Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Preclinical pharmacological profiles of vornorexant, a novel potent dual orexin receptor antagonist.","authors":"Hirohiko Hikichi, Yuichi Tokumaru, Atsuki Taruta, Yoshihiro Konno, Jun-Ichi Karasawa, Kenichi Fukumoto, Toshiyuki Marumo, Yasuyuki Fujii, Teisuke Takahashi, Takao Yoshimizu, Shigeyuki Chaki, Noriko Hino, Naoki Kojima","doi":"10.1016/j.jpet.2025.103624","DOIUrl":"10.1016/j.jpet.2025.103624","url":null,"abstract":"<p><p>Dual orexin receptor antagonists are known to inhibit the orexinergic signaling pathway, leading to promotion of sleep. Here, we report the pharmacological profiles of [(2S)-2-{[3-(5-Fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (vornorexant), also known as ORN0829. In in vitro assays, vornorexant exhibited a high affinity for OX₁ and OX₂ receptors, without any meaningful affinity for other receptors, transporters or ion channels, exerting receptor antagonist activity. Vornorexant had pharmacokinetic profiles with a relatively rapid absorption and short half-life, rapidly occupied the OX₁ and OX₂ receptors in the brain of rats after oral administration and rapidly dissociated from these receptors depending on the plasma concentration. In rats, daily oral administration of vornorexant just before the dark phase reduced the sleep onset latency and prolonged sleep time, and no tolerance developed up to 14 days. Vornorexant also reduced the sleep onset latency and prolonged sleep time in rats that had developed tolerance after daily treatment with the GABA_A receptor modulator, zolpidem. In addition, vornorexant also enhanced the sleep-promoting effects of zolpidem in rats. Moreover, vornorexant did not impair motor coordination in monotherapy and combination with ethanol in rats. These results indicate that vornorexant has desirable profiles with a rapid sleep onset latency and a short half-life, thereby a lowered risk of next-morning residual activity. Vornorexant could be a promising alternative therapeutic option to GABA_A receptor modulators for the treatment of insomnia. SIGNIFICANCE STATEMENT: Vornorexant is a novel and potent dual orexin receptor antagonist that was demonstrated to exert sleep-promoting effects by occupying the OX₁ and OX₂ receptors in the brain of rats. Moreover, vornorexant promoted sleep even after switching treatment from zolpidem or when administered in combination with zolpidem in rats. These results suggest that vornorexant possesses properties that are desirable for insomnia drugs.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103624"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506044","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":"Ethanol self-administration prior to cocaine self-administration reduces sensitivity to cocaine reinforcement in socially housed monkeys.","authors":"Mia I Allen, Emory Lewis, Cameron F Rough, Michael A Nader","doi":"10.1016/j.jpet.2025.103608","DOIUrl":"10.1016/j.jpet.2025.103608","url":null,"abstract":"<p><p>Co-use of alcohol is highly prevalent among individuals who use cocaine. However, the behavioral mechanisms underlying co-use are not fully characterized. Thus, this study aimed to examine how ethanol (EtOH) self-administration prior to cocaine self-administration influenced the maintenance of cocaine self-administration in socially housed male (n = 4) and female (n = 4) cynomolgus monkeys responding under a fixed-ratio schedule of reinforcement. For these experiments, food (1.0 g flavored pellets) and cocaine dose-response curves (0.001-0.3 mg/kg) were determined when monkeys had access to 1.5 g/kg of a sweetened EtOH solution or an equal volume of a sweetened vehicle solution for one hour prior to cocaine self-administration. EtOH and the sweetened vehicle were readily self-administered by all monkeys, and consumption did not affect fixed-ratio food-maintained responding. When cocaine was studied, EtOH significantly decreased the potency of cocaine to function as a reinforcer relative to when the sweetened vehicle was self-administered. This relationship also appeared dose-dependent such that monkeys that drank more EtOH prior to the session had greater rightward shifts in the cocaine dose-response curve. Neither sex nor social rank influenced these outcomes. These data may suggest that EtOH decreased the reinforcing effects of cocaine, and/or attenuated the discriminative stimulus effects of cocaine. Future research is needed to examine how EtOH may modify cocaine use in the presence of a nondrug alternative reinforcer and to evaluate whether interventions aimed at reducing drug use are less effective in the context of co-use. SIGNIFICANCE STATEMENT: Cocaine users commonly report co-using alcohol simultaneously or in close succession. The present study found that ethanol (EtOH) self-administration prior to cocaine self-administration decreased the potency of cocaine to function as a reinforcer in nonhuman primates. These findings suggest that EtOH may decrease the effects of cocaine, and although not directly assessed in this study, EtOH may be used in combination with cocaine to mitigate the negative effects associated with cocaine use.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103608"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234403","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":"Uncovering the pharmacological mechanisms of bifendate against chronic kidney disease using computational pharmacology and experimental verification.","authors":"Hrushikesh Kulkarni, Neha Dagar, Anil Bhanudas Gaikwad","doi":"10.1016/j.jpet.2025.103609","DOIUrl":"10.1016/j.jpet.2025.103609","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a progressive ailment identified by renal fibrosis, inflammation, and mitochondrial dysfunction, necessitating the development of novel therapeutic interventions. Bifendate (dimethyl diphenyl bicarboxylate [DDB]), a known hepatoprotective agent, has shown promising antifibrotic properties, but its potential in CKD remains unexplored. This study integrates computational pharmacology, molecular docking, and experimental validation to explicate the mechanisms of renoprotection by DDB. Curative targets for CKD and DDB were identified from DisGeNET, GeneCards, and SwissTargetPrediction. Potential DDB targets against CKD were analyzed via STRING for protein interactions. Gene ontology and pathway enrichment (Database for Annotation, Visualization, and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes) were conducted, followed by network construction and analysis using Cytoscape (Institute for Systems Biology, USA). Network analysis identified 89 overlapping targets between DDB and CKD, including key regulators such as NF-κB1, PTGS2, and PPARG, which were enriched in multiple pathways, including calcium, Ras, ROS, NF-κB, and cAMP signaling. To validate these findings, a unilateral ureteral obstruction model in Sprague-Dawley rats was employed. DDB administration significantly mitigated kidney fibrosis, improved renal function markers, and preserved kidney morphology. Histological analyses confirmed that DDB attenuated tubular injury, glomerulosclerosis, and excessive collagen deposition. Furthermore, immunohistochemical assessments demonstrated that DDB suppressed epithelial-mesenchymal transition by restoring E-cadherin and reducing α-smooth muscle actin expression. Mitochondrial biogenesis was enhanced through PGC-1α upregulation, while inflammatory responses were dampened via NF-κB pathway inhibition. These findings highlight DDB's multifaceted therapeutic potential in CKD, acting through fibrosis inhibition, mitochondrial protection, and anti-inflammatory mechanisms. This study provides a strong foundation for further clinical investigations into DDB as a potential treatment for CKD, offering new insights into its mechanistic pathways. SIGNIFICANCE STATEMENT: This study demonstrates bifendate's therapeutic potential for chronic kidney disease through network pharmacology, identifying 89 common targets. Experimental validation in a unilateral ureteral obstruction model confirmed its renoprotective effects, revealing multi-target mechanisms against renal fibrosis and injury.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103609"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285048","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":"Effects of NAD⁺ supplementation with oral nicotinamide riboside on vascular health and cognitive function in older adults with peripheral artery disease: Results from a pilot 4-week open-label clinical trial.","authors":"Zsofia Szarvas, Zeke A Reyff, Anna Peterfi, Camila B Pinto, Cameron D Owens, Zalan Kaposzta, Peter Mukli, Ana Clara da C Pinaffi-Langley, Cheryl A Adams, Mihaly Muranyi, Federico Silva Palacios, Beau Hawkins, Joseph A Baur, Faddi Saleh Velez, Calin I Prodan, Angelia C Kirkpatrick, Anna Csiszar, Zoltan Ungvari, Priya Balasubramanian, Sharon Negri, Stefano Tarantini, Kai Ding, Alexander A Buelow, Amir Akbari, J Mikhail Kellawan, Andriy Yabluchanskiy","doi":"10.1016/j.jpet.2025.103607","DOIUrl":"10.1016/j.jpet.2025.103607","url":null,"abstract":"<p><p>Peripheral artery disease (PAD) significantly contributes to increased morbidity and mortality among older adults. Characterized by generalized endothelial dysfunction, PAD is associated with a heightened risk for cerebral small vessel disease and vascular cognitive impairment. Together, these conditions exemplify the phenomenon of accelerated systemic vascular aging, highlighting the interconnections between vascular health and cognitive functions in the elderly. This pilot trial investigated the potential of nicotinamide riboside (NR), a precursor of NAD⁺, to counteract age-related vascular and cognitive decline in individuals with PAD. Over 4 weeks, we administered NR to 8 participants and measured its effects on peripheral endothelial function, functional cerebrovascular responses, and cognitive performance (NCT06534944). Additionally, we assessed the effects of circulating factors present in patient sera on oxidative stress and mitochondrial function in cultured cerebromicrovascular endothelial cells. Preliminary results indicate a positive trend in peripheral endothelial function, significant improvements in cerebrovascular response in the left dorsolateral prefrontal cortex, and cognitive enhancement across multiple domains postsupplementation. NAD⁺ supplementation with NR was associated with reduced oxidative stress and increased nitric oxide production and mitochondrial efficiency in endothelial cells treated with patient sera. These findings suggest that NR supplementation could ameliorate cognitive outcomes in older adults with PAD, potentially through mechanisms linked to improved endothelial health and decreased oxidative stress. This study underscores the importance of future research using controlled designs in larger cohorts to verify these effects and elucidate the long-term benefits of NAD⁺ enhancement in the context of accelerated vascular aging and its cognitive consequences. SIGNIFICANCE STATEMENT: Despite growing interest in NAD⁺ enhancement for vascular and cognitive health, research on nicotinamide riboside (NR) in peripheral artery disease (PAD) is limited. One clinical trial to date has assessed NR in PAD, focusing mainly on walking capacity. This pilot study provides critical evidence by examining peripheral endothelial function, cerebrovascular responses, and cognitive performance. Its multifaceted approach lays the groundwork for future trials to refine effect sizes and validate NR's potential to counter vascular aging and cognitive decline in PAD.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103607"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248413","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":"Modulating hormonally upregulated neu-associated kinase (HUNK) activity in breast cancer: The development of HUNK inhibitors.","authors":"Alexander E Kritikos, Anslyn C Freije, Elizabeth S Yeh","doi":"10.1016/j.jpet.2025.103604","DOIUrl":"10.1016/j.jpet.2025.103604","url":null,"abstract":"<p><p>Hormonally upregulated neu-associated kinase (HUNK) is a serine/threonine protein kinase in the sucrose non-fermenting 1/AMP-activated protein kinase family that promotes cell survival and plays an important role in breast cancer growth and metastasis. Robust methods to alter HUNK expression and activity are currently in use to advance our understanding of this kinase and its function. However, despite its role in the aggressive triple-negative cancer and human epidermal growth factor receptor 2 (HER2)+ breast cancer subtypes, targeted pharmacological inhibition of HUNK is still in its infancy. There are 2 goals of this review: first, to summarize the work done to modulate HUNK activity and advance scientific understanding of the kinase, and second, to describe the current work toward HUNK's pharmacological inhibition and the application of HUNK inhibitors. Clinically, HER2+ breast cancer often develops resistance to the HER2-targeted standard of care therapy, and experimental studies have shown that this can occur via a HUNK-dependent mechanism. In triple-negative breast cancer, where targeted treatments are lacking, HUNK has been shown to promote cancer progression to metastasis. Thus, further research on HUNK and its pharmacology may lead to novel therapeutics for patients with breast cancer and improved treatment outcomes. SIGNIFICANCE STATEMENT: Having recently been identified to promote aggressive breast cancers, hormonally upregulated neu-associated kinase is showing promise as a potential therapeutic target, yet drug discovery in this area is still at an early stage. This review aims to highlight recent efforts and methods to study the kinase and to identify novel inhibitors that may prove useful in continued basic science and translational research.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103604"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181604","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":"Xylazine exacerbates fentanyl-induced respiratory depression and bradycardia.","authors":"Catherine Demery, Sierra C Moore, Erica S Levitt, Jessica P Anand, John R Traynor","doi":"10.1016/j.jpet.2025.103616","DOIUrl":"10.1016/j.jpet.2025.103616","url":null,"abstract":"<p><p>Fatal opioid overdoses in the United States have nearly tripled during the past decade, with greater than 92% involving a synthetic opioid like fentanyl. Fentanyl potently activates the μ-opioid receptor to induce both analgesia and respiratory depression. The danger of illicit fentanyl has recently been exacerbated by adulteration with xylazine, an α2-adrenergic receptor agonist typically used as a veterinary anesthetic. In 2023, over a 1000% increase in xylazine-positive overdoses was reported in some regions of the United States. Xylazine has been shown to potentiate the lethality of fentanyl in mice, yet a mechanistic underpinning for this effect has not been defined. Herein, we evaluate fentanyl, xylazine, and their combination in whole-body plethysmography (to measure respiration) and pulse oximetry (to measure blood oxygen saturation and heart rate) in male and female CD-1 mice. We show that xylazine decreases breathing rate more than fentanyl by increasing the expiration time. In contrast, fentanyl primarily reduces breathing by inhibiting inspiration, and xylazine exacerbates these effects. Fentanyl but not xylazine decreased blood oxygen saturation, and when combined, xylazine did not change the maximum level of fentanyl-induced hypoxia. Xylazine also reduced heart rate more than fentanyl at higher doses. Finally, loss in blood oxygen saturation correlated with the frequency of fentanyl-induced severe apneas, but not breathing rate. Together, these findings provide insight into how the addition of xylazine to illicit fentanyl may increase the risk of overdose. SIGNIFICANCE STATEMENT: Xylazine, found in illicit fentanyl samples, exacerbates fentanyl-induced respiratory depression in mice. Fentanyl-induced reduction in blood oxygen levels correlates with the number of severe apneas. The findings show how the addition of xylazine to fentanyl may increase the risk of overdose.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103616"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340232","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":"Statin treatment alters the expression profile of plasma exosome-derived microRNAs in patients with familial hypercholesterolemia.","authors":"Carolina Dagli-Hernandez, Renata Caroline Costa de Freitas, Andre Ducati Luchessi, Thiago Dominguez Crespo Hirata, Cristina Moreno Fajardo, Jessica Bassani Borges, Victor Fernandes de Oliveira, Antonia Pereira Rosa Neta, Andre Arpad Faludi, Rodrigo Marques Gonçalves, Raul Hernandes Bortolin, Vanessa Barbosa Malaquias, Gisele Medeiros Bastos, Marcelo Ferraz Sampaio, Mario Hiroyuki Hirata, Rosario Dominguez Crespo Hirata","doi":"10.1016/j.jpet.2025.103626","DOIUrl":"10.1016/j.jpet.2025.103626","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) contribute to the variability in statin response by modulating genes involved in lipid metabolism. However, no studies evaluating exosomal miRNA profiles after statin treatment in patients with familial hypercholesterolemia (FH) have been performed. This study aimed to explore the effects of short-term statin treatment on the miRNA profile of plasma exosomes from patients with FH. Thirty-eight patients with FH on 6-week statin treatment and 32 normolipidemic subjects (control group) were selected. Plasma exosomes were isolated, and miRNA expression was analyzed by small RNA sequencing. Enrichment analysis was used to identify miRNA targets, interactions, and pathways. Expression of let-7a, miR-16, miR-92a, miR-122, and miR-486a was higher in the FH group than in the control group (fold change, ≥±1.5; P < .05). Statin treatment upregulated miR-92a and downregulated let-7b and miR-423 (P < .05) in plasma exosomes from patients with FH. In the overall group, baseline levels (normalized counts) of let-7a, miR-16, miR-92a, miR-122, and miR-486 were positively correlated with total and low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and inversely correlated with high-density lipoprotein cholesterol (P < .05). Let-7b and miR-423 were also correlated with total cholesterol and triglycerides. The FH- and statin-dysregulated miRNAs target genes involved in cell cycle and proliferation, protein catabolism, and other biological processes, in addition to cholesterol homeostasis and cardiovascular function. In conclusion, FH and statin treatment alter the profile of plasma exosome-derived miRNAs, which have potential application as biomarkers for FH assessment and statin treatment monitoring. Future studies with larger cohorts, extended treatment periods, and validation via quantitative polymerase chain reaction are warranted to elucidate the role of these miRNAs in FH and statin response. SIGNIFICANCE STATEMENT: This study describes the effects of short-term statin treatment on circulating microRNAs (miRNAs) expression in familial hypercholesterolemia (FH). Five miRNAs were upregulated in plasma exosomes from patients with FH compared with healthy subjects. Six-week statin treatment upregulated miR-92a and downregulated miR-423 and let-7b in patients with FH. These miRNAs target genes with multiple biological functions and possible involvement in FH pathogenesis and statin response, making them potential candidates as biomarkers for therapy monitoring.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103626"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560383","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":"Absorption, distribution, metabolism, and excretion of [¹⁴C]SHEN211, a nonpeptidic small-molecule 3CL^pro inhibitor, in rats.","authors":"Zihao Zhang, Mengting Jia, Feiyu Wang, Chen Yang, Huanhuan Shi, Yali Yuan, Zhuoran Tian, Congmei Ming, Jinwen Huang, Junfang Pan, Xiaokun Shen, Yuandong Zheng, Xingxing Diao","doi":"10.1016/j.jpet.2025.103623","DOIUrl":"10.1016/j.jpet.2025.103623","url":null,"abstract":"<p><p>SHEN211 is a selective 3-chymotrypsin-like protease inhibitor that can protect against severe acute respiratory syndrome coronavirus 2. It is currently being assessed in clinical trials in China, but few studies have reported its metabolism in preclinical and clinical settings. This study used radioactive isotope labeling to investigate the absorption, distribution, metabolism, and excretion of SHEN211 in rats. After a single intragastric administration of 2.0 mg/kg (100 μCi/kg) of [¹⁴C]SHEN211 in rats, the inhibitor was rapidly absorbed, with feces being the primary route of excretion. The results of tissue distribution indicated that SHEN211-related components were mainly concentrated in the liver. In total, 11 metabolites were identified in rat plasma, urine, feces, and bile, and SHEN211 was the major drug-related component in the systemic circulation. The main metabolic pathways of SHEN211 were N-dealkylation, oxidative defluorination, glucuronidation, and glutathione conjugation. In addition, a physiologically based pharmacokinetic model for rats was constructed and validated using GastroPlus software, and the model was extrapolated to healthy adult males to predict the pharmacokinetic characteristics of SHEN211 in humans, providing invaluable insights into the human mass balance of SHEN211 and paving the way for clinical studies. SIGNIFICANCE STATEMENT: This study characterized the absorption, distribution, metabolism, and excretion of SHEN211, a 3CL^pro inhibitor for severe acute respiratory syndrome coronavirus 2 in rats. SHEN211 exhibited rapid absorption and was mainly distributed in the liver. Fecal excretion was the primary elimination route. The prediction of human pharmacokinetic characteristics using the physiologically based pharmacokinetic model provides an invaluable reference for optimizing the clinical dosing strategy of SHEN211 and advancing its ongoing clinical trials in China.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103623"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540640","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":"Corrigendum to 'A gut response: Application of human enteroid monolayers to probe the mechanism of the goldenseal-mediated inhibition of metformin intestinal absorption' [The Journal of Pharmacology and Experimental Therapeutics 392 (2025) 103597].","authors":"Christopher M Arian, Eimear T O'Mahony, Preston K Manwill, Tyler N Graf, Nicholas H Oberlies, Nadja B Cech, John D Clarke, Jason G Smith, Mary F Paine, Edward J Kelly, Kenneth E Thummel","doi":"10.1016/j.jpet.2025.103628","DOIUrl":"10.1016/j.jpet.2025.103628","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103628"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285047","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":"The role of pyruvate metabolism in cardiovascular diseases.","authors":"Zijie Cheng, Haoqi Li, Dan Wu, Qingxun Hu","doi":"10.1016/j.jpet.2025.103619","DOIUrl":"10.1016/j.jpet.2025.103619","url":null,"abstract":"<p><p>Cardiovascular diseases remain the leading cause of mortality worldwide, with their incidence steadily rising in recent years. Pyruvate, the end product of glycolysis, serves as a critical metabolite in cellular energy metabolism by bridging cytoplasmic glycolysis and mitochondrial oxidative phosphorylation. Its synthesis, transport, and metabolic conversion are tightly regulated by a range of enzymes and transporters, including pyruvate kinase, mitochondrial pyruvate carriers, pyruvate dehydrogenase complex, glucose transporters, and lactate dehydrogenase. Emerging evidence suggests that dysregulation of pyruvate metabolism plays a pivotal role in the pathogenesis of various cardiovascular conditions, including heart failure, ischemia-reperfusion injury, diabetic cardiomyopathy, and pulmonary hypertension. This review aimed to provide a comprehensive and integrative overview of the role of pyruvate metabolism in cardiovascular diseases by systematically analyzing recent findings from both experimental and clinical studies. Unlike previous reviews that focus on isolated enzymes or specific disease types, we adopted a systemic perspective to elucidate the entire pyruvate metabolic network and its crosstalk with mitochondrial function, redox homeostasis, and inflammatory signaling pathways. We also discuss the regulatory roles of key signaling cascades, such as PI3K-AKT, and the implications of genetic variations in enzymes involved in pyruvate metabolism. Finally, we highlight potential molecular targets within this pathway that could be leveraged for therapeutic intervention. By mapping these interconnections, our review underscores the therapeutic potential of targeting pyruvate metabolism as a novel strategy for treating cardiovascular disorders. SIGNIFICANCE STATEMENT: Pyruvate metabolism plays a crucial role in cardiovascular disease development and has attracted growing interest. While previous reviews have examined enzymes like PDC and PKM2, they often focus narrowly on specific pathways or disease types. This review offers a more integrated, system-level perspective, highlighting the roles of pyruvate metabolism in mitochondrial function, redox balance, and inflammation. It also identifies potential metabolic targets, aiming to support future therapeutic strategies in treating cardiovascular conditions.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103619"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506046","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}