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Martin Ponschab, Martijn van Griensven, Stefan Heitmeier, Volker Laux, Christoph J Schlimp, Andreas Calatzis, Soheyl Bahrami, Heinz Redl, Herbert Schöchl
BACKGROUND: Platelets play a pivotal role in coagulation, inflammation and wound healing. Suitable animal models that have the potential to mimic human platelet function are limited. The objective of the current study was to compare platelet aggregation response in the whole blood of baboons and humans using impedance aggregometry. METHODS: Blood was drawn from 24 anesthetised male baboons and 25 healthy volunteers. The platelet aggregation response was determined by impedance aggregometry (Multiplate®)...
October 6, 2016: Thrombosis Research
Michael F Bode, Nigel Mackman
INTRODUCTION: Mice with a complete absence of tissue factor (TF) die during embryonic development whereas mice with low levels of TF (Low-TF mice) survive to adulthood. Low-TF mice exhibit spontaneous hemorrhage in various organs, including the lung. In contrast, mice can survive without protease-activated receptor (PAR)-4, which is the major thrombin receptor on mouse platelets. We determined the effect of combining a deficiency PAR-4 (primary hemostasis) with a deficiency in TF (secondary hemostasis) on embryonic development and survival of adult mice...
October 2016: Thrombosis Research
Abdulhameed Al-Ghabkari, Jing-Ti Deng, Paul C McDonald, Shoukat Dedhar, Mana Alshehri, Michael P Walsh, Justin A MacDonald
The selectivity of (4Z)-2-(4-chloro-3-nitrophenyl)-4-(pyridin-3-ylmethylidene)-1,3-oxazol-5-one (DI) for zipper-interacting protein kinase (ZIPK) was previously described by in silico computational modeling, screening a large panel of kinases, and determining the inhibition efficacy. Our assessment of DI revealed another target, the Rho-associated coiled-coil-containing protein kinase 2 (ROCKII). In vitro studies showed DI to be a competitive inhibitor of ROCKII (Ki, 132 nM with respect to ATP). This finding was supported by in silico molecular surface docking of DI with the ROCKII ATP-binding pocket...
2016: Scientific Reports
Reyaz Ur Rasool, Debasis Nayak, Souneek Chakraborty, Archana Katoch, Mir Mohd Faheem, Hina Amin, Anindya Goswami
Prostate apoptotic response 4 (Par-4) is coined as a therapeutic protein since owing to its diverse physiologically relevant properties, especially in the cancer perspective. Albeit, Par-4 expression is not restricted to any specific tissue/organ, apart from cell death promotion (due to challenging threats), the other biological role of Par-4 is convincingly emerging. In the recent years, several laboratories have intended to dissect the signaling or mechanisms involved in Par-4 activation to augment apoptosis cascades but new developments in Par-4 research have widened its therapeutic potential...
August 27, 2016: Clinical & Experimental Metastasis
Ji-Ye Han, Yun-Ji Lim, Ji-Ae Choi, Jung-Hwan Lee, Sung-Hee Jo, Sung-Man Oh, Chang-Hwa Song
Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that forms a complex with glucose-regulated protein 78 (GRP78) to induce apoptosis. Previously, we reported that ER stress-induced apoptosis is a critical host defense mechanism against Mycobacterium tuberculosis (Mtb). We sought to understand the role of Par-4 during ER stress-induced apoptosis in response to mycobacterial infection. Par-4 and GRP78 protein levels increased in response Mtb (strain: H37Ra) infection. Furthermore, Par-4 and GRP78 translocate to the surface of Mtb H37Ra-infected macrophages and induce apoptosis via caspase activation...
2016: Scientific Reports
Nikita Joshi, Anna K Kopec, Jessica L Ray, James P Luyendyk
Emerging evidence supports a protective effect of platelets in experimental cholestatic liver injury and cholangiofibrosis. Coagulation-mediated platelet activation has been shown to inhibit experimental chronic cholestatic liver necrosis and biliary fibrosis. This occurs through thrombin-mediated activation of protease activated receptor-4 (PAR-4) in mice. However, it is not known whether other pathways of platelet activation, such as adenosine diphosphate (ADP)-mediated receptor P2Y12 activation is also protective...
July 15, 2016: Toxicology
Ibtissem Ghouzali, Saïda Azhar, Christine Bôle-Feysot, Philippe Ducrotté, Pierre Déchelotte, Moïse Coëffier
Protease activated receptors (PARs) and the ubiquitin-proteasome system (UPS) regulate inflammatory response in intestinal cells. We aimed to elucidate putative connections between PARs and UPS pathways in intestinal epithelial cells. Caco-2 cells were treated by agonist peptides of PARs and/or IL-1β and/or proteasome inhibitors, bortezomib or MG132. Inflammatory response was evaluated by measuring IL-8 production. Proteasome activities were also evaluated. We showed that PAR-1 and -2 activation increased release of IL-8 compared with vehicle and independently of IL-1β...
October 2016: Cytokine
Suman Suman, Trinath P Das, Jim Moselhy, Deeksha Pal, Venkatesh Kolluru, Houda Alatassi, Murali K Ankem, Chendil Damodaran
We previously reported that withaferin A (WA), a natural compound, deters prostate cancer by inhibiting AKT while inducing apoptosis. In the current study, we examined its chemopreventive efficacy against carcinogenesis in the prostate using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Two distinct sets of experiments were conducted. To determine whether WA delays tumor progression, it was given before cancer onset, at week 6, and until week 44. To determine its effect after the onset of prostate cancer, it was given from weeks 12 to 35...
July 20, 2016: Oncotarget
Wu QiNan, Gan XiaGuang, Lei XiaoTian, Deng WuQuan, Zhang Ling, Chen Bing
Apoptosis of islet β cells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces islet β cell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro...
2016: Journal of Diabetes Research
Eileen Colella, Shaolin Li, Richard Roy
When faced with suboptimal growth conditions, Caenorhabditis elegans larvae can enter a diapause-like stage called "dauer" that is specialized for dispersal and survival. The decision to form a dauer larva is controlled by three parallel signaling pathways, whereby a compromise of TGFβ, cyclic guanosine monophosphate, or insulin/IGF-like signaling (ILS) results in dauer formation. Signals from these pathways converge on DAF-12, a nuclear hormone receptor that triggers the changes required to initiate dauer formation...
August 2016: Genetics
Marek Z Wojtukiewicz, Dominika Hempel, Ewa Sierko, Stephanie C Tucker, Kenneth V Honn
The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs...
June 2016: Cancer Metastasis Reviews
Kevin Brasseur, François Fabi, Pascal Adam, Sophie Parent, Laurent Lessard, Eric Asselin
We recently reported the caspase3-dependent cleavage of Par-4 resulting in the accumulation of a 25kDa cleaved-Par-4 (cl-Par-4) fragment and we investigated in the present study the mechanisms regulating this fragment using cl-Par-4-expressing stable clones derived from ovarian and endometrial cancer cell lines.Cl-Par-4 protein was weakly express in all stable clones despite constitutive expression. However, upon cisplatin treatment, cl-Par-4 levels increased up to 50-fold relative to baseline conditions. Treatment of stable clones with proteasome and translation inhibitors revealed that cisplatin exposure might in fact protect cl-Par-4 from proteasome-dependent degradation...
May 9, 2016: Oncotarget
T P Das, S Suman, H Alatassi, M K Ankem, C Damodaran
Growth factor-induced activation of protein kinase-B (PKB), also known as AKT, induces pro-survival signaling and inhibits activation of pro-apoptotic signaling molecules including the Forkhead box O-3a (FOXO3a) transcription factor and caspase in transformed prostate cells in vitro. Earlier we reported that Withaferin-A (WA), a small herbal molecule, induces pro-apoptotic response-4 (Par-4) mediated apoptosis in castration-resistant prostate cancer (CRPC) cells. In the present study, we demonstrate that inhibition of AKT facilitates nuclear shuttling of FOXO3a where it regulates Par-4 transcription in CRPC cells...
2016: Cell Death & Disease
Nehal Fayek Farid, Eglal A Abdelaleem
A sensitive, accurate and selective high performance thin layer chromatography (HPTLC) method was developed and validated for the simultaneous determination of paracetamol (PAR), its toxic impurity 4-aminophenol (4-AP), pseudoephedrine HCl (PSH) and loratidine (LOR). The proposed chromatographic method has been developed using HPTLC aluminum plates precoated with silica gel 60 F254 using acetone-hexane-ammonia (4:5:0.1, by volume) as a developing system followed by densitometric measurement at 254 nm for PAR, 4-AP and LOR, while PSH was scanned at 208 nm...
April 2016: Journal of Chromatographic Science
Mikhail A Kolpakov, Khadija Rafiq, Xinji Guo, Bahman Hooshdaran, Tao Wang, Liudmila Vlasenko, Yulia V Bashkirova, Xiaoxiao Zhang, Xiongwen Chen, Sahar Iftikhar, Joseph R Libonati, Satya P Kunapuli, Abdelkarim Sabri
Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice...
January 2016: Journal of Molecular and Cellular Cardiology
Vitaliy M Sviripa, Ravshan Burikhanov, Josiah M Obiero, Yaxia Yuan, Justin R Nickell, Linda P Dwoskin, Chang-Guo Zhan, Chunming Liu, Oleg V Tsodikov, Vivek M Rangnekar, David S Watt
Advanced prostate tumors usually metastasize to the lung, bone, and other vital tissues and are resistant to conventional therapy. Prostate apoptosis response-4 protein (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells by binding specifically to a receptor, Glucose-regulated protein-78 (GRP78), found only on the surface of cancer cells. 3-Arylquinolines or "arylquins" induce normal cells to release Par-4 from the intermediate filament protein, vimentin and promote Par-4 secretion that targets cancer cells in a paracrine manner...
January 7, 2016: Organic & Biomolecular Chemistry
Shayan Sarkar, Sumeet Jain, Vineeta Rai, Dipak K Sahoo, Sumita Raha, Sujit Suklabaidya, Shantibhusan Senapati, Vivek M Rangnekar, Indu B Maiti, Nrisingha Dey
The gene Par-4 (Prostate Apoptosis Response 4) was originally identified in prostate cancer cells undergoing apoptosis and its product Par-4 showed cancer specific pro-apoptotic activity. Particularly, the SAC domain of Par-4 (SAC-Par-4) selectively kills cancer cells leaving normal cells unaffected. The therapeutic significance of bioactive SAC-Par-4 is enormous in cancer biology; however, its large scale production is still a matter of concern. Here we report the production of SAC-Par-4-GFP fusion protein coupled to translational enhancer sequence (5' AMV) and apoplast signal peptide (aTP) in transgenic Nicotiana tabacum cv...
2015: Frontiers in Plant Science
Diya Zhang, Shenglai Li, Lingjing Hu, Lieping Sheng, Lili Chen
BACKGROUND: Protease-activated receptors (PARs) are G-protein-coupled receptors with an active role in mediating inflammation, pain and other functions. The oral pathogen Porphyromonas gingivalis (P. gingivalis) secretes proteases that activate PARs. The aim of this study was to elucidate the role of PARs in the pathogenesis of chronic periodontitis by expression analysis of PARs in human gingival epithelial cells (GECs) before and after P. gingivalis supernatants treatment. METHODS: GECs were isolated from healthy human gingival tissue samples...
2015: BMC Oral Health
Tim Lekic, Paul R Krafft, Damon Klebe, Jerry Flores, William B Rolland, Jiping Tang, John H Zhang
Germinal matrix hemorrhage (GMH) is the most common cause of neurological complications of prematurity and has lasting implications. PAR-1 and PAR-4 receptors are involved with upstream signaling pathways following brain hemorrhage in adult models of stroke, of which the mammalian target of rapamycin (mTOR) is a potential downstream mediator. Therefore, we hypothesized a role for PAR-1, -4/ mTOR signaling following GMH brain injury. Postnatal day 7 Sprague-Dawley rats were subjected to GMH through stereotactic infusion of collagenase into the right ganglionic eminence...
2016: Acta Neurochirurgica. Supplement
Tim Lekic, Paul R Krafft, Damon Klebe, William B Rolland, Jerry Flores, Jiping Tang, John H Zhang
Germinal matrix hemorrhage (GMH) is a major cause of brain damage in prematurity and has long-lasting neurological implications. The development of brain inflammation contributes to brain injury, leading to a lifetime of neurologic deficits. PAR-1 and 4 receptors are involved with inflammatory pathways after brain hemorrhage in adult models of stroke, of which cyclooxygenase-2 (COX-2) is a potential mediator. We therefore hypothesized a role for PAR-1, 4/ COX-2 signaling following GMH. Postnatal day 7 Sprague-Dawley rats were subjected to GMH induction, which entailed stereotactic collagenase infusion into the ganglionic eminence...
2016: Acta Neurochirurgica. Supplement
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