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Sarandeep Malhi, Nicholas Stesco, Samaa Alrushaid, Ted M Lakowski, Neal M Davies, Xiaochen Gu
A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay was developed and validated to simultaneously quantify anticancer drugs reparixin and paclitaxel in this study. The compounds were extracted from plasma and urine samples by protein precipitation with acetone (supplemented with 0.1% formic acid). Chromatographic separation was achieved using a C18 column, and drug molecules were ionized using dual ion source electrospray and atmospheric pressure chemical ionization (DUIS: ESI-APCI). Reparixin and paclitaxel were quantified using negative and positive multiple reaction monitoring (MRM) mode, respectively...
February 3, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Shih-Chieh Lin, Kuei-Yang Hsiao, Ning Chang, Pei-Chi Hou, Shaw-Jenq Tsai
Dual-specificity phosphatase 2 (DUSP2) is a negative regulator of mitogen-activated protein kinases. Our previous study showed that DUSP2 expression is downregulated in many human cancers and loss of DUSP2 promotes cancer progression; however, the underlying mechanism remains largely uncharacterized. Herein, we found that loss of DUSP2 induces angiogenesis while forced expression of DUSP2 inhibits microvessel formation in xenografted mouse tumours. Genome-wide screening of expression profiles, and meta-analysis of clinical data, identified that the level of interleukin-8 (IL-8) correlated negatively with that of DUSP2, suggesting it may be a downstream target of DUSP2...
December 27, 2016: Journal of Pathology
Rena L Pawlick, John Wink, Andrew R Pepper, Antonio Bruni, Nasser Abualhassen, Yasmin Rafiei, Boris Gala-Lopez, Mariusz Bral, A M James Shapiro
Quality of life in Type 1 diabetic patients may be improved with islet transplantation, but lifelong immunosuppression is required to prevent rejection. Allo-immune response is a key player in graft dysfunction and although the adaptive immune response is well characterized, the effect of the innate immune reaction after transplantation is only recently becoming appreciated. In this study, we address how the innate response affects long-term outcomes in a murine islet allotransplant model. CTLA-4 Ig treatment is known to significantly prolong kidney subcapsular islet allograft survival and enhance glucose tolerance...
September 2, 2016: Islets
Gustaf Wigerblad, Duygu B Bas, Cátia Fernades-Cerqueira, Akilan Krishnamurthy, Kutty Selva Nandakumar, Katarzyna Rogoz, Jungo Kato, Katalin Sandor, Jie Su, Juan Miguel Jimenez-Andrade, Anja Finn, Alex Bersellini Farinotti, Khaled Amara, Karin Lundberg, Rikard Holmdahl, Per-Johan Jakobsson, Vivianne Malmström, Anca I Catrina, Lars Klareskog, Camilla I Svensson
OBJECTIVE: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation...
April 2016: Annals of the Rheumatic Diseases
Akilan Krishnamurthy, Vijay Joshua, Aase Haj Hensvold, Tao Jin, Meng Sun, Nancy Vivar, A Jimmy Ytterberg, Marianne Engström, Cátia Fernandes-Cerqueira, Khaled Amara, Malin Magnusson, Gustaf Wigerblad, Jungo Kato, Juan Miguel Jiménez-Andrade, Kerry Tyson, Stephen Rapecki, Karin Lundberg, Sergiu-Bogdan Catrina, Per-Johan Jakobsson, Camilla Svensson, Vivianne Malmström, Lars Klareskog, Heidi Wähämaa, Anca I Catrina
OBJECTIVES: Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction. We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process. METHODS: Polyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA. Monoclonal ACPAs were isolated from single SF B-cells of patients with RA...
April 2016: Annals of the Rheumatic Diseases
Laura Brandolini, Loredana Cristiano, Alessia Fidoamore, Maria De Pizzol, Erica Di Giacomo, Tiziana Marilena Florio, Giuseppina Confalone, Angelo Galante, Benedetta Cinque, Elisabetta Benedetti, Pier Adelchi Ruffini, Maria Grazia Cifone, Antonio Giordano, Marcello Alecci, Marcello Allegretti, Annamaria Cimini
In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population...
December 22, 2015: Oncotarget
Chien-Tsai Chiu, Li-Li Wen, Hsin-Ping Pao, Ling-Yu Yang, Ya-Ni Huang, Jia-Yi Wang
AIMS: Bacterial meningitis causes high mortality and brain damage. The host immune response is associated with brain injury. Chemokine (C-X-C motif) (CXC) chemokines are neutrophil chemoattractants. This study focused on the beneficial effects of intracerebroventricular administration of reparixin, an inhibitor of chemokine (C-X-C motif) receptor (CXCR)1/2, to rats at 2 h following experimental Klebsiella pneumoniae meningoencephalitis. METHODS: We used a previously established meningoencephalitis animal model in which Sprague-Dawley rats were infected by K...
June 2016: Neuropathology and Applied Neurobiology
Elisabeth Wigenstam, Bo Koch, Anders Bucht, Sofia Jonasson
Chlorine (Cl2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1h after Cl2-exposure could improve protection against acute lung injury in Cl2-exposed mice...
February 3, 2015: Toxicology
P Opfermann, U Derhaschnig, A Felli, J Wenisch, D Santer, A Zuckermann, M Dworschak, B Jilma, B Steinlechner
Reparixin, a CXCR 1/2 antagonist, has been shown to mitigate ischaemia-reperfusion injury (IRI) in various organ systems in animals, but data in humans are scarce. The aim of this double-blinded, placebo-controlled pilot study was to evaluate the safety and efficacy of reparixin to suppress IRI and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG). Patients received either reparixin or placebo (n = 16 in each group) after induction of anaesthesia until 8 h after cardiopulmonary bypass (CPB)...
April 2015: Clinical and Experimental Immunology
Kuei-Yang Hsiao, Ning Chang, Shih-Chieh Lin, Yo-Hua Li, Meng-Hsing Wu
STUDY QUESTION: How does hypoxia-mediated down-regulation of dual specificity phosphatase-2 (DUSP2) promote endometriotic lesion development? SUMMARY ANSWER: Inhibition of DUSP2 by hypoxia enhances endometriotic lesion growth via promoting interleukin-8 (IL-8)-dependent angiogenesis. WHAT IS KNOWN ALREADY: Angiogenesis is a prerequisite for the development of endometriosis. DUSP2 is down-regulated in endometriotic stromal cells in a hypoxia inducible factor-1α-dependent manner...
December 2014: Human Reproduction
Antonio Citro, Andrea Valle, Elisa Cantarelli, Alessia Mercalli, Silvia Pellegrini, Daniela Liberati, Luisa Daffonchio, Olga Kastsiuchenka, Pier Adelchi Ruffini, Manuela Battaglia, Marcello Allegretti, Lorenzo Piemonti
Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets...
April 2015: Diabetes
Hideaki Matsushita, Masanori Hijioka, Hayato Ishibashi, Junpei Anan, Yuki Kurauchi, Akinori Hisatsune, Takahiro Seki, Koichi Shudo, Hiroshi Katsuki
We previously demonstrated that a synthetic retinoic acid receptor agonist, Am80, attenuated intracerebral hemorrhage (ICH)-induced neuropathological changes and neurological dysfunction. Because inflammatory events are among the prominent features of ICH pathology that are affected by Am80, this study investigated the potential involvement of proinflammatory cytokines/chemokines in the effect of Am80 on ICH. ICH induced by collagenase injection into mouse striatum caused prominent upregulation of mRNAs for interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, CXCL1, CXCL2, and CCL3...
August 2014: Journal of Neuroscience Research
Larissa Fonseca da Cunha Sousa, Fernanda Matos Coelho, David Henrique Rodrigues, Alline Cristina Campos, Luciola da Silva Barcelos, Mauro Martins Teixeira, Milene Alvarenga Rachid, Antonio Lucio Teixeira
OBJECTIVE: Ischemic stroke may result from transient or permanent reductions of regional cerebral blood flow. Polymorphonuclear neutrophils have been described as the earliest inflammatory cells to arrive in ischemic tissue. CXCR1/2 receptors are involved in the recruitment of these cells. However, the contribution of these chemokine receptors during transient brain ischemia in mice remains poorly understood. In this work, we investigated the effects of reparixin, an allosteric antagonist of CXCR1/2 receptors, in a model of middle cerebral artery occlusion and reperfusion in mice...
2013: Clinics
Antonio Citro, Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani, Valeria Sordi, Paola Magistretti, Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio, Lorenzo Piemonti
Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8)...
October 2012: Journal of Clinical Investigation
Erik Svensjö, Elvira M Saraiva, Rafael Silveira Amendola, Christina Barja-Fidalgo, Marcelo T Bozza, Ethan A Lerner, Mauro M Teixeira, Julio Scharfstein
Experiments were designed to determine if the vasodilatory peptides maxadilan and pituitary adenylate cyclase-activating peptide (PACAP-38) may cause plasma leakage through activation of leukocytes and to what extent these effects could be due to PAC1 and CXCR1/2 receptor stimulation. Intravital microscopy of hamster cheek pouches utilizing FITC-dextran and rhodamine, respectively, as plasma and leukocyte markers was used to measure arteriolar diameter, plasma leakage and leukocyte accumulation in a selected area (5mm(2)) representative of the hamster cheek pouch microcirculation...
March 2012: Microvascular Research
Hye Young Kim, Jin Hee Choi, Young Jin Kang, So Young Park, Hyoung Chul Choi, Hee Sun Kim
Reparixin, an inhibitor of CXCL8 receptor CXCR1 and CXCR2 activation, has been shown to attenuate inflammatory responses in various injury models. In the present study, the hypertension-related functional roles of reparixin were examined in hypertensive animals. Spontaneously hypertensive rats (SHR) at the age of 18 weeks were administered a subcutaneous injection of reparixin (5 mg/kg) daily for 3 weeks (SHR-R, n=5). Control groups consisted of normal saline-treated SHR (SHR-N, n=5) and normotensive Wistar-Kyoto rats (WKY-N, n=5)...
2011: Biological & Pharmaceutical Bulletin
D R Marsh, J M P Flemming
STUDY DESIGN: Female Wistar rats (225 g) underwent spinal cord injury (SCI) at the T4 segment and were assigned to one of the three groups treated with: (1) saline; (2) 7.5 mg kg(-1) Reparixin; or (3) 15 mg kg(-1) Reparixin. Reparixin is a small molecule, allosteric noncompetitive inhibitor of CXCR1 and CXCR2 chemokine receptors involved in inflammation. METHODS: Spinal cord homogenates at 12 and 72 h post-SCI were assayed for tumor necrosis factor α (TNF-α) and cytokine-induced neutrophil chemoattractant (CINC)-1 using enzyme-linked immunosorbant assay (ELISA)...
March 2011: Spinal Cord
Sam M Greenwood, Trevor J Bushell
Proteinase-activated receptor-2 (PAR-2) expression levels are altered in several CNS disorders with these changes being proposed to either exacerbate or diminish the disease state depending on the cell type in which this occurs. Here we present data investigating the consequence of PAR-2 activation on kainate (KA)-induced neurotoxicity in organotypic hippocampal slices cultures (OHSC). Exposure of OHSC to the PAR-2 activators trypsin or Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL) induced no neurotoxicity when applied alone but was neuroprotective against KA-induced neurotoxicity...
June 2010: Journal of Neurochemistry
S M Vieira, H P Lemos, R Grespan, M H Napimoga, D Dal-Secco, A Freitas, T M Cunha, W A Verri, D A Souza-Junior, M C Jamur, K S Fernandes, C Oliver, J S Silva, M M Teixeira, F Q Cunha
BACKGROUND AND PURPOSE: Chemokines orchestrate neutrophil recruitment to inflammatory foci. In the present study, we evaluated the participation of three chemokines, KC/CXCL1, MIP-2/CXCL2 and LIX/CXCL5, which are ligands for chemokine receptor 2 (CXCR2), in mediating neutrophil recruitment in immune inflammation induced by antigen in immunized mice. EXPERIMENTAL APPROACH: Neutrophil recruitment was assessed in immunized mice challenged with methylated bovine serum albumin, KC/CXCL1, LIX/CXCL5 or tumour necrosis factor (TNF)-alpha...
October 2009: British Journal of Pharmacology
Roberto Anacardio, Frank G P Mullins, Sally Hannam, Muhammed S Sheikh, Karen O'Shea, Andrea Aramini, Gaetano D'Anniballe, Loredana D'Anteo, Mauro P Ferrari, Marcello Allegretti
A sensitive and selective liquid chromatographic method coupled with tandem mass spectrometry (LC-MS/MS) was developed and validated for the quantification of methanesulfonamide (MSA) in human urine. MSA is a potential in vivo metabolite of reparixin, a specific inhibitor of the CXCL8 biological activity. In this study, a simple derivatization procedure with a new reagent, N-(4-methanesulfonyl-benzoyl)-imidazole, was set up to enable MSA and the internal standard (I.S.), ethanesulfonamide (ESA), to be analysed by LC-MS/MS...
July 15, 2009: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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