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Selective KCNQ2/3 Potassium Channel Opener ICA-069673 Inhibits Excitability in Mouse Vagal Sensory Neurons J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Hui Sun, Bradley J. Undem
Heightened excitability of vagal sensory neurons in inflammatory visceral diseases contributes to unproductive and difficult-to-treat neuronally based symptoms such as visceral pain and dysfunction. Identification of targets and modulators capable of regulating the excitability of vagal sensory neurons may lead to novel therapeutic options. KCNQ1–KCNQ5 genes encode KV7.1-7.5 potassium channel α-subunits
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NCP, a Dual Kappa and mu Opioid Receptor Agonist, Is a Potent Analgesic Against Inflammatory Pain without Reinforcing or Aversive Properties J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Peng Huang, Conrad K. Ho, Danni Cao, Saadet Inan, Scott M. Rawls, Mengchu Li, Boshi Huang, Piyusha P. Pagare, E. Andrew Townsend, Justin L. Poklis, Matthew S. Halquist, Matthew Banks, Yan Zhang, Lee-Yuan Liu-Chen
While agonists of μ (MOR) and κ (KOR) opioid receptors have analgesic effects, they produce euphoria and dysphoria, respectively. Other side effects include respiratory depression and addiction for MOR agonists and sedation for KOR agonists. We reported that 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-{[4′-(2′-cyanopyridyl)]carboxamido}cmorphinan (NCP) displayed potent KOR full agonist and MOR
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Pharmacokinetics of Panobinostat: Interspecies Difference in Metabolic Stability J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Wenqiu Zhang, Ju-Hee Oh, Wenjuan Zhang, Courtney C. Aldrich, Rachael W. Sirianni, William F. Elmquist
The deregulation of histone deacetylase (HDAC) expression is often seen in many cancers, and HDAC inhibitors have shown potency against a variety of cancer types. Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its efficacy for the treatment of tumors in the central nervous system (CNS)
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Humanization ofSLCO2B1in Rats Increases rCYP3A1 Protein Expression but Not the Metabolism of Erlotinib to OSI-420 J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Marta Rysz, Anima M. Schäfer, Nikolaos Paloumpis, Jonny Kinzi, Karin Brecht, Isabell Seibert, Seraina Schmidlin, Katja In-Albon, Daniel Ricklin, Henriette E. Meyer zu Schwabedissen
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Suppression of Mast Cell Activation by GPR35: GPR35 Is a Primary Target of Disodium Cromoglycate J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Masumi Oka, Sohta Akaki, Osamu Ohno, Maho Terasaki, Yuho Hamaoka-Tamura, Michiko Saito, Shinichi Kato, Asuka Inoue, Junken Aoki, Kenji Matsuno, Kazuyuki Furuta, Satoshi Tanaka
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Development of Cilofexor, an Intestinally-Biased Farnesoid X Receptor Agonist, for the Treatment of Fatty Liver Disease J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-15 Hollenback, D., Hambruch, E., Fink, G., Birkel, M., Schulz, A., Hornberger, M., Liu, K., Staiger, K. M., Krol, H. D., Deuschle, U., Steeneck, C., Kinzel, O., Liles, J. T., Budas, G., Watkins, W. J., Kremoser, C.
The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid
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Lucanthone, a Potential PPT1 Inhibitor, Perturbs Stemness, Reduces Tumor Microtube Formation, and Slows the Growth of Temozolomide-Resistant Gliomas In Vivo J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Daniel P. Radin, Sophie Shifman, Ian R. Outhwaite, Aryan Sharma, Robert Bases, Markus A. Seeliger, Stella E. Tsirka
Glioblastoma (GBM) is the most frequently diagnosed primary central nervous system tumor in adults. Despite the standard of care therapy, which includes surgical resection, temozolomide chemotherapy, radiation and the newly added tumor-treating fields, median survival remains only ∼20 months. Unfortunately, GBM has a ∼100% recurrence rate, but after recurrence there are no Food and Drug Administration-approved
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N-Acetylcysteine Alters Disease Progression and Increases Janus Kinase Mutation Frequency in a Mouse Model of Precursor B-Cell Acute Lymphoblastic Leukemia J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Mia P. Sams, James Iansavitchous, Madeline Astridge, Heidi Rysan, Li S. Xu, Bruno Rodrigues de Oliveira, Rodney P. DeKoter
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Endothelial Extracellular Vesicles Enriched in microRNA-34a Predict New-Onset Diabetes in Coronavirus Disease 2019 (COVID-19) Patients: Novel Insights for Long COVID Metabolic Sequelae J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-15 Mone, P., Jankauskas, S. S., Manzi, M. V., Gambardella, J., Coppola, A., Kansakar, U., Izzo, R., Fiorentino, G., Lombardi, A., Varzideh, F., Sorriento, D., Trimarco, B., Santulli, G.
Emerging evidence indicates that the relationship between coronavirus disease 2019 (COVID-19) and diabetes is 2-fold: 1) it is known that the presence of diabetes and other metabolic alterations poses a considerably high risk to develop a severe COVID-19; 2) patients who survived a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have an increased risk of developing new-onset
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The Neutrophil Dynamic Mass Redistribution Assay as a Medium throughput Primary Cell Screening Assay J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Lisa A. Stott, Armand Drieu la Rochelle, Susan Brown, Greg Osborne, Catherine J. Hutchings, Simon Poulter, Kirstie A. Bennett, Matt Barnes
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The Effects of Chronic Naltrexone on Reinstatement of Opioid-Induced Drug-Seeking Behavior and Antinociception J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-04-01 Sarah L. Withey, Jack Bergman, Carol A. Paronis
Opioid addiction is a chronic relapsing disorder in which drug-seeking behavior during abstinence can be provoked by exposure to a µ-opioid receptor (MOR) agonist or opioid-associated cues. Opioid self-administration behavior in laboratory subjects can be reinstated by priming with MOR agonists or agonist-related stimuli, providing a procedure suitable for relapse-related studies. The opioid antagonist
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Dosing time-dependent difference in the suppressive effect of empagliflozin on the development of mechanical pain hypersensitivity in diabetic mice J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-08 Ai Sato, Sai Yasukochi, Naho Iwanaka, Tomoaki Yamauchi, Akito Tsuruta, Satoru Koyanagi, Shigehiro Ohdo
A problem for patients with diabetes is the rise of complications, such as peripheral neuropathy, nephropathy and retinopathy. Among them, peripheral neuropathy, characterized by numbness and/or hypersensitivity to pain in the extremities, is likely to develop in the early stages of diabetes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor, exerts hypoglycemic effects by preventing
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Beclin-1-derived peptide MP1 attenuates renal fibrosis by inhibiting the Wnt/β-Catenin pathway J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-07 Jianfeng Zhang, Xiaocui Feng, Runling Yang, Jingya Bai, Feiyun Gao, Bangzhi Zhang
Renal fibrosis is distinguished by the abnormal deposition of extracellular matrix (ECM) and progressive loss of nephron function, with a lack of effective treatment options in clinical practice. In this study, we discovered that the Beclin-1-derived peptide MP1 significantly inhibits the abnormal expression of fibrosis and Epithelial-mesenchymal transition (EMT)-related markers, including α-Smooth
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Structure Activity Relationship and Voltage Dependence for the Drug-Drug Interaction between Amiodarone Analogs and MNI‑1 at the L-type Cav Channel J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-07 Jixin Wang, Haoyu Zeng, Grace Dong, Sherman Waddell, John McCauley, Armando Lagrutta
The drug-drug interaction (DDI) between Amiodarone (AMIO) and Sofosbuvir (SOF), a direct-acting Hepatitis-C NS5B Nucleotide Polymerase Inhibitor, has been associated with severe bradyarrhythmia in patients. Recent Cryo-EM data has revealed that this DDI occurs at the α-subunit of L-type Cav channels (LTCC), with AMIO binding at the fenestration site and SOF (or MNI-1: analog of SOF) binding at the
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Research progress on the correlation between acetaldehyde dehydrogenase 2 and hepatocellular carcinoma development J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-07 Dashuai Yang, Ying Hu, Junfa Yang, Liangsong Tao, Yue Su, Yincui Wu, Yan Yao, Shuxian Wang, Sheng Ye, Tao Xu
Hepatocellular carcinoma (HCC) is the predominant pathological type of primary liver cancer. It is a malignant tumor of liver epithelial cells. There are many ways to treat HCC, but the survival rate for HCC patients remains low. Therefore, understanding the underlying mechanisms by which HCC occurs and develops is critical to explore new therapeutic targets. Aldehyde dehydrogenase 2 (ALDH2) is an
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Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-07 Ahmed M. Elshazly, Aya A. Elzahed, David A. Gewirtz
The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2, and more recently also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains clinical efficacy. Multiple molecular mechanisms and signaling pathways
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Pharmacologic characterization of substituted nitazenes at mu, kappa and delta opioid receptors suggests high potential for toxicity J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-07 Laura B Kozell, Amy J. Eshleman, Katherine M Wolfrum, Tracy L Swanson, Shelley H Bloom, Sheila Benware, Jennifer L Schmachtenberg, Kamryn A. Schutzer, William E. Schutzer, Aaron Janowsky, Atheir I. Abbas
The benzimidazole opioids (BO, substituted nitazenes) are highly potent MOR agonists with heroin- or fentanyl-like effects. These compounds have caused hospitalizations and fatal overdoses. We characterized the in vitro pharmacology and structure-activity relationships of 19 nitazenes with substitutions at three positions of the benzimidazole core. Affinities were assessed using agonist radioligand
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Development of Cilofexor, an intestinally-biased Farnesoid X Receptor agonist, for the treatment of fatty liver disease J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-26 David Hollenback, Eva Hambruch, Gero Fink, Manfred Birkel, Andreas Schulz, Martin Hornberger, Kathy Liu, Kelly MacLennan Staiger, Helen Desiree Krol, Ulrich Deuschle, Christoph Steeneck, Olaf Kinzel, John T. Liles, Grant Budas, William J. Watkins, Claus Kremoser
The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic
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Comparison of theµ-opioid receptor antagonists methocinnamox (MCAM) and naloxone to reverse and prevent the ventilatory depressant effects of fentanyl, carfentanil, 3-methylfentanyl, and heroin in male rats J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-26 Takato Hiranita, Nicholas P Ho, Charles P. France
The number of opioid overdose deaths has increased significantly over the past decade. The life-threatening effect of opioids is hypoventilation that can be reversed by the µ-opioid receptor (MOR) antagonist naloxone; however, because of the very short duration of action of naloxone, re-emergence of MOR agonist-induced hypoventilation can occur, requiring additional doses of naloxone. The MOR antagonist
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Involvement of Extracellular Vesicles in the Proinflammatory Response to Clozapine: Implications for Clozapine-Induced Agranulocytosis J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-15 Sernoskie, S. C., Bonneil, E., Thibault, P., Jee, A., Uetrecht, J.
Most idiosyncratic drug reactions (IDRs) appear to be immune-mediated, but mechanistic events preceding severe reaction onset remain poorly defined. Damage-associated molecular patterns (DAMPs) may contribute to both innate and adaptive immune phases of IDRs, and changes in extracellular vesicle (EV) cargo have been detected post-exposure to several IDR-associated drugs. To explore the hypothesis that
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Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796 J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Peter Thornton, Valérie Reader, Zsofia Digby, Pamela Smolak, Nicola Lindsay, David Harrison, Nick Clarke, Alan P. Watt
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Target Cell Activation of a Structurally Novel NOD-Like Receptor Pyrin Domain-Containing Protein 3 Inhibitor NT-0796 Enhances Potency J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Pamela Smolak, MyTrang Nguyen, Christine Diamond, Heather Wescott, John R. Doedens, Kenneth Schooley, John N. Snouwaert, Mark G. Bock, David Harrison, Alan P. Watt, Beverly H. Koller, Christopher A. Gabel
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Anti-Inflammatory Effects of a Novel Nuclear Factor–κB Inhibitory Derivative Derived from Pyrazolo[3,4-d]Pyrimidine in Three Inflammation Models J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Hiroyuki Baba, Tadashi Hosoya, Ryosuke Ishida, Kenpei Tai, Saki Hatsuzawa, Yuma Kondo, Hiroyuki Kusuhara, Hiroyuki Kagechika, Shinsuke Yasuda
Nuclear factor–κB (NF-κB) plays a central role in inflammatory responses, and its physiologic functions are essential for cell survival and proliferation. Currently, drugs targeting NF-κB inhibition have not yet been applied in clinical practice. We investigated the physiologic effect of a novel NF-κB inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1), on three inflammatory
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Parthenolide As a Therapeutic for Disseminated Canine Neoplasms J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Lisa J. Schlein, Samuel A. Brill, Rachel V. Brady, Kristen B. Farrell, Barbara J. Rose, Travis K. Meuten, Craig T. Jordan, Douglas H. Thamm
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12-(S)-Hydroxyeicosatetraenoic Acid and GPR31 Signaling in Spinal Cord in Neuropathic Pain J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Luigino Antonio Giancotti, Filomena Lauro, Israel Olayide, Jinsong Zhang, Christopher Kent Arnatt, Daniela Salvemini
Neuropathic pain is a pressing unmet medical need requiring novel nonopioid-based therapeutic approaches. Using unbiased transcriptomic analysis, we found that the expression of Gpr31, a G protein–coupled receptor, increased in the dorsal horn of the spinal cord in rats with traumatic nerve injury–induced neuropathic pain. Daily intrathecal injections of siGpr31 reversed behavioral hypersensitivities
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Preclinical Evidence for the Glucocorticoid-Sparing Potential of a Dual Toll-Like Receptor 7/8 Inhibitor in Autoimmune Diseases J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Ankita Deshmukh, Albertina Pereira, Nicholas Geraci, Evgeni Tzvetkov, Melinda Przetak, Michelle D. Catalina, Eric F. Morand, Andrew T. Bender, Bharat Vaidyanathan
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Long-Lasting Control of LDL Cholesterol Induces a 40% Reduction in the Incidence of Cardiovascular Events: New Insights from a 7-Year Study J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Valentina Trimarco, Raffaele Izzo, Paola Gallo, Maria Virginia Manzi, Imma Forzano, Daniela Pacella, Gaetano Santulli, Bruno Trimarco
Recent studies have yielded controversial results on the long-term effects of statins on the risk of cardiovascular (CV) events. To fill this knowledge gap, we assessed the relationship between low-density lipoprotein cholesterol (LDL-C) levels and CV events in hypertensive patients without previous CV events and naïve to antidyslipidemic treatment within the “Campania Salute Network” in Southern Italy
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LDL Cholesterol and Cardiovascular Events in a Population Network: One More Twist of an Endless Story J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-03-01 Giorgio Minotti, Massimiliano Camilli
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Endothelial extracellular vesicles enriched in microRNA-34a predict new-onset diabetes in COVID-19 patients: novel insights for long-COVID metabolic sequelae J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-09 Pasquale Mone, Stanislovas S. Jankauskas, Maria Virginia Manzi, Jessica Gambardella, Antonietta Coppola, Urna Kansakar, Raffaele Izzo, Giuseppe Fiorentino, Angela Lombardi, Fahimeh Varzideh, Daniela Sorriento, Bruno Trimarco, Gaetano Santulli
Emerging evidence indicates that the relationship between COVID-19 and diabetes is twofold: 1) it is known that the presence of diabetes and other metabolic alterations poses a considerably high risk to develop a severe COVID-19; 2) patients who survived a SARS-CoV-2 infection have an increased risk of developing new-onset diabetes. However the mechanisms underlying this association are mostly unknown
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N-Acetylcysteine alters disease progression and increases Janus Kinase mutation frequency in a mouse model of precursor B cell acute lymphoblastic leukemia J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-09 Sams, M. P., Iansavitchous, J., Astridge, M., Rysan, H., Xu, L. S., Rodrigues de Oliveira, B., DeKoter, R. P.
B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreDPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence
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Chemotherapeutics Loaded Poly(Dopamine) Core-Shell Nanoparticles for Breast Cancer Treatment J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-31 Steeves, M., Combita, D., Whelan, W., Ahmed, M.
Chemophotothermal therapy is an emerging treatment for metastatic and drug resistant cancer anomalies. Among various photothermal agents tested, polydopamine provides an excellent biocompatible alternative that can be used to develop novel drug delivery carriers for cancer treatment. This study explores the synthesis of starch encapsulated, polydopamine coated core-shell nanoparticles, in a one pot
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A Pilot Study to Assess the Suitability ofRiboflavin as A Surrogate Marker of Breast Cancer Resistance Protein (BCRP) in Healthy Participants J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-31 Hong Shen, Runlan Huo, Yueping Zhang, Linna Wang, Nian Tong, Weiqi Chen, Andrew J. Paris, Kofi Mensah, Min Chen, Yongjun Xue, Wenying Li, Michael Sinz
We recently showed that riboflavin is a selected substrate of BCRP over P-gp and demonstrated its prediction performance in preclinical DDI studies. The aim of this study was to investigate the suitability of riboflavin to assess BCRP inhibition in humans. First, we assessed the substrate potential of riboflavin towards other major drug transporters using established transfected cell systems. Riboflavin
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Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-25 Candace B Johnson, Donna Walther, Matthew J Baggott, Lisa E. Baker, Michael H Baumann
3,4-Methylenedioxymethamphetamine (MDMA) has shown efficacy as a medication adjunct for treating post-traumatic stress disorder (PTSD). However, MDMA is also used in non-medical contexts that pose risk for cardiovascular and neurological complications. It is well established that MDMA exerts its effects by stimulating transporter-mediated release of the monoamines, 5‑hydroxytryptamine (5-HT), norepinephrine
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Phencyclidine-like abuse liability and psychosis-like neurocognitive effects of novel arylcyclohexylamine drugs of abuse in rodents J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-25 Hannah E Shaw, Dylan R Patel, Brenda M Gannon, Lauren R Fitzgerald, Theresa M Carbonaro, Chad R. Johnson, William E. Fantegrossi
Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male NIH Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl and 4-MeO analogs; PCE and its 3-OH and 3-MeO analogs; and ketamine and its
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Neurotoxicity profiling of aluminum salt-based nanoparticles as adjuvants for therapeutic cancer vaccine J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-25 Chen Chen, Changying Xue, Jiaxuan Jiang, Shisheng Bi, Zurui Hu, Ge Yu, Bingbing Sun, Chuanbin Mao
Therapeutic vaccines containing aluminum adjuvants have been widely used in the treatment of tumors due to their powerful immune-enhancing effects. However, the neurotoxicity of aluminum adjuvants with different physicochemical properties have not been completely elucidated. In this study, a library of engineered aluminum oxyhydroxide (EAOs) and aluminum hydroxyphosphate (EAHPs) nanoparticles was synthesized
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Involvement of extracellular vesicles in the proinflammatory response to clozapine: implications for clozapine-induced agranulocytosis J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-23 Sernoskie, S. C., Bonneil, E., Thibault, P., Jee, A., Uetrecht, J.
Most idiosyncratic drug reactions (IDRs) appear to be immune-mediated, but mechanistic events preceding severe reaction onset remain poorly defined. Damage-associated molecular patterns (DAMPs) may contribute to both innate and adaptive immune phases of IDRs, and changes in extracellular vesicle (EV) cargo have been detected post-exposure to several IDR-associated drugs. To explore the hypothesis that
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Effects of Repeated Treatment with the Monoacylglycerol Lipase Inhibitor MJN110on Pain-Related Depression of Nesting and Cannabinoid 1 Receptor Functionin Male and Female Mice J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-23 Clare M Diester, Hallie Balint, James C Gillespie, Aron H. Lichtman, Laura J Sim-Selley, Dana E Selley, S Stevens Negus
MJN110 inhibits the enzyme monoacylglycerol lipase (MAGL) to increase levels of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG), an endogenous high-efficacy agonist of cannabinoid 1 and 2 receptors (CB1/2R). MAGL inhibitors are under consideration as candidate analgesics, and we reported previously that acute MJN110 produced partial antinociception in an assay of pain-related behavioral depression
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Efficacy of BAY 60-2770, a soluble guanylate cyclase activator, for coronary spasm in animal models J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-23 Masashi Tawa, Keisuke Nakagawa, Mamoru Ohkita
Ischemia with non-obstructive coronary arteries (INOCA), caused by coronary artery spasm, has gained increasing attention owing to the poor quality of life of impacted patients. Therapeutic options to address INOCA remain limited, and developing new therapeutic agents is desirable. Herein, we examined whether soluble guanylate cyclase (sGC) activators could be beneficial in preventing coronary spasms
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Nitric Oxide Resistance in Priapism Associated with Sickle Cell Disease: Mechanisms, Therapeutic Challenges, and Future Directions. J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-23 Dalila Andrade Pereira, Fabiano Beraldi Calmasini, Fernando Ferreira Costa, Arthur L Burnett, Fábio Henrique Silva
Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular
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Anti-inflammatory effects of a novel NF-kB inhibitory derivative derived from pyrazolo[3,4-d]pyrimidine in three inflammation models J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-22 Baba, H., Hosoya, T., Ishida, R., Tai, K., Hatsuzawa, S., Kondo, Y., Kusuhara, H., Kagechika, H., Yasuda, S.
Nuclear factor-B (NF-B) plays a central role in inflammatory responses, while its physiological functions are essential for cell survival and proliferation. Currently, drugs targeting NF-B inhibition have not yet been applied in clinical practice. We investigated the physiological effect of a novel NF-kB inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1) on three inflammatory
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Inhibiting Inducible Nitric Oxide Synthase with 1400W Reduces Soman (GD)-Induced Ferroptosis in Long-Term Epilepsy-Associated Neuropathology: Structural and Functional Magnetic Resonance Imaging Correlations with Neurobehavior and Brain Pathology J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Marson Putra, Suraj S. Vasanthi, Nikhil S. Rao, Christina Meyer, Madison Van Otterloo, Lal Thangi, Daniel R. Thedens, Sridhar S. Kannurpatti, Thimmasettappa Thippeswamy
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Repeated Activation of Pyramidal Neurons in the Prefrontal Cortex Alters Microglial Phenotype in Male Mice J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Justin L. Bollinger, Matthew J. Horchar, Eric S. Wohleb
Aberrant neuronal activity in the cortex alters microglia phenotype and function in several contexts, including chronic psychologic stress and neurodegenerative disease. Recent findings even suggest that heightened levels of neuronal activity spur microglia to phagocytose synapses, with potential impacts on cognition and behavior. Thus, the present studies were designed to determine if activation of
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The Peptide DHα-(4-pentenyl)-ANPQIR-NH2Exhibits Antifibrotic Activity in Multiple Pulmonary Fibrosis Models Induced by Particulate and Soluble Chemical Fibrogenic Agents J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Jieru Li, Bochuan Deng, Jiao Zhang, Xiang Zhang, Lu Cheng, Guofeng Li, Ping Su, Xiaokang Miao, Wenle Yang, Junqiu Xie, Rui Wang
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The β-Blocker Carvedilol and Related Aryloxypropanolamines Promote ERK1/2 Phosphorylation in HEK293 Cells withKAValues Distinct From Their Equilibrium Dissociation Constants asβ2-Adrenoceptor Antagonists: Evidence for Functional Affinity J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Omar Hamed, Varuna Jayasinghe, Mark A. Giembycz
The determination of affinity by using functional assays is important in drug discovery because it provides a more relevant estimate of the strength of interaction of a ligand to its cognate receptor than radioligand binding. However, empirical evidence for so-called, “functional affinity” is limited. Herein, we determined whether the affinity of carvedilol, a β-adrenoceptor antagonist used to treat
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The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiotensin II-Infused Mice J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Marta Martínez-Casales, Raquel Hernanz, Zoe González-Carnicero, María T. Barrús, Angela Martín, Ana M. Briones, Patrycja Michalska, Rafael León, Estefano Pinilla, Ulf Simonsen, María J. Alonso
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Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Robert C. Barnes, Satish Banjara, Melissa C. McHann, Sharilyn Almodovar, Angela N. Henderson-Redmond, Daniel J. Morgan, Isabel Castro-Piedras, Josée Guindon
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Ketamine Produces Antidepressant Effects by Inhibiting Histone Deacetylases and Upregulating Hippocampal Brain-Derived Neurotrophic Factor Levels in a Diisopropyl Fluorophosphate–Based Rat Model of Gulf War Illness J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Ana Ribeiro-Davis, Dalia Y. Al Saeedy, Fay M. Jahr, Elisa Hawkins, Joseph L. McClay, Laxmikant S. Deshpande
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Aminopyridines Restore Ventilation and Reverse Respiratory Acidosis at Late Stages of Botulism in Mice J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 William T. McClintic, Zachary D. Chandler, Lalitha M. Karchalla, Celinia A. Ondeck, Sean W. O’Brien, Charity J. Campbell, Alan R. Jacobson, Patrick M. McNutt
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Oxidant-Dependent Sensitizing, Protective, and Mitigative Effects in X-Ray–Irradiated Pulmonary Endothelial Cells J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Linda L. Pearce, Xi Zheng, Daniel S. Wilen, Andrea A. Cronican, Kristin L. Frawley, Jim Peterson
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Pharmacologic Inhibition of Transient Receptor Potential Ion Channel Ankyrin 1 Counteracts 2-Chlorobenzalmalononitrile Tear Gas Agent-Induced Cutaneous Injuries J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-17 Achanta, S., Chintagari, N. R., Balakrishna, S., Liu, B., Jordt, S.-E.
Deployment of the tear gas agent 2-chlorobenzalmalononitrile (CS) for riot control has significantly increased in recent years. The effects of CS have been believed to be transient and benign. However, CS induces severe pain, blepharospasm, lachrymation, airway obstruction, and skin blisters. Frequent injuries and hospitalizations have been reported after exposure. We have identified the sensory neuronal
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Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-17 Moore, K. H., Boitet, L. M., Chandrashekar, D. S., Traylor, A. M., Esman, S. K., Erman, E. N., Srivastava, R. K., Khan, J., Athar, M., Agarwal, A., George, J. F.
Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced
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A Potential Antidote for Both Azide and Cyanide Poisonings J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Linda L. Pearce, Kimberly K. Garrett, Yookyung Bae, Kristin L. Frawley, Samantha Carpenter Totoni, Jim Peterson
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Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Jaclynn A. Meshanni, Jordan M. Lee, Kinal N. Vayas, Rachel Sun, Chenghui Jiang, Grace L. Guo, Andrew J. Gow, Jeffrey D. Laskin, Debra L. Laskin
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Mesna Improves Outcomes of Sulfur Mustard Inhalation Toxicity in an Acute Rat Model J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-17 Nick, H. J., Johnson, C. A., Stewart, A. R., Christeson, S. E., Bloomquist, L. A., Appel, A. S., Donkor, A. B., Veress, L. A., Logue, B. A., Bratcher, P. E., White, C. W.
Inhalation of high levels of sulfur mustard (SM), a potent vesicating and alkylating agent used in chemical warfare, results in acutely lethal pulmonary damage. Sodium 2-mercaptoethane sulfonate (mesna) is an organosulfur compound that is currently Food and Drug Administration (FDA)-approved for decreasing the toxicity of mustard-derived chemotherapeutic alkylating agents like ifosfamide and cyclophosphamide
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A Murine Model of Vesicant-Induced Acute Lung Injury J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Iram Zafar, Shajer Manzoor, Nithya Mariappan, Shama Ahmad, Mohammad Athar, Veena Antony, Aftab Ahmad
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Countermeasures against Pulmonary Threat Agents J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Jacqui Marzec, Srikanth Nadadur
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HSP90, a Common Therapeutic Target for Suppressing Skin Injury Caused by Exposure to Chemically Diverse Classes of Blistering Agents J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-01-17 Srivastava, R. K., Muzaffar, S., Khan, J., Crossman, D. K., Agarwal, A., Athar, M.
Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates, namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES), respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of
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Dermal Exposure to Vesicating Nettle Agent Phosgene Oxime: Clinically Relevant Biomarkers and Skin Injury Progression in Murine Models J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Dinesh G. Goswami, Satyendra K. Singh, Ebenezar O.M. Okoyeocha, Andrew K. Roney, Omid Madadgar, Rick Tuttle, William Sosna, Poojya Anantharam, Claire R. Croutch, Rajesh Agarwal, Neera Tewari-Singh
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Treatment of Sulfur Mustard Corneal Injury by Augmenting the DNA Damage Response (DDR): A Novel Approach J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Robert Shalwitz, Tovah Day, Anna Kotsakis Ruehlmann, Lindsay Julio, Shellaina Gordon, Adrianna Vandeuren, Marian Nelson, Megan Lyman, Kyle Kelly, Amber Altvater, Celinia Ondeck, Sean O’Brien, Tracey Hamilton, Ryan L. Hanson, Kayla Wayman, Alexandrea Miller, Isaiah Shalwitz, Eric Batchelor, Patrick McNutt
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The Involvement of Unfolded Protein Response in the Mechanism of Nitrogen Mustard–Induced Ocular Toxicity J. Pharmacol. Exp. Ther. (IF 3.5) Pub Date : 2024-02-01 Assylbek Zhylkibayev, Trong Thuan Ung, James Mobley, Mohammad Athar, Marina Gorbatyuk