Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Reperfusion of ischemia in the heart or brain.","authors":"Victor Gurewich, David Segarnick","doi":"10.1016/j.jpet.2025.103392","DOIUrl":"10.1016/j.jpet.2025.103392","url":null,"abstract":"<p><p>The current treatment of choice for an acute myocardial infarction (AMI) is an interventional procedure like percutaneous coronary intervention (PCI), which takes 2 to 3 hours and is not appropriate for clots in arteries smaller than the catheter. Because PCI requires inpatient catheterization, there is an inevitable delay in reperfusion of the ischemia. This delay was shown to have a linear relationship with AMI mortality. The longer the delay, from <5 minutes to >3 hours, the greater the cardiovascular disease mortality. Instead of PCI, a sequential combination of tissue-type plasminogen activator and prourokinase is the most effective treatment for conditions like AMI and ischemic stroke that mirrors the endogenous fibrinolytic process.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103392"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of the correlation between the anti-ischemic stroke mechanism of 4-hydroxybenzaldehyde and its response to reactive oxygen species in brain metabolism.","authors":"Jin Feng, Qian Yang, Ming Chen, Long Ning, Yan Wang, Dan Luo, Dongxiong Hu, Qing Lin, Fangyan He","doi":"10.1016/j.jpet.2025.103395","DOIUrl":"10.1016/j.jpet.2025.103395","url":null,"abstract":"<p><p>The active ingredient of Gastrodia elata, 4-hydroxybenzaldehyde (4-HBd), can rapidly enter the brain and undergo massive oxidation to produce the metabolite 4-hydroxybenzoic acid, which has no significant activity after equal dose gavage. It is crucial to clarify the metabolic pathway of 4-HBd and its correlation with the anti-ischemic stroke mechanism. The objective of this study was to explore the possible mechanism of 4-HBd in clearing reactive oxygen species (ROS) and protecting blood-brain barrier from oxidative stress damage during brain metabolism from the perspective of ROS response. A rat model of cerebral ischemia-reperfusion injury and a cellular oxidative stress response model were replicated to simulate the accumulation process of ROS in the brain. The changes in ROS and peroxidation products before and after 4-HBd intervention were detected, and the changes in oxidative metabolism were also measured to confirm the correlation between antioxidant stress damage and ROS capture/clearance in oxidative metabolism. 4-HBd has significant antioxidant stress resistance both in vitro and in vivo, and can reduce the levels of malondialdehyde and 4-hydroxy-2-nonenal in ischemic brain tissue. It can capture O₂⋅^- and ⋅OH in vitro and use the captured ROS to oxidize and metabolize 4-hydroxybenzoic acid. The oxidative metabolism process of 4-HBd in the brain is one of its mechanisms for exerting antioxidant stress damage and protecting blood-brain barrier. SIGNIFICANCE STATEMENT: The active ingredient 4-hydroxybenzaldehyde of Gastrodia elata can be converted into metabolite 4-hydroxybenzoic acid in the brain mainly through oxidative metabolic pathway. The mechanism of its action against oxidative stress damage of blood-brain barrier is related to the oxidative metabolic process in the brain that traps/clears reactive oxygen species and forms stable intermediates to terminate the free radical chain reaction. This is one of the main mechanisms of 4-hydroxybenzaldehyde's anti-ischemic stroke effect in the brain.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103395"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidepressants for inflammatory bowel disease? Multimodal effects of amitriptyline in murine colitis.","authors":"Diane E Peters","doi":"10.1016/j.jpet.2024.103382","DOIUrl":"10.1016/j.jpet.2024.103382","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103382"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin alleviates sphingolipids dysregulation and improves obesity-related kidney disease in high-fat diet rats.","authors":"Lin Xing, Shanyu Wu, Ying Shi, Lin Wei, Fangzhi Yue, Sin Man Lam, Guanghou Shui, Ryan Russell, Dongmei Zhang","doi":"10.1016/j.jpet.2025.103388","DOIUrl":"10.1016/j.jpet.2025.103388","url":null,"abstract":"<p><p>Obesity-related kidney disease (ORKD) has recently become a global health issue. Metformin is widely used in patients with type 2 diabetes with concomitant obesity, but its effects on ORKD are insufficiently understood. Accumulation of lipid species including sphingolipids has been reported to disrupt glomerular functions and drive progression of chronic kidney disease. The present study aimed to test the hypothesis that metformin could exert beneficial effects on ORKD, which may be associated with changes in renal lipidomics. Male Sprague-Dawley rats were divided into normal chow diet (ND) group or high-fat diet (HFD)-fed group. After 8 weeks, HFD-fed group was subdivided into metformin treatment (HFD-Met) group and control (HFD-C) group for an additional 8 weeks. Sphingolipids and phospholipids in renal cortex were measured by targeted lipidomics. Compared with ND group, HFD-C group developed histopathological features of ORKD. Metformin alleviated dyslipidemia, renal dysfunction, proteinuria, glomerular hypertrophy, podocyte damage, and renal fibrosis in HFD-fed rats. Renal sphingolipid analysis showed elevations of total ceramide, sphingosine, glucosylceramide, and galactosylceramide levels in HFD-C versus ND group. Specific species, such as ceramide d18:1/22:0, glucosylceramide d18:1/20:0, and galactosylceramide d18:1/16:0, which were positively associated with oxidative stress and insulin resistance, were reduced in HFD-Met versus HFD-C group. Renal phospholipid analysis showed increased levels of total phosphatidylcholine and lysophosphatidylcholine (LPC) in HFD-C rats versus ND rats. The ratio of saturated and monounsaturated LPCs to polyunsaturated LPCs was significantly reduced in HFD-Met rats. These results suggest that metformin alleviates sphingolipids dysregulation and improves ORKD in HFD-fed rats. SIGNIFICANCE STATEMENT: To date, this is the first report to explore effects of metformin on renal lipidomics. These findings reveal specific changes of renal lipid species, which are crucial for deeper understanding the underlying mechanisms of obesity-related kidney disease and effects of metformin on it. The associated signature sphingolipids and phospholipids in the study may have significant implications for developing targeted therapeutic strategies for obesity-related kidney disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103388"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NP10679: A new horizon for neuroprotection in aneurysmal subarachnoid hemorrhage.","authors":"Lidia Garcia-Bonilla","doi":"10.1016/j.jpet.2025.103390","DOIUrl":"10.1016/j.jpet.2025.103390","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103390"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined stress and alcohol exposure: Synergistic effects on alcohol-seeking behaviors and neuroinflammation.","authors":"L J Wills, B Schwartz, B McGuffin, J T Gass","doi":"10.1016/j.jpet.2025.103386","DOIUrl":"10.1016/j.jpet.2025.103386","url":null,"abstract":"<p><p>Posttraumatic stress disorder and alcohol use disorder are frequently co-occurring conditions that can create a synergistic effect, worsening symptoms of both disorders. This heightened comorbidity suggests a shared pathological basis rooted in maladaptive learning process that amplifies drug- and fear-related behaviors. The present study investigates the combined effects of stress and chronic alcohol exposure on alcohol-seeking behaviors and neuroinflammation in male and female rats. Additionally, we investigate the potential of metabotropic glutamate receptor type 5 (mGlu5) modulation as a therapeutic strategy for this co-occurring condition. Adult Wistar rats received restraint stress (Stress), chronic intermittent ethanol (CIE) vapor inhalation, both (Stress + CIE), or no exposure (Control). We assessed ethanol self-administration, extinction learning, reinstatement of alcohol-seeking behavior, and tumor necrosis factor-⍺ protein expression in the infralimbic (IfL) and prelimbic subregions of the prefrontal cortex. Additionally, we examined the effects of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), a mGlu5 positive allosteric modulator, on these outcomes. Stress + CIE exposure significantly increased ethanol self-administration, impaired extinction learning, and heightened reinstatement compared with all other groups. Interestingly, CDPPB treatment improved extinction learning and reduced reinstatement in males but not females. Furthermore, Stress + CIE exposure elevated tumor necrosis factor-⍺ levels specifically in the IfL, and CDPPB normalized this effect in males only. The current study demonstrates a synergistic effect of stress and alcohol exposure on alcohol-seeking behaviors and suggests a potential role for neuroinflammation in the IfL. Our findings also highlight sex-specific therapeutic strategies targeting mGlu5 signaling to prevent relapse in individuals with comorbid posttraumatic stress disorder and alcohol use disorder. SIGNIFICANCE STATEMENT: This research demonstrates that combined stress and alcohol exposure worsen alcohol-seeking behavior in rats, potentially via neuroinflammation in the infralimbic cortex, a region known to be involved in extinction learning. Notably, metabotropic glutamate receptor type 5 modulation was able to prevent alcohol-seeking behaviors and inflammation in a sex-dependent manner. These findings pave the way for developing personalized treatments to prevent relapse in individuals with co-occurring posttraumatic stress disorder/alcohol use disorder.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103386"},"PeriodicalIF":3.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring new frontiers in the treatment of HIV-associated neurocognitive disorder.","authors":"Barkha J Yadav-Samudrala, Sylvia Fitting","doi":"10.1016/j.jpet.2024.100040","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100040","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100040"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding CXCR2 antagonism with a dynamic allosteric ternary complex model.","authors":"Rui Li, Richard Frisbie, Fabien Vincent, Atli Thorarensen","doi":"10.1016/j.jpet.2024.100049","DOIUrl":"10.1016/j.jpet.2024.100049","url":null,"abstract":"<p><p>The CXC chemokine receptor 2 (CXCR2) antagonist SB265610 displays different patterns of antagonism using in vitro binding and cell-based assays. In addition, CXCR2 antagonists, although likely sharing a similar allosteric binding mechanism, display different patterns in the same cell-based assays. Furthermore, clinical studies with CXCR2 antagonists had mixed success in demonstrating target modulation and efficacy, despite favorable exposures based on published binding affinities. Herein, we aimed to understand the mechanism leading to these apparent inconsistencies with a dynamic allosteric ternary complex model. The model was applied in analyzing both in vitro data and clinical neutrophil counts data of CXCR2 antagonists. We extended previous hypotheses into a unified hypothesis, which postulates that, although allosteric binding of a CXCR2 antagonist is not affected by the endogenous agonist, the antagonism is surmountable as the antagonist loses its potency with increased concentrations of endogenous agonist because of the hyperbolic relationship between agonist-occupied receptor and biological response (which is possibly a result of receptor reserve). Antagonists with slow binding kinetics are apparently insurmountable, but only under unsteady-state conditions. Dynamic allosteric ternary complex model following this hypothesis can describe both in vitro and clinical data of CXCR2 antagonists. The inconsistent patterns of CXCR2 antagonism are interpreted as potential receptor reserve in cell-based assays with unsteady-state binding for some compounds. Because the binding process likely reaches quasi steady state in clinical trials, the lack of pharmacology effect for some antagonists is due to suboptimal potency rather than fast binding kinetics. This model may be applicable to other receptors to help predict clinical responses of allosteric antagonists. SIGNIFICANCE STATEMENT: Known CXC chemokine receptor 2 (CXCR2) antagonists are allosteric and do not compete with endogenous agonists. However, this antagonism is surmountable in some assays, but not others, and for some antagonists, but not others. This study proposes a unified hypothesis to explain observed inconsistent antagonism patterns and apply a mechanistic model to link in vitro findings with clinical outcomes. This study improves our understanding of the pharmacology of CXCR2 antagonists and facilitates the future discovery of antagonists with similar mechanisms for CXCR2 or other G protein-coupled receptors.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100049"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLK1 phosphorylates WRN at replication forks.","authors":"Lei Wang, Daheng He, Qianjin Li, David Orren, Chi Wang, Jinpeng Liu, Zhiguo Li, Xiaoqi Liu","doi":"10.1016/j.jpet.2024.100051","DOIUrl":"10.1016/j.jpet.2024.100051","url":null,"abstract":"<p><p>Prostate cancer, particularly castration-resistant prostate cancer, remains a serious public health issue. Androgen signaling inhibitors have emerged as a major treatment approach but with limited success. Thus, identification of novel treatment targets is of high clinical relevance. Polo-like kinase 1 (PLK1) has documented roles in various aspects of prostate cancer, including resistance to androgen inhibitors. Radiotherapy is another major approach for treating prostate cancer, but how Plk1 might regulate the efficacy of radiotherapy is unknown. Nonhomologous end joining (NHEJ) and homologous recombination (HR) are 2 major DNA repair pathways, with cellular choices between NHEJ and HR being elegantly regulated by end-processing. However, how the long-range DNA end resection is regulated remains poorly understood. It has been documented that Werner syndrome protein (WRN) is actively involved in the long-range resection pathway. In this study, we demonstrate that PLK1-associated phosphorylation of WRN regulates end resection at double-strand breaks, thereby promoting HR and chromosome stability. Cells expressing the WRN nonphosphorylatable mutant show the phenotype similar to WRN null cells because they lack the ability for long-range resection and increase NHEJ. In summary, we reveal that PLK1-associated Mre11, Rad50 and Nbs1 phosphorylation promotes end resection, eventually affecting cellular choices for double-strand break repair pathways. SIGNIFICANCE STATEMENT: Both DNA damage repair and PLK1 play critical roles in the efficacy of radiotherapy of prostate cancer. The data presented here will provide guidance on how to manipulate PLK1 to improve the efficacy of radiotherapy in clinical settings.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100051"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia.","authors":"Dwight Douglas Harris, Christopher Stone, Mark Broadwin, Meghamsh Kanuparthy, Sharif A Sabe, Ju-Woo Nho, Jad Hamze, M Ruhul Abid, Frank W Sellke","doi":"10.1016/j.jpet.2024.100532","DOIUrl":"10.1016/j.jpet.2024.100532","url":null,"abstract":"<p><p>Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n = 9) or LIN 2.5 mg (n = 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P < .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100532"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}