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Journal articles on the topic "PHD inhibitor"
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Miyata, Toshio, Shunya Takizawa, and Charles van Ypersele de Strihou. "Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets." American Journal of Physiology-Cell Physiology 300, no. 2 (2011): C226—C231. http://dx.doi.org/10.1152/ajpcell.00430.2010.
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A variety of human disorders, e.g., ischemic heart disease, stroke, kidney disease, eventually share the deleterious consequences of a common, hypoxic and oxidative stress pathway. In this review, we utilize recent information on the cellular defense mechanisms against hypoxia and oxidative stress with the hope to propose new therapeutic tools. The hypoxia-inducible factor (HIF) is a key player as it activates a broad range of genes protecting cells against hypoxia. Its level is determined by its degradation rate by intracellular oxygen sensors prolyl hydroxylases (PHDs). There are three different PHD isoforms (PHD1–3). Small molecule PHD inhibitors improve hypoxic injury in experimental animals but, unfortunately, may induce adverse effects associated with PHD2 inhibition, e.g., angiogenesis. As yet, no inhibitor specific for a distinct PHD isoform is currently available. Still, the specific disruption of the PHD1 gene is known to induce hypoxic tolerance, without angiogenesis and erythrocytosis, by reprogramming basal oxygen metabolism with an attendant decreased oxidative stress in hypoxic mitochondria. A specific PHD1 inhibitor might therefore offer a novel therapy against hypoxia. The nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates the basal and inducible expression of numerous antioxidant stress genes. Disruption of its gene exacerbates oxidative tissue injury. Nrf2 activity is modulated by Kelch-like ECH-associated protein 1 (Keap1), an intracellular sensor for oxidative stress. Inhibitors of Keap 1 may prove therapeutic against oxidative tissue injury.
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Li, Ningjun, Fan Yi, Christina M. Sundy, et al. "Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys." American Journal of Physiology-Renal Physiology 292, no. 1 (2007): F207—F216. http://dx.doi.org/10.1152/ajprenal.00457.2005.
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Hypoxia inducible factor (HIF) prolyl-4-hydroxylase domain-containing proteins (PHDs) promote the degradation of HIF-1α. Because HIF-1α is highly expressed in the renal medulla and HIF-1α-targeted genes such as nitric oxide synthase, cyclooxygenase, and heme oxygenase are important in the regulation of renal medullary function, we hypothesized that PHD regulates HIF-1α levels in the renal medulla and, thereby, participates in the control of renal Na+ excretion. Using real-time RT-PCR, Western blot, and immunohistochemical analyses, we have demonstrated that all three isoforms of PHD, PHD1, PHD2, and PHD3, are expressed in the kidneys and that PHD2 is the most abundant isoform. Regionally, all PHDs exhibited much higher levels in renal medulla than cortex. A furosemide-induced increase in renal medullary tissue Po2 significantly decreased PHD levels in renal medulla, whereas hypoxia significantly increased mRNA levels of PHDs in cultured renal medullary interstitial cells, indicating that O2 regulates PHDs. Functionally, the PHD inhibitor l-mimosine (l-Mim, 50 mg·kg−1·day−1 ip for 2 wk) substantially upregulated HIF-1α expression in the kidneys, especially in the renal medulla, and remarkably enhanced (by >80%) the natriuretic response to renal perfusion pressure in Sprague-Dawley rats. Inhibition of HIF transcriptional activity by renal medullary transfection of HIF-1α decoy oligodeoxynucleotides attenuated l-Mim-induced enhancement of pressure natriuresis, which confirmed that HIF-1α mediated the effect of l-Mim. These results indicate that highly expressed PHDs in the renal medulla make an important contribution to the control of renal Na+ excretion through regulation of HIF-1α and its targeted genes.
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Xing, Weirong, Sheila Pourteymoor, and Subburaman Mohan. "Ascorbic acid regulates osterix expression in osteoblasts by activation of prolyl hydroxylase and ubiquitination-mediated proteosomal degradation pathway." Physiological Genomics 43, no. 12 (2011): 749–57. http://dx.doi.org/10.1152/physiolgenomics.00229.2010.
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Mouse genetic studies reveal that ascorbic acid (AA) is essential for osteoblast (OB) differentiation and that osterix (Osx) was a key downstream target of AA action in OBs. To determine the molecular pathways for AA regulation of Osx expression, we evaluated if AA regulates Osx expression by regulating production and/or actions of local growth factors and extracellular matrix (ECM) proteins. Inhibition of actions of IGFs by inhibitory IGFBP-4, BMPs by noggin, and ECM-mediated integrin signaling by RGD did not block AA effects on Osx expression in OBs. Furthermore, blockade of components of MAPK signaling pathway had no effect on AA-induced Osx expression. Because AA is required for prolyl hydroxylase domain (PHD) activity and because PHD-induced prolyl-hydroxylation targets proteins to proteosomal degradation, we next tested if AA effect on Osx expression involves activation of PHD to hydroxylate and induce ubiquitin-proteosome-mediated degradation of transcriptional repressor(s) of Osx gene. Treatment of OBs with dimethyloxallyl glycine and ethyl 3, 4-dihydroxybenzoate, known inhibitors of PHD, completely blocked AA effect on Osx expression and OB differentiation. Knockdown of PHD2 expression by Lentivirus-mediated shRNA abolished AA-induced Osx induction and alkaline phosphatase activity. Furthermore, treatment of OBs with MG115, inhibitor of proteosomal degradation, completely blocked AA effects on Osx expression. Based on these data, we conclude that AA effect on Osx expression is mediated via a novel mechanism that involves PHD2 and proteosomal degradation of a yet to be identified transcriptional repressor that is independent of BMP, IGF-I, or integrin-mediated signaling in mouse OBs.
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Uchida, Lisa, Tetsuhiro Tanaka, Hisako Saito, et al. "Effects of a prolyl hydroxylase inhibitor on kidney and cardiovascular complications in a rat model of chronic kidney disease." American Journal of Physiology-Renal Physiology 318, no. 2 (2020): F388—F401. http://dx.doi.org/10.1152/ajprenal.00419.2019.
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Cardiovascular disease (CVD) is the main cause of death in patients with kidney disease. Hypoxia plays a crucial role in the progression of chronic kidney disease (CKD) and cardiovascular disease, which is associated with fibrosis, inflammation, and oxidative injury. Previous studies have indicated that prolyl hydroxylase (PHD) inhibitors, stabilizers of hypoxia-inducible factors (HIFs), can be used to treat acute organ injuries such as renal ischemia-reperfusion, myocardial infarction, and, in some contexts, CKD. However, the effects of PHD inhibitors on cardiovascular complications in CKD remain unknown. In the present study, we investigated whether HIF activation has a beneficial effect on kidney and cardiovascular outcomes in the remnant kidney model. We used the 5/6 nephrectomy model with the nitric oxide synthase inhibitor Nω-nitro-l-arginine (20 mg/L in the drinking water). Rats received diet with 0.005% enarodustat (PHD inhibitor) or vehicle for 8 wk starting 2 wk before 5/6 nephrectomy. Activation of HIF by the PHD inhibitor reduced cardiac hypertrophy and ameliorated myocardial fibrosis in association with restored capillary density and improvement in mitochondrial morphology. With regard to kidneys, enarodustat ameliorated fibrosis in association with reduced proinflammatory cytokine expression, reduced apoptosis, and restored capillary density, even though renal endpoints such as proteinuria and serum creatinine levels were not significantly affected by enarodustat, except for blood urea nitrogen levels at 4 wk. In addition, cardiac hypertrophy marker genes, including atrial natriuretic peptide, were suppressed in P19CL6 cells treated with enarodustat. These findings suggest that PHD inhibitors might show beneficial effects in cardiovascular complications caused by CKD.
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Schultz, Kelly, Vanishree Murthy, Jeffrey B. Tatro та Debbie Beasley. "Prolyl hydroxylase 2 deficiency limits proliferation of vascular smooth muscle cells by hypoxia-inducible factor-1α-dependent mechanisms". American Journal of Physiology-Lung Cellular and Molecular Physiology 296, № 6 (2009): L921—L927. http://dx.doi.org/10.1152/ajplung.90393.2008.
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Arterial O2 levels are thought to modulate vascular smooth muscle cell (VSMC) proliferation and vascular remodeling, but the mechanisms involved are poorly understood. Here, we tested the hypothesis that PHD2, a prolyl hydroxylase domain (PHD)-containing O2 sensor, modulates growth factor-induced proliferative responses of human pulmonary artery SMC (HPASMC). We found that both PHD1 and PHD2 were robustly expressed by HPASMC, and inhibiting prolyl hydroxylase activity pharmacologically by using the nonselective dioxygenase inhibitor dimethyloxalylglycine (DMOG) inhibited proliferation and cyclin A expression induced by PDGF-AB or FGF-2. Specific knockdown of PHD2 using small interfering RNAs had similar effects. The inhibitory effects of DMOG and PHD2 knockdown on proliferation and cyclin A expression were seen under both normoxic (20% O2) and moderately hypoxic (5% O2) conditions, and PHD2 expression was not affected by O2 level nor by stimulation with PDGF or FGF-2, indicating that the proproliferative influence of PHD2 does not involve alterations of its expression. Knockdown of PHD2 increased hypoxia-inducible factor (HIF)-1α expression, as expected, but we also found that HIF-1α knockdown abolished the inhibitory effect of PHD2 knockdown on PDGF-induced cyclin A expression. Therefore, we conclude that PHD2 promotes growth factor-induced responses of human VSMC, acting by HIF-1α-dependent mechanisms. Given the role of PHD2 as an oxygen sensor in mammalian cells, these results raise the possibility that PHD2 links VSMC proliferation to O2 availability.
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Frost, Julianty, Alessio Ciulli, and Sonia Rocha. "RNA-seq analysis of PHD and VHL inhibitors reveals differences and similarities to the hypoxia response." Wellcome Open Research 4 (January 29, 2019): 17. http://dx.doi.org/10.12688/wellcomeopenres.15044.1.
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Background:Hypoxia-inducible factor (HIF) transcription factors are well known to control the transcriptional response to hypoxia. Given the importance of cellular response to hypoxia, a number of pharmacological agents to interfere with this pathway have been developed and entered pre-clinical or clinical trial phases. However, how similar or divergent the transcriptional response elicited by different points of interference in cells is currently unknown.Methods:We performed RNA-sequencing to analyse the similarities and differences of transcriptional response in HeLa cells treated with hypoxia or chemical agents that stabilise HIF by inhibiting components of the hypoxia signalling pathway – prolyl hydroxylase (PHD) inhibitor or von Hippel–Lindau (VHL) inhibitor.Results:This analysis revealed that hypoxia produces the highest changes in gene transcription, with activation and repression of genes being in large numbers. Treatment with the PHD inhibitor IOX2 or the VHL inhibitor VH032 led mostly to gene activation, majorly via a HIF-dependent manner. These results were also confirmed by qRT-PCR using more specific and/or efficient inhibitors, FG-4592 (PHDs) and VH298 (VHL).Conclusion:PHD inhibition and VHL inhibition mimic gene activation promoted by hypoxia via a HIF-dependent manner. However, gene repression is mostly associated with the hypoxia response and not common to the response elicited by inhibitors of the pathway.
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Sugahara, Mai, Shinji Tanaka, Tetsuhiro Tanaka, et al. "Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice." Journal of the American Society of Nephrology 31, no. 3 (2020): 560–77. http://dx.doi.org/10.1681/asn.2019060582.
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BackgroundProlyl hydroxylase domain (PHD) inhibitors, which stimulate erythropoietin production through the activation of hypoxia-inducible factor (HIF), are novel therapeutic agents used for treating renal anemia. Several PHD inhibitors, including enarodustat, are currently undergoing phase 2 or phase 3 clinical trials. Because HIF regulates a broad spectrum of genes, PHD inhibitors are expected to have other effects in addition to erythropoiesis, such as protection against metabolic disorders. However, whether such beneficial effects would extend to metabolic disorder–related kidney disease is largely unknown.MethodsWe administered enarodustat or vehicle without enarodustat in feed to diabetic black and tan brachyury (BTBR) ob/ob mice from 4 to 22 weeks of age. To elucidate molecular changes induced by enarodustat, we performed transcriptome analysis of isolated glomeruli and in vitro experiments using murine mesangial cells.ResultsCompared with BTBR ob/ob mice that received only vehicle, BTBR ob/ob mice treated with enarodustat displayed lower body weight, reduced blood glucose levels with improved insulin sensitivity, lower total cholesterol levels, higher adiponectin levels, and less adipose tissue, as well as a tendency for lower macrophage infiltration. Enarodustat-treated mice also exhibited reduced albuminuria and amelioration of glomerular epithelial and endothelial damage. Transcriptome analysis of isolated glomeruli revealed reduced expression of C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) in enarodustat-treated mice compared with the vehicle-only group, accompanied by reduced glomerular macrophage infiltration. In vitro experiments demonstrated that both local HIF-1 activation and restoration of adiponectin by enarodustat contributed to CCL2/MCP-1 reduction in mesangial cells.ConclusionsThese results indicate that the PHD inhibitor enarodustat has potential renoprotective effects in addition to its potential to protect against metabolic disorders.
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Kosyna, Friederike K., Marie Nagel, Larissa Kluxen, Kim Kraushaar та Reinhard Depping. "The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways". Biological Chemistry 396, № 12 (2015): 1357–67. http://dx.doi.org/10.1515/hsz-2015-0171.
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Abstract Hypoxia-inducible transcription factors (HIFs) regulate hundreds of genes involved in cellular adaptation to reduced oxygen availability. HIFs consist of an O2-labile α-subunit (primarily HIF-1α and HIF-2α) and a constitutive HIF-1β subunit. In normoxia the HIF-α subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1-3, resulting in recognition by von Hippel-Lindau protein, ubiquitination and proteasomal degradation. In contrast, reduced oxygen availability inhibits PHD activity resulting in HIF-1α stabilisation and nuclear accumulation. Nuclear import of HIF-1α mainly depends on classical nuclear localisation signals (NLS) and involves importin α/β heterodimers. Recently, a specific inhibitor of nuclear import has been identified that inhibits importin α/β-dependent import with no effects on a range of other nuclear transport pathways involving members of the importin protein family. In this study we evaluated the physiological activity of this importin α/β-inhibitor (Ivermectin) in the hypoxia response pathway. Treatment with Ivermectin decreases binding activity of HIF-1α to the importin α/β-heterodimer. Moreover, HIF-1α nuclear localisation, nuclear HIF-1α protein levels, HIF-target gene expression, as well as HIF-transcriptional activity are reduced upon Ivermectin treatment. For the first time, we demonstrate the effect of specific importin α/β-inhibition on the hypoxic response on the molecular level.
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Chaturvedi, Anuhar, Michelle Maria Araujo Cruz, Ramya Goparaju, et al. "Prolyl Hydroxylase 3 (Phd3) Is a Therapeutic Target in Isocitrate Dehydrogenase 1 (IDH1) Mutated Acute Myeloid Leukemia." Blood 132, Supplement 1 (2018): 759. http://dx.doi.org/10.1182/blood-2018-99-110425.
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Abstract Background: About 40% of IDH1 mutated (IDH1mut) acute myeloid leukemia (AML) patients respond to IDH1 inhibitors with a median duration of response of 8.2 months. A better understanding of the biology of IDH1mut leukemia may further improve the treatment of these patients. IDH1mut produces R-2-hydroxyglutarate (R-2HG), which activates PHD1 and PHD2 but have negligible effects on PHD3. In the present study we assessed whether PHD3 plays a role in the pathogenesis of IDH1 mutated leukemia and can be targeted in a patient-derived xenograft (PDX) model of IDH1 mutated AML. Methods: Bone marrow cells from Phdwt and Phd3ko mice were immortalized with HoxA9, and IDH1wildtype (IDH1wt) and IDH1mut respectively, were constitutively expressed. The effects on cell proliferation, apoptosis and colony formation were evaluated in vitro, whereas the leukemic potential was evaluated in vivo by transplantation in syngeneic mice. To show that PHD3 is a therapeutic target, either IDH1mut cells from AML patients were transduced with shRNA against PHD3 and transplanted in immunocompromised mice, or leukemic cells from an AML patient with mutated IDH1 were xenografted in immunocompromised mice and treated with the PHD inhibitor molidustat. Results: In in-vitro functional assays loss of Phd3 specifically impaired proliferation, apoptosis and clonogenic capacity of HoxA9-IDH1mut but not HoxA9-IDH1wt cells. Likewise, in mouse transplantation assays, loss of Phd3 eliminated HoxA9-IDH1mut induced leukemia. However, Phd3 was dispensable to the engraftment and proliferation of HoxA9-IDH1wt cells. Additionally, the IDH1-independent model of MN1-induced leukemia remained unaltered in the absence of Phd3, indicating the specificity of the role of Phd3 in mutant IDH1-induced transformation. To identify molecular pathways that might explain in vitro and in vivo phenotypes gene expression profiling was performed. Immune and stress-response pathways as well as metabolism-related genes were most prominently dysregulated in Phd3ko IDH1-mutant cells. Analysis of dysregulated transcription factors by gene set enrichment analysis revealed a depletion of key oncogenic transcription factors (Myc, Rb, Stk33, and Rps14) in Phd3ko IDH1mut cells compared to Phd3ko IDH1wt cells. To study if IDH1mut signals to Phd3 through R-2HG, we transduced Phd3kocells, with a splice variant of mutant IDH1, which does not produce R-2HG but causes leukemia in mice with similar kinetics as in mice with the full-length IDH1 mutant protein. Interestingly, loss of Phd3 also eliminated leukemia in these mice, which demonstrates that mutant IDH1 signals through Phd3 independently of R-2HG. To study the functional relevance of PHD3 inhibition in patients, cells from an IDH1 mutated AML patient were transduced with an shRNA against PHD3 and were transplanted in immunodeficient NSG mice. Inhibition of PHD3 depleted human AML cells in the IDH1-mutated PDX model. Moreover, the PHD inhibitor molidustat was 50-fold more active in IDH1mut (80 nM) compared to IDH1wt AML patient cells (4000 nM) in colony-forming unit assays. In a xenograft model of IDH1 mutated AML, molidustat significantly prolonged survival compared to control-treated mice (P<.001). Conclusion: We demonstrate that the leukemogenic activity of the mutant IDH1 protein depends on PHD3 independently of R-2HG. We identified inhibition of PHD3 as a novel therapeutic strategy in IDH1 mutated AML. Since PHD3 can be targeted pharmacologically, combinatorial treatment of PHD3 and IDH1 inhibitors is warranted to improve eradication of leukemic stem cells in IDH1 mutated AML. #AC and MMAC share first authorship Disclosures Ganser: Novartis: Membership on an entity's Board of Directors or advisory committees. Heuser:Karyopharm: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; BergenBio: Research Funding; Astellas: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
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Nakano, Daisuke, Li Lei, and Akira Nishiyama. "Modulistat, a PHD inhibitor, ameliorated erythropoiesis in adenine-induced nephropathy mice." Proceedings for Annual Meeting of The Japanese Pharmacological Society 93 (2020): 2—O—059. http://dx.doi.org/10.1254/jpssuppl.93.0_2-o-059.
Full textDissertations / Theses on the topic "PHD inhibitor"
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Cheung, Douglas Guy. "Action of CDK Inhibitor PHA-848125 in ER-negative Breast Cancer with MicroRNA-221/222 Overexpression." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu150054220454799.
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Eerland, Martijn [Verfasser], Herbert [Akademischer Betreuer] Waldmann, and Christian [Gutachter] Hedberg. "Design, synthesis and evaluation of PHP inhibitors / Martijn Eerland. Betreuer: Herbert Waldmann. Gutachter: Christian Hedberg." Dortmund : Universitätsbibliothek Dortmund, 2015. http://d-nb.info/1110894252/34.
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Deschamps, Joshua Douglas. "Mechanistic and inhibitory investigations of human liposygenase isozymes /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2006. http://uclibs.org/PID/11984.
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Wheelock, Craig Edward. "Novel tools for the investigation of carboxylesterase inhibitor potency and substrate selectivity /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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Holt-Martyn, James. "Novel and selective small molecule inhibitors and activators for the prolyl hydroxylase domain enzyme." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:4b3613c5-5ff3-43b0-a07e-cf3116a37c1b.
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Hypoxia Inducible Factors (HIF) functions are master regulators of oxygen homeostasis and have a key role in the physiological responses to hypoxia including angiogenesis and erythropoiesis. Under hypoxia, levels of HIF-α subunits increase, they hetereodimerise with HIF-1β sub unit and promote the initiation of transcription of target genes. Under normoxia, oxygen dependent HIF-α degradation is promoted by hydroxylation of either of two proline residues (Pro402 and Pro564). The interaction of prolylhydroxylated HIF-α with the Von Hippel-Lindau protein (pVHL) promotes hydrolytic degradation of HIFα through an E3 ubiquitin ligase proteasomal pathway. HIF prolyl hydroxylation is catalysed by three 2-oxoglutarate (2OG)-dependent oxygenases known as prolyl hydroxylase domain (PHD 1-3) proteins, through an Fe(II) mediated catalytic process using 2OG, and oxygen. The PHDs are part of the family of Fe(II) bound 2OG dependent oxygenases. There are approximately 70 human 2OG oxygenases many of which have biologically important roles. Small-molecule inhibitors have reached advanced clinical trials; however, many clinical candidates inhibit other structurally similar 2OG oxygenases (OGFOD1 and vCPH) potentially altering the therapeutic effect. This thesis describes the design and synthesis of potent and 2OG oxygenase selective inhibitors for the PHDs. The 1,3,8-triazaspiro[4.5]decane-2,4-dione and 4-hydroxy-2-(pyrazole)pyrimidine-5-amide series were chosen as initial 'hits' (reported in the patent literature). The main analogues of the series were characterised in vitro and in cells as potent and selective PHD inhibitors over structurally similar 2OG oxygenases (Chapter 2). Broad structure activity relationship (SAR) of both initial series demonstrated the sensitivity for PHD2 inhibition (Chapter 3). Combination of SAR work described in Chapters 2 and 3 lead to the development of the novel 4-hydroxy pyridine series. In-depth SAR resulted in optimised analogues including 1 (IC50 69 nM) and highly selective over structurally similar 2OG oxygenases including OGFOD1. The completed SAR work led to the development of two novel pharmacophores 2 and 3. Both pharmacophores displayed potent PHD inhibition and selectivity over OGFOD1. Analogues including 1 and 3 displayed on target cellular activity stabilising HIF-1α at 20 μM (Chapter 4). The 4-dimethylamine pyridine analogue displayed an increase in substrate hydroxylation on PHD2 in contrast to the DMSO control (Chapter 3). SAR and cellular characterisation indicated that the effect observed was not an assay artifact (Chapter 5). Fenofibrate was used as a starting point for the development of novel inhibitors of the oxygen consumption rate (OCR) via mitochondrial inhibition (Chapter 6). Analogues were synthesised in order to conduct broad SAR and on-target cellular activity was observed in a Seahorse XF assay (50% reduction in the OCR at 1 μM). A selection of amino and amide analogues warrant further investigation.
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Alber, Andreas. "Role of macrophages in healing the fibrotic lung : pan hydroxylase inhibition as a potential therapeutic mechanism." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/16248.
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Pulmonary fibrosis is a common consequence of lung inflammation, leading to organ dysfunction and significant morbidity and mortality. Macrophages, through their diverse functions associated with polarisation status, play a role in lung homeostasis and alternatively activated (M2) macrophages have been associated with lung fibrosis. Prolyl hydroxylases (PHDs) are the main oxygen sensors and regulators of hypoxia inducible factors (HIFs). The PHD/HIF pathway is known to play a role in tissue inflammation and fibrosis, but their role in macrophage polarisation is not fully understood. Aim To study the role of the PHD/HIF pathway in macrophage polarisation and lung fibrosis, and specifically in Idiopathic Pulmonary Fibrosis (IPF). Hypothesis It was hypothesised that pan hydroxylase inhibition alters macrophage polarisation and modulates lung inflammation and fibrosis. Methods A combination of pharmacological (pan hydroxylase inhibitors DMOG and FG41) and genetic (HIF and PHD-null) tools were used to manipulate the PHD/HIF pathway. The bleomycin induced lung fibrosis model was used to define the effect of pan hydroxylase inhibition during the early, inflammatory or the late, fibrotic phase of this model. Murine bone marrow derived macrophages (BMDM), human monocyte derived macrophages and alveolar macrophages obtained from patients with lung fibrosis were used to study the effect of pan hydroxylase inhibition on macrophage polarisation. Bronchoalveolar lavage fluid (BALF) from patients was used to define the association between lung CCL18, an M2 associated chemokine, and disease progression in IPF. Results DMOG therapy during the early phase of the bleomycin model significantly reduced lung fibrosis at day 24. In contrast, late phase pan hydroxylase inhibition enhanced lung fibrosis at day 24. In both instances there was evidence of enhanced alveolar macrophage M2-like polarisation following pan hydroxylase inhibition. Reduced fibrosis after early pan hydroxylase inhibition was not a consequence of reduced acute lung inflammation or direct inhibition of collagen synthesis. In BMDM, pan hydroxylase inhibition resulted in an ‘augmented M2-like’ macrophage. Using LysM-Cre HIF-1α, HIF-2α and PHD-3 KO mice as well as chetomin, a potent inhibitor of HIF-1α and HIF-2α mediated gene expression, the HIF-dependent and HIF-independent polarisation markers were defined. PHD-3 deficiency was not sufficient to enhance M2 skewing. In contrast to murine BMDM, in human monocyte derived macrophages and alveolar macrophages from healthy volunteers and patients with interstitial lung disease including IPF, pan hydroxylase inhibition did not augment M2 polarisation and indeed significantly inhibited macrophage CCL18 expression. CCL18 studies in clinical BALF samples confirmed that CCL18 was elevated in the lungs of patients with IPF and other ILDs compared to controls. However, baseline BALF CCL18 concentrations did not correlate with disease severity or with disease progression, suggesting this is not a useful biomarker in IPF. Further, a unique study of serial BAL in IPF patients showed no association between 12-month change in CCL18 and disease progression over the same period. Indeed CCL18 concentrations mostly fell over 12 months in patients that did progress, strongly suggesting that CCL18 does not play a major pathogenic role in IPF. Concluding, it was shown that in both BMDM and murine lung pan hydroxylase inhibition promoted an ‘augmented M2-like’ polarisation. Pharmacological pan hydroxylase inhibition during the late fibrotic phase of injury enhanced fibrosis but it is not known if there was a causal association between M2 macrophages and lung fibrosis. Similarly, the functional relevance of finding enhanced M2 polarisation observed during early DMOG therapy, which subsequently resulted in attenuated fibrosis, is not known. In human macrophages, pan hydroxylase inhibition unexpectedly attenuated CCL18 production, a chemokine associated with an M2-like phenotype in man whilst other M2 markers were unchanged. However, there was no evidence to support a pathogenic role for CCL18 in IPF, and therefore there is little potential for using pan hydroxylase inhibition to target CCL18 and treat IPF.
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Davis, Benjamin Boyce. "Novel treatments for atherosclerosis with inhibitors of soluble epoxide hydrolase /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2005. http://uclibs.org/PID/11984.
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Hawkins, Rachel Marina. "Design, synthesis and biological evaluation of novel PBD-heterocycle and conjugates as potential transcription factor binding inhibitors." Thesis, University College London (University of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498774.
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Bello, Marcus. "The effect of major environmental factors on archaeal and bacterial ammonia oxidisers in soil." Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=236940.
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Nitrification is the conversion of ammonia to nitrate via nitrite and is performed by ammonia oxidising archaea (AOA), complete ammonia-oxidiser (comammox) and ammonia and nitrite oxidising bacteria (AOB and NOB). The aim of this study is to examine the effect of ammonia concentration, temperature, drought and inhibitors on activity of AOA and AOB using soil microcosms and cultures. Ammonia concentration in soil increases during drought due to the reduced soil water content and, with desiccation stress or a combination of both factors, may result in reported greater inhibition of AOA than AOB during drought. The independent effects of both matric potential and initial ammonium concentration on AOA and AOB amoA abundances and nitrate production were studied in soil microcosms. AOA were more susceptible to increased desiccation stress than AOB, irrespective of initial soil ammonium concentration, and AOA cultures were more sensitive than AOB to osmotic stress induced by different concentrations of NaCl or sorbitol. This may represent an additional niche differentiating factor between AOA and AOB in soil. The effect of temperature and supply of high levels of inorganic ammonium on ammonia oxidation by AOA and AOB were also investigated in soil microcosms. Activity and growth of AOA and AOB were observed in soil amended with high ammonium concentration with increasing temperature, suggesting that AOA can contribute to nitrification in highly fertilised soil, particularly at 25 oC. Inhibition of AOA by simvastatin was investigated in culture and in soil. Simvastatin selectively inhibited AOA in both systems and soil microcosm studies provided evidence for oxidation of ammonia by AOB at low ammonium concentration. Generally, the results show the benefits of combining soil microcosm and culture-based approaches in soil microbiology. The findings advance our understanding of the influence of ammonium supply, temperature and osmotic stress on soil nitrification and its role in controlling the availability of ammonium-based fertilisers for plant uptake.
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Krüger, Hannah Marie. "The reference frame of inhibition of return." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=202099.
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Against a plethora of visual input, visual attention filters and selects relevant information and disengages from irrelevant items. One possible mechanism to enable disengagement is reflected in inhibition of return (IOR), the finding that previously visited locations are responded to slower than locations that have not been investigated before. In line with the proposal that IOR reflects a mechanism to facilitate visual search, evidence suggests that IOR is coded in space-based (“spatiotopic”) coordinates, despite the largely retina-based (“retinotopic”) coding scheme of the visual system. For IOR to efficiently facilitate visual search it should be coded solely in spatiotopic coordinates, but recent investigations show retinotopic IOR effects alongside spatiotopic IOR. The putative function of IOR has also been challenged by the observation that the eyes return to previously visited locations more frequently than would be predicted based on chance. The presented program of research examines the factors that influence whether, and how, IOR is implemented in a way that would facilitate visual search. Firstly, it was examined whether it is an efferent signal about an upcoming eye movement or a more general prediction-based mechanism that maintains IOR in spatiotopic coordinates across eye movements. IOR was observed in both retinotopic and spatiotopic coordinates across eye movements, but was observed in a weakened form and only in location-based coordinates when objects, instead of the eyes, were moved. These results suggest that efferent signals about upcoming eye movements contribute to updating and maintaining IOR tags in useful locations when the eyes move. Secondly, the relative strength and robustness of retinotopic and spatiotopic IOR were examined; the relative frequency of cue-target pairings in retinotopic and spatiotopic references frames had no significant effect on the presence of retinotopic IOR, whereas practice with the experimental task strengthened spatiotopic IOR III and eliminated retinotopic IOR. Thirdly, spatiotopic IOR was observed to be more robust than retinotopic IOR for both saccadic and manual responses. Fourthly, for responses to targets appearing in the brief interval before the eye movement (< 150ms), IOR was observed in the future retinotopic location of the target, suggesting that IOR was remapped predictively. Finally, it was demonstrated that IOR is reduced for intermediate locations along pre-planned sequences of saccades. Taken together the findings of the presented series of research suggest that IOR is updated into spatiotopic coordinates across eye movements. Spatiotopic IOR involves the efferent signal of the eye movement and is updated predictively before the saccade, extending the notion that predictive remapping updates attentional pointers to updating of inhibitory effects. Retinotopic IOR was consistently weaker than spatiotopic IOR across all experiments, and was eliminated with practice, consistent with retinotopic IOR being an undesirable, but avoidable, consequence of inhibiting locations while moving the eyes. Finally, the reduction of IOR for intermediate locations along preplanned saccade sequences is consistent with the idea that the degree to which a location was attended can determine how inhibited that location subsequently becomes. It also could explain why refixations are commonly observed in free visual search, which would typically contain many such pre-planned sequences. Taken together, the findings are additional evidence that IOR reflects a mechanism that facilitates visual search under the conditions in which search normally occurs, that is, across overt eye movements and sequences of eye movements.
Books on the topic "PHD inhibitor"
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Moerdler, Scott, and Xingxing Zang. PD-1/PDL-1 Inhibitors as Immunotherapy for Ovarian Cancer. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190248208.003.0010.
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Programmed death 1 (PD-1), a member of the B7-CD28 immunoglobulin superfamily, and its ligands PD-L1/PD-L2 inhibit T-cell activation. They also play a key role in the tumor microenvironment, allowing for cancer immune escape. PD-1 is induced on a variety of immune cells, including tumor-infiltrating lymphocytes (TILs), while PD-L1 is found on many types of solid tumors including ovarian cancer and some TILs. The use of immunocheckpoint inhibitors like anti-PD-1 and anti-PD-L1 therapies has been shown to reactivate the immune system to attack tumor cells. Ovarian cancers have been shown to be responsive to anti-PD-1 and anti-PD-L1 therapies, though immunocheckpoint inhibitors are not enough. Current research is evaluating combination therapies to improve response rates.
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Wong, Han Hsi, Basma Greef, and Tim Eisen. Treatment of metastatic renal cancer. Edited by James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0089.
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Metastatic renal cancer is resistant to standard chemotherapy. Although some patients with indolent disease can be initially managed with observation, the majority of patients will require aggressive treatment soon after diagnosis. Options include cytoreductive nephrectomy, resection of a solitary metastasis in highly selected cases, or systemic therapy options. The TKIs sunitinib and pazopanib are currently the first-line treatments of choice. Whilst axitinib and cabozantinib have important roles in the second line the PD-1 checkpoint inhibitor, nivolumab, is now established as standard second line therapy. Inhibitors of the mammalian target of rapamycin (mTOR) pathway, everolimus and temsirolimus, interleukin-2 as well as the anti-angiogenic antibody bevacizumab have also been shown to be effective. The treatment paradigm of metastatic renal cancer is constantly changing as evidence from clinical trials continues to emerge. With the development of agents addressing novel targets such as T-cell regulation, the future certainly looks brighter for patients diagnosed with this disease.
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Rongve, Arvid, and Dag Aarsland. Dementia with Lewy bodies and Parkinson’s disease dementia. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199644957.003.0035.
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Dementia with Lewy bodies and Parkinson’s disease dementia belong to the α-synucleinopathies, a family of diseases pathologically characterized by aggregation of α-synuclein in Lewy bodies in the brain. In this chapter we present the epidemiological data for both conditions including new data on MCI. Clinical diagnostic criteria are reviewed and the different neuropathology staging systems for DLB and PDD and the most important genetic findings are considered. Biomarkers in DLB and PDD with particular focus on imaging techniques like CIT-SPECT and MRI are described. Important clinical symptoms in both conditions are presented in detail and the most important clinical differential diagnoses are discussed. Pharmacological and non- pharmacological treatment of different symptoms in both conditions are discussed with particular emphasis on the choline esterase inhibitors and antipsychotic medications.New data on memantine are presented.
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Cummings, Jeffrey L., and Kate Zhong. Clinical Trials and Drug Development in Neurodegenerative Diseases. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190233563.003.0018.
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This chapter describes the common therapeutic targets, approaches to clinical trial design, biomarkers, and therapeutic interventions across neurodegenerative disorders (NDDs). Each unique NDD-Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), etc.-has a unique phenotype associated with the regional cell population most affected. Each disease, however, is associated with protein misfolding, oxidation, inflammation, apoptosis, and cell death. If vulnerable cell populations include transmitter source nuclei, transmitter deficits also emerge (e.g. cholinergic abnormalities in AD and dopaminergic deficits in PD). Biomarkers show regionally appropriate brain atrophy or process-related cerebrospinal deficits. Clinical trial designs share features for symptomatic interventions (e.g. cholinesterase inhibitors in AD and dopamine agents in PD) and disease-modifying therapies. Biomarkers play similar roles in trials for NDD, including demonstrating target engagement and supporting disease modification. No disease-modifying therapies have been approved for any NDDs; all programs face similar pharmacokinetic, pharmacodynamic, and regulatory challenges in therapeutic development.
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Calabrò, Fabio, and Cora N. Sternberg. Treatment of metastatic bladder cancer. Edited by James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0079.
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Although bladder cancer is considered a chemosensitive malignancy, the prognosis of patients with metastatic disease is poor, with a median survival of approximately 12–14 months in good prognosis patients and with cure in only a minority. The addition of new drugs to the standard cisplatin-based regimens has not improved these outcomes. In this chapter, we highlight the role of chemotherapy and the impact of the new targeted agents in the treatment of metastatic bladder carcinoma. A better understanding of the underlying biology and the molecular patterns of urothelial bladder cancer has led to clinical investigation of several therapeutic targets. To date, these agents have yet to demonstrate an improvement in overall survival. Urothelial cancer is extremely sensitive to checkpoint inhibition with both anti PD-1 and anti PDL1 antibodies. The future seems brighter with the advent of these new therapies.
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Goodman, Wayne K., and Mark S. George. Neuromodulation and Psychiatric Disorders. Edited by Dennis S. Charney, Eric J. Nestler, Pamela Sklar, and Joseph D. Buxbaum. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190681425.003.0010.
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An increasing number of approaches permit psychiatrists to directly stimulate the brain. Such therapies are sometimes referred to as neuromodulation, as psychiatrists can either excite or inhibit neuronal firing in the brain. This chapter reviews two such technologies—transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS). Both techniques have FDA approval and are moving into mainstream therapeutic use. Daily prefrontal TMS for 4–6 weeks is FDA approved for treating depression, with minimal side effects. It is now accepted in most treatment algorithms as an approach for patients who have not responded to medications or talking therapy. DBS has virtually replaced ablative neurosurgery for use in medication-refractory movement disorders such as Parkinson’s Disease (PD), where it has the advantages of being reversible (explantable) and adjustable. DBS is now being studied in severe psychiatric conditions, such as intractable obsessive-compulsive disorder (OCD) and treatment resistant depression (TRD).
Book chapters on the topic "PHD inhibitor"
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Muth, Aaron, and Paul R. Thompson. "Development of the Protein Arginine Deiminase (PAD) Inhibitors." In Protein Deimination in Human Health and Disease. Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-58244-3_23.
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Subramanian, Venkataraman, Daniel J. Slade, and Paul R. Thompson. "Picking the PAD Lock: Chemical and Biological Approaches to Identify PAD Substrates and Inhibitors." In Protein Deimination in Human Health and Disease. Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-8317-5_21.
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Moscarello, Mario A. "Protein Hypercitrullination in CNS Demyelinating Disease Reversed by PAD Inhibition." In Protein Deimination in Human Health and Disease. Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-8317-5_11.
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Clement, Cristina C., Anna Babinska, Elizabeth Kornecki, and Manfred Philipp. "Isothermal Titration Calorimetry and Inhibition of Platelets Aggregation by [D-Phe/(Transcinnamoyl)-Pro-D-Arg-P1'-CONH2] Peptides Inhibitors of Thrombin." In Advances in Experimental Medicine and Biology. Springer New York, 2009. http://dx.doi.org/10.1007/978-0-387-73657-0_255.
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Van Eylen, F., P. Gourlet, A. Vandermeers, P. Lebrun, and A. Herchuelz. "Phe—Met—Arg—Phe—NH2 (FMRFa)-Related Peptides Inhibit Na/Ca Exchange in Pancreatic B Cells." In Advances in Experimental Medicine and Biology. Springer US, 1997. http://dx.doi.org/10.1007/978-1-4899-1819-2_30.
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Alva, A. K., and E. Q. Chen. "Hydrogen ion inhibition of copper uptake by citrus seedlings." In Plant-Soil Interactions at Low pH: Principles and Management. Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-0221-6_100.
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Claeson, G., S. Elgendy, L. Cheng, et al. "Design of Novel Types of Thrombin Inhibitors Based on Modified D-Phe-Pro-Arg Sequences." In Advances in Experimental Medicine and Biology. Springer US, 1993. http://dx.doi.org/10.1007/978-1-4899-2418-6_8.
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Gontarewicz, Artur, and Tim H. Brümmendorf. "Danusertib (formerly PHA-739358) – A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor." In Recent Results in Cancer Research. Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-642-01222-8_14.
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Puthota, Valentine, Rocio Cruz-Ortega, Jerry Johnson, and James Ownby. "An ultrastructural study of the inhibition of mucilage secretion in the wheat root cap by aluminium." In Plant-Soil Interactions at Low pH. Springer Netherlands, 1991. http://dx.doi.org/10.1007/978-94-011-3438-5_88.
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Claeson, G., L. Cheng, N. Chino, et al. "Novel peptide mimetics as highly efficient inhibitors of thrombin based on modified D-Phe-Pro-Arg sequences." In Peptides. Springer Netherlands, 1992. http://dx.doi.org/10.1007/978-94-011-2264-1_334.
Full textConference papers on the topic "PHD inhibitor"
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Tans, G., T. Janssen-Claessen, J. Rosing, and J. H. Griffin. "APPLICATION OF SPECIFIC SERINE PROTEASE INHIBITORS IN ASSAYS FOR ACTIVATED CONTACT FACTORS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643301.
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We developed amidolytic assays to determine human Factor Xlla, Factor XIa and plasma kallikrein in mixtures containing variable amounts of each enzyme. The commercially available chromogenic substrates pro-phe-arg-pNA (S2302 or chromozym PK), glu-pro-arg-pNA (S2366), ile-glu-(piperidyl)-gly-arg-pNA (S2337), and ile-glu-gly-arg-pNA (S2222) were tested for their suitability as substrates in these assays. 8-Factor Xlla, Factor XIa and plasma kallikrein each exhibit considerable activity towards a number of these substrates. This precludes direct quantitation of the individual enzymes when large amounts of other activated contact factors are present. Several serine protease inhibitors were tested on their ability to selectively inhibit those contact factors that may interfere with the factor tested for. Soybean trypsin inhibitor efficiently inhibits kallikrein, inhibits Factor XIa at moderate concentrations, but did not affect the amidolytic activity of Factor Xlla. Therefore, this inhibitor can be used to abolish a kallikrein and Factor XIa contribution in a Factor Xlla assay. We also report the rate constants of inhibition of contact activation factors by three different chloromethylketones. D-phe-pro-arg-CH 2 Cl was moderately active against contact factors (k - 2271 M-ls-1 at pH 8.3) but showed no differences in specif ity. D-phe-phe-arg-CH2 Cl was a very efficient inhibitor of kallikrein (k = 118,000 M-ls-1 at pH 8.3) whereas it slowly inhibited Factor Xlla (k = 1389 M-ls-1) and Factor XIa (k = 110 M-ls-1). Also dansyl-glu-gly-arg-CH2Cl was more reactive towards kallikrein (k 15,662 M-ls-1) than towards Factor Xlla (k = 462 M-ls-1) and Factor XIa (k = 63 M-ls-1). Since phe-phe-arg-CH2Cl is highly specific for kallikrein it can be used in a Factor XIa assay to selectively inhibit kallikrein. Based on the catalytic efficiencies of chromogenic substrate conversion and the inhibition characteristics of serine protease inhibitors and chloromethyl ketones we were able to develop quantitative assays for Factor Xlla, Factor XIa and kallikrein in mixtures of contact activation factors.
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Agarwal, Kailash C. "NEW INSIGHTS INTO THE ANTIPLATELET ACTIVITY OF FORSKOLIN: ROLE OF PLASMA ADENOSINE AND SPECIES DIFFERENCES." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643584.
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Forskolin stimulates adenylate cyclase by interacting with the catalytic subunit and inhibits platelet aggregation. This inhibition is greatly potentiated by adenosine (Ado) which stimulates adenylate cyclase through membrane-bound Ado receptors. Forskolin is 2-4 fold more potent as an inhibitor of collagen-induced rat platelet aggregation as compared to human platelets (IC50 values, in rat PRP, 0.5-0.8 μM; in human PRP, 1.5-2 μM). However, if the blood is pretreated with adenosine deaminase (ADA), an enzyme that degrades Ado to inosine, the inhibitory action of forskolin is greatly reduced producing similar effects both in human and rat PRPs (IC50, 2-3 μM) and whole blood (IC50, 4.6 μM). Both 5’-methylthioadenosine (MTA, 50-100 μM), an antagonist of Ado receptors, and 2’,5’-dideoxyadenosine (DDA, 100 μM), an inhibitor of adenylate cyclase, reverse the inhibition of platelet aggregation in rat PRP, whereas, no reversal is seen in human PRP. When Ado in the rat plasma is degraded by ADA pretreatment, DDA or MTA shows no reversal as seen in human PRP. The inhibitory action of forskolin (1-2 μM), which is only weakly inhibitory alone (<20%) in human whole blood, can be greatly potentiated (100% inhibition) by the inhibitors of nucleoside transport, dipyridamole (10 μM) or dilazep (2 μM). Only slight potentiation is seen in rat whole blood suggesting that rat plasma Ado levels are not affected significantly perhaps due to weakly active erythrocytic nucleoside transport system. Sato and Ui (In: Physiology and Pharmacology of Adenosine, Daly et al, Eds. Raven Press, 1983, 1-11), have shown that rat plasma contains much higher Ado levels (7.55 ± 0.51 pM) than human plasma (0.29 ± 0.08 μM). These studies demonstrate that plasma adenosine plays an important role in the forskolin antiplatelet activity which can be greatly potentiated in human whole blood by the clinically used drugs, dipyridamole and dilazep. (Supported by US PHS Grant CA 07340).
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Bagdy, D., É. Bara-bás, L. Sebestyén, et al. "CORRELATION BETWEEN THE ANTICOAGULANT AND ANTIPLATELET EFFECT OF D-PHE-PRO-ARG-H (RG-2958)." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643448.
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Anticoagulants usually have no antiplatelet effect and platelet function inhibitors do not interact with the coagulation factors. Since thrombin has a decisive role in thrombus formation (growth and stabilization), inhibitors of the effect of thrombin on platelets may be of special importance in developing a novel type of anticoagulant with antiplatelet properties.D-Phe-Pro-Arg-H /I/ designed and synthetized in our Institute was found to be a highly specific,reversible non-competitive inhibitorgOf thrombin,a specific platelet agonist. (K.= 1x10-8 M). /I/ was administered parenterally and orally to white New Zealand rabbits and to beagle dogs. The kinetics of action was recorded by measuring the WBCT, APTT, PT, TT,platelet count (PC) and platelet aggregation (PA). Optimum degree of anticoagulation was considered by the values proposed by Verstraete and Verwilghen. /I/ was shown to be a highly specific inhibitor of PA induced by thrombin.No direct interaction between the inhibitor and the platelet membrane could be detected. Aggregability of human platelets in citrated PRP and that of the gel-filtrated platelets induced by ADP or collagen did not change after incubation with /I/. The antiplatelet effect of /I/ was studied by ex vivo experiments where the inhibitor was the anticoagulant ( 30 ug/ml whole blood ) instead of citrate. Comparing the aggregability caused by several inducers in citrated human PRP with that of in /I/-PRP a significant difference was observed when epinephrine was the PA-inducer. /I/ acts via formation of an enzyme-inhibitor complex that inhibits the binding of thrombin on their receptor-sites at the platelet membrane. In vivo experiments showed a close correlation between TT and PA induced by thrombin. /I/ proved completely harmless to platelets and red blood cells. No significant change in PC could be detected.
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Ofosu, F. A., G. J. Modi, M. R. Buchanan, J. Hirsh, and M. A. Blajchman. "HEPARIN IS NOT AN EFFICIENT INHIBITOR OF THE FACTOR Xa-DEPENDENT ACTIVATION OF FACTOR V AND FACTOR VIII." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642931.
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We have previously proposed that the steps in coagulation most sensitive to inhibition by heparin are the thrombin-dependent activation of factor V and factor VIII. This observation was based on the demonstration that therapeutic concentrations of heparin or 1μM of the thrombin specific inhibitor, phe-pro-arg CH2Cl (PPACK) completely inhibited the activation of prothrombin when contact-activated plasma (CAP) was recalcified for up to 1 min. Under similar conditions, heparin and PPACK only partially inhibited the activation of factor X. Moreover, the addition of thrombin (lOnM) to CAP 1 min before that of heparin or PPACK reversed their inhibitory effects. We now provide further support for our hypothesis by showing that when the activity of thrombin is suppressed by heparin or PPACK, efficient activation of radiolabelled prothrombin occurs only when the factor Xa then present activates factor V and factor VIII. We compared the effects of HEP of PPACK on the following four systems for initiating the activation of prothrombin: (1) CAP; (2) CAP + lOnM thrombin; (3) CAP + InM Xa and (4) unactivated plasma + InM Xa + InM Va + coagulant phospholipids. In each system, the enzymes were added 1 min before the heparin or PPACK. In the absence of heparin or PPACK, all four systems generated the same amount of thrombin activity in 45s. Complete inhibition of prothrombin activation by heparin and PPACK was observed only in system 1 which did not contain exogenous thrombin or factor Xa. No inhibition by heparin or PPACK was observed when thrombin or factor Xa was added to CAP in systems (2) and (3). Only partial inhibition was observed in system (4) which contained exogenous prothrombi-nase complex. Factor Xa thus provides an effective by-pass mechanism for the activation of factor VIII and factor V in plasma containing therapeutic concentrations of heparin. Our data provide further evidence that the heparin-antithrombin III system is not effective in inactivating factor Xa. These results support the hypothesis that in unactivated normal plasma, the primary anticoagulant effect of heparin is the inhibition of the thrombin-dependent activation of factor V and factor VIII.
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Broeseker, T. A., M. D. P. Boyle, and R. Lottenberg. "PATHOGENIC BACTERIA HAVE HIGH AFFINITY RECEPTORS SPECIFIC FOR PLASMIN." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644391.
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Binding of the key fibrinolytic enzyme, plasmin, to certain pathogenic group A streptococci was studied. In these experiments the ability of a group A streptococcal strain, 64/14, to bind either 125I-human plasminogen or the same label following activation with urokinase was measured. It was found that this strain bound <10% of the labeled plasminogen but >70% of labeled plasmin. This property distinguishes the plasmin receptor from streptokinase. These bacteria did not express a common serine protease receptor/inhibitor since they failed to bind labeled trypsin or urokinase. Maximal binding of plasmin occurred between pH 6.0 and 8.0 and in the ionic strength range of 50-200 mM salt. The Kd of plasmin binding to bacteria was approximately 10-10 M at pH 7.4 in 150 mM salt. This was determined by a non-linear least squares analysis of equilibrium binding data. Binding was reversibly inhibited by either epsilon aminocaproic acid (I50 of 0.2 mM) or lysine (I50 of 3.0 mM) suggesting the involvement of the high affinity lysine binding site of plasmin in its binding to bacteria. Bacterial bound plasmin retains its enzymatic activity, being capable of cleaving chromogenic substrates and solubilizing a fibrin- clot. The bacterial bound enzyme activity was inhibited by the low molecular weight inhibitors aprotinin and phe-pro-arg chloromethyl ketone but not by alpha-2 plasmin inhibitor. The ability of bacteria to acquire membrane associated proteolytic activity which cannot be physiologically inhibited may contribute to their tissue invasive properties.
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Levy-Toledano, D., D. Weill, J. Maclouf, F. Rendu, and C. Soria. "INHIBITORY EFFECT OF SIN 1 ON PLATELET FUNCTION:POSSIBLE INTEREFRENCE WITH PHOSPHOLIPASE C AND FIBRINOGEN BINDING." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643424.
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The mode of action of SIN 1, the main metabolite of an antianginal drug (Molsidomine) was investigated in vitro on huma platelet functions. SIN 1 inhibited dose dependently platelet activation as reflected by aggregation and release of serotonin induced by arachidonic acid, prostaglandin endoperoxydes analogues (U 46619, U 44069), collagen, and ADP (figst and second wave). The maximal inhibition was reached at 10−5 M. The thromboxane (TX) synthesis was inconsis^antly impaired even at high concentrations of SIN 1 (104 M) suggesting a discrepancy between the inhibitory effect on platelet activation and TX formation. The main cofactor of ADP-stimulated aggregation is fibrinogen ; SIN 1 dose-dependently inhibited the fibrinogen binding to platelets thereby explaining it antiaggregatory properties.In order to further investigate the mechanism of action of this drug on platelet activation we tested SIN 1 on the thrombin-induced phg^phosinositide metabolism and protein phosphorylation on 32P-prelabelled isolated platelets.P-phosphatidate (PA) formation was greatly inhibited. Phosphorylations of the myosin light chain (P20) and of 43 kDa protein (P43) were also reduced. These effects were accompanied by an inhibition of serotoninrelease, TXB2 synthsei^, and platelet aggregation.SIN rl_would seem to act on early biochemical events and more especially at thelevel of the membrane phospholipase C.
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Wang, Yue, Wei-Hua Cai, Tong-Zhou Wei, Lu Wang, and Feng-Chen Li. "Experimental Study on Two-Oscillating Grid Turbulence With Polymer Additives." In ASME/JSME/KSME 2015 Joint Fluids Engineering Conference. American Society of Mechanical Engineers, 2015. http://dx.doi.org/10.1115/ajkfluids2015-7904.
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In order to investigate the polymer effect on grid turbulence, the experiments study on grid turbulence has been built based on Particle Image Velocimetry. The Newtonian fluid flow and 200ppm polymer solution flow in grid turbulence were carried out at different grid oscillating frequency, such as 5Hz, 7.5Hz, 10Hz and 12.5Hz. The experimental results show that the viscous dissipation rate and vortex vector ωz is smaller and more regular in space distribution in polymer solution case at grid oscillating frequency with 5Hz. It indicates that the existence of polymer additives inhibits enormously the viscous dissipation rate and vortex vector, but this phenomenon can be attenuated with the increase of grid oscillating frequency. From this result, it shows that there exists a critical Reynolds number for the inhibition of polymer effect, which is the same as that in turbulent channel flows with polymers. Then, proper orthogonal decomposition (POD) has been used to extract coherent structures in grid turbulence. It is found that it needs 24 and 4 POD eigenfunctions to examine coherent structure in the Newtonian fluid and the polymer solution cases respectively at grid oscillating frequency with 10Hz. It suggests that the coherent structures can be inhibited due to the existence of polymers so as to the flow field to be more regular. But, with the increase of grid oscillating frequency, the number of POD eigenfunctions for the Newtonian fluid case and the polymer solution case respectively are approaching the same. Through this analysis, it can be also seen that the inhibition effect of polymers is close relation with the grid oscillating frequency.
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Liu, Hua-zhen, Wei Chen, Qi-ying Liu, Xia Zhang, Li-xiu Wang, and Cheng-wu Chi. "A NEW PEPTIDE THROMBIN INHIBITOR FROM STREPTOMYCES GRISEUS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644330.
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A new peptide thrombin inhibitor was found in the Streptomyces griseus strain 254 isolated from a soil sample from Tongan, Fujian province, China, the inhibitor being a secondary metabolic product. The production of the inhibitor reached a maximum after 3 days culture of bacteria at 28°C in a rotary shaker. The inhibitor excreted in the culture filtrate was purified by absorption on macroporous resin, followed by ion exchange chromatography on DEAE-52, CM-32 cellulose, affinity chromatography on the immobilized thrombin and high performance liquid chromatography. The amino acid composition of the inhibitor was determined to be Val(2), Met(l), Ile(l), Leu(2) and Arg (1), similar to that of the amino acid residues around the reactive site of human antithrombin III, the critical plasma inhibitor of thrombin. The NH2-terminal residue of the inhibitor seems to be blocked by the alkyl group due to the negative reaction to ninhydrin, whereas the COO-terminal residue is most likely to be arginal because of that Arg was not found in the amino acid analysis, unless the peptide was oxidized by performic acid before acid hydrolysis. The chromogen substrates Bz-Phe-Val-Arg-PNA and Bz-Gly-Pro-Lys-PNA were used to determine the thrombin and plasmin activities, respectively. Besides thrombin, the purified inhibitor also exhibits a weak inhibitory activities on trypsin and much weak on plasmin, but not on chymotrypsin and other protein-ases.
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Seifried, E., and P. Tanswell. "IN VITRO EFFECTS OF RECOMBINANT TISSUE TYPE PLASMINOGEN ACTIVATOR ON FIBRINOLYTIC AND COAGULATION PARAMETERS AND ITS PREVENTION BY SPECIFIC ANTIBODY, D-PHE-PRO-ARG-CTUCl AND APROTININ." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643119.
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Monitoring of systemic effects during rt-PA therapy has shown of depletion of fibrinogen-antiplasmin, plasminogen and other hemostatic factors. Because in vitro activation of plasminogen may occur between blood collection and freezing and thawing before assaying we analysed the influence of 0,0.2, 2.0 and 10.0,ug rt-PA/ml citrate blood (final conc.) on hemostatic and fibrinolytic parameters and its inhibition by 3 different inhibitors. Addition of rt-PA to citrated whole blood without an inhibitor induced a concentration-dependent depletion of Fbg, Plgα2-Apl,α2-M, C1 - I, α2-Atrp, a loss of activity of FV, VIII,IX, XIII and alterations of the global coagulation assays. No effect of rt-PA was observed on F II, VII, X, XI, XII, AT III and Protein C. To prevent in vitro fibrinogenolysis 0.1, 0.5 and 1 mg/ml of a polyclonal sheep anti-rt-PA-antibody, 0.3, 1.0 and 10 Aimol/1 PPACK (D-Phe-Pro-Arg-CH2Cl), 75 and 150 KlU/ml aprotinin (final conc.) and saline as a control were added to pooled citrate blood.All samples containing rt-PA and/or inhibitors and/or saline were incubated for 45 min on ice, centrifuged, aliquotted, snap frozen and stored at ™20° C until analysis. Pretreatment of blood samples with anti-rt-PA IgG prevented interferences with all fibrinolytic and most clotting assays in plasma at a dose of 2 ,ug rt-PA/ ml. PPACK was of limited utility in clotting assays, but enabled correct analysis of fibrinolytic assays. Aprotinin was suitable only for a restricted range of both assay types. It is concluded that collection of blood samples on an appropriate antibody may be the most suitable procedure to get correct measurements of in-vivo effects of rt-PA on the hemostatic system in patients undergoing fibrinolytic therapy.
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Selak, M. A., M. Chignard, and J. B. Smith. "CHARACTERIZATION OF A NEUTROPHIL CPYMOTRYPSIN-LIKE ENZYME THAT ACTIVATES PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643157.
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Communication between neutrophils and platelets was previously investigated by measuring platelet aggregation, serotonin release and changes in cytosolic free calcium subsequent to specific stimulation of neutrophils by fMet-Leu-Phe (FMLP) in a suspension of both cell types. The addition of the chemotactic peptide was shown to elicit secondary platelet activation as a consequence of primary stimulation of neutrophils. Cell-free supernatants from FMLP-stimulated neutrophils were capable of inducing platelet activation thus demonstrating that a factor released bv neutrophils was responsible for the observed platelet responses. After eliminating classical platelet agonists as the acitive agent, it was shown that an enzyme termed neutroohilin induced platelet calcium mobilization, secretion and aggregation. The current studies were conducted to characterize the mediator released bv neutrophils. Neutrophilin bound bo cation exchange resins but failed to bind to anion exchangers. The biological activity associated with neutroohilin was unaffected by leupeptin, only very weakly diminished by N-bosyl-Lvs-chloromethvl ketone and was strongly inhibited by N-tosvl-Phe-chloromethvl ketone, aloha-l-antitrvpsin, soybean trypsin inhibitor and Z-Glv-Leu-Phe-chloromethvl ketone. Neutroohilin was released from stimulated neutrophils only after cytochalasin B treatment, as was beta-glucuronidase, suggesting that both enzymes are located in azurophilic granules. Neutroohilin-induced platelet activation was inhibited bv antiserum to human catheosin G in a dose-deoendent manner but was unaffected by antiserum to human elastase or alpha-fetoprotein. The inhibitor sensitivity, immunological cross-reactivity, ionic properties and probable subcellular localization indicate that neutrophilin is a cationic chymotrvosin-like enzyme related, if not identical to, catheosin G. Neutroohilin-induced platelet activation could explain different pathological events in which platelets and neutroohils are known to be involved.
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