Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"PRT-064040: A nasal spray of novel, potent, and selective calcitonin gene-related peptide receptor antagonist for migraine.","authors":"Shuwen Du, Hao Yang, Jingmei Yue, Hairong Wang, Rui Kou, Yashu Chen, Chengran Liu, Anle Yang, Dewei Zhang, Zhenyu Wang","doi":"10.1016/j.jpet.2026.104966","DOIUrl":"10.1016/j.jpet.2026.104966","url":null,"abstract":"<p><p>Calcitonin gene-related peptide (CGRP), a neuropeptide, has been implicated in autoimmune diseases, endometriosis, tumors, and primary headaches, including migraine. The development of a novel, fast-acting CGRP receptor antagonist administered via nasal spray could address current clinical demands. PRT-064040, a novel, potent, and selective CGRP receptor antagonist, was discovered and developed by Sichuan Purity Pharmaceutical Co, Ltd. Its pharmacological characteristics were investigated through a series of experimental studies. In vitro assays, including radioligand binding and cAMP accumulation functional assays, demonstrated that PRT-064040 possesses high affinity for the human CGRP receptor (K_i = 26.67 ± 6.27 pM) and effectively inhibited human αCGRP-induced cAMP production (IC₅₀ = 22.29 pM). The compound exhibited high selectivity within the calcitonin family member, with an IC₅₀ of 5.38 nM for amylin receptor 1 and no inhibitory activity on other closely related receptors at concentrations up to 10 μM. In vivo efficacy was evaluated using a human αCGRP-induced dermal blood flow model in cynomolgus monkeys, in which PRT-064040 dose-dependently attenuated αCGRP-mediated dermal vasodilation. Following nasal administration in rats, brain penetration of PRT-064040 was minimal. Pharmacokinetic profiling in cynomolgus monkeys revealed rapid absorption (time to maximum concentration (Tmax) = 10-15 minutes) postnasal delivery. Collectively, these findings indicate that PRT-064040 functions as a competitive antagonist with high affinity, potency, and selectivity for the human CGRP receptor. Moreover, a potent, concentration-dependent relationship was observed between plasma levels of PRT-064040 and inhibition of αCGRP-mediated physiological effects. SIGNIFICANCE STATEMENT: This study demonstrates that PRT-064040 is a competitive antagonist exhibiting high affinity, potency, and selectivity for the human calcitonin gene-related peptide receptor. Its rapid absorption at low doses may not only facilitate a fast-onset action but also suggest a potential for reduced adverse events in clinical practice.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 8","pages":"104966"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536281","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":"Preclinical pharmacology of N-pyrrolidino \"nitazene\" opioids appearing in nonmedical drug markets.","authors":"Grant C Glatfelter, Alexander D Maitland, Nicholas R Gonzalez, Donna Walther, Li Chen, Lei Shi, Michael H Baumann","doi":"10.1016/j.jpet.2026.104977","DOIUrl":"10.1016/j.jpet.2026.104977","url":null,"abstract":"<p><p>N-pyrrolidino (PYR) nitazenes are a subset of 2-benzylbenzimidazole opioids appearing in illicit drug markets, but there is limited information about the pharmacology of these compounds. Here, we examined the opioid-like effects of PYR nitazenes with varying alkoxy chain lengths (ie, methoxy, ethoxy, propoxy, and isopropoxy) compared with fentanyl. Opioid receptor binding and functional assays were employed to determine affinities and potencies of the compounds in vitro. Acute opioid-like effects were examined in mice, using hot plate antinociception, motor activity, and body temperature measures. PYR nitazenes displayed high affinity at the μ-opioid receptor (K_i = 1-12 nM), with weaker affinities at δ and κ sites. The compounds were potent and efficacious agonists in assays measuring μ-opioid receptor-mediated inhibition of cAMP formation (EC₅₀ = 0.03-0.91 nM, E_max = 104%-106%) compared with fentanyl (EC₅₀ = 0.23 nM, E_max = 100%). The nitazenes also induced β-arrestin 2 recruitment, but with weaker potencies. In mouse studies, the compounds induced dose-dependent antinociception, hyperactivity, and hypothermia. Across in vivo measures, the ethoxy, propoxy, and isopropoxy compounds (ED₅₀ = 0.002-0.033 mg/kg) were more potent than fentanyl (ED₅₀ = 0.081-0.178 mg/kg). The acute in vivo effects of ethoxy and isopropoxy analogs were fully or partially reversed by naloxone (0.3 mg/kg). PYR nitazenes with intermediate alkoxy chain lengths are most potent for eliciting opioid-like effects in vitro and in mice. In particular, the ethoxy, propoxy, and isopropoxy analogs are more potent than fentanyl, highlighting an elevated risk for overdose with these compounds. SIGNIFICANCE STATEMENT: The present study characterized the pharmacology of N-pyrrolidino nitazene opioids that vary by alkoxy chain length and are associated with overdose cases in humans. The ethoxy, isopropoxy, and propoxy N-pyrrolidino nitazenes were found to be more potent than fentanyl in both in vitro and in vivo assays, suggesting that these compounds pose a serious overdose risk to humans who are unknowingly exposed to the compounds in the illicit opioid supply.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104977"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13552262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148604178","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":"Peptide-drug conjugates in breast cancer therapy: Emerging targets, translational challenges, and optimization strategies.","authors":"Hui Zhang, Xue Wei, Jiaojie Wang, Bowen Wang, Jinghui Hong, Ming Yang","doi":"10.1016/j.jpet.2026.104997","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.104997","url":null,"abstract":"<p><p>Peptide-drug conjugates (PDCs) have emerged as a promising class of targeted therapeutics for breast cancer, offering distinct advantages over antibody-based systems, including improved tumor penetration, lower immunogenicity, and flexible chemical synthesis. In recent years, significant progress has been made in identifying novel peptide ligands targeting overexpressed receptors and tumor-associated microenvironment components, thereby enhancing the specificity and efficacy of drug delivery. This review summarizes the latest advances in PDC design for breast cancer therapy, with a focus on emerging molecular targets, linker strategies, and payload selection. Despite encouraging preclinical outcomes, several challenges hinder the clinical translation of PDCs, including limited in vivo stability, rapid clearance, and suboptimal pharmacokinetics. Strategies to overcome these barriers, such as peptide modification, nanocarrier integration, and rational structural optimization are discussed. Overall, PDCs represent a versatile and evolving platform for precision drug delivery, and continued interdisciplinary efforts are essential to accelerate their translation into clinically effective therapies for breast cancer. SIGNIFICANCE STATEMENT: Peptide-drug conjugates represent a promising targeted modality for breast cancer, with the potential to overcome the limited tumor penetration and heterogeneity associated with antibody-based therapies. This review summarizes breast cancer-specific targets and key design principles, and discusses translational barriers and strategies to improve stability, pharmacokinetics, and therapeutic efficacy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"104997"},"PeriodicalIF":4.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062032","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":"Transient receptor potential melastatin 3-dependent disruption of hypothalamic paraventricular nucleus-medial prefrontal cortex serotonergic signaling promotes depressive-like behavior in ovariectomized rats.","authors":"Sanjay N Awathale, Kamini R Shirasath, Sameer N Goyal, Kartik T Nakhate","doi":"10.1016/j.jpet.2026.104991","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.104991","url":null,"abstract":"<p><p>Menopause is a natural biological process in women driven by estrogen deficiency and is associated with multiple postmenopausal physiological and behavioral changes. Notably, menopause increases the risk of depression. However, the precise neural mechanisms by which estrogen deficiency contributes to depressive phenotypes remain poorly understood. Estrogen deficiency has been reported to activate transient receptor potential melastatin 3 (TRPM3) channels and promote neuroinflammation by inducing microglial activation and upregulating proinflammatory cytokines. Although the paraventricular nucleus of hypothalamus (PVN) plays a central role in integrating the physiological response to stress, the role of TRPM3 channels in this region remains unexplored. We hypothesized that estrogen deficiency during menopause activates TRPM3 channels in the PVN, promoting neuroinflammation and disrupting medial prefrontal cortex (mPFC) function, thereby contributing to depressive-like phenotypes. Using a bilateral ovariectomy rat model, we demonstrated that estrogen loss induces robust depression-like behaviors, accompanied by increased TRPM3 expression and interleukin-1β levels in the PVN, as well as reduced dendritic complexity and serotonin levels in the mPFC. In the present study, retrograde 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) tracing confirmed direct PVN-mPFC connectivity, and immunofluorescence revealed coexpression of TRPM3 and the serotonin transporter in PVN neurons, implicating TRPM3 in serotonergic regulation. Notably, intraperitoneal administration of the TRPM3 inhibitor, naringenin reversed behavioral deficits, restored dendritic arborization in PVN, attenuated neuroinflammation, and normalized mPFC serotonin levels. These findings indicate that TRPM3-mediated PVN neuroinflammation disrupts mPFC serotonin signaling, contributing to menopause-associated depressive phenotypes and identifying TRPM3 as a potential therapeutic target. SIGNIFICANCE STATEMENT: This study identifies TRPM3 as a key mechanistic link between estrogen deficiency and depression during menopause. Current treatments, including hormone therapy and conventional antidepressants, often provide incomplete relief in menopausal depression, highlighting the need for more targeted strategies. This study shows that TRPM3 activation in the PVN drives neuroinflammation, disrupts mPFC serotonin signaling, and induces depression-like behaviors. Importantly, TRPM3 inhibition reverses these effects, suggesting its therapeutic potential and offering a novel target for menopause-associated depression.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"104991"},"PeriodicalIF":4.3,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111154","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":"Interoceptive effects of N₁-substituted lysergamides in rats: Role of agonist affinity at 5-hydroxytryptamine receptors and in vivo metabolism to lysergic acid diethylamide.","authors":"Michael D Berquist, Brenda M Gannon, Kevin M Honeywell, Hannah E Shaw, Theresa M Carbonaro, Laura A Kozell, Atheir I Abbas, William E Schutzer, Marina Avram, Jeffrey H Moran, William E Fantegrossi","doi":"10.1016/j.jpet.2026.104988","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.104988","url":null,"abstract":"<p><p>Novel analogs of the psychedelic lysergic acid diethylamide (LSD) have emerged on the gray market in recent years, typically containing substitutions to the ergoline scaffold on the indole (N₁) nitrogen or at the diethylamide moiety. In these studies, we screened 4 N₁-substituted drugs (1A-LSD, 1P-LSD, 1B-LSD, and 1CP-LSD) and 1 diethylamide-substituted drug (LSZ) in assays of serotonin receptor binding, LSD-like discriminative stimulus effects, and disposition in rat blood after systemic injection. As compared with LSD, we found that all of the N₁-substituted drugs exhibited worse affinity for and/or weaker efficacy at 5-hydroxytryptamine (5-HT)_1A, 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors, while LSZ displayed an LSD-like binding profile at these sites. Despite their impaired receptor affinities and efficacies, the N₁-substituted compounds all fully substituted for LSD in the rat, as did the diethylamide-substituted LSZ. Following systemic injection of the N₁-substituted drugs at doses producing full substitution for LSD, we detected similar high blood levels of LSD at time points relevant to the behavioral assay, suggesting that these compounds are converted to LSD in vivo. In contrast, LSZ was the only species detected after its administration, which, combined with its high-affinity binding and intrinsic efficacy at psychedelic-relevant receptors, implies that it is biologically active on its own. These studies highlighted the role of pharmacokinetics and analytical chemistry in connecting seemingly disparate in vitro and in vivo drug profiles and strongly implied that variability in human metabolism of these compounds may result in dramatically different pharmacologic effects across individuals. SIGNIFICANCE STATEMENT: Four N₁-substituted lysergamides (1A-lysergic acid diethylamide [LSD], 1P-LSD, 1B-LSD, and 1CP-LSD) and 1 diethylamide-substituted drug were screened for serotonin receptor binding, LSD-like discriminative stimulus effects, and disposition in rat blood. Despite their generally impaired receptor binding profiles compared with LSD, all the N₁-substituted lysergamides were LSD-like in vivo, most likely through metabolic conversion to LSD. In contrast, the diethylamide-substituted drug exhibited LSD-like affinities and efficacy at 5-hydroxytryptamine receptors, was not metabolically converted to LSD, and elicited potent LSD-like interoceptive effects.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104988"},"PeriodicalIF":4.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794799","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":"Placenta-derived mesenchymal stem cells attenuate acute brain injury and neuroinflammation after intracerebral hemorrhage.","authors":"Kun Hu, Hui Liu, Lu Ding, Jiahui Li, Shue Gu, Xu Zhang, Songlin Guo","doi":"10.1016/j.jpet.2026.104982","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.104982","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and limited treatment options. This study evaluated the safety and therapeutic potential of human placenta-derived mesenchymal stem cells (PD-MSCs) in acute ICH. PD-MSCs were isolated, characterized, and assessed for tumorigenicity by subcutaneous implantation in nude mice. Acute ICH was induced in rats by collagenase injection, followed by in situ PD-MSC transplantation. Neurological function, brain water content, and hematoma volume were evaluated, and perihematomal biological changes were examined using immunofluorescence staining, ELISA, and transcriptomic sequencing. PD-MSCs displayed typical mesenchymal stem cell characteristics and showed no evidence of tumorigenicity under the present experimental conditions. In ICH rats, PD-MSC transplantation reduced brain edema and hematoma volume and partially improved neurological outcomes compared with those in untreated controls. PD-MSC treatment also modulated astrocytic responses, as reflected by altered glial fibrillary acidic protein expression and astrocyte morphology, and decreased the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α. Transcriptomic analysis indicated that PD-MSCs influenced inflammation-related and immune-regulatory pathways in perihematomal tissues. AKR1B1, SNAI2, and ADGRE5 were identified as candidate genes potentially associated with PD-MSC-mediated responses after ICH. These findings provide preliminary evidence that PD-MSCs are nontumorigenic and may attenuate acute brain injury after ICH, although longer follow-up, expanded behavioral testing, dose optimization, and mechanistic validation are needed to confirm their long-term safety and therapeutic efficacy. SIGNIFICANCE STATEMENT: Acute intracerebral hemorrhage lacks effective therapeutic options, and secondary neuroinflammatory injury contributes substantially to neurological deterioration. This study provides preliminary evidence that placenta-derived mesenchymal stem cells may attenuate acute brain injury and modulate inflammation-associated responses after experimental intracerebral hemorrhage, supporting further investigation of placenta-derived mesenchymal stem cell-based therapeutic strategies for hemorrhagic stroke.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":" ","pages":"104982"},"PeriodicalIF":4.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813426","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":"Therapeutic potential of crystal-engineered berberine cocrystals ameliorates PCOS phenotypes via AMPK-IRS1/PI3K/Akt axis: An integrative computational and preclinical study.","authors":"Umanath Kamalakannan, Anuja Venkata Sai Durga Surampudi, Vyshnavi Racha, Ramars Amanchy, Nishant Jain, Kathirvel Muralidharan","doi":"10.1016/j.jpet.2026.104937","DOIUrl":"10.1016/j.jpet.2026.104937","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by hyperandrogenism, chronic anovulation, and insulin resistance, with hyperinsulinemia playing a pivotal role in exacerbating ovarian dysfunction. Although berberine (BBR) exhibits insulin-sensitizing properties, its therapeutic potential is limited by poor oral bioavailability. Our previous study developed BBR cocrystals with gallic and gentisic acid, achieving a 1.8-fold increase in C_max to overcome bioavailability issues. The present study evaluated berberine-gallic acid (BBR-GAL) and berberine-gentisic acid (BBR-GEN) using an integrated in silico and in vivo approach in a letrozole-induced PCOS mouse model. Molecular docking simulations suggested stronger predicted binding of BBR relative to gallic acid and gentisic acid across all receptor systems, supporting its role as the dominant binder. Further, the coformers exhibited weaker but spatially proximal interactions, indicating potential indirect effects on the local binding environment. In vivo, letrozole administration induced hallmark PCOS features, including weight gain, impaired glucose tolerance, hyperandrogenism, ovarian inflammation, and disruption of hepatic insulin signaling. Treatment with BBR-GAL and BBR-GEN significantly improved metabolic parameters and restored insulin responsiveness. Notably, treatment with cocrystals was associated with increased adenosine monophosphate-activated protein kinase activation and reduced insulin receptor substrate-1 Ser307 phosphorylation, leading to enhanced phosphatidylinositol 3-kinase/protein kinase B signaling. Furthermore, treatment attenuated ovarian inflammation by downregulating interleukin 1-beta, interleukin 6, and tumor necrosis factor-alpha, and normalized luteinizing hormone receptor and androgen receptor expression. Collectively, these findings support the further investigation of BBR-GAL and BBR-GEN as multitarget agents that integrate insulin sensitization, antiinflammatory activity, and hormonal regulation for the management of PCOS. SIGNIFICANCE STATEMENT: This study demonstrates that crystal-engineered BBR cocrystals show improved efficacy against metabolic and reproductive dysfunction in an experimental model of PCOS. By restoring hepatic insulin signaling through modulation of the adenosine monophosphate-activated protein kinase-insulin receptor substrate-1/phosphatidylinositol 3-kinase/protein kinase B axis and attenuating ovarian inflammation, these formulations provide mechanistic validation for improved therapeutic efficacy. These findings indicate that crystal-engineered BBR could be a useful approach in improving the endocrine-metabolic phenotypes of preclinical PCOS.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 7","pages":"104937"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226342","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":"Antiproliferative effects of HIV integrase strand transfer inhibitors in experimental models for cancer research: A narrative review.","authors":"Isabella Zanella, Matteo Manenti, Federico Cesanelli, Silvia Codenotti, Alessandro Fanzani, Francesco Castelli, Eugenia Quiros-Roldan","doi":"10.1016/j.jpet.2026.104965","DOIUrl":"10.1016/j.jpet.2026.104965","url":null,"abstract":"<p><p>A growing body of literature suggests that integrase strand transfer inhibitors (INSTIs), a cornerstone of antiretroviral therapy for the treatment of HIV infection, seem to possess antiproliferative properties against some types of cancer and/or anti-invasion effects. Preclinical studies describe as INSTIs, including dolutegravir, raltegravir, cabotegravir, and elvitegravir and some 1,2,3-triazole derivatives, can inhibit the growth of various cancer cell lines and some of them seem to also have direct inhibitory effects on human endogenous retrovirus reactivation. This review comprehensively synthesizes and analyzes this evidence, detailing the proposed multimechanistic actions behind these effects, such as induction of DNA damage, inhibition of key oncogenic pathways, triggering of oxidative stress and diverse cell death modalities. All described compounds seem to have potential effects on cancerous cells, and these effects may be also independent from their antiretroviral activity, that is, may be separated from the mere effect on suppression of human endogenous retrovirus reactivation in cancerous cells. Although the type of target cancer, the mechanisms of action (ie, enzyme or protein inhibition, oxidative stress, DNA methylation, and DNA damage) or the ultimate effects (ie, cell proliferation, migration, or invasion) were different in most of the studies and sometimes inconsistent, all these studies suggest several potential targets of INSTIs that deserve further investigations. Although the incidence of many cancers is higher in people with HIV infection compared with the general population, the relative risk has been decreasing over time for many cancers. Further studies are then needed to assess the effects of INSTI therapies on malignancies in people living with HIV. SIGNIFICANCE STATEMENT: Currently, the effects of using integrase strand transfer inhibitors (INSTIs) on cancer development in people living with HIV are difficult to determine because of the multifactorial cause of cancer in these patients and the long period in which cancer manifests. This review examines the antiproliferative properties of INSTIs, describing the proposed mechanisms through which they may exert this effect in preclinical studies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 7","pages":"104965"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382247","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 intelectin 1-bestrophin-2-glutamate axis regulates glutamate homeostasis and suppresses colorectal cancer progression.","authors":"Di Lu, Yang Zhou, Han Zhang, Jiannan Wang, Kai Lu, Yaonan Li, Cheng Guo, Yuanzeng Zhu","doi":"10.1016/j.jpet.2026.104941","DOIUrl":"10.1016/j.jpet.2026.104941","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a highly prevalent malignancy with a poor prognosis, and metabolic reprogramming (eg, glutamic acid metabolism) drives its progression. However, the key regulators of glutamic acid homeostasis in CRC remain undefined. We analyzed the expression and prognostic significance of bestrophin-2 (BEST2) and intelectin 1 (ITLN1) using The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Stable cell lines with BEST2/ITLN1/glutamine synthetase (GS) overexpression or knockdown were constructed, and functional assays including Cell Counting Kit-8, flow cytometry, and ELISA were performed to explore their roles in cell proliferation, apoptosis, and glutamic acid metabolism. Coimmunoprecipitation/immunofluorescence were used to validated BEST2-GS interaction. A nude mouse xenograft model was used to confirm the in vivo effects of the ITLN1-BEST2-GS axis. BEST2 and ITLN1 were downregulated in CRC tissues, and their expression correlated with a favorable prognosis in patients with CRC. BEST2 suppressed CRC cell proliferation and promoted apoptosis by reducing intracellular glutamic acid levels, which was mediated by its membrane-localized interaction with GS to modulate GS activity. ITLN1 acted as an upstream positive regulator of BEST2 by enhancing its promoter activity and exerted tumor-suppressive effects in a BEST2-dependent manner. The ITLN1-BEST2-GS axis orchestrated glutamic acid homeostasis, and ITLN1 overexpression significantly inhibited xenograft tumor growth in nude mice. The ITLN1-BEST2-GS axis regulates glutamic acid metabolism to suppress CRC progression, thus identifying novel potential therapeutic targets for this malignancy. SIGNIFICANCE STATEMENT: The intelectin 1-bestrophin-2-glutamine synthetase axis modulates glutamic acid metabolism and exerts a tumor-suppressive effect in colorectal cancer.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 7","pages":"104941"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163417","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":"Destabilization of TIP60-PXR complex by rifampicin impairs wound-induced cell migration.","authors":"Ekta Gupta, Ashish Gupta","doi":"10.1016/j.jpet.2026.104950","DOIUrl":"10.1016/j.jpet.2026.104950","url":null,"abstract":"<p><p>The Tat interactive protein 60 (TIP60)-pregnane and xenobiotic receptor (PXR) complex plays a pivotal role in regulating cell migration during wound healing, and disruption of this complex can impair this function. Because PXR is a ligand-activated transcription factor responsive to structurally diverse compounds, we investigated how different ligands can influence the structural and functional integrity of the TIP60-PXR complex. Using an integrated computational approach, we assessed how various PXR ligands affect complex stability and among them, rifampicin, an established PXR activator, emerged as a notable disruptor. Although most ligands exhibited comparable docking energies in both PXR alone and the TIP60-PXR complex, rifampicin showed a significantly higher binding energy when docked with the complex, suggesting destabilization. Molecular dynamics simulations revealed that rifampicin disrupts key interface residues, with significant root mean square deviation fluctuations and a failure to stabilize the complex. Molecular mechanics Poisson-Boltzmann surface area binding free energy calculations further confirmed rifampicin's destabilizing effect. To validate these findings in a cellular context, we conducted live-cell imaging and coimmunoprecipitation assays. Rifampicin treatment drastically reduced the intracellular colocalization and physical interaction between TIP60 and PXR, thereby significantly compromising their ability to support wound-induced cell migration. This was evident across multiple cell lines, correlating with PXR expression levels. Our findings establish a direct mechanistic link between ligand-induced structural changes in PXR and the functional impairment of the TIP60-PXR complex. This study provides a critical platform for understanding how small molecules modulate coregulator interactions and offers new insights for designing targeted therapeutics aimed at enhancing tissue repair. SIGNIFICANCE STATEMENT: This study identifies ligand-dependent disruption of the TIP60-pregnane and xenobiotic receptor (PXR) complex as a critical regulatory mechanism controlling wound-induced cell migration. By combining computational modeling with cellular validation, it reveals that rifampicin uniquely destabilizes the TIP60-PXR interaction despite being a known PXR activator. These findings uncover how small molecules can selectively modulate coregulator complexes, linking ligand-induced structural changes to impaired tissue repair. The work provides mechanistic insight with important implications for drug safety and regenerative therapeutic design.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 7","pages":"104950"},"PeriodicalIF":4.3,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252276","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}