Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Glycine attenuates double-stranded RNA-induced autoimmune cholangitis and pancreatitis by modulating innate immune signaling in mice.","authors":"Akira Uchiyama, Kazuyoshi Kon, Kumiko Arai, Kei Ishizuka, Masahiro Tada, Maki Morinaga, Hiroo Fukada, Reiko Yaginuma, Kyoko Fukuhara, Shunhei Yamashina, Kenichi Ikejima","doi":"10.1016/j.jpet.2026.104971","DOIUrl":"10.1016/j.jpet.2026.104971","url":null,"abstract":"<p><p>Autoimmunity plays a central role in hepatobiliary and pancreatic diseases; however, the mechanisms underlying the initiation and progression of autoimmune cholangitis and pancreatitis remain incompletely understood. Glycine, a nutritionally nonessential amino acid, has immunomodulatory and hepatoprotective properties. This study investigated the effects of dietary glycine on innate and adaptive immune responses induced by double-stranded RNA. Chronic administration of polyinosinic-polycytidylic acid for 24 weeks induced cholangitis- and pancreatitis-like phenotypes, characterized by elevated serum alkaline phosphatase and amylase levels, increased levels of autoantibodies, including antimitochondrial M2 and anti-lactoferrin antibodies, and periductal infiltration of macrophages, T cells, and B cells. These changes were accompanied by the induction of proinflammatory cytokines and type I interferons. Dietary glycine supplementation significantly attenuated these pathological features in both preventive and therapeutic settings. Glycine suppressed early innate immune activation, as evidenced by reduced hepatic expression of tumor necrosis factor α, interleukin (IL)-1β, IL-6, IL-12b, and type I interferons. Furthermore, glycine modulated downstream adaptive immune responses, including suppression of T helper (Th)2-related cytokines (IL-4 and IL-13), the Th17-related cytokine IL-23a, and the regulatory cytokine IL-10, along with reduced autoantibody production. These findings suggest that glycine acts upstream in the inflammatory cascade by attenuating innate immune signaling that drives downstream adaptive immune responses. In conclusion, dietary glycine suppresses double-stranded RNA-induced innate and autoimmune responses in the liver and pancreas, supporting its potential as a safe, mechanism-based therapeutic strategy for autoimmune hepatobiliary and pancreatic diseases. SIGNIFICANCE STATEMENT: Dietary glycine suppresses double-stranded RNA-triggered innate immune activation and autoantibody production, preventing autoimmune-like cholangitis and pancreatitis. By modulating upstream toll-like receptor 3/pattern-recognition receptor and type I interferon pathways, glycine provides broad yet pharmacologically safe immunoregulation with potential relevance to autoimmune hepatobiliary and pancreatic diseases such as primary biliary cholangitis and autoimmune pancreatitis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104971"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin enhances the pathological response in nondiabetic patients with rectal cancer undergoing neoadjuvant chemoradiotherapy: A randomized controlled trial.","authors":"Omar Mohamed Awad, Mona Ali Saber, Nada Hussein Ali Sholkamy, Ahmad Mostafa Abdel-Azeez, Eman Mohamed Sadek, Fatma Mohamed Mady","doi":"10.1016/j.jpet.2026.104970","DOIUrl":"10.1016/j.jpet.2026.104970","url":null,"abstract":"<p><p>This randomized, single-blind controlled pilot phase II trial evaluated whether adding metformin to neoadjuvant chemoradiotherapy (nCRT) increases pathological complete response (pCR) rates in nondiabetic patients with locally advanced rectal adenocarcinoma. Eighty-five nondiabetic patients treated between May 2024 and June 2025 were randomized to receive standard nCRT-radiotherapy 50.4 Gy in 28 daily fractions with concurrent oral capecitabine 825 mg/m² twice daily (group A, n = 43)-or the same regimen plus oral metformin 1000 mg twice daily (group B, n = 42). Metformin was started 1 to 2 weeks before nCRT and continued until 30 days after completion. The primary endpoint was pCR, defined as the absence of residual tumor in the resected specimen; a composite endpoint combining pCR and clinical complete response (cCR) was also assessed. Group B achieved a significantly higher pCR rate than group A (28% vs 9%, P = .010). The combined pCR/cCR outcome was likewise superior in the metformin group (38% vs 14%, P = .011). In multivariable logistic regression adjusting for potential confounders, metformin remained an independent predictor of combined pCR/cCR (adjusted odds ratio 3.98, P = .031). Metformin added to nCRT appears to enhance tumor response and early clinical outcomes in nondiabetic patients with locally advanced rectal cancer and may represent a low-cost, low-toxicity radiosensitizer. Larger, long-term studies are warranted to confirm these findings and clarify their impact on survival and recurrence. The study was registered at ClinicalTrials.gov Identifier: NCT06728982. SIGNIFICANCE STATEMENT: This randomized trial shows that adding the common antidiabetic drug metformin to standard preoperative chemoradiotherapy significantly increases complete tumor response rates in nondiabetic patients with locally advanced rectal cancer. These findings highlight a simple, low-cost radiosensitizing strategy that could improve downstaging, organ preservation, and long-term outcomes if confirmed in larger studies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104970"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456107","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":"M1 muscarinic receptor modulation drives sex-specific alterations of Alzheimer's pathophysiology in APPswe/PSEN1ΔE9 mice.","authors":"Wesam Bassiouni, Emily Ye, Tash-Lynn L Colson, Stephen S G Ferguson, Khaled S Abd-Elrahman","doi":"10.1016/j.jpet.2026.104980","DOIUrl":"10.1016/j.jpet.2026.104980","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, where females account for 60% of diagnosed cases. AD is featured by β-amyloid deposition, which influences the activity of M1 muscarinic acetylcholine receptors (M1 mAChRs) that are essential for memory and learning. We previously demonstrated that VU0486846, a M1 mAChR positive allosteric modulator, improves cognitive function in AD mice by ameliorating β-amyloid pathology. However, it remains unclear how changes in M1 mAChR signaling and subcellular localization in AD brain influences its mechanism and how this differs between sexes. Nine-month-old male and female APPswe/PSEN1ΔE9 (APP/PS1) and wild-type mice were treated with VU0486846 (10 mg/kg/day) or vehicle via drinking water for 8 weeks. Elevated extracellular signal-regulated kinase 1/2 signaling, a plausible driver for β-amyloid pathology, was observed in female but not male APP/PS1 mice cortices, whereas VU0486846 mitigated this change. Additionally, VU0486846 enhanced the phosphorylation of the neuronal transcription factor cAMP response element-binding protein and increased the level of c-Fos, which regulate neuronal survival, in female wild-type and APP/PS1 mice only. In contrast, only male APP/PS1 mice exhibited increased levels of p62/SQSTM1 and decreased glycogen synthase kinase-3β activity, indicative of impaired autophagic flux, a change that was ameliorated by VU0486846 treatment. In subcellular fractions obtained from mice cortices, VU0486846 only increased cytosolic M1 mAChR level in female wild-type and APP/PS1 mice but not in males. Our findings indicate that M1 mAChR signaling is disrupted in APP/PS1 mice in a sex-dependent manner. VU0486846 enhances prosurvival signaling in females, potentially by increasing the cytosolic pool of M1 mAChRs, while modulating autophagy pathways in males, highlighting a sex-specific mechanism of action and underscoring its therapeutic potential. SIGNIFICANCE STATEMENT: The study highlights the sex-specific role of M1 muscarinic acetylcholine receptor (M1 mAChR) in Alzheimer's disease (AD) pathophysiology, providing evidence that the ability of M1 mAChR positive allosteric modulation to alleviate β-amyloid pathology occurs through distinct mechanisms. It rescues neuronal activity in females, which could be linked to enhanced cytosolic receptor pooling, while restoring autophagic flux in males. The study also reinforces the therapeutic potential of M1 mAChR positive allosteric modulators and supports the development of sex-tailored interventions for AD.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104980"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148604171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel NAD(P)H:quinone oxidoreductase 1-responsive vascular endothelial growth factor-targeted antibody-drug conjugate induces dual apoptosis and ferroptosis in glioblastoma.","authors":"Kai Liu, Yuchao Dong, Wei Ren, Dapeng Li, Zihao Wang, Shiyong Fan, Yuping Zong, Chengyuan Ma","doi":"10.1016/j.jpet.2026.104974","DOIUrl":"10.1016/j.jpet.2026.104974","url":null,"abstract":"<p><p>Glioblastoma is a highly malignant and refractory brain tumor with limited treatment options and poor prognosis. Although antibody-drug conjugate (ADC) have shown potential in glioblastoma therapy, their clinical utility is hampered by off-target toxicity. This study aimed to develop a novel NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive ADC, NRBM-25, to enhance targeting specificity and safety, and to investigate its antitumor mechanisms. NRBM-25 was constructed using an NQO1-enzyme-responsive linker to conjugate a vascular endothelial growth factor-targeting antibody with the cytotoxic payload monomethyl auristatin E, enabling tumor-specific activation. The NQO1-dependent activation mechanism was validated in isogenic and native cell models. In vitro and in vivo, NRBM-25 exhibited potent and selective cytotoxicity against NQO1-high glioblastoma cells while sparing NQO1-low normal cells. The conjugate induced dual modes of cell death-apoptosis and ferroptosis-accompanied by mitochondrial dysfunction, oxidative stress, and cell cycle arrest. In animal models, NRBM-25 significantly inhibited tumor growth, prolonged survival with minimal systemic toxicity, and outperformed temozolomide at medium-to-high doses. This approach of using an enzyme-dependent linker to dually induce apoptosis and ferroptosis offers a potential strategy to overcome treatment resistance, representing a new exploration in ADC-based therapy for glioblastoma. SIGNIFICANCE STATEMENT: A novel antibody-drug conjugate targeting glioblastoma was developed, which uses a tumor-specific enzyme activation mechanism and demonstrates favorable safety and antitumor efficacy in preclinical models. This candidate represents a new exploration in antibody-drug conjugate-based therapy for glioblastoma.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104974"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148447601","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":"Computational pharmacology and in silico clinical trials for the development of drugs from natural products: A review of advances, opportunities, and challenges.","authors":"Chinonyelum Emmanuel Agbo, Chinemelum Kingsley Nwankwo, Jennifer Chinaecherem Onyehalu, Mercy Chisom Agu, Chinonso Opah, Chukwuemeka Sylvester Nworu","doi":"10.1016/j.jpet.2026.104986","DOIUrl":"10.1016/j.jpet.2026.104986","url":null,"abstract":"<p><p>Natural products have inspired the discovery of several drug candidates and US Food and Drug Administration-approved drugs. However, the conventional drug development pathway has several limitations, necessitating innovative strategies. Computational pharmacology and in silico clinical trials (ISCTs) have emerged as a potential to optimize the drug discovery process. Current literature rarely discusses these 2 domains together, leaving limited guidance on how computational tools used in natural product research can complement ISCT frameworks. This review addresses this gap by summarizing key computational methods used for natural products and highlighting how their outputs can inform ISCT-based evaluation of efficacy, safety, and translational potential. Computational approaches such as molecular docking, pharmacophore modeling, quantitative structure-activity relationship analysis, absorption-distribution-metabolism-excretion-toxicity prediction, and molecular dynamics simulations have been applied in natural products-based drug discovery. The findings of these studies are promising and suggest favorable prospects for the use of computational methods in identifying, optimizing, and evaluating bioactive natural compounds. Notably, this approach minimizes the attrition rate in later clinical stages, as the most promising compounds with auspicious pharmacokinetic and pharmacodynamic profiles are chosen. ISCTs further hold considerable value in drug discovery through investigating the safety and efficacy of investigational drugs using simulated or virtual patient populations, ensuring a lower attrition rate when wet-lab clinical trials are conducted. Although the ISCTs on natural products are limited, the integration of computational pharmacology and ISCTs shows potential in the discovery of valuable natural compounds and the acceleration of drug development from natural products. Despite existing challenges in data quality and regulatory acceptance, the integration of emerging technologies such as machine learning, artificial intelligence, and hybrid platforms shows promise in advancing natural product-based therapeutics and precision medicine. SIGNIFICANCE STATEMENT: This review brings together computational pharmacology and in silico clinical trials to address persistent challenges in natural product drug development. It highlights how early computational screening, absorption-distribution-metabolism-excretion-toxicity prediction, and dynamic modeling can inform virtual clinical evaluation, reduce attrition, and accelerate translation. The paper offers a clear and practical roadmap for improving efficiency, strengthening safety assessment, and advancing precision in the development of natural product-based drugs.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104986"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697582","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":"α-Synuclein regulates monoamine transporter capacity and amphetamine-induced efflux via modulation of transporter expression.","authors":"Iina Ludwig, Samuel Moser, Marina Lukenic, Michael Connor, Amila Sofic, Samantha Kaltenbrunner, Constantin Pätzold, Alexander Hausleitner, Catherine Gilbert, Sonja Sucic, Marko Roblek, Thomas Steinkellner","doi":"10.1016/j.jpet.2026.104981","DOIUrl":"10.1016/j.jpet.2026.104981","url":null,"abstract":"<p><p>α-Synuclein (α-syn) is a presynaptic protein implicated in Parkinson disease and related synucleinopathies, but its physiological function remains incompletely understood. Monoamine transporters, including the dopamine transporter (DAT) and serotonin transporter (SERT), are key determinants of neurotransmitter clearance and primary targets of psychostimulant drugs. Although α-syn has been reported to interact with these transporters, its impact on transporter function remains unresolved. In the present study, we systematically manipulated α-syn expression in cellular models to determine its effects on DAT and SERT function. Overexpression of α-syn increased substrate uptake at both transporters, reflected by a selective increase in maximal transport velocity (V_max) without significant changes in substrate affinity (K_M). This effect was accompanied by elevated total DAT and SERT protein levels. Conversely, small interfering RNA-mediated knockdown or CRISPR/Cas9-mediated knockout of α-syn reduced transporter expression and decreased uptake capacity. In addition, amphetamine-induced transporter-mediated efflux was significantly attenuated in α-syn-deficient cells. These findings identify α-syn as a positive regulator of monoamine transporter expression and transport capacity. By controlling transporter abundance, α-syn modulates both substrate uptake and psychostimulant-induced reverse transport. This regulatory mechanism has important implications for monoamine homeostasis and for the pharmacological actions of transporter-targeting drugs such as D-amphetamine or 3,4-methylenedioxymethamphetamine (\"ecstasy\"). SIGNIFICANCE STATEMENT: The physiological role of α-synuclein (α-syn), a protein central to Parkinson disease, is not fully understood. This study demonstrates that α-syn enhances the expression and transport capacity of dopamine and serotonin transporters, thereby regulating monoamine clearance and amphetamine-induced efflux. This identifies α-syn as a key modulator of monoaminergic signaling and provides a mechanistic framework linking its normal function to disease-related alterations in neurotransmission.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104981"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148604152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat shock factor 1 signaling: A novel pathway implicated in Rett syndrome pathophysiology.","authors":"Sonia Gonzalez, Amanda M Vanderplow, Theresa R Wilsterman, Matthew P Stratton, Mackenzie L Smith, Grace E Dodis, Lauren M Lane, Colleen M Niswender, Rocco G Gogliotti","doi":"10.1016/j.jpet.2026.104967","DOIUrl":"10.1016/j.jpet.2026.104967","url":null,"abstract":"<p><p>Rett syndrome (RTT) is a neurodevelopmental disorder that is associated with loss-of-function mutations in the methyl CpG binding protein 2 (MECP2) gene. MECP2 regulates transcription both locally and globally, making it challenging to distinguish between genes that are pathogenic and those that constitute transcriptional noise. A rare subpopulation of patients lack MECP2 mutations despite presenting with sufficient symptoms to warrant a clinical diagnosis of RTT. These patients are classified as having atypical and MECP2 mutation-negative forms of the disorder. We hypothesized that identifying pathways with conserved disruption between typical and atypical forms of RTT would be a viable mechanism to reduce transcriptional noise and identify the genes that are most critical to their shared clinical presentation. To test this theory, we conducted differential RNA sequencing using 5 atypical RTT, 6 typical RTT (R255X), and 9 neurotypical control temporal cortex autopsy samples. Pathways associated with heat shock factor 1 (HSF1) signaling were among the most enriched in both RTT populations. Validation studies using 37 patient temporal cortex samples showed that increased HSF1 signaling was enriched in those with classically severe MECP2 mutations. To investigate whether increased HSF1 signaling is compensatory or pathogenic, we conducted in vivo hyperthermia experiments complemented by cellular stress array analyses. These experiments established that RTT model mice exhibit faster and larger induction of cellular stress-associated proteins. Pharmacological induction of HSF1 in Mecp2^+/- mice was consistent with hyperthermia experiments, showing seizure-like phenotypes and lethality. Conversely, chronic inhibition of HSF1 signaling improved RTT-like phenotypes in domains of motor learning and general health. Together, these data suggest that promiscuous HSF1 signaling is likely a pathogenic amplifier of severe phenotypes and provide a rationale that inhibiting this pathology may hold therapeutic potential in RTT and related disorders. SIGNIFICANCE STATEMENT: Rett syndrome is a devastating neurodevelopmental disorder with limited therapeutic options. This manuscript identifies heat shock factor 1-signaling as a novel therapeutic target and proposes a molecular mechanism by which cellular stress responses are regulated in Rett syndrome.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104967"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456097","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 \"Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors\".","authors":"","doi":"10.1016/j.jpet.2026.104961","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.104961","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104961"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850899","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's κ relatively potent opioid agonist activity is not shared with other US Food and Drug Administration-approved α₂-adrenergic agonists.","authors":"Xi-Ping Huang, Brian E Krumm, Madigan L Bedard, Zoe A McElligott, Bryan L Roth","doi":"10.1016/j.jpet.2026.104969","DOIUrl":"10.1016/j.jpet.2026.104969","url":null,"abstract":"<p><p>Xylazine is an α₂-adrenergic agonist typically used in as a sedative and analgesic in veterinary medicine. For some years, xylazine has been reported as an additive to fentanyl on the illicit drug market and has been associated with severe side-effects including severe ulcerations and potential amputations at the sites of injection along with an increased risk of respiratory depression and death. We recently reported that xylazine has modest κ opioid agonist activity in vitro and in vivo and asked if other α₂-adrenergic agonists had similar off-target activities. To test this hypothesis, we profiled US Food and Drug Administration-approved α₂-adrenergic agonists at 320 G protein coupled receptors to identify potentially deleterious and/or beneficial off-targets. Although all other tested α₂-adrenergic agonists were devoid of κ opioid agonist activity, each had a distinct pattern of activity at various G protein coupled receptors and differential patterns of signaling bias at α_2-receptor subtypes. These findings suggest potential molecular targets for both side-effects and therapeutic activities among known α₂-adrenergic agonists. SIGNIFICANCE STATEMENT: Xylazine was recently shown to be a κ-opioid receptor agonist and we examined other US Food and Drug Administration-approved α₂-agonists for κ-opioid activity. Xylazine is unique in having κ-agonist activity.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104969"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing thyroid hormone receptor interactor 13/kinetochore-associated 1 inhibits DNA damage repair and enhances Olaparib sensitivity in ovarian cancer.","authors":"Xingzi Guo, Jie Tang, He Li, Saiping Mao, Yan-Xiang Tang, Zhen-Zi Tang, Lianghui Gong","doi":"10.1016/j.jpet.2026.104964","DOIUrl":"10.1016/j.jpet.2026.104964","url":null,"abstract":"<p><p>Ovarian cancer (OC) is associated with high mortality and frequent resistance to poly (ADP-ribose) polymerase inhibitors, such as Olaparib, particularly in patients with breast cancer gene-proficient tumors. To explore the potential mechanisms underlying Olaparib resistance, Olaparib-resistant OC cell lines were established through stepwise drug induction. Candidate resistance-related genes were screened using bioinformatic analyses and subsequently validated in clinical specimens. Their biological functions and underlying mechanisms were further investigated through gene silencing, coimmunoprecipitation, immunofluorescence, comet assays, and an OVCAR3 xenograft model. Bioinformatic analyses indicated that thyroid hormone receptor interactor 13 (TRIP13) and kinetochore-associated 1 (KNTC1) were highly expressed in Olaparib-resistant cells and were associated with poor prognosis. Their elevated expression was further confirmed by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. Functional studies showed that silencing either TRIP13 or KNTC1 inhibited cell proliferation and induced apoptosis in Olaparib-resistant OC cells. Mechanistically, coimmunoprecipitation and immunofluorescence analyses confirmed a cytoplasmic interaction between TRIP13 and KNTC1. TRIP13 knockdown impaired nonhomologous end joining (NHEJ)-mediated DNA repair, as evidenced by decreased expression of NHEJ-related proteins, increased γH2AX accumulation, and enhanced comet tail formation. Conversely, TRIP13 overexpression promoted NHEJ repair and reduced Olaparib-induced DNA damage, whereas these effects were partially reversed by the NHEJ inhibitor SCR130. In vivo, TRIP13 overexpression promoted tumor growth and reduced sensitivity to Olaparib, whereas KNTC1 knockdown reversed these effects. Collectively, these findings suggest that TRIP13 and KNTC1 cooperatively promote NHEJ-mediated DNA repair, thereby contributing to Olaparib resistance in breast cancer gene-proficient OC. Targeting the TRIP13/KNTC1 axis may therefore enhance the therapeutic efficacy of Olaparib and provide a promising strategy for overcoming poly (ADP-ribose) polymerase inhibitor resistance. SIGNIFICANCE STATEMENT: Olaparib resistance remains a major obstacle to effective ovarian cancer treatment. This study demonstrates that the thyroid hormone receptor interactor 13/kinetochore-associated 1 axis promotes Olaparib resistance in ovarian cancer by enhancing nonhomologous end joining-mediated DNA damage repair. Targeting this axis restored Olaparib sensitivity in resistant cells, thereby highlighting thyroid hormone receptor interactor 13/kinetochore-associated 1 as a potential therapeutic target for improving the response to poly (ADP-ribose) polymerase inhibitors.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104964"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456192","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}