A5055919570- Immune Response and Inflammation
- Asthma and respiratory diseases
- Adenosine and Purinergic Signaling
- Immune Cell Function and Interaction
- Genomics, phytochemicals, and oxidative stress
- Amino Acid Enzymes and Metabolism
- Muscle and Compartmental Disorders
- Immunotherapy and Immune Responses
- Glutathione Transferases and Polymorphisms
- Transplantation: Methods and Outcomes
- Cancer, Hypoxia, and Metabolism
- Renal Transplantation Outcomes and Treatments
- Allergic Rhinitis and Sensitization
- RNA modifications and cancer
- Systemic Lupus Erythematosus Research
- Pancreatic function and diabetes
- Diabetes Management and Research
- Monoclonal and Polyclonal Antibodies Research
- Acute Myocardial Infarction Research
- Poisoning and overdose treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Electroconvulsive Therapy Studies
- Pediatric health and respiratory diseases
- Mitochondrial Function and Pathology
- Chronic Lymphocytic Leukemia Research
Creighton University
2024-2025
Phoenix (United States)
2025
C4X Discovery (United Kingdom)
2017-2024
University School
2024
AstraZeneca (United Kingdom)
2009-2019
Loughborough University
2005-2018
Lund University
2008
University College Cork
2000-2005
Imperial College London
2005
Cork University Hospital
1999-2005
Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step tumorigenesis. Lactic acid is mainly transported by two H(+)/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed blocking MCT1/2 Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, and tumor growth, whereas ectopic expression MCT4 these cells conferred resistance to inhibition...
In the present study we characterize properties of potent MCT1 (monocarboxylate transporter 1) inhibitor AR-C155858. Inhibitor titrations L-lactate transport by in rat erythrocytes were used to determine Ki value and number AR-C155858-binding sites (Et) on turnover (kcat). Derived values 2.3+/-1.4 nM, 1.29+/-0.09 nmol per ml packed cells 12.2+/-1.1 s-1 respectively. When expressed Xenopus laevis oocytes, MCT2 potently inhibited AR-C155858, whereas MCT4 was not. Inhibition shown be...
// Nicola J. Curtis 1 , Lorraine Mooney Lorna Hopcroft 2 Filippos Michopoulos Nichola Whalley Haihong Zhong 3 Clare Murray 4,6 Armelle Logie Mitchell Revill Kate F. Byth 5 Amanda D. Benjamin 4 Mike A. Firth Stephen Green Paul Smith and Susan E. Critchlow iMED Oncology, AstraZeneca, Alderley Park, Cheshire, UK Cambridge, MedImmune, One MedImmune Way, Gaithersburg, MD, USA DSM, Gatehouse Waltham, Massachusetts, MA, 6 C4X Discovery, Manchester, Correspondence to: Critchlow, email: Keywords :...
In mammalian cells, MCTs (monocarboxylate transporters) require association with an ancillary protein to enable plasma membrane expression of the active transporter. Basigin is preferred binding partner for MCT1, MCT3 and MCT4, embigin MCT2. rat rabbit erythrocytes, MCT1 associated basigin respectively, but its sensitivity inhibition by AR-C155858 was found be identical. Using RT (reverse transcription)-PCR, we have shown that Xenopus laevis oocytes contain endogenous basigin, not embigin....
Abstract Background Atherosclerosis is potentiated by stimulation of Toll‐like receptors (TLRs), which serve to detect pathogen associated molecular patterns (PAMPs). However little known PAMPs may be present in atheroma, or capable stimulating inflammatory signalling vascular cells. Materials and Methods DNA extracted from human carotid atheroma samples was amplified sequenced using broad‐range 16S gene specific primers establish historical exposure bacterial PAMPs. Responsiveness primary...
Nrf2 regulates cellular antioxidant defence in lung cells, including epithelial cells and alveolar macrophages (AM). The Nrf2/Keap-1 pathway can be modulated by activators with different modes of action; electrophilic compounds protein-protein interaction (PPI) inhibitors. We assessed Keap-1 protein gene levels COPD compared to controls the effect on AM.Lung resected tissue from non-smokers, smokers patients were analysed for AM expression imunoshistochemistry qPCR isolated AM. cultured...
Novel small molecular weight compounds that act by inhibiting the monocarboxylate transporter (MCT1) receptor have been found to cause profound inhibition of T-cell responses alloantigen in vitro. Here, we investigated ability one compound this series, AR-C117977, a potent MCT1 inhibitor, prevent acute and chronic rejection vascularized nonvascularized allografts mouse. Treatment with AR-C117977 or cyclosporin A (CsA) administered at dose 30 mg/kg subcutaneously for 15 days adult CBA. Ca...
BACKGROUND AND PURPOSE Toll-like receptor 7 (TLR7) agonists have potential in the treatment of allergic diseases. However, therapeutic utility current low molecular weight TLR7 is limited by their systemic activity, resulting unwanted side effects. We developed a series TLR7-selective 'antedrugs', including SM-324405 and AZ12441970, which contain an ester group rapidly cleaved plasma to reduce exposure. EXPERIMENTAL APPROACH Agonist activity at parent acid metabolite was assessed vitro...
Abstract Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) that regulates fibrinolysis, cell adhesion and motility via its interactions with plasminogen activators vitronectin. PAI-1 has been shown to play role in number of diverse pathologies including cardiovascular diseases, obesity cancer therefore an attractive therapeutic target. However the multiple patho-physiological roles PAI-1, understanding relative contributions these any one disease setting, make...
Summary The presence of interleukin‐4 (IL‐4) during the generation dendritic cells (DC) from precursor results in measurable increases IL‐12 supernatants but IL‐4 secretion has not been reported. However, DC have receptors and are able to make IL‐4. We therefore sought evidence for autocrine effects on DC. gene expression was low generated bone‐marrow stem granulocyte–macrophage colony‐stimulating factor up‐regulated by exposure developing Exposure also induced intracellular production...
Summary Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory‐tract DC (hRTDC) atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation hRTDC may contribute to pathogenesis. Objective To investigate influence on balance between atopy and subjects determine whether expression is modulated during asthmatic inflammation. Methods Sputum were induced from steroid‐naïve,...
Background. In a search for immunosuppressive drugs having novel mechanisms, monocarboxylate transporter (MCT-1) inhibitors were identified that markedly inhibited immune responses. Here, we report the effects of AR-C117977, potent MCT-1 inhibitor, on alloimmune responses in rat. Methods. vitro activity was determined rat mixed lymphocyte response (MLR). vivo tested graft versus host (GVHR) and both high (DA to PVG) low (PVG DA) responder cardiac allograft models. To assess induction...
TLR7 agonists modulate Th2 immune responses through mechanisms that have not been fully elucidated. Suppression of IL-5 production from Ag- or phytohemagglutinin-stimulated human PBMCs by the antedrug AZ12441970 was mediated via type I IFN-dependent and IFN-independent activation plasmacytoid dendritic cells, B monocytes. The inhibition T cell-derived IFN-α acting directly on activated cells. IL-10 shown to be involved in mechanism required cell-cell interaction. Notch signaling implicated...
Triggering innate immune responses through TLRs is expected to be a novel therapeutic strategy for the treatment of allergic diseases. TLR agonists are able modulate Th2 undefined mechanisms. We investigated mechanism action suppression with antedrug TLR7 agonist. The rapidly metabolized by plasma esterases an acid reduced activity limit systemic responses. Topical administration this compound inhibited features airway inflammatory response in rat and murine airways model. Type I IFN played...
A substantial challenge in phenotypic drug discovery is the identification of molecular targets that govern a response interest. Several experimental strategies are available for this, so-called target deconvolution process. Most these approaches exploit affinity between small-molecule compound and its putative or use large-scale genetic manipulations profiling. Each methods has strengths but also limitations such as bias toward high-affinity interactions risks from compensation. The...