Santos, Enio Chaves de Oliveira, Patricia Massara Martinelli, Débora d'Avila Reis
Chagas disease is an infection caused by the parasite Trypanosoma cruzi that affects millions of people worldwide and is endemic in Latin America. Megacolon is the most frequent complication of the digestive chronic form and happens due to lesions of the enteric nervous system. The neuronal lesions seem to initiate in the acute phase and persist during the chronic phase, albeit the mechanisms involved in this process are still debated. Among the cells of the immune system possibly involved in this pathological process is the mast cell (MC) due to its well-known role in the bi-directional communication between the immune and nervous systems...
April 2018: Parasitology Research
https://www.readbyqxmd.com/read/29443899/protease-activated-receptor-4-par4-a-promising-target-for-antiplatelet-therapy
#16
REVIEW
Gamariel Rwibasira Rudinga, Ghulam Jilany Khan, Yi Kong
Cardiovascular diseases (CVDs) are currently among the leading causes of death worldwide. Platelet aggregation is a key cellular component of arterial thrombi and major cause of CVDs. Protease-activated receptors (PARs), including PAR1, PAR2, PAR3 and PAR4, fall within a subfamily of seven-transmembrane G-protein-coupled receptors (GPCR). Human platelets express PAR1 and PAR4, which contribute to the signaling transduction processes. In association with CVDs, PAR4 not only contributes to platelet activation but also is a modulator of cellular responses that serve as hallmarks of inflammation...
February 14, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29415278/protease-activated-receptor-2-facilitates-bacterial-dissemination-in-pneumococcal-pneumonia
#17
Florry E van den Boogaard, Xanthe Brands, JanWillem Duitman, Sacha F de Stoppelaar, Keren S Borensztajn, Joris J T H Roelofs, Morley D Hollenberg, C Arnold Spek, Marcus J Schultz, Cornelis van 't Veer, Tom van der Poll
Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor 2 (PAR2) is expressed by different cell types in the lungs and can mediate inflammatory responses. We sought to determine the role of PAR2 during pneumococcal pneumonia. Pneumococcal pneumonia or sepsis was induced in wild-type and PAR2 knock-out (Par2-/-) mice by infection with viable S. pneumoniae. Par2-/- mice demonstrated improved host defense, a largely preserved lung barrier integrity, and reduced mortality during pneumococcal pneumonia...
April 11, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29383785/neutrophilia-gelatinase-release-and-microvascular-leakage-induced-by-human-mast-cell-tryptase-in-a-mouse-model-lack-of-a-role-of-protease-activated-receptor-2-par2
#18
Mogibelrahman M S Khedr, Ahmed M Abdelmotelb, Sylvia L F Pender, Xiaoying Zhou, Andrew F Walls
BACKGROUND: Tryptase, the most abundant protease of the human mast cell, has been implicated as a key mediator of allergic inflammation that acts through activation of PAR2. OBJECTIVES: To investigate the contribution of PAR2 in the pro-inflammatory actions mediated by tryptase in a mice model. METHODS: We have injected recombinant human βII-tryptase into the peritoneum of PAR2-deficient and wild-type C57BL/6 mice. After 6, 12 and 24 hours mice were euthanized, peritoneal lavage performed and inflammatory changes investigated...
January 31, 2018: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29345066/protease-activated-receptor-2-is-necessary-for-neutrophil-chemorepulsion-induced-by-trypsin-tryptase-or-dipeptidyl-peptidase-iv
#19
Michael J V White, Luis E Chinea, Darrell Pilling, Richard H Gomer
Compared to neutrophil chemoattractants, relatively little is known about the mechanism neutrophils use to respond to chemorepellents. We previously found that the soluble extracellular protein dipeptidyl peptidase IV (DPPIV) is a neutrophil chemorepellent. In this report, we show that an inhibitor of the protease activated receptor 2 (PAR2) blocks DPPIV-induced human neutrophil chemorepulsion, and that PAR2 agonists such as trypsin, tryptase, 2f-LIGRL, SLIGKV, and AC55541 induce human neutrophil chemorepulsion...
January 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29339138/hyperglycaemia-disrupts-conducted-vasodilation-in-the-resistance-vasculature-of-db-db-mice
#20
Hamish A L Lemmey, Xi Ye, Hong C Ding, Christopher R Triggle, Christopher J Garland, Kim A Dora
Vascular dysfunction in small resistance arteries is observed during chronic elevations in blood glucose. Hyperglycaemia-associated effects on endothelium-dependent vasodilation have been well characterized, but effects on conducted vasodilation in the resistance vasculature are not known. Small mesenteric arteries were isolated from healthy and diabetic db/db mice, which were used as a model of chronic hyperglycaemia. Endothelium-dependent vasodilation via the Gq/11 -coupled proteinase activated receptor 2 (PAR2) was stimulated with the selective agonist SLIGRL...
January 12, 2018: Vascular Pharmacology
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