The Experts below are selected from a list of 11550 Experts worldwide ranked by ideXlab platform
Raymond Dingledine - One of the best experts on this subject based on the ideXlab platform.
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a rat model of organophosphate induced status epilepticus and the beneficial effects of ep2 Receptor inhibition
Neurobiology of Disease, 2020Co-Authors: Asheebo Rojas, Thota Ganesh, Wenyi Wang, Jennifer Wang, Raymond DingledineAbstract:Abstract This review describes an adult rat model of status epilepticus (SE) induced by diisopropyl fluorophosphate (DFP), and the beneficial outcomes of transient inhibition of the Prostaglandin-E2 Receptor EP2 with a small molecule antagonist, delayed by 2–4 h after SE onset. Administration of six doses of the selective EP2 antagonist TG6-10-1 over a 2–3 day period accelerates functional recovery, attenuates hippocampal neurodegeneration, neuroinflammation, gliosis and blood-brain barrier leakage, and prevents long-term cognitive deficits without blocking SE itself or altering acute seizure characteristics. This work has provided important information regarding organophosphate-induced seizure related pathologies in adults and revealed the effectiveness of delayed EP2 inhibition to combat these pathologies.
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inhibition of the Prostaglandin E2 Receptor ep2 prevents status epilepticus induced deficits in the novel object recognition task in rats
Neuropharmacology, 2016Co-Authors: Asheebo Rojas, Thota Ganesh, Zahra Manji, Theon Oneill, Raymond DingledineAbstract:Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the Prostaglandin E2 Receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6–12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 Receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP.
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inhibition of the Prostaglandin Receptor ep2 following status epilepticus reduces delayed mortality and brain inflammation
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jianxiong Jiang, Yi Quan, Thota Ganesh, Wendy Pouliot, Edward F Dudek, Raymond DingledineAbstract:Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible Prostaglandin Receptors have not been fully identified. We developed a potent and selective antagonist for the Prostaglandin E2 Receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood–brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the Prostaglandin Receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 Receptor antagonism as an adjunctive therapeutic strategy to treat SE.
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small molecule antagonist reveals seizure induced mediation of neuronal injury by Prostaglandin E2 Receptor subtype ep2
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Jianxiong Jiang, Yi Quan, Thota Ganesh, Geidy Serrano, Min Qui, Iris Speigel, Asheebo Rojas, Nadia Lelutiu, Raymond DingledineAbstract:With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, Prostaglandin Receptors provide alternative targets for the treatment of COX-2–mediated pathological conditions in both the periphery and the central nervous system. Activation of Prostaglandin E2 Receptor (PGE2) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the Prostaglandin EP2 Receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 Receptor with KB 2–20 nM in Schild regression analysis and 268- to 4,730-fold selectivity over the Prostaglandin EP4 Receptor. A brain-permeant compound completely suppressed the up-regulation of COX-2 mRNA in rat cultured microglia by EP2 activation and significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of this novel group of antagonists raise the possibility that selective block of EP2 signaling via small molecules can be an innovative therapeutic strategy for inflammation-related brain injury.
Thorsten Blume - One of the best experts on this subject based on the ideXlab platform.
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identification of a benzimidazolecarboxylic acid derivative bay 1316957 as a potent and selective human Prostaglandin E2 Receptor subtype 4 hep4 r antagonist for the treatment of endometriosis
Journal of Medicinal Chemistry, 2019Co-Authors: Stefan Baurle, Jens Nagel, Olaf Peters, Antonius Ter Laak, Cornelia Preusse, Antje Rottmann, Dieter Heldmann, Ulrich Bothe, Nico Brauer, Thorsten BlumeAbstract:The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes—the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of Prostaglandin E2 (PGE2) Receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this Receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure–activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with exc...
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Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis
2019Co-Authors: Stefan Bäurle, Jens Nagel, Olaf Peters, Nico Bräuer, Antonius Ter Laak, Cornelia Preusse, Antje Rottmann, Dieter Heldmann, Ulrich Bothe, Thorsten BlumeAbstract:The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processesthe latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of Prostaglandin E2 (PGE2) Receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this Receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure–activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient’s quality of life
Bulent Ozpolat - One of the best experts on this subject based on the ideXlab platform.
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ptger3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up regulation ras mapk erk ets1 elk1 cftr1 axis
EBioMedicine, 2019Co-Authors: Cristian Rodriguezaguayo, Emine Bayraktar, Cristina Ivan, Burcu Aslan, Junhua Mai, Lingegowda S Mangala, Dahai Jiang, Archana S Nagaraja, Bulent OzpolatAbstract:Abstract Background Inflammatory mediator Prostaglandin E2–Prostaglandin E2 Receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. Methods An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Findings Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2’-F-phosphorodithioate-siRNA–mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. Interpretation These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. Fund National Institutes of Health/National Cancer Institute, USA.
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ptger3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up regulation ras mapk erk ets1 elk1 cftr1 axis
Social Science Research Network, 2018Co-Authors: Cristian Rodriguezaguayo, Emine Bayraktar, Cristina Ivan, Burcu Aslan, Junhua Mai, Lingegowda S Mangala, Dahai Jiang, Archana S Nagaraja, Bulent Ozpolat, Arturo ChavezreyesAbstract:Inflammatory mediator Prostaglandin E2-Prostaglandin E2 Receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2'-F-phosphorodithioate-siRNA-mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. Funding: This work was supported in part by grants from the National Institutes of Health/National Cancer Institute (R44GM086937, P50 CA093459, U54 CA151668, P50 CA083639, P50 CA098258, R21 CA180145, UH3TR000943, RO1CA160687 and U54 CA96300), the Cancer Prevention Research Institute of Texas (RP120214), the FRANK McGraw Memorial Chair in Cancer Research, and the American Cancer Society Research Professor Award. This research was performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672. Declaration of Interest: The authors have no potential conflicts of interest to disclose. X. Yang is a full-time employee at AM Biotechnologies. Ethical Approval: Animal studies were conducted in accordance with the guidelines set forth by the American Association for Accreditation of Laboratory Animal Care and the US Public Health Service policy on Humane Care and Use of Laboratory Animals. All mouse studies were approved and supervised by The University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee.
Emine Bayraktar - One of the best experts on this subject based on the ideXlab platform.
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ptger3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up regulation ras mapk erk ets1 elk1 cftr1 axis
EBioMedicine, 2019Co-Authors: Cristian Rodriguezaguayo, Emine Bayraktar, Cristina Ivan, Burcu Aslan, Junhua Mai, Lingegowda S Mangala, Dahai Jiang, Archana S Nagaraja, Bulent OzpolatAbstract:Abstract Background Inflammatory mediator Prostaglandin E2–Prostaglandin E2 Receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. Methods An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Findings Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2’-F-phosphorodithioate-siRNA–mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. Interpretation These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. Fund National Institutes of Health/National Cancer Institute, USA.
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ptger3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up regulation ras mapk erk ets1 elk1 cftr1 axis
Social Science Research Network, 2018Co-Authors: Cristian Rodriguezaguayo, Emine Bayraktar, Cristina Ivan, Burcu Aslan, Junhua Mai, Lingegowda S Mangala, Dahai Jiang, Archana S Nagaraja, Bulent Ozpolat, Arturo ChavezreyesAbstract:Inflammatory mediator Prostaglandin E2-Prostaglandin E2 Receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2'-F-phosphorodithioate-siRNA-mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. Funding: This work was supported in part by grants from the National Institutes of Health/National Cancer Institute (R44GM086937, P50 CA093459, U54 CA151668, P50 CA083639, P50 CA098258, R21 CA180145, UH3TR000943, RO1CA160687 and U54 CA96300), the Cancer Prevention Research Institute of Texas (RP120214), the FRANK McGraw Memorial Chair in Cancer Research, and the American Cancer Society Research Professor Award. This research was performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672. Declaration of Interest: The authors have no potential conflicts of interest to disclose. X. Yang is a full-time employee at AM Biotechnologies. Ethical Approval: Animal studies were conducted in accordance with the guidelines set forth by the American Association for Accreditation of Laboratory Animal Care and the US Public Health Service policy on Humane Care and Use of Laboratory Animals. All mouse studies were approved and supervised by The University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee.
Cristian Rodriguezaguayo - One of the best experts on this subject based on the ideXlab platform.
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ptger3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up regulation ras mapk erk ets1 elk1 cftr1 axis
EBioMedicine, 2019Co-Authors: Cristian Rodriguezaguayo, Emine Bayraktar, Cristina Ivan, Burcu Aslan, Junhua Mai, Lingegowda S Mangala, Dahai Jiang, Archana S Nagaraja, Bulent OzpolatAbstract:Abstract Background Inflammatory mediator Prostaglandin E2–Prostaglandin E2 Receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. Methods An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Findings Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2’-F-phosphorodithioate-siRNA–mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. Interpretation These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. Fund National Institutes of Health/National Cancer Institute, USA.
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ptger3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up regulation ras mapk erk ets1 elk1 cftr1 axis
Social Science Research Network, 2018Co-Authors: Cristian Rodriguezaguayo, Emine Bayraktar, Cristina Ivan, Burcu Aslan, Junhua Mai, Lingegowda S Mangala, Dahai Jiang, Archana S Nagaraja, Bulent Ozpolat, Arturo ChavezreyesAbstract:Inflammatory mediator Prostaglandin E2-Prostaglandin E2 Receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2'-F-phosphorodithioate-siRNA-mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. Funding: This work was supported in part by grants from the National Institutes of Health/National Cancer Institute (R44GM086937, P50 CA093459, U54 CA151668, P50 CA083639, P50 CA098258, R21 CA180145, UH3TR000943, RO1CA160687 and U54 CA96300), the Cancer Prevention Research Institute of Texas (RP120214), the FRANK McGraw Memorial Chair in Cancer Research, and the American Cancer Society Research Professor Award. This research was performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672. Declaration of Interest: The authors have no potential conflicts of interest to disclose. X. Yang is a full-time employee at AM Biotechnologies. Ethical Approval: Animal studies were conducted in accordance with the guidelines set forth by the American Association for Accreditation of Laboratory Animal Care and the US Public Health Service policy on Humane Care and Use of Laboratory Animals. All mouse studies were approved and supervised by The University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee.
