ACS Pharmacology and Translational Science最新文献

{"title":"osa-miR166g-3p Mimic Reduces Hepatic Triglyceride Accumulation in Mice","authors":"Yun Lin,&nbsp;Motofumi Kumazoe,&nbsp;Ryouya Watanabe,&nbsp;Chihiro Inoue,&nbsp;Yu Shimada,&nbsp;Yoshinori Fujimura,&nbsp;Hirofumi Tachibana","doi":"10.1021/acsptsci.6c00406","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00406","url":null,"abstract":"<p>Hepatictriglyceride accumulation reflects an imbalancein hepaticlipid metabolism, and pharmacological approaches that enhance fattyacid utilization may provide a strategy for reducing excessive lipidaccumulation in the liver. Here, we evaluated the effects of a syntheticosa-miR166g-3p mimic, corresponding to a microRNA sequence originallyidentified in <em>Oryza sativa</em> L., on hepaticlipid metabolism in mice and hepatic cell models. Systemic administrationof the osa-miR166g-3p mimic reduced hepatic triglyceride levels inmice without significant short-term changes in serum aminotransferaseactivities, body weight, or adipose tissue weight. In HFD-fed mice,the osa-miR166g-3p mimic significantly reduced hepatic triglyceridecontent and increased hepatic AMP-activated protein kinase (AMPK)phosphorylation compared with NC mimic treatment. In HepG2 cells,the osa-miR166g-3p mimic increased FAOBlue fluorescence, a cellularreadout associated with fatty acid β-oxidation, and increasedPPARα and CPT1A expression. These changes were accompanied byincreased AMPK phosphorylation. Selected time-dependent transcriptionalresponses were also observed in NMuLi cells. In addition, target prediction,sequence analysis, and reduced <em>PPP2R5C/Ppp2r5c</em> mRNAexpression in HepG2 and NMuLi cells supported PPP2R5C/Ppp2r5c as apredicted candidate target requiring direct validation. Collectively,these findings provide short-term pharmacological proof-of-conceptthat the osa-miR166g-3p mimic modulates hepatic lipid metabolism inassociation with fatty acid β-oxidation-related and AMPK-relatedsignaling. Further studies are required to validate its direct moleculartarget(s), characterize its tissue distribution and pharmacokinetics,and determine its long-term efficacy and safety.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2928–2938"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody Affinity Maturation by Yeast Mating against a Diverse Antigen Library Enhances Antibody Resistance to Viral Mutations","authors":"Ryan Hard,&nbsp;Young Su Ko,&nbsp;Jonathan Parkinson,&nbsp;Wei Wang","doi":"10.1021/acsptsci.6c00213","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00213","url":null,"abstract":"<p>Antibodies suffer from resistance mutations in theirtargets, whichdiminishes their efficacy. Most antibody library screens use a singleantigen yet should ideally use many antigens to ensure that the hitshave broad-binding capacity. As a test case, we used the receptor-bindingdomain (RBD) of SARS COV-2 and CR3022 as the starting antigen/antibodypair. We screened a CR3022 library against a large panel of RBDs (94)and isolated a hit (C8) that has improved affinity for 95/102 testedRBDs. C8 has improved affinity to variants unseen in the library screening,indicating that C8 is more resistant to future antigen variants. Thisstudy, to our knowledge, represents the largest interaction screen(10⁷) performed to date using synthetic agglutination inyeast.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2806–2820"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferritin Complex Vaccine against Influenza A Using Screened Immunogenic Sequences from Fv-Antibody Library","authors":"Tae-Hun Kim,&nbsp;Soonil Kwon,&nbsp;Jaeyong Jung,&nbsp;Jeong Soo Sung,&nbsp;Dong-Ho Han,&nbsp;Min-Jung Kang,&nbsp;Joachim Jose,&nbsp;Misu Lee,&nbsp;Jae-Chul Pyun","doi":"10.1021/acsptsci.6c00419","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00419","url":null,"abstract":"<p>A ferritin-based influenza A vaccine was developed. Theimmunogenicsequences of the nucleoprotein (NP) were screened using an autodisplayedFv-antibody library, and the paratopes with a high-affinity bindingaffinity were analyzed through docking simulations. The resultingantigenic sequences were engineered into single-domain constructsusing a nonimmunogenic linker. These immunogenic sequences were thenexpressed in conjunction with ferritin heavy-chain proteins to formspherical nanoparticles through self-assembly. These NP-ferritin complexvaccines were subsequently injected into mice, and antibody responses,cytokine secretion, and T-cell activation profiles were subsequentlyanalyzed to demonstrate that the ferritin-based NP vaccines activatedinnate as well as acquired immune responses.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2939–2949"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Blockade of Cannabinoid CB1 and CB2 Receptors Increases Force Generation in Reserpine-Treated Mice, but Only CB1 Blockade Extends the Duration of Effort","authors":"Beatriz Carminati dos Santos,&nbsp;Izabely Guedes da Rosa,&nbsp;Laíze de Freitas Mazzardo,&nbsp;Naiara de Souza Santos,&nbsp;Izabel Feltrin Fabro,&nbsp;Tatyana Nery,&nbsp;Amanda Leite Bastos Pereira,&nbsp;Aderbal S. Aguiar Jr","doi":"10.1021/acsptsci.6c00206","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00206","url":null,"abstract":"<p>Motor impairmentin parkinsonism extends beyond the classical triadto weakness and a reduced capacity to sustain motor output, whoseneuromodulatory control is poorly resolved. The endocannabinoid systemis a candidate regulator, but CB1 and CB2 receptors have not beenseparated within one preparation. Reserpine-treated adult female Swissmice received vehicle, the CB1 antagonist AM251, or the CB2 antagonistAM630 into the lateral ventricle; catalepsy was recorded across threetrials and neuromuscular performance in a grip force task. Both antagonistsincreased the force generated at task onset, by amounts these datacannot distinguish: AM630 by 53.9 gf (95% CI 22.5–85.3) andAM251 by 41.2 gf (95% CI 8.8–73.6). They separated on duration.AM251 increased grip time by 619 ms (95% CI 113–1125), whereasAM630 did not (−70 ms, 95% CI −560 to +421). An interactioncontrast on the force–time balance followed from that difference:AM630 shifted the balance toward force (−2.03 SD, <em>P</em> = 0.008), AM251 did not (−0.36 SD, <em>P</em> = 0.66),and the two differed from each other by 1.67 SD (<em>P</em> = 0.022). AM251 also reduced the odds of a cataleptic response (OR0.16, 95% CI 0.03–0.89). Adjusting for body mass left bothforce effects unchanged. The dissociation is therefore in the durationof effort rather than in its force: both antagonists raise force,and only CB1 blockade also extends the time over which it is maintained.Delivered intracerebroventricularly, these effects are central inorigin but not anatomically localized.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2783–2794"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of the Wound-Healing Properties of Almond Oil in a Murine Excisional Wound Model: Biochemical Mechanisms and Translational Perspectives","authors":"Alessia Arangia,&nbsp;Regina Aparo,&nbsp;Marika Cordaro,&nbsp;Roberta Fusco,&nbsp;Giuseppina Mandalari,&nbsp;Rosanna Di Paola,&nbsp;Salvatore Cuzzocrea,&nbsp;Ramona D’Amico,&nbsp;Rosalba Siracusa,&nbsp;Daniela Impellizzeri","doi":"10.1021/acsptsci.6c00453","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00453","url":null,"abstract":"<p>Wound healing is a complex biological process involvingoverlappingphases of hemostasis, inflammation, proliferation, and remodeling,coordinated by a network of cytokines, growth factors, and cellularresponses. Natural products, particularly plant oils, are increasinglybeing studied for their antioxidant, anti-inflammatory, and regenerativeproperties. Specifically, this study evaluated the healing potentialof almond oil through topical application in an excisional wound modelinduced in mice, treated once daily for 7 days. Histological, biochemical,and molecular analyses demonstrated that topical treatment with almondoil accelerates wound healing, collagen deposition, and re-epithelialization,and stimulates angiogenesis. At the molecular level, almond oil reducedthe expression of MMP-9, increased TGF-β and VEGF, and activatedthe Nrf2/HO-1 antioxidant pathway, helping limit oxidative and nitrosativestress. Furthermore, it inhibited NF-κB activation and reducedlevels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6).These results indicate that almond oil promotes skin healing throughsynergistic anti-inflammatory, antioxidant, and regenerative actions,supporting its use as a natural and sustainable topical agent forwound management in clinical settings.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2973–2982"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Daffodils to Drug Leads: Amaryllidaceae Alkaloids Target Protein Translation in Chronic Lymphocytic Leukemia to Induce Selective Apoptosis","authors":"Rong Chen,&nbsp;Ryan Rutledge,&nbsp;Carson W. King,&nbsp;Yuling Chen,&nbsp;Ping Xiong,&nbsp;William G. Wierda,&nbsp;Puppala Sathish,&nbsp;Antonio Evidente,&nbsp;Travis Anderson,&nbsp;William Plunkett,&nbsp;Alexander Kornienko","doi":"10.1021/acsptsci.6c00139","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00139","url":null,"abstract":"<p>Targeting protein translation is a promising strategyin oncology,especially for malignancies dependent on short-lived survival factors.The clinical translation inhibitor homoharringtonine (HHT) was recentlydiscontinued in the U.S. due to poor solubility and cardiotoxicity,creating an urgent need for new leads. We investigated structurallydistinct Amaryllidaceae alkaloids, narciclasine (NCS), lycorine (LYC),and haemanthamine (HAEM), in models of chronic lymphocytic leukemia(CLL) and Richter transformation (RT). Using an optimized 10 L Soxhletextraction of ’Carlton’ daffodil bulbs, an unprecedentedNCS yield of 250 mg/kg was achieved, doubling previous laboratoryrecords. NCS showed potent activity against primary CLL cells andthe RT-derived HPRT1 line (IC₅₀ = 50 nM), while normalT-cell viability remained largely unaffected at doses producing near-completeCLL cell depletion, indicating a favorable therapeutic window. <em>O</em>-Propargyl-puromycin incorporation and [³H]-leucineassays confirmed dose-dependent inhibition of de novo protein synthesis,triggering selective depletion of the short-lived anti-apoptotic proteinMcl-1 while leaving stable Bcl-2 unaffected. Mcl-1 loss induced mitochondrialdepolarization, Annexin V/PI positivity, and PARP cleavage. Combinationstudies with the Bcl-2 inhibitor venetoclax revealed synergistic activityacross all compounds, most pronounced for HAEM, consistent with itscomparatively modest Mcl-1 depletion. These findings establish thatAmaryllidaceae alkaloids exploit the ″translational addiction″of leukemia cells to Mcl-1 and validate the isocarbostyril and phenanthridinescaffolds as mechanistically characterized leads. SAR-guided analogueoptimization to improve pharmacokinetic properties while preservingthe translational inhibition pharmacophore represents the plannednext stage of this program.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2758–2771"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G-Protein-Coupled Receptor 41 (GPR41) as a Therapeutic Target for Metabolic Endotoxemia: Mechanistic Insights into AR420626-Induced Autophagy and Nuclear Factor kappa B (NF-κB) Suppression","authors":"Do-Hyung Lee,&nbsp;So-Young Chun,&nbsp;Hun Young Kim,&nbsp;Kyungsoo Oh","doi":"10.1021/acsptsci.6c00135","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00135","url":null,"abstract":"<p>G-protein-coupled receptor 41 (GPR41/FFAR3) functionsas a crucialmetabolic sensor of gut microbiota-derived short-chain fatty acids(SCFAs). However, the precise mechanisms by which GPR41 suppressesmetabolic endotoxemia caused by translocation of gut-derived lipopolysaccharide(LPS) into the circulation remain unclear. In this study, we investigatedthe protective effects of AR420626 (AR), a selective GPR41 agonist,against endotoxemia using RAW 264.7 macrophages to mimic an endotoxinstress environment. Our results showed that AR-induced activationof GPR41 significantly suppressed the production of nitric oxide (NO)and interleukin-6 (IL-6), key pro-inflammatory mediators implicatedin the pathogenesis of endotoxemia, through inhibition of the nuclearfactor kappa B (NF-κB) signaling pathway. In addition, AR-mediatedGPR41 activation significantly reduced the expression of monocytechemoattractant protein-1 (MCP-1) and inducible nitric oxide synthase(iNOS). These protective effects were mechanistically linked to enhancedautophagic activity, as evidenced by increased conversion of LC3-Ito LC3-II. Importantly, pharmacological inhibition of autophagy abolishedthe ability of AR to suppress NF-κB activation, suggesting thatthe GPR41-autophagy axis is essential for preserving macrophage homeostasisagainst LPS-induced endotoxemia damage. Furthermore, GPR41 knockdownmarkedly abrogated the AR-mediated regulation of iNOS, phosphorylatedNF-κB, and p62 under LPS stimulation, confirming that theseprotective effects are specifically mediated through GPR41. Theseresults suggest that pharmacological activation of GPR41 to enhanceautophagy may represent a novel therapeutic strategy for the treatmentof endotoxemia.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2746–2757"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Microbial Metabolism Inactivates Trifluridine and Drives Loss of Anticancer Efficacy","authors":"Saeed Ahmad,&nbsp;Jimoh Olamilekan Igbalaye,&nbsp;Vince Perez,&nbsp;Elizabeth Wenning,&nbsp;Sophie Gauthier,&nbsp;Jason Ridlon,&nbsp;Joseph Irudayaraj","doi":"10.1021/acsptsci.6c00329","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00329","url":null,"abstract":"<p>Human-associated gut bacteria harbor diverse geneticand metabolicpotential. Orally administered therapeutic drugs can interact withthese bacteria in the gastrointestinal tract. Recent evidence showsmodifications of multiple drugs via gut bacteria, influencing therapeuticoutcomes. Trifluridine, a fluoropyrimidine drug used in colorectalcancer treatment, is susceptible to microbial metabolism and prematureinactivation, yet the breadth and functional consequences of thismetabolism remain incompletely defined. In this work, we further explorethe potential of additional gut bacterial strains that can metabolizetrifluridine and characterize how this microbial metabolism impactscancer cell responses. Sequence-based similarity search revealed trifluridinemetabolizing homologues in multiple <em>Enterobacteriaceae</em> species including <em>Klebsiella oxytoca</em>. LCMS analysis confirms that gut isolates, <em>Escherichia coli</em> NS-12 and <em>K. oxytoca</em> S-22, efficiently degraded TF within 2 h. Tipiracil, the clinicalinhibitor of host thymidine phosphorylase, only partially blockedmicrobial TF metabolism dependent on oxygen availability and the bacterialstrain. Functionally, the treatment efficacy of TF was reduced, andit lost its cytotoxic potential in cancer when pre-exposed to <em>E. coli</em> and <em>K. oxytoca</em>. Also, microbially degraded TF could not induce the oncogenic p53-dependentpathways in cancer cells compared to the intact TF drug. These findingsdemonstrate that microbial TF metabolism is widespread across thegut bacteria and can directly undermine its anticancer efficacy andhighlight the need to consider gut microbial composition when optimizingTF-based cancer therapies.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2842–2852"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging RNA-Based Therapeutic Strategies for Inflammatory Ophthalmic Disorders of the Anterior Segment: Mechanistic Insights and Translational Potential","authors":"Alpana Kumari,&nbsp;Atul Kabra","doi":"10.1021/acsptsci.6c00443","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00443","url":null,"abstract":"<p>Anteriorsegment ocular inflammatory disorders, including conjunctivitis,keratitis, scleritis, dry eye disease, and anterior uveitis, representa major cause of visual impairment worldwide. Conventional pharmacologicaltherapies such as antihistamines, corticosteroids, and immunomodulatorsprimarily provide symptomatic relief but are limited by their adverseeffects, poor long-term efficacy, and lack of disease-modifying potential.In this review, RNA-based therapeutics are discussed in detail, emergingas promising and targeted approaches for modulating the molecularmechanisms underlying ocular anterior segment inflammatory conditions.These strategies include small interfering RNA (siRNA), short hairpinRNA (shRNA), antisense oligonucleotides (ASOs), messenger RNA (mRNA),microRNA (miRNA), and long noncoding RNA (lncRNA), each offering distinctmechanisms to regulate gene expression and inflammatory signalingpathways. RNA therapeutics enable precise silencing or modulationof key mediators such as cytokines, transcription factors, and immuneregulators involved in Th2-driven and immune-mediated inflammatoryresponses. Recent advances in nanotechnology-based delivery systems,including lipid nanoparticles, polymeric carriers, and viral vectors,have significantly improved RNA stability, bioavailability, and targetedocular delivery. Despite these advances, challenges such as ocularsurface barriers, rapid tear clearance, enzymatic degradation, off-targeteffects, and potential immunogenicity remain significant hurdles.Overall, RNA-based therapies hold substantial potential as next-generation,disease-modifying treatments for anterior segment inflammatory disorders,including DED, warranting further translational and clinical investigation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2712–2733"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149153242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P2X4 Receptor Antagonists Exert Anti-Inflammatory Effects via NLRP3 Inflammasome in a Murine Model of Colitis","authors":"Vanessa D’Antongiovanni,&nbsp;Clelia Di Salvo,&nbsp;Matteo Fornai,&nbsp;Laura Benvenuti,&nbsp;Gianfranco Natale,&nbsp;Larisa Ryskalin,&nbsp;Lorenzo Bertani,&nbsp;Elena Lucarini,&nbsp;Lorenzo Di Cesare Mannelli,&nbsp;Carla Ghelardini,&nbsp;Zoltan H. Nemeth,&nbsp;György Haskó,&nbsp;Luca Antonioli","doi":"10.1021/acsptsci.6c00336","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00336","url":null,"abstract":"<p>Pharmacological inhibition of P2X4 receptors (P2X4Rs)has emergedas a potential therapeutic approach for the management of severalimmune/inflammatory diseases. However, the contribution of P2X4Rsin the pathophysiological mechanisms underlying colitis-associatedintestinal inflammation remain partially unclear. Here, we investigatedthe anti-inflammatory effects of two novel and selective P2X4R antagonists,NC-2600 and NP-1815-PX, in rats with 2,4-dinitrobenzenesulfonic acid(DNBS)-induced colitis. In addition, the molecular mechanisms of theiraction were also characterized. Oral treatment with either drug ordexamethasone (DEX) was initiated immediately after DNBS administrationand continued for 6 consecutive days. NC-2600 and NP-1815-PX attenuatedthe body weight loss induced by colitis, whereas DEX had no effecton this parameter. The increase in spleen weight and the macroscopicseverity of colonic lesions were reduced by all three treatments.Furthermore, NC-2600, NP-1815-PX, and DEX decreased colonic IL-1βlevels and caspase-1 activity. A reduction in tumor necrosis factorlevels was observed only following DEX treatment, as neither P2X4Rantagonist affected the colitis-associated increase in this cytokine.By contrast, the loss of colonic occludin expression was reversedby NC-2600 and NP-1815-PX, but remained unaffected by DEX. In THP-1cells, combined exposure to lipopolysaccharide (LPS) and adenosinetriphosphate (ATP) increased IL-1β release and the expressionof NLRP3, caspase-1, caspase-5, and caspase-8, whereas caspase-4 expressionwas unchanged. NC-2600 and NP-1815-PX prevented these LPS/ATP-inducedalterations. In conclusion, these findings support the potential ofselective P2X4R blockade as a therapeutic strategy for intestinalinflammation, possibly through the modulation of NLRP3 inflammasome-relatedsignaling.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 10","pages":"2853–2865"},"PeriodicalIF":3.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}