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Petra Mrozkova, Diana Spicarova, Jiri Palecek
Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear...
2016: PloS One
Oleg Palygin, Daria V Ilatovskaya, Alexander Staruschenko
Protease-activated receptors (PARs) are a well-known family of transmembrane G-protein-coupled receptors (GPCRs). To date, four PARs have been identified and PAR1 and PAR2 are the most abundant receptors, which were shown to be expressed in the kidney vascular and tubular cells. PAR signaling is mediated by an N-terminus tethered ligands that can be unmasked by serine protease cleavage. PARs are activated by endogenous serine proteases, such as thrombin (acts on PARs 1, 3 and 4) and trypsin (PAR2). PARs can be involved in glomerular, microvascular and inflammatory regulation of renal function in both normal and pathological conditions...
October 12, 2016: American Journal of Physiology. Renal Physiology
Nandan P Deshpande, Marc R Wilkins, Natalia Castaño-Rodríguez, Emily Bainbridge, Nidhi Sodhi, Stephen M Riordan, Hazel M Mitchell, Nadeem O Kaakoush
The epithelial response to the opportunistic pathogen Campylobacter concisus is poorly characterised. Here, we assessed the intestinal epithelial responses to two C. concisus strains with different virulence characteristics in Caco-2 cells using RNAseq, and validated a subset of the response using qPCR arrays. C. concisus strains induced distinct response patterns from intestinal epithelial cells, with the toxigenic strain inducing a significantly more amplified response. A range of cellular functions were significantly regulated in a strain-specific manner, including epithelial-to-mesenchymal transition (NOTCH and Hedgehog), cytoskeletal remodeling, tight junctions, inflammatory responses and autophagy...
September 28, 2016: Scientific Reports
Ai Kanemaru, Koji Yamamoto, Makiko Kawaguchi, Tsuyoshi Fukushima, Chen-Yong Lin, Michael D Johnson, Eric Camerer, Hiroaki Kataoka
Cancer-associated fibroblasts (CAFs) are known to contribute to cancer progression. We have reported that cell surface expression of hepatocyte growth factor activator inhibitor 1 (HAI-1) is decreased in invasive oral squamous cell carcinoma (OSCC) cells. This study examined if HAI-1-insufficiency contributes to CAF recruitment in OSCC. Serum-free conditioned medium (SFCM) from a human OSCC line (SAS) stimulated the migration of 3 human fibroblast cell lines, NB1RGB, MRC5 and KD. SFCM from HAI-1-knockdown SAS showed an additive effect on the migration of NB1RGB and MRC5, but not KD...
September 12, 2016: International Journal of Cancer. Journal International du Cancer
Andrew M Shearer, Rajashree Rana, Karyn Austin, James D Baleja, Nga Nguyen, Andrew Bohm, Lidija Covic, Athan Kuliopulos
Chronic liver inflammation and fibrosis in NASH can lead to cirrhosis and liver failure for which there are currently no approved treatments. Protease Activated Receptor-2 (PAR2) is an emerging new target expressed on liver stellate cells and hepatocytes that regulates the response to liver injury and inflammation. Here, we identified a pepducin to block the deleterious actions of PAR2 in promoting liver fibrosis. Non-alcoholic fatty liver disease (NAFLD) and early fibrosis was induced by the methionine-choline deficient diet (MCD) in mice...
September 9, 2016: Journal of Biological Chemistry
Amit Jairaman, Chelsea H Maguire, Robert P Schleimer, Murali Prakriya
Aberrant immune responses to environmental allergens including insect allergens from house dust mites and cockroaches contribute to allergic inflammatory diseases such as asthma in susceptible individuals. Airway epithelial cells (AECs) play a critical role in this process by sensing the proteolytic activity of allergens via protease-activated receptors (PAR2) to initiate inflammatory and immune responses in the airway. Elevation of cytosolic Ca(2+) is an important signaling event in this process, yet the fundamental mechanism by which allergens induce Ca(2+) elevations in AECs remains poorly understood...
2016: Scientific Reports
Nam-Chul Cho, Seoung-Hwan Seo, Dohee Kim, Ji-Sun Shin, Jeongmin Ju, Jihye Seong, Seon Hee Seo, Iiyoun Lee, Kyung-Tae Lee, Yun Kyung Kim, Kyoung Tai No, Ae Nim Pae
Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library...
August 2016: Journal of Computer-aided Molecular Design
Camille Ettelaie, Mary E W Collier, Sophie Featherby, John Greenman, Anthony Maraveyas
Restriction of tissue factor (TF) activity at the cell surface and TF release are critical for prevention of excessive coagulation. This study examined the regulation of TF dephosphorylation and its release through ubiquitination. A plasmid containing the sequence to express the tandem protein TF-tGFP was mutated to include an arginine-substitution at Lys255 within TF. MDA-MB-231 cell line, and HCAEC endothelial cells were transfected and subsequently activated with PAR2-agonist peptide. The wild-type and mutant TF-tGFP were immunoprecipitated from the cell lysates and the ubiquitination and phosphorylation state of TF examined...
September 3, 2016: Biochimica et Biophysica Acta
Hye One Kim, Yong Se Cho, Sook Young Park, In Suk Kwak, Min Gyu Choi, Bo Young Chung, Chun Wook Park, Jun Young Lee
Post burn pruritus is a common distressing sequela of burn wounds. Empirical antipruritic treatment often fails to have a satisfactory outcome, as the mechanism of it has not been fully elucidated. The aim of this study was to evaluate the manifestation of transient receptor potential vanilloid 3 (TRPV3), transient receptor potential ankyrin 1 (TRPA1) and other related receptors in post burn pruritus. Sixty-five burn patients with (n = 40) or without (n = 25) pruritus were investigated, including skin biopsies...
August 19, 2016: Wound Repair and Regeneration
Jin Joo Kim, Nayoung Kim, Yoon Jin Choi, Joo Sung Kim, Hyun Chae Jung
Transient receptor potential vanilloid-1 (TRPV1) receptor and proteinase-activated receptor 2 (PAR2) have been implicated in the mechanism of acid-induced inflammation in gastroesophageal reflux disease (GERD). We aimed to evaluate TRPV1 and PAR2 mRNA expression levels in the GERD patients and their relationship with endoscopic findings and reflux symptoms.Sixteen healthy controls, 45 patients with erosive reflux disease (ERD), and 14 nonerosive reflux disease (NERD) patients received endoscopy and completed questionnaires...
August 2016: Medicine (Baltimore)
Franziska Mußbach, Hendrik Ungefroren, Bernd Günther, Kathrin Katenkamp, Petra Henklein, Martin Westermann, Utz Settmacher, Lennart Lenk, Susanne Sebens, Jörg P Müller, Frank-Dietmar Böhmer, Roland Kaufmann
BACKGROUND: Previous studies have established that proteinase-activated receptor 2 (PAR2) promotes migration and invasion of hepatocellular carcinoma (HCC) cells, suggesting a role in HCC progression. Here, we assessed the impact of PAR2 in HCC stromal cells on HCC growth using LX-2 hepatic stellate cells (HSCs) and Hep3B cells as model. METHODS: PAR2 expression and function in LX-2 cells was analysed by RT-PCR, confocal immunofluorescence, electron microscopy, and [Ca(2+)]i measurements, respectively...
2016: Molecular Cancer
Hans Gamperl, Corinna Plattfaut, Annika Freund, Tabea Quecke, Friederike Theophil, Frank Gieseler
Elevated levels of extracellular vesicles (EVs) have been correlated with inflammatory diseases as well as progressive and metastatic cancer. By presenting tissue factor (TF) on their membrane surface, cellular microparticles (MPs) activate both the coagulation system and cell-signaling pathways such as the PAR/ERK pathway. We have shown before that malignant effusions are a rich source of tumor cell-derived EVs. Here, we used EVs from malignant effusions from three different patients after serial low-speed centrifugation steps as recommended by the ISTH (lsEV)...
October 2016: Cell Biology International
T Lieu, E Savage, P Zhao, L Edgington-Mitchell, N Barlow, R Bron, D P Poole, P McLean, R-J Lohman, D P Fairlie, N W Bunnett
BACKGROUND AND PURPOSE: Diverse proteases cleave protease-activated receptor-2 (PAR2) on primary sensory neurons and epithelial cells to evoke pain and inflammation. Trypsin and tryptase activate PAR2 by a canonical mechanism that entails cleavage within the extracellular N-terminus revealing a tethered ligand that activates the cleaved receptor. Cathepsin-S and elastase are biased agonists that cleave PAR2 at different sites to activate distinct signalling pathways. Although PAR2 is a therapeutic target for inflammatory and painful diseases, the divergent mechanisms of proteolytic activation complicate the development of therapeutically useful antagonists...
September 2016: British Journal of Pharmacology
D Q Wang, Y Y Shen, J H Xu, H Tang
This study aimed to investigate the effects of the house dust mite allergen Der p 1 on the secretion of tryptase from the human mast cell line HMC-1. Flow cytometry was used to determine the expression levels of protease-activated receptor-2 (PAR2) on the surface of HMC-1 cells. HMC-1 cells were treated with Der p 1, SLIGRL-NH2 (PAR2 agonist), LRGILS-NH2 (control peptide for PAR2), or Der p 1 + FSLLRY (PAR2 antagonist), and the tryptase levels were measured using enzyme-linked immunosorbent assay. The biological functions of PAR2 were determined using the calcium green indicator, and intracellular calcium fluorescence intensity in the different groups (Der p 1, SLIGRL-NH2, LRGILS- NH2, Der p 1 + FSLLRY, tryptase, tryptase + FSLLRY, or cell culture medium) was detected by laser scanning confocal microscopy...
2016: Genetics and Molecular Research: GMR
Robson Q Monteiro, Luize G Lima, Nathália P Gonçalves, Mayara R Arruda DE Souza, Ana C Leal, Marcos A Almeida Demasi, Mari C Sogayar, Tatiana C Carneiro-Lobo
Hypoxia and necrosis are fundamental features of glioma, and their emergence is critical for the rapid biological progression of this fatal tumor. The presence of vaso-occlusive thrombus is higher in grade IV tumors [glioblastoma multiforme (GBM)] compared with lower grade tumors, suggesting that the procoagulant properties of the tumor contribute to its aggressive behavior, as well as the establishment of tumor hypoxia and necrosis. Tissue factor (TF), the primary cellular initiator of coagulation, is overexpressed in GBMs and likely favors a thrombotic microenvironment...
July 2016: Oncology Letters
Imen Nasri, Delphine Bonnet, Bailey Zwarycz, Emilie d'Aldebert, Sokchea Khou, Raoudha Mezghani-Jarraya, Muriel Quaranta, Corinne Rolland, Chrystelle Bonnart, Emmanuel Mas, Audrey Ferrand, Nicolas Cenac, Scott Magness, Laurianne Van Landeghem, Nathalie Vergnolle, Claire Racaud-Sultan
Protease-activated receptors PAR1 and PAR2 play an important role in the control of epithelial cell proliferation and migration. However, the survival of normal and tumor intestinal stem/progenitor cells promoted by proinflammatory mediators may be critical in oncogenesis. The glycogen synthase kinase-3β (GSK3β) pathway is overactivated in colon cancer cells and promotes their survival and drug resistance. We thus aimed to determine PAR1 and PAR2 effects on normal and tumor intestinal stem/progenitor cells and whether they involved GSK3β...
August 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Yuji Oe, Sakiko Hayashi, Tomofumi Fushima, Emiko Sato, Kiyomi Kisu, Hiroshi Sato, Sadayoshi Ito, Nobuyuki Takahashi
OBJECTIVE: The role of hypercoagulability in the pathogenesis of diabetic nephropathy (DN) remains elusive. We recently reported the increased infiltration of macrophages expressing tissue factor in diabetic kidney glomeruli; tissue factor activates coagulation factor X (FX) to FXa, which in turn stimulates protease-activated receptor 2 (PAR2) and causes inflammation. APPROACH AND RESULTS: Here, we demonstrated that diabetes mellitus increased renal FX mRNA, urinary FXa activity, and FX expression in glomerular macrophages...
August 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Xiao-Jing Liu, Zhang-Lei Mu, Yan Zhao, Jian-Zhong Zhang
BACKGROUND: Tetracycline (TET) has been found to have both antibiotic and anti-inflammatory properties. The anti-inflammatory effect of topical TET on atopic dermatitis (AD) has not been reported. The purpose of this study was to explore the potential role of topical TET and its anti-inflammatory effects in a mouse model of AD. METHODS: The 2% TET was applied topically to ears of MC903-induced AD-like BALB/c mice once a day. AD-like symptoms and severity were evaluated by assessing skin scoring of dermatitis, ear thickness, and frequency of scratching...
June 20, 2016: Chinese Medical Journal
Franziska Zeeh, David Witte, Thomas Gädeken, Bernhard H Rauch, Evelin Grage-Griebenow, Nadja Leinung, Sofie Joline Fromm, Stephanie Stölting, Koichiro Mihara, Roland Kaufmann, Utz Settmacher, Hendrik Lehnert, Morley D Hollenberg, Hendrik Ungefroren
Pancreatic ductal adenocarcinoma (PDAC) is characterized by high expression of transforming growth factor (TGF)-β and the G protein-coupled receptor proteinase-activated receptor 2 (PAR2), the latter of which functions as a cell-surface sensor for serine proteinases asscociated with the tumour microenvironment. Since TGF-β and PAR2 affect tumourigenesis by regulating migration, invasion and metastasis, we hypothesized that there is signalling crosstalk between them. Depleting PDAC and non-PDAC cells of PAR2 by RNA interference strongly decreased TGF-β1-induced activation of Smad2/3 and p38 mitogen-activated protein kinase, Smad dependent transcriptional activity, expression of invasion associated genes, and cell migration/invasion in vitro...
May 27, 2016: Oncotarget
Oskar Eriksson, Åsa Thulin, Anna Asplund, Geeta Hegde, Sanjay Navani, Agneta Siegbahn
BACKGROUND: Tissue Factor (TF) forms a proteolytically active complex together with coagulation factor VIIa (FVIIa) and functions as the trigger of blood coagulation or alternatively activates cell signaling. We recently described that EphA2 of the Eph tyrosine kinase receptor family is cleaved directly by the TF/FVIIa complex. The aim of the present study was to further characterize the cross-talk between TF/FVIIa and EphA2 using in vitro model systems and human cancer specimens. METHODS: Cleavage and phosphorylation of EphA2 was studied by Western blot...
2016: BMC Cancer
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