The Journal Of Pharmacology And Experimental Therapeutics[JOURNAL]
Sun
200 papers
Special collection on novel targeted therapies for advanced prostate cancer.
Chen M, Wang QJ
J Pharmacol Exp Ther · 2026 Jan · PMID 41412092 · Publisher ↗
Abstract loading — click title to view on PubMed.
Matrix metalloproteinases and their association with preeclampsia/eclampsia with maternal age: A potential link to cardiovascular disease in later life.
Taherkhani S, Sheibani M, Ahmadi R … +4 more , Mohammadkhanizadeh A, Virag JAI, de Castro Braz LE, Azizi Y
J Pharmacol Exp Ther · 2026 Jan · PMID 41412091 · Publisher ↗
Maternal age is a well established risk factor for preeclampsia and eclampsia, with advanced maternal age (>35 years) associated with a significantly increased risk of developing these disorders. Preeclampsia and eclamps...
Maternal age is a well established risk factor for preeclampsia and eclampsia, with advanced maternal age (>35 years) associated with a significantly increased risk of developing these disorders. Preeclampsia and eclampsia are 2 of the most severe and life-threatening complications of pregnancy, affecting approximately 2%-8% of pregnancies worldwide. These disorders are characterized by high blood pressure, proteinuria, and multiorgan dysfunction, which can lead to maternal and fetal morbidity and mortality if left untreated. Despite advances in medical technology and prenatal care, the etiology of preeclampsia and eclampsia remains poorly understood, and there is a pressing need for the identification of novel biomarkers and therapeutic targets. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have a functional role in the degradation and remodeling of the extracellular matrix. MMP expression and activity changes in women with preeclampsia and eclampsia. For example, MMP-2 and MMP-9 have been shown to be elevated in the serum and placenta of women with preeclampsia, whereas MMP-1 and MMP-3 have been found to be decreased. These changes in MMP expression and activity may contribute to the development of preeclampsia and eclampsia by promoting inflammation, endothelial dysfunction, and vascular remodeling. The dysregulation of MMPs in preeclampsia/eclampsia can lead to the breakdown of the maternal-fetal interface, resulting in the release of proinflammatory cytokines and the activation of immune cells. Addressing MMP dysfunction in preeclampsia and eclampsia requires a multifaceted approach, combining pharmacological interventions, genetic insights, and a focus on oxidative stress to improve maternal and fetal health outcomes. SIGNIFICANCE STATEMENT: This study highlights the critical role of maternal age and matrix metalloproteinases (MMPs) in preeclampsia and eclampsia, severe pregnancy complications with high morbidity and mortality. Advanced maternal age increases risk, whereas dysregulated MMPs contribute to inflammation, endothelial dysfunction, and vascular remodeling, disrupting the maternal-fetal interface. Understanding MMP alterations offers potential for novel biomarkers and therapeutic targets, aiming to improve outcomes through integrated pharmacological and genetic approaches addressing immune and oxidative stress pathways.
Enhancing local glioblastoma treatment via in vitro synergistic pairing of Janus kinase/signal transducer and activator of transcription-3 inhibitor with antiepileptic drugs.
Bărăian AI, Raduly L, Zănoagă O … +3 more , Iacob BC, Berindan-Neagoe I, Bodoki E
J Pharmacol Exp Ther · 2026 Jan · PMID 41406909 · Publisher ↗
The heterogeneity and treatment resistance of glioblastoma (GBM) can be addressed through multidrug combination therapies that target multiple biological pathways simultaneously. In this study, we explored the repurposin...
The heterogeneity and treatment resistance of glioblastoma (GBM) can be addressed through multidrug combination therapies that target multiple biological pathways simultaneously. In this study, we explored the repurposing of antiepileptic drugs with potential antitumor effects, combined with the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3) inhibitor ruxolitinib (RUX), as an alternative local therapeutic approach for GBM. The cytotoxic effects of valproic acid (VPA), oxcarbazepine (OXC), and gabapentin (GBP) were evaluated on A172 and U251 GBM cells. Both VPA and OXC significantly reduced cell viability, prompting further investigation of their effects in combination with RUX. When tested in 3-dimensional multicellular tumorspheres, the combinations at their IC50 exhibited suboptimal effectiveness compared with single-agent treatment. Using a factorial experimental design based on a minimal combination approach to analyze dose-response data, followed by subsequent Bliss synergy analysis, synergistic interactions were revealed exclusively for RUX + VPA on A172 cells. Although the interaction between RUX and OXC was additive, GBM cells displayed increased sensitivity to this combination, suggesting potential therapeutic value. Ultimately, the most effective drug ratios were assessed using live/dead cell fluorescence staining in 3-dimensional multicellular tumorspheres. The variable treatment response observed among GBM cell lines underscores the need for personalized treatment strategies tailored to the specific molecular profile of individual tumors. SIGNIFICANCE STATEMENT: Given the unmet needs in glioblastoma treatment, the study explores novel combinations of Janus kinase/signal transducer and activator of transcription-3 inhibitor ruxolitinib and antiepileptics for local codelivery, aiming to overcome resistance and heterogeneity through synergistic effects and sustained release via molecularly imprinted reservoirs.
Social stress cue exposure heightens opioid preference and locus coeruleus neuroimmune activity in female rats.
Smiley CE, Childress TE, Bielicki BH … +1 more , Wood SK
J Pharmacol Exp Ther · 2026 Jan · PMID 41406908 · Publisher ↗
Stress exposure is often a precipitating factor underlying drug-seeking behavior that can lead to the establishment of comorbid posttraumatic stress disorder and substance use disorder (SUD) in clinical populations. The...
Stress exposure is often a precipitating factor underlying drug-seeking behavior that can lead to the establishment of comorbid posttraumatic stress disorder and substance use disorder (SUD) in clinical populations. The vicarious witness stress (WS) model is a potent ethologically relevant stressor that imparts many of its deleterious effects through heightened neuroimmune signaling in key stress sensitive brain regions. The present set of studies were designed to determine the impact of this psychosocial stressor on oxycodone place preference and central immune activity in female rats. In this way, we aim to better understand the neural correlates of stress-induced drug seeking in an effort to establish novel treatment targets for stress-related posttraumatic stress disorder/SUD. Female Sprague-Dawley rats were exposed to WS or nonstress control conditions prior to training for conditioned place preference with 3.0 mg/kg oxycodone. Following conditioned place preference training, rats with a history of stress were either exposed to the WS cues or left undisturbed and compared to controls for oxycodone place preference. Acute exposure to the WS cues led to the highest amount of time spent in the drug-paired compartment and this stress-induced augmentation of opioid preference was accompanied by significant increases in proinflammatory cytokines in the locus coeruleus. Taken together, these experiments established a comorbid model of stress and drug preference in female rats and have begun to identify potential brain regions that could be targeted to prevent stress-related sensitization to SUDs in females. SIGNIFICANCE STATEMENT: These studies offer insights into neuroimmune targets for the prevention of stress-induced opioid seeking with the overall goal of testing translationally relevant pharmacotherapies to prevent stress-sensitized drug-seeking responses in females.
Investigating the effectiveness and adverse events of medicinal cannabis for patients with muscle spasticity or spasms.
Nastatos XL, Schubert EA, Wheate NJ
J Pharmacol Exp Ther · 2026 Jan · PMID 41386046 · Publisher ↗
Appropriate treatment of muscle spasticity and spasms is important as these conditions may significantly impair patients' quality of life. Conventional pharmacological treatments for these conditions have poor effectiven...
Appropriate treatment of muscle spasticity and spasms is important as these conditions may significantly impair patients' quality of life. Conventional pharmacological treatments for these conditions have poor effectiveness and/or tolerability. Cannabis is being explored as a treatment. This was a longitudinal study of patient use of different cannabis products. Data was collected from patient surveys, clinic records, and changes in Patient Reported Outcome Measures Information System 29-Item scores over time. Patient-reported responses on health-related quality of life adverse events (n = 150) and outcomes (n = 78) from treatment for spasticity or spasms were analyzed. No improvements in physical functioning were observed for either group of patients across all product types. However, patients with spasticity who were using cannabidiol-only products experienced an improvement in sleep disturbance, fatigue, pain interference, and pain intensity. Patients with spasms who were using balanced, cannabidiol-dominant, or tetrahydrocannabinol-dominant products also experienced improvements in these 4 outcomes. Commonly reported adverse events were dry mouth, drowsiness, fatigue, dizziness, and nausea. Despite no observation of improvement in physical functioning, the results suggest that cannabis may help relieve some of the secondary complications associated with these conditions, such as poor sleep and pain. SIGNIFICANCE STATEMENT: This longitudinal study highlights differential benefits across cannabis product types, with cannabidiol-only formulations aiding spasticity-related symptoms and tetrahydrocannabinol- or cannabidiol-dominant products benefiting those with spasms. These findings support the potential of cannabis as a potential therapy to improve health-related quality of life in patients with limited options from conventional pharmacological treatments.
Targeting of Brahma-related gene-1 (BRG1) overcomes paclitaxel-induced multidrug resistance caused by overexpression of the subset of ATP-binding cassette (ABC) transporters.
Gronkowska K, Michlewska S, Płoszaj T … +5 more , Strachowska M, Stępień A, Borowiec M, Bednarek A, Robaszkiewicz A
J Pharmacol Exp Ther · 2025 Dec · PMID 41371092 · Publisher ↗
Multidrug resistance of cancer cells is attributed to drug-induced alteration of numerous intracellular processes. Using clinically relevant models of triple-negative breast and non-small lung cancer cells we previously...
Multidrug resistance of cancer cells is attributed to drug-induced alteration of numerous intracellular processes. Using clinically relevant models of triple-negative breast and non-small lung cancer cells we previously showed that these cells respond to repeated paclitaxel exposure by inter alia lysosome enrichment in ABCC3, ABCC5, and ABCC10, which contribute to drug sequestration in these organelles and reduced drug cytotoxicity. In this study, we provide experimental evidence that transcription of the above-mentioned ABCC genes is enabled by BRG1-based SWI/SNF chromatin remodeling complex. Pharmacological inhibition of SWI/SNF with PFI3 or ACBI1, the PROTAC degrader of SMARCA2/4, substantially reduced transcription of ABCC3, ABCC5, and ABCC10. A similar effect was caused by transient silencing of SMARCA4 (BRG1), but not SMARCA2 (BRM). The deficiency of BRG1 led to extralysosomal distribution of anticancer drugs, their deeper penetration of spheroids, and substantial increase in drug cytotoxicity. Interestingly, in BRG1-deficient cell line paclitaxel triggered mutations, which reverted BRG1 truncating deletion in SMARCA4, thereby restoring SWI/SNF ATPase expression in paclitaxel-resistant cells and increasing transcription of ABCC. Acquisition of drug resistance was associated with BRG1 redistribution in the genome, de novo occurrence at the promoters of genes functionally linked to endolysosomal system, and stronger co-occurrence with EP300. Our study indicates possible target--SWI/SNF complex for anticancer combinatorial interventions in paclitaxel-induced multidrug resistant phenotypes. SIGNIFICANCE STATEMENT: This study provides evidence that BRG1 inhibition with PFI3 and degradation of SMARCA4 mRNA substantially declines lysosomal drug sequestration and potentiate drug toxicity. Therefore, BRG1 targeting can be considered as candidate for combinatorial anticancer therapy with some standard chemotherapy drugs.
Investigation into ligand selectivity and bias at the formyl peptide receptor family.
Jack CE, Thomson CM, Dall'Angelo S … +2 more , Thompson D, Hislop JN
J Pharmacol Exp Ther · 2026 Jan · PMID 41371001 · Full text
Formyl peptide receptors (FPRs) mediate both proinflammatory and resolution phases of the inflammatory response involved in many disease states. Harnessing their potential for pharmaceutical development requires an accur...
Formyl peptide receptors (FPRs) mediate both proinflammatory and resolution phases of the inflammatory response involved in many disease states. Harnessing their potential for pharmaceutical development requires an accurate picture of their signaling and regulation to the many test compounds developed. This study compares distinct responses of mouse and human FPR subtypes to several ligands in an attempt to clarify the dual nature of FPR signaling. Here, we expressed human and mouse variants of FPR1 and FPR2 in HEK293 cells and assessed competition binding, bioluminescence resonance energy transfer assays to measure the interaction between receptors and either Arrestin 3 or mini-Gsi, internalization, and extracellular signal-regulated kinase 1/2 phosphorylation. Concentration-response curves for 11 distinct ligands at each subtype were generated, then analyzed to determine EC50s, Emax values, and ligand bias. All compounds were less potent than WKYMVm across receptor subtypes, with the strength of signaling correlating with affinity estimates. The rank order of potency was maintained across the signaling pathways. Notably, MMK1 was specific for human FPR2, and BMS-986235 was selective for FPR2 over FPR1 in both species. Little evidence of pathway bias was detectable, with the notable exception of the recently described pepducin F2Pal10. The majority of tested ligands exhibit efficacy at each subtype, meaning conclusions of physiological receptor function based on these compounds should be treated circumspectly. It is not possible to determine distinct signaling profiles that would explain proresolution versus inflammatory physiology, and the most likely explanation for these data would be a combination of FPR1 and FPR2 responses. SIGNIFICANCE STATEMENT: No evidence of ligand bias between G-protein activation, arrestin recruitment, or internalization was found at formyl peptide receptors for 11 distinct agonists. Differences in physiological outcome are more likely to reflect efficacy at both subtypes rather than inherent signaling bias.
A 5'-(R)-CH-substituted 5-fluoro-2'-deoxyuridine monophosphate reduces off-target toxicities while maintaining efficacy in a colorectal cancer model.
Monaco CM, Pribut N, Musonda CC … +5 more , Sun CQ, Petros JA, Liu KH, Miller EJ, Liotta DC
J Pharmacol Exp Ther · 2026 Jan · PMID 41352320 · Publisher ↗
Since its approval in the early 1960s, 5-fluorouracil (5-FU) has remained an important therapeutic for the treatment of late-stage and metastatic colorectal cancer (CRC). It acts through intracellular conversion to 5-flu...
Since its approval in the early 1960s, 5-fluorouracil (5-FU) has remained an important therapeutic for the treatment of late-stage and metastatic colorectal cancer (CRC). It acts through intracellular conversion to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) to inhibit thymidylate synthase (TYMS), leading to nucleotide pool imbalance, DNA damage, and disruption of tumor cell proliferation. However, 5-FU is limited by rapid clearance and off-target toxicities, which affects a large proportion of patients with CRC. To address these issues, we developed 5'-(R)-CH-FdUMP (Me-FdUMP), a 5'-(R)-CH-substituted analog of FdUMP that retains inhibitory activity against purified TYMS. Here, we show that Me-FdUMP is resistant to metabolism by phosphatases and kinases, reduces 5-FU formation, and enhances TYMS inhibition in a human CRC cell line. In mice, Me-FdUMP treatment led to markedly lower 5-FU exposure in the heart and bone marrow, 2 key sites of clinical toxicity. Furthermore, in a mouse xenograft model of human CRC, Me-FdUMP maintained antitumor efficacy comparable to FdUMP. Taken together, these results suggest 5'-(R)-CH-substituted FdUMP could be a promising new approach for improving the safety of fluoropyrimidine-based therapeutics. SIGNIFICANCE STATEMENT: Current fluoropyrimidine-based therapeutics for colorectal cancer suffer from metabolic liabilities that can often lead to severe and dose-limiting side-effects. Results reported here highlight a new fluoropyrimidine derivative with enhanced on-target activity in vitro, maintenance of antitumor efficacy in vivo, and impaired metabolism that can reduce exposure of toxic metabolites. This work represents a new strategy to address the shortcomings of current fluoropyrimidine-based therapeutics with the potential to improve patient outcomes.
The nicotine paradox: Weak primary reinforcer, strong enhancer.
Bevins RA, Barrett ST, McNealy KR … +1 more , Wakabayashi KT
J Pharmacol Exp Ther · 2026 Jan · PMID 41352319 · Publisher ↗
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Targeting X-box-binding protein-1 by Decoy oligodeoxynucleotide modulates fibrogenic features of activated hepatic stellate cells.
Solhi R, Lotfinia M, Abdi Z … +4 more , Sahebghadam Lotfi A, Nüssler AK, Zarrabi A, Vosough M
J Pharmacol Exp Ther · 2026 Jan · PMID 41352318 · Publisher ↗
Because of their pivotal role in liver fibrosis, activated hepatic stellate cells (aHSCs) may serve as a promising target for innovative medical treatments. Endoplasmic reticulum stress activation through inositol-requir...
Because of their pivotal role in liver fibrosis, activated hepatic stellate cells (aHSCs) may serve as a promising target for innovative medical treatments. Endoplasmic reticulum stress activation through inositol-requiring enzyme1 (IRE1)-X-box-binding protein-1 (XBP1) is a significant event associated with hepatic stellate cells (HSC) activation. We evaluated the potential impact of treatment with XBP1-specific decoy oligodeoxynucleotide (ODN) on modulation of aHSC. To activate HSCs, LX-2 cells were treated with transforming growth factor β (5 ng/mL). Meanwhile, the sequence of XBP1-specific decoy ODN was designed using the JASPAR (open-access transcription factor binding profile data base) and CLC Main Workbench (Qiagen) software. The outcome of treatment with ODN on aHSC was analyzed using quantitative reverse transcription polymerase chain reaction, immunoblotting, scratch assay, and ELISA. Transfection of activated LX-2 cells with 1 μg XBP1 decoy ODN downregulated the expression level of lysyl oxidase, tissue inhibitor of matrix metalloproteinase, α-smooth muscle actin, and fibronectin genes. In addition, the immunoblotting analysis and ELISA assay showed that XBP1 decoy ODN significantly reduced protein expression of α-smooth muscle actin and collagen secretion, respectively, compared to control cells. Our research may lead to innovative treatments for liver fibrosis, providing hope for better outcomes for patients with this chronic condition. SIGNIFICANCE STATEMENT: This study applied a novel decoy oligodeoxynucleotide targeting X-box-binding protein-1 to suppress the activation of hepatic stellate cells, a key driver of liver fibrosis. By modulating endoplasmic reticulum stress and fibrogenic gene expression, this strategy offers a promising therapeutic avenue for chronic liver diseases.
Erythropoietin as a multifaceted antiaging agent: Mechanisms and clinical potential.
Wang T, Tang Y, Xiao Y
J Pharmacol Exp Ther · 2025 Dec · PMID 41317607 · Publisher ↗
Human aging is driven by several interconnected hallmarks, including genomic instability, mitochondrial dysfunction, and cellular senescence, which collectively underlie pathologies such as neurodegeneration and metaboli...
Human aging is driven by several interconnected hallmarks, including genomic instability, mitochondrial dysfunction, and cellular senescence, which collectively underlie pathologies such as neurodegeneration and metabolic decline. Despite advances in identifying senescence-associated biomarkers and pathways, conventional antiaging compounds such as resveratrol and fisetin, lack regulatory approval owing to insufficient evidence from large-scale trials. Drug repurposing provides a cost-efficient strategy to target aging pathways by leveraging existing pharmacologic safety profiles. Erythropoietin (EPO) exemplifies this approach, demonstrating pleiotropic antiaging effects through modulation of cell survival pathways and tissue-protective mechanisms. Recent advancements in nonhematopoietic EPO derivatives, such as carbamylated EPO, further unlock its development potential by decoupling therapeutic benefits from erythropoietic activity. This review analyzes EPO molecular antiaging mechanisms and clinical applications in age-related diseases (2015-2025), focusing on multiorgan systemic effects and derivative development beyond anemia. SIGNIFICANCE STATEMENT: This review highlights erythropoietin (EPO) as a promising repurposed drug for combating aging, targeting hallmarks such as oxidative stress and cellular senescence. Crucially, nonhematopoietic EPO derivatives circumvent traditional safety risks while retaining multipathway protective effects in brain, cardiovascular, and metabolic tissues. By leveraging established pharmacology, EPO offers a cost-efficient strategy to advance aging interventions, addressing age-related pathologies beyond anemia.
Discovering the role of sulfur against atopic dermatitis via the AC010336.1/miR-3929/GPI axis with a machine-learning power.
Zheng A, Saimaiti W, Aireken W … +1 more , Han C
J Pharmacol Exp Ther · 2025 Dec · PMID 41314062 · Publisher ↗
Sulfur is clinically used for treating scabies and pruritus and shows potential in treating atopic dermatitis (AD), though its mechanism remains unclear. The potential targets of sulfur and the differentially expressed g...
Sulfur is clinically used for treating scabies and pruritus and shows potential in treating atopic dermatitis (AD), though its mechanism remains unclear. The potential targets of sulfur and the differentially expressed genes of AD in the GSE237920 and GSE121212 datasets from the Gene Expression Omnibus database were identified. The intersecting genes were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. A protein-protein interaction network was established using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Through Least Absolute Shrinkage and Selection Operator, Random Forest, and Support Vector Machine-Recursive Feature Elimination algorithms, we screened the core targets. The core genes were validated using receiver operating characteristic analysis, gene set enrichment analysis, and immune cell infiltration analysis. Long noncoding RNA (lncRNA)-microRNA (miRNA)-mRNA bioinformatics networks were predicted using databases. The core lncRNA-miRNA-mRNA axis was identified by intersecting bioinformatics networks with GSE168694. Subsequently, the expression of each node in the axis was verified through animal experiments. Using machine learning and bioinformatics analysis, glucose-6-phosphate isomerase (GPI) was identified as a core target. We then predicted 5 miRNAs and 141 lncRNAs. By validating the results using the GSE168694 dataset, the AC010336.1/miR-3929/GPI axis was identified as the key competing endogenous RNA regulatory axis. Animal experiments demonstrated that sulfur exerted therapeutic effects against AD by restoring epidermal barrier function, reducing immune cell infiltration, and mitigating pruritus. Additionally, animal experiments confirmed that sulfur alleviated AD by modulating the AC010336.1/miR-3929/GPI axis. These novel findings provide valuable insights and guidance for future investigations on the competing endogenous RNA mechanism of traditional Chinese medicine in AD therapy. SIGNIFICANCE STATEMENT: This study investigates the therapeutic mechanisms of sulfur, a traditional Chinese medicine, in the treatment of atopic dermatitis, with elucidate extending to the single-gene regulatory level.
The effects of buprenorphine on fentanyl-induced respiratory depression in rats.
Baehr CA, Gebo A, Vigliaturo J … +1 more , Raleigh MD
J Pharmacol Exp Ther · 2025 Dec · PMID 41308414 · Publisher ↗
The opioid antagonists, naloxone and nalmefene, are used clinically to rapidly reverse opioid overdose, but often precipitate withdrawal symptoms in opioid-dependent individuals. This study compared 2 medications used fo...
The opioid antagonists, naloxone and nalmefene, are used clinically to rapidly reverse opioid overdose, but often precipitate withdrawal symptoms in opioid-dependent individuals. This study compared 2 medications used for opioid use disorder, buprenorphine and methadone, to naloxone for reversing fentanyl-induced effects in rats. Buprenorphine alone did not produce significant respiratory depression at 0.5-5.0 mg/kg. Rats were challenged with 0.1 mg/kg fentanyl, which resulted in a significant reduction in oxygen saturation (SpO), and naloxone 0.1 mg/kg, buprenorphine 3.0 mg/kg, methadone 2.25 mg/kg, or saline control was given to reverse fentanyl effects. Antinociception and SpO were restored to baseline by 15 minutes after administration of naloxone and buprenorphine. The saline group showed a slow return to baseline SpO within 30 minutes, whereas methadone extended the duration of, but did not enhance, the effects of fentanyl. To determine whether buprenorphine could rapidly (within minutes) reverse fentanyl-induced respiratory depression, rats were given a dose of fentanyl 0.1 mg/kg s.c., followed by saline, naloxone 0.1 mg/kg, or buprenorphine 3.0 mg/kg, and SpO was monitored continuously for 10 minutes. Both naloxone and buprenorphine reversed fentanyl effects within 3.5 minutes, whereas the saline group did not return to baseline levels during the monitoring period. Buprenorphine at 0.3 and 1.0 mg/kg also reversed fentanyl effects, with a slower onset of reversal. In a follow-up study, rats received fentanyl followed by saline, buprenorphine, or methadone for reversal, and blood and brain levels were measured. Fentanyl concentration in the brain was not significantly affected by methadone and buprenorphine treatment, suggesting that differences in SpO were not attributable to pharmacokinetic interactions. These data support repurposing buprenorphine for the treatment of opioid overdose. SIGNIFICANCE STATEMENT: Opioid overdoses cause ∼80,000 annual deaths in the United States. Buprenorphine is an opioid partial agonist used for opioid use disorder. This study used a rat model to compare buprenorphine to naloxone for efficacy in reversing fentanyl-induced respiratory depression.
Lysine demethylase 5D promotes CHEK1 inhibitor sensitivity through p38-mediated cyclooxygenase-2 expression in castration-resistant prostate cancer cells.
Zheng W, Li S, West RE … +4 more , Donahue ER, Nolin TD, Li S, Wang QJ
J Pharmacol Exp Ther · 2025 Dec · PMID 41308413 · Full text
CHEK1 (CHK1) is a key regulator of the G2/M checkpoint and DNA damage response. Although CHK1 inhibitors (CHK1is) show promise in multiple clinical trials, their further advancement is hampered by the lack of reliable pr...
CHEK1 (CHK1) is a key regulator of the G2/M checkpoint and DNA damage response. Although CHK1 inhibitors (CHK1is) show promise in multiple clinical trials, their further advancement is hampered by the lack of reliable predictive biomarkers. Our previous study demonstrated a nearly 20-fold difference in the sensitivity to a clinical-stage CHK1i SRA737 in prostate cancer (PC) cells. Through bioinformatics analysis, an epigenetic regulator, lysine demethylase 5D (KDM5D), was identified as a potential mediator of differential responses to SRA737. Gain- or loss-of-function studies were performed to investigate how altered KDM5D expression affects CHK1i sensitivity and the underlying mechanisms. Our data demonstrated that higher KDM5D expressions correlated with greater sensitivity to CHK1is in PC cells. In patients with castration-resistant PC (CRPC), a high KDM5D score predicted a better patient response to CHK1i. Knockdown of KDM5D in SRA737-sensitive KDM5D-expressing cells caused resistance to SRA737. Correspondingly, a higher sensitivity to SRA737 was observed in a docetaxel-resistant CRPC cell line with elevated KDM5D, and silencing KDM5D caused resistance to this inhibitor. Mechanistically, depletion of KDM5D activated p38 and induced cyclooxygenase-2 (COX-2) and ATP-binding cassette transporter expression. Inhibition of p38 or COX-2 partially reversed the resistance to CHK1i induced by KDM5D knockdown. Additionally, silencing of p38 increased KDM5D protein expression, indicating a negative feedback loop that may serve to maintain a homeostatic balance between the 2 genes. These data support a key role for KDM5D in modulating CHK1i sensitivity through a novel p38/COX-2 prosurvival pathway in PC cells, with potential predictive value for patients with CRPC receiving these anticancer agents. SIGNIFICANCE STATEMENT: This study demonstrated an important role of an epigenetic regulator KDM5D in regulating CHK1 inhibitor sensitivity via a p38/COX-2-mediated prosurvival pathway in certain castration- or drug-resistant PC cells. Our results indicate that PC cells expressing KDM5D may be more sensitive to targeted inhibition of CHK1 kinase, highlighting the potential predictive value of this gene for CHK1-targeted therapies in PC.
Spontaneous daily sleep disruptions associated with morphine dependence and withdrawal in rats.
McKelvey HA, Pierce BE, Lynch JM … +7 more , Kim AL, Holter KM, Gadient RA, Sheffler DJ, Velicelebi G, Cosford NDP, Gould RW
J Pharmacol Exp Ther · 2025 Dec · PMID 41273898 · Full text
Sleep disturbances are prominent symptoms of opioid withdrawal that contribute to relapse in individuals with opioid use disorder (OUD). Although preclinical studies often examine protracted withdrawal after sustained ab...
Sleep disturbances are prominent symptoms of opioid withdrawal that contribute to relapse in individuals with opioid use disorder (OUD). Although preclinical studies often examine protracted withdrawal after sustained abstinence, few address the repeated, spontaneous withdrawal cycles that model human patterns of use. Moreover, targeting sleep disruptions provides a novel strategy to reduce relapse risk. The present studies characterized the effects of repeated spontaneous daily withdrawal on sleep and quantitative electroencephalography (qEEG) after once-daily morphine administration in male Sprague-Dawley rats. Daily withdrawal produced persistent sleep disruptions, including reduced rapid eye movement (REM) and non-REM sleep, increased time awake, and sleep fragmentation. Notably, tolerance did not develop to the acute pharmacological effects of morphine or spontaneous daily withdrawal effects on sleep across the 30-day study. Relative spectral analysis (qEEG) revealed progressive shifts from low (δ) to high (γ) frequency power across withdrawal phases, with significant and persistent increases in wake and non-REM relative γ band power during later stages of daily and protracted withdrawal. There were few correlations between somatic behavioral signs and sleep or qEEG supporting our hypothesis that sleep, and brain activity disturbances represent distinct withdrawal phenotypes that should be studied and treated separately from somatic withdrawal behaviors. Together, these findings highlight the chronic and multifaceted nature of opioid withdrawal, particularly its effect on disrupted sleep and brain activity. Collectively, these studies characterized a translationally relevant preclinical model incorporating both sleep and qEEG as potential behavioral and physiological biomarkers for evaluating putative pharmacotherapies for withdrawal-related sleep dysfunction in OUD. SIGNIFICANCE STATEMENT: Sleep disruptions associated with withdrawal in opioid use disorder represent a contributing factor for relapse yet lack targeted treatments. This study reports consistent, spontaneous daily sleep disruptions in rats after once-daily morphine administration, providing a model that can be used for treatment development.
A special collection on targeting the immune system-Editorial.
Rothlin C, Gutkind JS
J Pharmacol Exp Ther · 2025 Dec · PMID 41273897 · Publisher ↗
Abstract loading — click title to view on PubMed.
Aspirin inhibition and recovery of cyclooxygenase activity and thromboxane biosynthesis in human megakaryocytes: a translational surrogate model.
Mallah ZI, Petrucci G, Ayoub AJ … +9 more , Farhoud MA, Jelwan JG, Lucchisani S, Fakih AK, Badran B, Hamade E, Patrono C, Rocca B, Habib A
J Pharmacol Exp Ther · 2025 Dec · PMID 41265381 · Full text
Low-dose aspirin irreversibly acetylates cyclooxygenase (COX)-1 in anucleate platelets and progenitor megakaryocytes, permanently suppressing thromboxane (TX)A-dependent platelet activation. Although aspirin pharmacodyna...
Low-dose aspirin irreversibly acetylates cyclooxygenase (COX)-1 in anucleate platelets and progenitor megakaryocytes, permanently suppressing thromboxane (TX)A-dependent platelet activation. Although aspirin pharmacodynamics is well characterized in platelets, the kinetics of COX inhibition and recovery in human megakaryocytes remains poorly defined, due to ethical issues associated with invasive, bone-marrow trephine sampling, and low megakaryocyte yield. We studied aspirin pharmacodynamics in human megakaryocytic cell lines as a reliable and feasible surrogate model. We characterized COX-1 and COX-2 expression and activity in MEG-01 and CHRF-288-11 megakaryocytic cell lines, treated with a range of aspirin concentrations and exposure duration. COX activity was quantified by the production of TXB from exogenous arachidonic acid. A single 10-μM aspirin exposure suppressed TXB by 90 ± 2% (MEG-01) and 85 ± 4% (CHRF-288-11), with full recovery within 48-72 hours. Both COX-isozymes were detected by western blot and immunohistochemistry; however, selective COX-1 inhibition by SC-560 reduced TXB by >75%, whereas COX-2 inhibition by NS-398 had minimal effect. Repeated aspirin exposure every 24 hours produced concentration- and time-dependent TXB suppression, achieving 89 ± 2% inhibition by day 2 at 1 μM and 73 ± 3% by day 4 at 0.1 μM. TXB biosynthesis recovered by 86 ± 2% and 99 ± 10% at days 2 and 3, respectively. These findings identify COX-1 as the principal source of TXA in megakaryocytes and demonstrate that aspirin inhibits megakaryocyte COX-1 time- and dose-dependently, with delayed recovery likely reflecting de novo synthesis of COX-1 protein, thereby providing mechanistic insight into the sustained antiplatelet effect of low-dose aspirin in humans. SIGNIFICANCE STATEMENT: In human megakaryocyte cell lines, once-daily aspirin treatment at low-concentration range time-dependently inhibits COX-1 with delayed recovery after aspirin withdrawal. This closely mimics the kinetics of platelets, supporting the translational utility of the megakaryocyte-based surrogate model.
Pancreastatin inhibitor PSTi8 alleviates insulin resistance and ovarian dysfunction in a dehydroepiandrosterone-high-fat diet rat model of polycystic ovary syndrome.
Yadav S, Dadge S, Rathaur S … +3 more , Maity D, Prajapati VM, Gayen JR
J Pharmacol Exp Ther · 2025 Dec · PMID 41259826 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder characterized by hyperandrogenism and frequently associated with insulin resistance (IR), a key pathogenic factor in PCOS. However, insulin s...
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder characterized by hyperandrogenism and frequently associated with insulin resistance (IR), a key pathogenic factor in PCOS. However, insulin sensitizers commonly used to treat PCOS are often recommended off-label and may cause side effects. This study investigated the therapeutic effects of pancreastatin inhibitor 8 (PSTi8), an insulin sensitizer, in a PCOS rat model. The PCOS rat model was established by daily feeding with a high-fat diet and administering subcutaneous injections of dehydroepiandrosterone at a dose of 60 mg/kg body weight for 21 days and further, followed by 21 days of treatment with PSTi8 (10 mg/kg) and metformin (300 mg/kg). Body weight, estrous cycle, glucose, and insulin tolerance test results were monitored. Ovarian morphology, estrous cycle changes, oxidative stress and inflammatory markers, steroidogenic hormone levels and protein expression, and insulin signaling pathway were assessed to evaluate the therapeutic effectiveness of PSTi8 in PCOS rats. This study found that PSTi8 improved IR and reduced body weight in PCOS rats. PSTi8 lowered serum levels of insulin (27%), testosterone (56%), estradiol (2-fold), progesterone (21%), sex hormone-binding globulin (7.5%), and luteinizing hormone/follicle stimulating hormone ratio (57%). Additionally, PSTi8 helped to restore ovarian morphology, estrous cycle, and improve dyslipidemia. PSTi8 treatment also reduces the oxidative stress level of total superoxide ismutase (16%), glutathione peroxidase (26%), and inflammation in PCOS rats. Furthermore, PSTi8 restores the steroidogenic protein expression and increases PI3K/Akt phosphorylation in PCOS rats. These findings demonstrate PSTi8 exhibited comparable efficacy to metformin in ameliorating IR and ovarian dysfunction in the studied PCOS model. SIGNIFICANCE STATEMENT: Polycystic ovary syndrome (PCOS) increases risk of reproductive and metabolic disorders, partly due to systemic inflammation. This study combined dehydroepiandrosterone with high-fat diet and successfully induced PCOS-like features in rats. PSTi8, a pancreastatin inhibitor known for insulin-sensitizing effects in various disease models, effectively reversed PCOS-associated pathophysiology. PSTi8 improves insulin sensitivity by activating the PI3K/AKT signaling pathway and ameliorates oxidative stress and inflammation in PCOS rats. Additionally, PSTi8 treatment normalized steroidogenesis protein expression and reduced circulating biomarkers linked to cardiovascular risk.
Attenuation of the discriminative stimulus and reinforcing effects of positive GABA modulators after Shisa7 knockdown in rats.
Morris TM, Henderson AS, Melton SM … +3 more , Abdurrahman A, Aiyar A, Winsauer PJ
J Pharmacol Exp Ther · 2025 Dec · PMID 41242192 · Full text
γ-aminobutyric acid type-A receptors associate with auxiliary proteins such as Shisa7 and have allosteric binding sites for benzodiazepines, barbiturates, and alcohols. In this study, Shisa7 was knocked down to assess it...
γ-aminobutyric acid type-A receptors associate with auxiliary proteins such as Shisa7 and have allosteric binding sites for benzodiazepines, barbiturates, and alcohols. In this study, Shisa7 was knocked down to assess its involvement in the discriminative-stimulus effects of drugs from each class and in the positive reinforcing effects of alcohol. Twelve male Long-Evans rats were trained to respond in a drug-discrimination procedure with 6 trained to discriminate ethanol (1 g/kg) from saline and 6 trained to discriminate alprazolam (1.8 mg/kg) from cyclodextrin. Following training, cumulative dose-effect curves for ethanol, alprazolam, and pentobarbital were established before and after Shisa7 knockdown was achieved using an intravenous dicer substrate small-interfering ribonucleic acid. A separate group of 6 rats was also trained to consume ethanol orally to assess ethanol intake before and after Shisa7 knockdown. In general, before Shisa7 knockdown, alprazolam and pentobarbital partially substituted for ethanol in ethanol-trained subjects up to doses that decreased response rate, whereas pentobarbital, but not ethanol, partially substituted for alprazolam in alprazolam-trained subjects. After Shisa7 knockdown, the dose-effect curve for ethanol-lever responding in ethanol-trained subjects was shifted downward, the curve for alprazolam-lever responding in alprazolam-trained subjects was shifted rightward, and the curve for pentobarbital was shifted rightward in both ethanol- and alprazolam-trained subjects. Shisa7 knockdown did not affect response rates. In rats orally consuming ethanol, both ethanol intake and dose were significantly decreased after Shisa7 knockdown compared with the dicer substrate small-interfering ribonucleic acid control. These findings demonstrate that reducing Shisa7 levels attenuated the discriminative-stimulus effects of 3 positive allosteric modulators of γ-aminobutyric acid type-A receptors and decreased ethanol's reinforcing effects. SIGNIFICANCE STATEMENT: This study demonstrates that Shisa7, an auxiliary protein associated with γ-aminobutyric acid type-A receptor, plays a crucial role in mediating the discriminative-stimulus effects of ethanol, alprazolam, and pentobarbital, as well as the reinforcing effects of ethanol. By demonstrating that Shisa7 knockdown attenuates the behavioral effects of these drugs, the findings provide new insights into the molecular mechanisms underlying γ-aminobutyric acid type-A receptor-mediated drug effects and potentially identify Shisa7 as a key modulatory mechanism through which these drugs produce their effects.
Phosphodiesterase 7 inhibition reduces L-DOPA-induced dyskinesias in parkinsonian nonhuman primates.
Kochoian BA, Coletta S, Shi H … +5 more , Bure C, Onrust R, Gaitanaris G, Demopulos G, Papa SM
J Pharmacol Exp Ther · 2025 Dec · PMID 41240765 · Publisher ↗
The mechanisms underlying L-DOPA-induced dyskinesia (LID) largely arise from maladaptive plasticity in striatal circuits leading to altered neuronal responses to dopamine (DA) signaling. Cyclic nucleotides play a major r...
The mechanisms underlying L-DOPA-induced dyskinesia (LID) largely arise from maladaptive plasticity in striatal circuits leading to altered neuronal responses to dopamine (DA) signaling. Cyclic nucleotides play a major role in the molecular cascades of DA signaling, and particularly cAMP is known to be associated with LID mechanisms. Cyclic nucleotide levels in striatal neurons are regulated by phosphodiesterases (PDEs), and 1 isoenzyme with selective affinity for cAMP and high expression in the striatum is PDE7. Here, the PDE7 inhibitor OMS-401 was evaluated for antidyskinetic effects in a nonhuman primate (NHP) model of advanced Parkinson's disease. A series of systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration followed by chronic L-DOPA treatment were used to induce advanced parkinsonism and reproducible LID in a group of 3 macaques. The effects of the PDE7 inhibitor OMS-401 were analyzed with a dose-response curve design in coadministration trials for 2 doses of L-DOPA (optimal and suboptimal). Motor disability, LID, and drug adverse reactions were assessed using standardized scales for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated NHPs. OMS-401 significantly reduced LIDs in a dose-dependent fashion without interacting with the antiparkinsonian action of L-DOPA or inducing side effects in parkinsonian NHPs. Results confirm that cAMP levels in striatal neurons play a critical role in LID mechanisms, and that PDE7 inhibition may be a strategy to control LID over the long-term DA replacement therapy in Parkinson's disease. SIGNIFICANCE STATEMENT: This study shows that selective phosphodiesterase 7 inhibition with OMS-401 reduces dyskinesia in a Parkinson's primate model without affecting L-DOPA's benefits. Phosphodiesterase 7 inhibition may offer a promising approach for L-DOPA-induced dyskinesia management, providing an alternative to treatments with dose-limiting side effects.
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