المؤلفون: Xin Zhuo, Yue Wu, Xiujuan Fu, Jianbin Li, Yuxin Xiang, Xiaoyu Liang, Canquan Mao, Yuhong Jiang

المصدر: Acta Pharmaceutica Sinica B, Vol 14, Iss 3, Pp 1441-1456 (2024)

مصطلحات موضوعية: Protease-activated receptor 2 (PAR2), CRISPR-Cas9, Gene editing, Inflammation, Acute lung inflammation, NLRP3, Therapeutics. Pharmacology, RM1-950

الوصف: Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases, immune cell infiltration and protease-driven tissue damages. It is an urgent need to explore potential drug strategies for mitigating lung inflammation. Protease-activated receptor 2 (PAR2) as a vital molecular target principally participates in various inflammatory diseases via intracellular signal transduction. However, it has been rarely reported about the role of PAR2 in lung inflammation. This study applied CRISPR-Cas9 system encoding Cas9 and sgRNA (pCas9-PAR2) for PAR2 knockout and fabricated an anionic human serum albumin-based nanoparticles to deliver pCas9-PAR2 with superior inflammation-targeting efficiency and stability (TAP/pCas9-PAR2). TAP/pCas9-PAR2 robustly facilitated pCas9-PAR2 to enter and transfect inflammatory cells, eliciting precise gene editing of PAR2 in vitro and in vivo. Importantly, PAR2 deficiency by TAP/pCas9-PAR2 effectively and safely promoted macrophage polarization, suppressed pro-inflammatory cytokine releases and alleviated acute lung inflammation, uncovering a novel value of PAR2. It also revealed that PAR2-mediated pulmonary inflammation prevented by TAP/pCas9-PAR2 was mainly dependent on ERK-mediated NLRP3/IL-1β and NO/iNOS signalling. Therefore, this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211383523003179Test; https://doaj.org/toc/2211-3835Test

الوصول الحر: https://doaj.org/article/608b7220f53c431f91279a64cd355fccTest

المؤلفون: Gal Reches, Lynn Khoon, Narmeen Ghanayiem, Assaf Malka, Ron Piran

المصدر: Biomedicine & Pharmacotherapy, Vol 175, Iss , Pp 116622- (2024)

مصطلحات موضوعية: Type 1 diabetes, Protease Activated Receptor 2 (Par2), Autoimmunity, Tissue-specific mutation, Pancreatic β-cells, Therapeutics. Pharmacology, RM1-950

الوصف: Background: Type 1 diabetes (T1D) is a challenging autoimmune disease, characterized by an immune system assault on insulin-producing β-cells. As insulin facilitates glucose absorption into cells and tissues, β-cell deficiency leads to elevated blood glucose levels on one hand and target-tissues starvation on the other. Despite efforts to halt β-cell destruction and stimulate recovery, success has been limited. Our recent investigations identified Protease-Activated Receptor 2 (Par2) as a promising target in the battle against autoimmunity. We discovered that Par2 activation’s effects depend on its initial activation site: exacerbating the disease within the immune system but fostering regeneration in affected tissue. Methods: We utilized tissue-specific Par2 knockout mice strains with targeted Par2 mutations in β-cells, lymphocytes, and the eye retina (as a control) in the NOD autoimmune diabetes model, examining T1D onset and β-cell survival. Results: We discovered that Par2 expression within the immune system accelerates autoimmune processes, while its presence in β-cells offers protection against β-cell destruction and T1D onset. This suggests a dual-strategy treatment for T1D: inhibiting Par2 in the immune system while activating it in β-cells, offering a promising strategy for T1D. Conclusions: This study highlights Par2's potential as a drug target for autoimmune diseases, particularly T1D. Our results pave the way for precision medicine approaches in treating autoimmune conditions through targeted Par2 modulation.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332224005067Test; https://doaj.org/toc/0753-3322Test

الوصول الحر: https://doaj.org/article/057c94efd7544f7f916eec1ae6cb0856Test

المؤلفون: Makoto Nakano, Satoshi Yasuda, Yuhi Hasebe, Kotaro Nochioka, Koji Fukuda, Jun Takahashi, Hiroaki Shimokawa

المصدر: International Journal of Cardiology: Heart & Vasculature, Vol 52, Iss , Pp 101387- (2024)

مصطلحات موضوعية: Direct oral anticoagulants, Protease-activated-receptor, Diseases of the circulatory (Cardiovascular) system, RC666-701

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2352906724000538Test; https://doaj.org/toc/2352-9067Test

الوصول الحر: https://doaj.org/article/f03fb9e07ebf4ea0a94d4fe9270e1dc5Test

المؤلفون: Hao-Chien Hung, Ming-Huei Fan, Daniel Wang, Carol H. Miao, Pong Su, Chao-Lien Liu

المصدر: BMC Medicine, Vol 21, Iss 1, Pp 1-19 (2023)

مصطلحات موضوعية: Pancreatic ductal adenocarcinoma (PDAC), Pancreatic cancer, Protease-activated receptor 1 (PAR1), Chimeric antigen receptor (CAR), TGF-β, Medicine

الوصف: Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year survival rate of 6% following a diagnosis, and novel therapeutic modalities are needed. Protease-activated receptor 1 (PAR1) is abundantly overexpressed by both tumor cells and multiple stroma cell subsets in the tumor microenvironment (TME), thereby offering a suitable immunotherapy target. Methods A chimeric antigen receptor (CAR) strategy was applied to target PAR1 using a human anti-PAR1 scFv antibody fused to the transmembrane region with two co-stimulatory intracellular signaling domains of cluster of differentiation 28 (CD28) and CD137 (4-1BB), added to CD3ζ in tandem. Results The engineered PAR1CAR-T cells eliminated PAR1 overexpression and transforming growth factor (TGF)-β-mediated PAR1-upregulated cancer cells by approximately 80% in vitro. The adoptive transfer of PAR1CAR-T cells was persistently enhanced and induced the specific regression of established MIA PaCa-2 cancer cells by > 80% in xenograft models. Accordingly, proinflammatory cytokines/chemokines increased in CAR-T-cell-treated mouse sera, whereas Ki67 expression in tumors decreased. Furthermore, the targeted elimination of PAR1-expressing tumors reduced matrix metalloproteinase 1 (MMP1) levels, suggesting that the blocking of the PAR1/MMP1 pathway constitutes a new therapeutic option for PDAC treatment. Conclusions Third-generation PAR1CAR-T cells have antitumor activity in the TME, providing innovative CAR-T-cell immunotherapy against PDAC.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1741-7015Test

الوصول الحر: https://doaj.org/article/c6596f5c0f934ffe888caea449003de4Test

المؤلفون: Ho Young Lee, Dorothy J. You, Alexia Taylor-Just, Logan J. Tisch, Ryan D. Bartone, Hannah M. Atkins, Lauren M. Ralph, Silvio Antoniak, James C. Bonner

المصدر: Particle and Fibre Toxicology, Vol 20, Iss 1, Pp 1-19 (2023)

مصطلحات موضوعية: Carbon nanotubes, Allergens, Protease-activated receptor 2, Lung, Inflammation, Fibrosis, Toxicology. Poisons, RA1190-1270, Industrial hygiene. Industrial welfare, HD7260-7780.8

الوصف: Abstract Background Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been reported to exert strong pro-inflammatory and pro-fibrotic adjuvant effects in mouse models of allergic lung disease. However, the molecular mechanisms through which MWCNTs exacerbate allergen-induced lung disease remain to be elucidated. We hypothesized that protease-activated receptor 2 (PAR2), a G-protein coupled receptor previously implicated in the pathogenesis of various diseases including pulmonary fibrosis and asthma, may play an important role in the exacerbation of house dust mite (HDM) allergen-induced lung disease by MWCNTs. Methods Wildtype (WT) male C57BL6 mice and Par2 KO mice were exposed to vehicle, MWCNTs, HDM extract, or both via oropharyngeal aspiration 6 times over a period of 3 weeks and were sacrificed 3-days after the final exposure (day 22). Bronchoalveolar lavage fluid (BALF) was harvested to measure changes in inflammatory cells, total protein, and lactate dehydrogenase (LDH). Lung protein and RNA were assayed for pro-inflammatory or profibrotic mediators, and formalin-fixed lung sections were evaluated for histopathology. Results In both WT and Par2 KO mice, co-exposure to MWCNTs synergistically increased lung inflammation assessed by histopathology, and increased BALF cellularity, primarily eosinophils, as well as BALF total protein and LDH in the presence of relatively low doses of HDM extract that alone produced little, if any, lung inflammation. In addition, both WT and par2 KO mice displayed a similar increase in lung Cc1-11 mRNA, which encodes the eosinophil chemokine CCL-11, after co-exposure to MWCNTs and HDM extract. However, Par2 KO mice displayed significantly less airway fibrosis as determined by quantitative morphometry compared to WT mice after co-exposure to MWCNTs and HDM extract. Accordingly, at both protein and mRNA levels, the pro-fibrotic mediator arginase 1 (ARG-1), was downregulated in Par2 KO mice exposed to MWCNTs and HDM. In contrast, phosphorylation of the pro-inflammatory transcription factor NF-κB and the pro-inflammatory cytokine CXCL-1 was increased in Par2 KO mice exposed to MWCNTs and HDM. Conclusions Our study indicates that PAR2 mediates airway fibrosis but not eosinophilic lung inflammation induced by co-exposure to MWCNTs and HDM allergens.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1743-8977Test

الوصول الحر: https://doaj.org/article/32e1e4ddbe73477b8a60b356f6b92171Test

المؤلفون: Meilang Xue, Christopher J. Jackson, Haiyan Lin, Ruilong Zhao, Hai Po H. Liang, Hartmut Weiler, John H. Griffin, Lyn March

المصدر: International Journal of Molecular Sciences, Vol 25, Iss 2, p 1255 (2024)

مصطلحات موضوعية: skin inflammation, immune cells, mutant activated protein C, protease-activated receptor, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Endothelial protein C receptor (EPCR) is a receptor for the natural anti-coagulant activated protein C (aPC). It mediates the anti-inflammatory and barrier-protective functions of aPC through the cleavage of protease-activated receptor (PAR)1/2. Allergic contact dermatitis is a common skin disease characterized by inflammation and defective skin barrier. This study investigated the effect of EPCR and 3K3A-aPC on allergic contact dermatitis using a contact hypersensitivity (CHS) model. CHS was induced using 1-Fluoro-2,4-dinitrobenzene in EPCR-deficient (KO) and matched wild-type mice and mice treated with 3K3A-aPC, a mutant form of aPC with diminished anti-coagulant activity. Changes in clinical and histological features, cytokines, and immune cells were examined. EPCRKO mice displayed more severe CHS, with increased immune cell infiltration in the skin and higher levels of inflammatory cytokines and IgE than wild-type mice. EPCR, aPC, and PAR1/2 were expressed by the skin epidermis, with EPCR presenting almost exclusively in the basal layer. EPCRKO increased the epidermal expression of aPC and PAR1, whereas in CHS, their expression was reduced compared to wild-type mice. 3K3A-aPC reduced CHS severity in wild-type and EPCRKO mice by suppressing immune cell infiltration/activation and inflammatory cytokines. In summary, EPCRKO exacerbated CHS, whereas 3K3A-aPC could reduce the severity of CHS in both EPCRKO and wild-type mice.

العلاقة: https://www.mdpi.com/1422-0067/25/2/1255Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/e08203ffcafc4f3191c95b87fadfeb7cTest

الإتاحة: https://doi.org/10.3390/ijms25021255Test
https://doaj.org/article/e08203ffcafc4f3191c95b87fadfeb7cTest

المؤلفون: Tianyi Wang, Mingcui Fu, Xiangming Yan, Hongcheng Song, Weiping Zhang

المصدر: Frontiers in Pediatrics, Vol 11 (2023)

مصطلحات موضوعية: ureteropelvic junction obstruction, protease activated receptor, SIP syncytium, hydronephrosis, children, Pediatrics, RJ1-570

الوصف: ObjectiveTo explore the expression and clinical implications of protease activated receptors (PARs) in the pathogenesis of children with ureteropelvic junction obstruction (UPJO).Material and methodsImmunohistochemistry was employed to investigate the distribution of PARs in both normal human ureteropelvic junction (UPJ) and cases of UPJO. Furthermore, PAR gene expression levels were assessed using real-time PCR (RT-PCR), and the patients in the UPJO group were stratified according to the Onen grading system. Subsequently, the clinical implications of PARs in UPJO were explored through RT-PCR analysis.ResultsImmunofluorescence showed robust PAR2 expression in the control group compared with the UPJO group. The results of RT-PCR analysis revealed a significant decrease in the relative mRNA expression of PAR2 in the UPJO group compared to the control group. Notably, the relative RNA expression of PAR1 was significantly lower in the Onen-4 group compared to the control group. Furthermore, the relative mRNA expression of PAR2 exhibited a statistically significant difference among the Onen-3 group, Onen-4 group, and control group.ConclusionsPARs are widely distributed throughout the SIP syncytium of the UPJ and play a role in maintaining smooth muscle cells (SMCs) membrane potential by interacting with interstitial cells of Cajal (ICCs), as well as platelet-derived growth factor receptor alpha-positive cells (PDGFR α+ cells). The decreased expression of PAR1 suggests a higher preoperative Onen grade in UPJO patients. Furthermore, the downregulation of PAR2 effects at the UPJ may be involved in the loss of inhibitory neuromuscular transmission, disrupting the rhythmic peristalsis of the UPJ.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fped.2023.1286786/fullTest; https://doaj.org/toc/2296-2360Test

الوصول الحر: https://doaj.org/article/e489ccc8defa4ce7bdbfb16c62a3eb43Test

المؤلفون: Samira Merali, Zhaoqing Wang, Charles Frost, Stephanie Meadows-Shropshire, Dara Hawthorne, Jing Yang, Dietmar Seiffert

المصدر: Platelets, Vol 34, Iss 1 (2023)

مصطلحات موضوعية: antiplatelet, antithrombotic therapy, clinical trial, par4, pharmacokinetics, platelet, protease-activated receptor, Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; N = 60) study; a multiple-ascending-dose (MAD; N = 32) study; and a Japanese MAD (JMAD; N = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25–100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 μM and 25 μM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/0953-7104Test; https://doaj.org/toc/1369-1635Test

الوصول الحر: https://doaj.org/article/5d6aa285a574403e9e5a960e90e20ae0Test

المؤلفون: Ravinder Singh, Varinder Singh, Md. Altamash Ahmad, Chirag Pasricha, Pratima Kumari, Thakur Gurjeet Singh, Rupinder Kaur, Somdutt Mujwar, Tanveer A. Wani, Seema Zargar

المصدر: Pharmaceuticals, Vol 17, Iss 4, p 454 (2024)

مصطلحات موضوعية: protease-activated receptor 1, COVID-19, inflammation, diabetes mellitus, cytokines, Medicine, Pharmacy and materia medica, RS1-441

الوصف: Inflammation is a distinguished clinical manifestation of COVID-19 and type 2 diabetes mellitus (T2DM), often associated with inflammatory dysfunctions, insulin resistance, metabolic dysregulation, and other complications. The present study aims to test the hypothesis that serum concentrations of PAR-1 levels differ between COVID-19 diabetic patients (T2DM) and non-diabetic COVID-19 patients and determine their association with different biochemical parameters and inflammatory biomarkers. T2DM patients with COVID-19 (n = 50) with glycated hemoglobin (HbA1c) levels of (9.23 ± 1.66) and non-diabetic COVID-19 patients (n = 50) with HbA1c levels (4.39 ± 0.57) were recruited in this study. The serum PAR-1 levels (ELISA method) were determined in both groups and correlated with parameters such as age, BMI, inflammatory markers including CRP, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), D-dimer, homocysteine, and N-terminal pro–B-type natriuretic peptide (NT-proBNP). Demographic variables such as BMI (29.21 ± 3.52 vs. controls 21.30 ± 2.11) and HbA1c (9.23 ± 1.66 vs. controls 4.39 ± 0.57) were found to be statistically elevated in COVID-19 T2DM patients compared to non-diabetic COVID-19 patients. The concentrations of several inflammatory biomarkers and PAR-1 were remarkably increased in the COVID-19 T2DM group when compared with the non-diabetic COVID-19 group. The univariate analysis revealed that increased serum PAR-1 estimations were positively correlated with enhanced HbA1c, BMI, inflammatory cytokines, D-dimer, homocysteine, and NT-proBNP. The findings in the current study suggest that increased levels of serum PAR-1 in the bloodstream could potentially serve as an independent biomarker of inflammation in COVID-19 patients with T2DM.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1424-8247/17/4/454Test; https://doaj.org/toc/1424-8247Test

الوصول الحر: https://doaj.org/article/d7ea81eae349449fa08b0d9b26ea9c72Test

المؤلفون: Julian Friebel, Max Wegner, Leon Blöbaum, Philipp-Alexander Schencke, Kai Jakobs, Marianna Puccini, Emily Ghanbari, Stella Lammel, Tharusan Thevathasan, Verena Moos, Marco Witkowski, Ulf Landmesser, Ursula Rauch-Kröhnert

المصدر: International Journal of Molecular Sciences, Vol 25, Iss 7, p 4109 (2024)

مصطلحات موضوعية: atrial fibrillation, atrial myopathy, thrombo-inflammation, thrombin, protease-activated receptor 1, PAR1, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Patients with first-diagnosed atrial fibrillation (FDAF) exhibit major adverse cardiovascular events (MACEs) during follow-up. Preclinical models have demonstrated that thrombo-inflammation mediates adverse cardiac remodeling and atherothrombotic events. We have hypothesized that thrombin activity (FIIa) links coagulation with inflammation and cardiac fibrosis/dysfunction. Surrogate markers of the thrombo-inflammatory response in plasma have not been characterized in FDAF. In this prospective longitudinal study, patients presenting with FDAF (n = 80), and 20 matched controls, were included. FIIa generation and activity in plasma were increased in the patients with early AF compared to the patients with chronic cardiovascular disease without AF (controls; p < 0.0001). This increase was accompanied by elevated biomarkers (ELISA) of platelet and endothelial activation in plasma. Pro-inflammatory peripheral immune cells (TNF-α+ or IL-6+) that expressed FIIa-activated protease-activated receptor 1 (PAR1) (flow cytometry) circulated more frequently in patients with FDAF compared to the controls (p < 0.0001). FIIa activity correlated with cardiac fibrosis (collagen turnover) and cardiac dysfunction (NT-pro ANP/NT-pro BNP) surrogate markers. FIIa activity in plasma was higher in patients with FDAF who experienced MACE. Signaling via FIIa might be a presumed link between the coagulation system (tissue factor-FXa/FIIa-PAR1 axis), inflammation, and pro-fibrotic pathways (thrombo-inflammation) in FDAF.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/25/7/4109Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/2bda6dadaec14868bee5bf04ce01427cTest