Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Effects of the μ-opioid peptide and nociceptin/orphanin FQ peptide receptor agonist BU08028 on cocaine self-administration in male rhesus monkeys.","authors":"Marissa B Costa, Miracle A Collier, Phillip M Epperly, Stephen M Husbands, Gerta Cami-Kobeci, Shoaib Manzoor, Paul W Czoty","doi":"10.1016/j.jpet.2025.103708","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103708","url":null,"abstract":"<p><p>Cocaine use disorder (CUD) persists as a major public health concern. The lack of US Food and Drug Administration-approved pharmacotherapies for CUD underscores the critical need for developing novel pharmacological treatments. Evidence from rodent models indicates that stimulating brain receptors for the nociceptin/orphanin FQ peptide can decrease self-administration of abused drugs, including cocaine. In the present study, effects of the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxy morphinan- 7-yl]-3,3-dimethylpentan-2-ol (BU08028), an agonist at both μ-opioid peptide and NOP receptors, were characterized in a nonhuman primate model of CUD. Ten male rhesus monkeys responded under a multiple schedule consisting of a fixed-ratio 5 schedule of food pellet delivery followed by a fixed-ratio 30 schedule of intravenous injections of cocaine (0.003-0.1 mg/kg) on a separate manipulandum. After characterizing the effects of acutely administered BU08028 (0.003-0.17 mg/kg, i.v; n = 8), the drug was administered chronically in 4 monkeys using a translational model of pharmacotherapy evaluation. BU08028 was studied during self-administration of a lower (0.01 mg/kg per injection) and a higher (0.1 mg/kg per injection) cocaine dose. BU08028 acutely enhanced the reinforcing effects of cocaine in most monkeys. However, when given chronically, BU08028 decreased the reinforcing effects of the low cocaine dose for several weeks without the development of tolerance, almost no hypersalivation and only transient decreases in food-maintained responding. Self-administration of the higher cocaine dose was unaffected. These data support the development of bifunctional agonists as novel pharmacotherapies for less severe forms of CUD. SIGNIFICANCE STATEMENT: Drugs that stimulate μ-opioid peptide and nociceptin/orphanin FQ peptide receptors have shown promise as cocaine use disorder pharmacotherapies in rodent models. In monkeys, chronic treatment with BU08028 decreased cocaine reinforcement in most subjects.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103708"},"PeriodicalIF":3.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212898","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":"Interactions between cardiorespiratory effects of fentanyl and xylazine and their reversal in male and female Sprague-Dawley rats.","authors":"Gorana Puzovic, Matthew J Wolan, Yonggong Shi, Gregory T Collins","doi":"10.1016/j.jpet.2025.103711","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103711","url":null,"abstract":"<p><p>Fentanyl continues to drive overdose deaths in the United States; however, the use of fentanyl adulterated with xylazine, an α₂ adrenergic receptor (α₂AR) agonist, results in severe overdoses that are at least partially resistant to reversal by naloxone. The present study used collar-based pulse oximetry to characterize the cardiorespiratory effects of fentanyl and xylazine, administered alone and in combination, as well as the ability of naloxone and atipamezole to reverse these effects in male and female rats. Administered alone, fentanyl and xylazine dose dependently decreased heart rate, blood oxygenation (SpO₂), and respiratory rate. Dose addition analyses indicated that fixed-ratio (3:1, 1:1, and 1:3) mixtures of fentanyl and xylazine exhibited additive interactions for all 3 cardiorespiratory endpoints, although a subadditive interaction was observed for the effects of the 1:1 mixture of fentanyl and xylazine on SpO₂. Naloxone reversed the cardiorespiratory effects of fentanyl but was slower and less effective at reversing the effects of mixtures of fentanyl and xylazine. Atipamezole reversed the cardiorespiratory effects of xylazine but was ineffective at reversing the effects of mixtures of fentanyl and xylazine. Combining naloxone with atipamezole sped the recovery of SpO₂ but induced a transient rebound tachycardia followed by sustained bradycardia, raising concerns about cardiovascular instability. These studies provide direct evidence of additive and subadditive interactions between the cardiorespiratory effects of fentanyl and xylazine and an inability of naloxone to fully reverse the cardiorespiratory effects of mixtures fentanyl and xylazine, highlighting the need for novel treatment strategies to reverse overdoses involving opioids and α₂AR agonists. SIGNIFICANCE STATEMENT: This study demonstrates that the cardiorespiratory effects of fentanyl and xylazine exhibit additive or subadditive interactions in rats and that current reversal agents, including naloxone, are insufficient to fully reverse their combined effects. These findings highlight the urgent need for improved strategies to treat overdoses involving opioids adulterated with α₂ adrenergic receptor agonists, such as xylazine.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103711"},"PeriodicalIF":3.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212966","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":"Protective functions of metformin in LPS-induced H9C2 injury by miR-497-5p/BTRC/IκBα axis-mediated NF-κB pathway activation.","authors":"Fan Xiao-Guang, Li Shu-Yuan, Cui Wen-Juan, Zhang Zhi-Kun, Hong Shu-Kun, Yang Guang-Hu, Liu Jian, Zhang Xue-Zhong, Wang Heng, Qiao Lu-Jun, Li Hua","doi":"10.1016/j.jpet.2025.103703","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103703","url":null,"abstract":"<p><p>Sepsis is a life-threatening organ dysfunction syndrome triggered by infection and uncontrolled inflammatory responses, with sepsis-associated myocardial dysfunction being a leading cause of mortality and morbidity. Metformin, a widely prescribed antihyperglycemic drug, has shown emerging protective effects beyond glucose control. In this study, we investigated the protective role of metformin against LPS-induced injury and inflammation in H9C2 and AC16 cardiomyocytes and explored the underlying mechanisms. LPS stimulation significantly reduced cell viability, promoted apoptosis, and upregulated proinflammatory cytokines (TNFα, IL-6, and IL-1β) in H9C2 and AC16 cells. Metformin treatment markedly alleviated these effects, indicating its protective role against LPS-induced cytotoxicity and inflammation. Mechanistically, metformin significantly upregulated microRNA miR-497-5p, which directly suppressed β-transducin repeat containing E3 ubiquitin-protein ligase (BTRC) expression, leading to inhibition of IκBα degradation and NF-κB pathway activation. Importantly, miR-497-5p knockdown or BTRC overexpression partially reversed the protective effects of metformin, restoring NF-κB signaling and inflammatory cytokine production. These findings collectively demonstrate that metformin protects H9C2 and AC16 cardiomyocytes from LPS-induced injury through miR-497-5p/BTRC axis-mediated suppression of NF-κB activation and highlight the functional importance of miR-497-5p and BTRC in this regulatory process. SIGNIFICANCE STATEMENT: This study highlights the protective effects of metformin against LPS-induced H9C2 and AC16 cell injury and inflammation, revealing a novel mechanism involving miR-497-5p/BTRC axis-mediated NF-κB pathway inhibition. These findings offer insights into potential therapeutic strategies for sepsis-associated myocardial dysfunction.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103703"},"PeriodicalIF":3.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238974","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 β2-adrenoceptor agonist formoterol reverses metabolic dysfunction in the diabetic proximal tubule.","authors":"Kristan H Cleveland, Natalie E Scholpa, Rick G Schnellmann","doi":"10.1016/j.jpet.2025.103698","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103698","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is characterized by metabolic dysregulation and mitochondrial dysfunction that are in part driven by elevated glucose. This study assessed the metabolic changes in the renal proximal tubule in the early onset of DKD. Furthermore, we evaluated the effect of the β2-adrenoceptor agonist formoterol in reversing metabolic disruptions in diabetic mouse kidneys. Metabolomic analysis using liquid chromatography-mass spectrometry detected 270 biochemicals in each sample. Thirteen-week-old diabetic db/db mice treated with vehicle were characterized by increased aromatic and branched-chain amino acids in renal cortex compared to vehicle-treated db/+ mice. In contrast, glycine, sarcosine, and alanine were decreased. Conversely, 8 out of 11 biochemicals associated with the glycolysis pathway, including glucose, glucose-6-phosphate, and glucose-1-phosphate, were reduced in the renal cortex of vehicle-treated db/db mice compared to db/+ mice. Furthermore, carnitines, lysolipids, cholesterol, and the steroid hormone corticosterone were increased in vehicle-treated db/db mice compared to db/+ control mice. Treatment with formoterol restored amino acid profiles and corrected glycolytic and glycogen pathways, indicating an improved metabolic balance. Formoterol treatment normalized lipid and steroid levels and mitigated markers of lipid dysregulation. These data provide insights into the early metabolic alterations in hyperglycemia and mitochondrial dysfunction in the renal cortex. Importantly, this work demonstrates that formoterol treatment reverses many of these early metabolic signatures, further supporting its use as a therapeutic for DKD. SIGNIFICANCE STATEMENT: This study identifies metabolic alterations in the kidneys of diabetic mice and is the first to evaluate the effect of the β2-adrenoceptor agonist formoterol on metabolism in the kidney. The study results showed that formoterol restores amino acid, carbohydrate, and nucleotide metabolism in a mouse model of diabetic kidney disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103698"},"PeriodicalIF":3.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181947","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":"Identification of a small molecule of nitric oxide donor-aurovertin hybrids as a GPX4 inhibitor inducing ferroptosis and apoptosis in acute T lymphocytic leukemia cells.","authors":"Minhui Song, Chenying Jiang, Chenjun Shen, Yumei Sun, Hongtao Hu, Chen Wang, Zhihui Zhu","doi":"10.1016/j.jpet.2025.103689","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103689","url":null,"abstract":"<p><p>T-cell acute lymphoblastic leukemia is a malignant cancer with high morbidity and mortality in children. However, due to its abnormal proliferation and lack of effective therapeutic drugs, clinical treatment faces significant challenges. A series of nitric oxide donor-aurovertin B hybrids were synthesized and used to test the antiproliferative activity against triple-negative breast cancer. Particularly, the structure of the preferred compound was optimized to synthesize a new compound, 4D, which was formed by coupling a nitric oxide donor with aurovertin B hybrids. In this study, we investigated the effect of compound 4D in acute T-cell lymphoblastic leukemia cells. The results demonstrated that 4D effectively suppressed T-cell acute lymphoblastic leukemia cell proliferation while concurrently inducing apoptosis via the caspase pathway and ferroptosis through lipid peroxidation. Notably, as a ferroptosis inducer, 4D inhibited GPX4 by covalently binding, thereby suppressing both enzymatic activity and gene transcription levels. SIGNIFICANCE STATEMENT: The implications of this study are that a small molecule of furazan nitrogen oxide of nitric oxide donor coupled with aurovertin B hybrids, 4D, inhibited GPX4 through covalently binding to GPX4 to induce ferroptosis in acute T lymphocytic leukemia cells. This study identified a promising drug candidate for the development of an anti-T-cell acute lymphoblastic leukemia agent in the future.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103689"},"PeriodicalIF":3.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149607","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":"Morusin reverses paclitaxel resistance by inhibiting the stem cell-like properties of non-small cell lung cancer in a β-catenin-dependent manner.","authors":"Huaming Li, Hongliang Hui, Lei Zhang, Yangui Lin, Dan Li, Bo Jiang","doi":"10.1016/j.jpet.2025.103692","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103692","url":null,"abstract":"<p><p>Drug resistance is the common factor inducing failure of chemotherapy for non-small cell lung cancer (NSCLC), whereas β-catenin-regulated stem cell-like characteristics exert an important effect on tumor cell resistance. Antitumor activity of morusin is well established; however, its impact on paclitaxel (PTX) resistance of NSCLC is largely unexplored. The present work successfully established PTX-resistant NSCLC cells, and applied morusin as an intervention. We used methylthiazolyldiphenyl-tetrazolium bromide assay for assessing drug resistance level. Apoptosis rate was measured through flow cytometry. Additionally, stem cell characteristics marker expression (ALDH1, SOX2, OCT4, and NANOG) was analyzed through quantitative real-time polymerase chain reaction. We also conducted tumor sphere formation assay for evaluating stem cell-like properties in NSCLC cells. Immunofluorescence and Western blotting assays were performed to examine β-catenin protein level and localization. Ultimately, we established PTX-resistant NSCLC cell lines with β-catenin overexpression to investigate the potential molecular mechanisms underlying morusin's ability to reverse PTX resistance of NSCLC cells. As suggested by our findings, PTX-resistant NSCLC cells exhibited reduced PTX susceptibility, augmented stem cell-like properties, upregulated β-catenin, and enhanced β-catenin nuclear accumulation. Morusin effectively reversed PTX resistance, enhanced PTX-induced apoptosis, and attenuated stem cell-like properties of PTX-resistant NSCLC cells. Interestingly, morusin downregulated β-catenin protein level while inhibiting the nuclear translocation of PTX-resistant NSCLC cells. However, β-catenin overexpression significantly augmented both resistance to PTX and stem cell-like properties in PTX-resistant NSCLC cells. Moreover, effects induced by morusin on these phenomena were effectively counteracted by the overexpression of β-catenin. In conclusion, morusin may reverse resistance of NSCLC cells to PTX through suppressing β-catenin-mediated stem cell-like properties. SIGNIFICANCE STATEMENT: Cancer stem cells represent the most fundamental cause of drug resistance. Morusin can enhance the efficacy of paclitaxel by inhibiting β-catenin-mediated stem cell-like properties in non-small cell lung cancer cells, and thus holds promise for contributing to the clinical management of paclitaxel resistance.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103692"},"PeriodicalIF":3.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149535","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 methamphetamine-induced sleep disruption on intradimensional/extradimensional attentional set-shifting in adult rhesus monkeys.","authors":"Daniel A Borgatti, James K Rowlett, Lais F Berro","doi":"10.1016/j.jpet.2025.103693","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103693","url":null,"abstract":"<p><p>Cognitive performance has been shown to be negatively affected by both methamphetamine use and sleep disruption, independently. However, few studies have investigated the effects of methamphetamine-induced sleep disruptions on next-day executive functioning. The aim of the present study was to investigate the next-day cognitive effects of methamphetamine-induced sleep disruption on executive functioning in adult rhesus monkeys. Monkeys (4 males and 1 female) were fitted with primate collars to which actigraphy monitors were attached. Actigraphy-based sleep measures were assessed at night during baseline conditions and after methamphetamine administration (0.3 and 0.56 mg/kg, i.m.) 3 hours before \"lights off.\" The monkeys then completed an intradimensional/extradimensional attentional set-shifting task (Cambridge Neuropsychological Test Automated Battery touchscreen system) the following day. Methamphetamine administration disrupted actigraphy-based sleep parameters, significantly decreasing sleep efficiency and increasing % wake, sleep latency, and sleep fragmentation at the highest dose tested (0.56 mg/kg) compared with baseline. Sleep impairment was associated with next-day cognitive deficits after treatment with methamphetamine at the dose of 0.56 mg/kg, with significantly increased total trials to completion, total errors, and total perseverative errors and decreased mean task accuracy compared with cognitive performance during baseline. Significant correlations were observed between actigraphy-based sleep measures and cognitive performance across all experimental conditions, with greater wake time and lower sleep efficiency being associated with worse cognitive performance. Our findings indicate that the sleep-disrupting effects of methamphetamine may play a role in this drug's cognition-disrupting effects. SIGNIFICANCE STATEMENT: The present study shows that methamphetamine-induced sleep disruption is associated with next-day impairments in cognitive measures in nonhuman primates. Addressing sleep disruptions may offer a novel treatment strategy to improving cognitive deficits associated with use of this stimulant.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103693"},"PeriodicalIF":3.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182179","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":"Interactions between fentanyl and 2,5-dimethoxy-4-methylamphetamine: Ventilatory effects in nonhuman primates.","authors":"David R Maguire","doi":"10.1016/j.jpet.2025.103691","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103691","url":null,"abstract":"<p><p>Increasing interest in the therapeutic potential of psychedelics, combined with expanding availability, decreasing perceived risk, and widening efforts toward decriminalization, underscore the need to investigate potential consequences that might emerge with their use, including interactions that occur when psychedelics are taken in combination with other drugs such as opioids. This study examined effects of 2,5-dimethoxy-4-methylamphetamine (DOM) on fentanyl-induced ventilatory depression in rhesus monkeys (n = 6) using head plethysmography. Fentanyl (0.001-0.1 mg/kg) and DOM (0.01-0.32 mg/kg) were studied alone and in pairwise mixtures. Fentanyl alone dose-dependently decreased tidal volume while DOM alone had no effect. However, in a majority of monkeys, combining DOM with fentanyl reduced ventilation to a greater extent than the same doses of fentanyl alone. Taken together with previous studies, these data suggest that, although DOM as well as other serotonergic hallucinogens fail to enhance other abuse-related effects of opioids, they might exacerbate opioid-induced ventilatory depression, which would increase risk for overdose. Whether ventilatory effects of DOM-fentanyl mixtures extend to combinations of other opioids and other drugs with similar pharmacological properties remains unclear. SIGNIFICANCE STATEMENT: Growing interest in psychedelics underscores the need to understand risks associated with their use, including interactions with other drugs. In this this study, 2,5-dimethoxy-4-methylamphetamine enhanced the ventilatory effects of fentanyl, revealing a novel potential adverse effect of psychedelics.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103691"},"PeriodicalIF":3.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182089","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":"Estrogen elicits ferroptosis-related myocardial oxidative stress and dysfunction in male rats.","authors":"Syed Anees Ahmed, Abdel A Abdel-Rahman","doi":"10.1016/j.jpet.2025.103690","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103690","url":null,"abstract":"<p><p>Clinical evidence showed estrogen (E2)-mediated adverse cardiac effects in transgender women. This study aimed to determine if this paradoxical cardiac effect occurs in male rats and to elucidate the mechanisms for this unexplained detrimental cardiac effect of E2. Male Sprague-Dawley rats were divided into 2 groups: one group received E2, whereas the other received vehicle. Blood pressure and echocardiographic assessments were performed over 8 weeks following chronic E2 or vehicle administration. At the conclusion of the study, hearts were collected for ex vivo biochemical and molecular analyses. E2-treated male rats exhibited significant cardiac dysfunction, as evidenced by reduced heart rate, ejection fraction, and fractional shortening. Ex vivo molecular analyses of cardiac tissues from E2-treated rats, compared to vehicle-treated controls, revealed (1) a significant downregulation of the circadian clock protein Per2 and cardiac-specific miRNAs (1, 133a, 208a, and 499); (2) marked suppressions of key redox enzymes, including mitochondrial aldehyde dehydrogenase 2, catalase, along with nuclear factor erythroid 2-related factor 2 expression; and (3) increases in cardiac ferroptosis, pro-oxidant heme oxygenase-1 levels, and oxidative stress, indicating disrupted redox homeostasis and heightened oxidative damage. Our novel findings corroborated the clinical paradoxical adverse cardiac effects of chronic E2 in transgenders. The suppressions in interrelated cardioprotective factors, including Per2, miRNAs, and redox enzymes, along with the upregulation of ferroptosis, may contribute to the disrupted cardiac redox homeostasis and impaired cardiac function in E2-treated male rats. SIGNIFICANCE STATEMENT: The study findings reveal the paradoxical adverse effects of chronic estrogen treatment on cardiac redox status and function in male rats. Estrogen-treated male rats exhibited reduced cardiac function, decreased expression of the circadian clock protein Period 2, impaired redox balance, and elevated levels of ferroptosis mediators. These preclinical findings are highly relevant to the sex-specific adverse cardiac effects associated with gender-affirming estrogen therapy in transgender women, offering insights into their increased cardiovascular risk.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 10","pages":"103690"},"PeriodicalIF":3.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182149","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":"Beyond epilepsy: The expanding role of valproic acid in Alzheimer disease therapy - a review.","authors":"Magdalena Markowicz-Piasecka, Zuzanna Miłkowska, Santosh Kumar Adla, Kristiina M Huttunen, Bogusława Pietrzak","doi":"10.1016/j.jpet.2025.103658","DOIUrl":"10.1016/j.jpet.2025.103658","url":null,"abstract":"<p><p>Valproic acid (VPA), a well-established anticonvulsant and mood stabilizer, has gained significant attention for its potential neuroprotective effects in neurodegenerative diseases, particularly Alzheimer disease (AD). As a histone deacetylase inhibitor, VPA influences gene expression, synaptic plasticity, and neuronal survival, making it a promising candidate for therapeutic intervention. Preclinical studies have demonstrated that VPA reduces β-amyloid accumulation, inhibits tau hyperphosphorylation, modulates oxidative stress, and attenuates neuroinflammation-key pathological hallmarks of AD. Additionally, VPA enhances neurogenesis and supports synaptic function, further contributing to its neuroprotective properties. Despite encouraging in vitro and in vivo findings, clinical trials investigating VPA's efficacy in AD have yielded mixed results. While some studies reported benefits in managing behavioral symptoms, large-scale trials, including the Alzheimer's Disease Cooperative Study Valproate Trial, failed to demonstrate significant cognitive improvement and revealed notable side effects. These findings highlight the need for further research to optimize VPA's clinical application, including targeted drug delivery, combination therapies, and patient-specific approaches. This review explores the molecular mechanisms underlying VPA's neuroprotective effects, evaluates its therapeutic potential in AD and other neurodegenerative disorders, and discusses the challenges that must be addressed before its widespread clinical implementation. SIGNIFICANCE STATEMENT: Valproic acid shows promise for treating Alzheimer disease by targeting key pathological mechanisms. This review highlights valproic acid's neuroprotective potential, summarizes preclinical and clinical findings, and outlines the critical challenges that must be addressed to advance its use in Alzheimer disease therapy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103658"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768730","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}