Article
Cardiac & Cardiovascular Systems
Christine Joseph, Eva Maria Berghausen, Arnica Behringer, Bernhard Rauch, Henrik Ten Freyhaus, Leoni Luisa Gnatzy-Feik, Maximilian Krause, Dickson W. L. Wong, Peter Boor, Stephan Baldus, Marius Vantler, Stephan Rosenkranz
Summary: This study characterizes the effects of thrombin and Factor Xa on PASMCs and their involvement in pulmonary vascular remodeling through PAR-1 and PAR-2. Inhibition of PAR-1 and PAR-2 significantly reduces vascular muscularization and improves right ventricular function in PAH. These findings suggest that PARs, rather than their activators, could be potential targets for PAH treatment.
CARDIOVASCULAR RESEARCH
(2022)
Article
Hematology
Sujuan Li, Weili Wang, Lisha Lin, Lian Yang, Ying Cai, Xingzhi Yang, Taocui Zhang, Chuang Xiao, Hui Yan, Na Gao, Jinhua Zhao
Summary: An oligosaccharide HS-11, derived from sea cucumber Holothuria fuscopunctata, inhibits thrombin-mediated platelet activation and aggregation by directly binding to thrombin exosite II, demonstrating its antiplatelet and antithrombotic activity.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Shi-Jye Chu, Shih-En Tang, Hsin-Ping Pao, Shu-Yu Wu, Wen- Liao
Summary: This study demonstrates that the PAR-1 antagonist SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-kappa B, and MAPK pathways, reducing IR-induced acute lung injury. These findings suggest that PAR-1 antagonist could be a potential therapeutic candidate for lung protection following IR injury.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Elena Pompili, Valerio De Franchis, Claudia Giampietri, Stefano Leone, Elena De Santis, Francesco Fornai, Lorenzo Fumagalli, Cinzia Fabrizi
Summary: Schwann cells play a crucial role in peripheral nerve regeneration by promptly activating, dedifferentiating, and assisting axon regrowth after nerve injury. PAR1, a thrombin receptor present on Schwann cell plasma membrane, is emerging as a possible regulator of Schwann cells' pro-regenerative capacity. This review summarizes recent literature on the contribution of PAR1 and PAR1-activating proteases in regulating peripheral nerve regeneration.
Article
Hematology
Maria Isabel Fleischer, Nadine Roehrig, Verena K. Raker, Juliane Springer, Detlef Becker, Sandra Ritz, Matthias Bros, Henner Stege, Maximilian Haist, Stephan Grabbe, Jessica Haub, Christian Becker, Sabine Reyda, Jennifer Disse, Talkea Schmidt, Karsten Mahnke, Hartmut Weiler, Wolfram Ruf, Kerstin Steinbrink
Summary: The study found increased PAR2(+) infiltrating myeloid cells in ACD patients and CHS mice. Deletion of PAR2 in myeloid cells and PAR2 cleavage insensitivity reduced skin inflammation and Tc1/Th1 cell response.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Pharmacology & Pharmacy
Mohd Aslam Saifi, Shivaraju Annaldas, Chandraiah Godugu
Summary: The study revealed the therapeutic effect of a direct thrombin inhibitor on tubulointerstitial fibrosis in chronic kidney disease by improving kidney injury and fibrosis through inhibition of thrombin-activated PAR-1 expression.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Sukanya Tripathy, Bader O. Almutairi, Sanjay Singh, Atul Rawat, Durgesh Dubey, Monisha Banerjee, Dinesh R. Modi, Anand Prakash
Summary: Thrombin-activated receptor-1 (PAR1) plays a crucial role in tumor angiogenesis, cell proliferation, and invasion. The present study investigated the expression of PAR1 in human glioma cell lines D54 and U87, as well as its downstream signaling pathway. The results showed that PAR1 was highly expressed in D54 cells compared to U87 cells. Activation of PAR1 led to increased ERK1/2 activity and enhanced migration and invasion. The antagonist SCH79797 significantly inhibited the migration and invasion of the glioma cell lines. Moreover, PAR1 activation affected intracellular Ca+2 concentration ([Ca+2]i). Thrombin and TFLLR induced an increase in [Ca+2]i, which was suppressed by the PAR1 inhibitor SCH79797. The study suggests that PAR1 signaling contributes to glioma progression and may serve as a potential therapeutic target for glioma prevention.
JOURNAL OF KING SAUD UNIVERSITY SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Shani Berkowitz, Shany Guly Gofrit, Shay Anat Aharoni, Valery Golderman, Lamis Qassim, Zehavit Goldberg, Amir Dori, Nicola Maggio, Joab Chapman, Efrat Shavit-Stein
Summary: The study found that there is an interaction between neuroinflammation and coagulation, and enoxaparin can protect against inflammation induced by LPS, reducing neuronal damage. The findings may provide a new pharmacological mechanism for intervening in neuroinflammation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Jing Yang, Claudio Mapelli, Zhaoqing Wang, Chi Shing Sum, Ji Hua, R. Michael Lawrence, Yan Ni, Dietmar A. Seiffert
Summary: Protease-activated receptor 4 (PAR4) is a promising drug target for improving the efficacy and safety of antiplatelet agents. However, the current PAR4 agonist peptides have limited utility in pharmacodynamic assays due to their high concentrations required to elicit an agonist response. This study developed a more potent PAR4 agonist peptide and a platelet aggregation assay for evaluating PAR4 antagonists, providing a valuable tool for the clinical development of PAR4 antagonists.
Article
Biochemistry & Molecular Biology
Danielle Kamato, Mai Gabr, Hirushi Kumarapperuma, Zheng J. Chia, Wenhua Zheng, Suowen Xu, Narin Osman, Peter J. Little
Summary: This study aimed to investigate the role of proximal G proteins in PAR-1 transactivation-dependent signaling. The findings showed that G alpha q is involved in PAR-1-mediated proteoglycan modification, while G alpha 11 has no effect. These findings are significant for the study of other GPCRs involved in vascular pathology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Aditi Kothari, Matthew J. Flick
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with a low 5-year survival rate due to its aggressive nature and late-stage diagnosis. The coagulation system plays a crucial role in PDAC progression and dissemination, promoting tumor growth and spread.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Julian Friebel, Eileen Moritz, Marco Witkowski, Kai Jakobs, Elisabeth Straessler, Andrea Doerner, Daniel Steffens, Marianna Puccini, Stella Lammel, Rainer Glauben, Franziska Nowak, Nicolle Kraenkel, Arash Haghikia, Verena Moos, Heinz-Peter Schutheiss, Stephan B. Felix, Ulf Landmesser, Bernhard H. Rauch, Ursula Rauch
Summary: The study found that vorapaxar may reduce inflammation in atherosclerosis by inhibiting the PAR1 signaling pathway, potentially helping to lower the risk of thrombo-inflammatory events in patients.
Article
Gastroenterology & Hepatology
Ying Xie, Lindsey Fontenot, Andrea Chupina Estrada, Becca Nelson, Jiani Wang, David Q. Shih, Wendy Ho, S. Anjani Mattai, Florian Rieder, Dane D. Jensen, Nigel W. Bunnett, Hon Wai Koon
Summary: The study demonstrates that Elafin can suppress collagen synthesis in intestinal fibroblasts by inhibiting protease-activated receptor 2, which is dependent on cathelin S, leading to a reduction in intestinal fibrosis.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2022)
Article
Cell Biology
Julian Friebel, Marco Witkowski, Max Wegner, Leon Bloebaum, Stella Lammel, Philipp-Alexander Schencke, Kai Jakobs, Marianna Puccini, Daniela Reissner, Daniel Steffens, Verena Moos, Heinz-Peter Schutheiss, Ulf Landmesser, Ursula Rauch
Summary: This study investigates the role of thrombin receptor (PAR1) in thrombo-inflammation mediated by cytotoxic CD8(+) T lymphocytes in patients with first-diagnosed atrial fibrillation (AF). The results demonstrate that PAR1 activation is associated with inflammation and cytotoxic function, and its activation is correlated with adverse cardiac remodeling and atrial dysfunction biomarkers. Interventions targeting this cascade may be a promising approach for reducing disease progression and vascular complications of AF.
Article
Neurosciences
Willian Link Papalia, Alexandre Seixas Nascimento, Gokul Krishnan, Nubia Broetto, Ana Flavia Furian, Mauro Schneider Oliveira, Luiz Fernando Freire Royes, Michele Rechia Fighera
Summary: Understanding neurovascular dysregulation after TBI is crucial for establishing scientific-based rehabilitative strategies, with physical exercise potentially playing a significant role. However, there are caveats to consider when interpreting the effect of physical exercise on neurovascular dysregulation after TBI.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Surgery
Pablo D. Becker, Kulachelvy Ratnasothy, Monica Sen, Qi Peng, Marco Romano, Jordan Bazoer, Erik Suvitra, Anas Stout, Shannon G. Hylton, Anthony Dorling, Robert I. Lechler, Lesley A. Smyth, Giovanna Lombardi
Summary: B cells play a crucial role in transplant rejection by controlling indirect T cell responses, either through antibody-mediated mechanisms or by presenting donor antigens to T cells. Depletion of B cells prolongs skin graft survival, highlighting their contribution to indirect pathway sensitization. Additionally, B cells may present alloantigens via acquisition of MHC-peptide complexes, and combining B cell depletion with regulatory T cell transfer further enhances skin graft survival.
AMERICAN JOURNAL OF TRANSPLANTATION
(2021)
Article
Surgery
Adarsh Babu, Natasha Khovanova, Olivia Shaw, Sian Griffin, David Briggs, Nithya S. Krishnan, Simon Fletcher, Christopher Imray, Adrienne Seitz, Richard Baker, Matthew Wellberry-Smith, Brendan Clarke, Katherine Cullen, Tracey Rees, Frankie Edwards, Emma Burrows, Louise Howe, Chloe Martin, Anthony Dorling, Daniel Zehnder, Robert M. Higgins, Daniel A. Mitchell, Sunil Daga
TRANSPLANT INTERNATIONAL
(2020)
Letter
Surgery
Caroline Dudreuilh, Anthony Dorling
TRANSPLANT INTERNATIONAL
(2020)
Article
Multidisciplinary Sciences
Hannah Wilkinson, Hugh Leonard, Daxin Chen, Toby Lawrence, Michael Robson, Pieter Goossens, John H. McVey, Anthony Dorling
Summary: Research has shown that in chronic inflammation, the PAR-1 signal is crucial for granuloma formation, with this signal acting on macrophages through the activation of Thrombin. The results of the experiment indicate that Thrombin signaling significantly enhances macrophage sensitivity to IFN-γ, leading to enhanced cell polarization.
Review
Immunology
Caroline Dudreuilh, Sumoyee Basu, Cristiano Scotta, Anthony Dorling, Giovanna Lombardi
Summary: Regulatory T cells like Tregs play a crucial role in maintaining immune balance and preventing autoimmune diseases. Specifically, Tfr cells regulate interactions between B cells and Tfh cells, and their potential applications in transplantation and immunosuppression warrant further exploration.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Surgery
Benedict L. Phillips, Maria Ibrahim, George H. B. Greenhall, Lisa Mumford, Anthony Dorling, Chris J. Callaghan
Summary: The presence of DGF does not impact long-term graft or patient survival, but a DGF duration of more than 14 days is associated with significantly worse longer-term outcomes.
AMERICAN JOURNAL OF TRANSPLANTATION
(2021)
Article
Urology & Nephrology
Narayan Karunanithy, Emily J. Robinson, Farhan Ahmad, James O. Burton, Francis Calder, Simon Coles, Neelanjan Das, Anthony Dorling, Colin Forman, Ounali Jaffer, Sarah Lawman, Raghuram Lakshminarayan, Rhys Lewlellyn, Janet L. Peacock, Raymond Ramnarine, Irene Rebollo Mesa, Shoaib Shaikh, James Simpson, Kate Steiner, Rebecca Suckling, Laszlo Szabo, Douglas Turner, Ashar Wadoodi, Yanzhong Wang, Graeme Weir, C. Jason Wilkins, Leanne M. Gardner, Michael G. Robson
Summary: The study aimed to evaluate the efficacy of paclitaxel-coated balloons in arteriovenous fistulas, but found no additional benefit from the use of these balloons following angioplasty.
KIDNEY INTERNATIONAL
(2021)
Article
Urology & Nephrology
Hannah Burton, Laura McLaughlin, Kin Yee Shiu, Olivia Shaw, Nizam Mamode, Jo Spencer, Anthony Dorling
Summary: B cells play crucial roles in cell-mediated alloimmune responses. Studying antigen-specific B cells may identify new targets for intervention. HLA-binding B cells are strongly associated with interferon-gamma production and may not be suppressible by endogenous Tregs.
KIDNEY INTERNATIONAL
(2022)
Editorial Material
Urology & Nephrology
Sumoyee Basu, Anthony Dorling
Summary: The cellular mechanisms underlying donor-specific antibody formation and antibody-mediated rejection are still unknown. This study reveals that specific subsets of T-regulatory cells and B-regulatory transitional cells are simultaneously reduced in patients with donor-specific antibody and subsequent antibody-mediated rejection. Furthermore, alterations in specific cytokines and costimulatory molecules are identified as important mechanisms by which these cells suppress donor-specific antibody formation and independently contribute to the progression of antibody-mediated rejection.
KIDNEY INTERNATIONAL
(2022)
Article
Immunology
Hannah Wilkinson, Hugh Leonard, Michael G. Robson, Richard Smith, ElLi Tam, John H. McVey, Daniel Kirckhofer, Daxin Chen, Anthony Dorling
Summary: TF-mediated PAR-1 and PAR-2 signaling determines the response of myeloid cells to IFN gamma in a homeostatic manner. The use of 3-MP, an agent that inhibits PAR-1 while delivering a PAR-2 signal, can effectively abolish immune responses dependent on M1 polarization, potentially providing therapeutic potential for various diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Qi Peng, Anna Nowocin, Kulachelvy Ratnasothy, Richard A. Smith, Lesley A. Smyth, Robert I. Lechler, Anthony Dorling, Giovanna Lombardi
Summary: Thrombin inhibition enhances the infiltration of anti-inflammatory cells and improves renal ischemia-reperfusion injury. In a transplant model, combined therapy of thrombin inhibition and regulatory T cell infusion leads to prolonged graft survival and reduced inflammation.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Medicine, General & Internal
Pankaj Chandak, Benedict L. Phillips, Danothy Bennett, Raphael Uwechue, Nicos Kessaris, Olivia Shaw, Tim Maggs, Luke Woodford, David Veniard, Ranmith Perera, Kiran Parmar, Beverley J. Hunt, Chris Callaghan, Anthony Dorling, Nizam Mamode
Summary: This study successfully established a clinically relevant model of antibody-mediated rejection using human kidneys and ex-vivo normothermic machine perfusion, providing a new platform for studying and preventing antibody-mediated rejection.
Editorial Material
Urology & Nephrology
Sumoyee Basu, Anthony Dorling, Anita S. Chong
Summary: Borderline allograft rejection can lead to acute rejection and graft loss in certain patients. Cherukuri et al. have developed a novel test based on transitional T1 B cells that produce interleukin-10 and tumor necrosis factor-a, which can identify high-risk patients for poor outcomes. Further research is needed to understand the potential mechanisms of how transitional T1 B cells modulate alloreactivity, but this biomarker has the potential to stratify patients and guide early intervention.
KIDNEY INTERNATIONAL
(2023)
Article
Urology & Nephrology
C. Dudreuilh, P. Jarvis, N. Beadle, I Pilecka, O. Shaw, L. Gardner, C. Scotta, N. Mamode, D. S. Game, A. Sanchez-Fueyo, G. Lombardi, A. Learoyd, A. Douiri, A. Dorling
Summary: This study aims to suppress memory T and B cell responses against specific HLA antigens in highly sensitised kidney transplant patients by introducing autologous polyclonally expanded regulatory T cells. It is a two-part prospective clinical trial, with the first part being an observational phase and the second part being an interventional phase. The results will help determine the feasibility of using Treg therapy to modulate memory immune responses.
Article
Surgery
Dennis A. J. van den Broek, Soufian Meziyerh, Klemens Budde, Carmen Lefaucheur, Emanuele Cozzi, Dominique Bertrand, Covadonga Lopez del Moral, Anthony Dorling, Marie-Paule Emonds, Maarten Naesens, Aiko P. J. de Vries
Summary: Solid phase immunoassays have improved the detection of donor-specific antibodies (DSA) to human leukocyte antigens (HLA) in kidney transplantation, but the monitoring of DSA in recipients with stable graft function is not universally accepted as standard care. This consensus report aims to assess the clinical utility of DSA monitoring in recipients without signs of graft dysfunction using the Wilson & Junger criteria and presents the findings and recommendations of a dedicated workgroup on subclinical DSA monitoring.
TRANSPLANT INTERNATIONAL
(2023)