Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Does the drug enter the brain? If so, how much?","authors":"Margareta Hammarlund-Udenaes","doi":"10.1016/j.jpet.2024.100043","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100043","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100043"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074718","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":"Efficacy of fluoxetine and (R,S)-ketamine in attenuating conditioned fear behaviors in male mice.","authors":"Megan Wells, Jan Hoffmann, Autumn Stage, Isabella Enger, Jayme Pomper, Lily Briggs, Amber LaCrosse","doi":"10.1124/jpet.124.002252","DOIUrl":"https://doi.org/10.1124/jpet.124.002252","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is caused by exposure to a traumatic or stressful event. Symptoms related to this disorder include persistent re-experiencing of memories and fear of generalization. Current pharmacological treatments for PTSD are insufficient, with fewer than 30% of patients reporting symptom remission. This study aims to determine the efficacy of acute (R,S)-ketamine and chronic fluoxetine (FLX) in reducing fear memory and fear generalization. In rodents, fear conditioning (FC) is commonly used in the literature to induce behaviors related to symptoms of PTSD, and the open field test (OFT) can assess anxiety and fear generalization behaviors during the exploration of a novel environment. In this study, FC consisted of a white noise cue stimulus and 4 inescapable foot shocks. Treatments began 4 hours after FC. Fear and anxiety behaviors were recorded during re-exposure to the FC stimuli at 24 hours and 2 weeks. The OFT was conducted 1 day before the last FC re-exposure. Results support the combined use of acute ketamine and chronic FLX as a treatment for reducing behaviors indicative of fear memory during re-exposure at 2 weeks, but not behaviors indicative of anxiety and fear generalization in the OFT. FLX alone was most effective in reducing behaviors related to fear generalization. This study contributes to the existing literature on pharmacological treatment for fear and anxiety behaviors relating to fear memory and fear generalization. Continued research is necessary to replicate results, optimize treatment protocols, and investigate the molecular adaptations to trauma and treatment. SIGNIFICANCE STATEMENT: Up to 6% of people in the United States will develop PTSD within their lifetime, and less than half of those individuals will find relief from their symptoms given the current therapeutic options. This study offers preliminary support for the efficacy of ketamine and FLX in reducing PTSD-like behaviors induced by fear-conditioning in mice. Compared with current standard treatments, the results of the current study indicate the potential for a more effective therapeutic option for those with stress-related disorders, such as PTSD.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100028"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074721","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 elucidation of species-specific receptor pharmacology: A case study using subtype-selective para- and meta-carborane estrogen receptor agonists.","authors":"Adeoluwa A Adeluola, Hanna S Radomska, Tyler A Wilson, Samuel K Kulp, Alyssa Kabat, Timothy H Helms, Abigail K Mayo, Emma J Montgomery, Justin Thomas, Lynn M Marcho, Travis Costa, Mayu Fukuda, Diana D Kang, Sandip Vibhute, Dasheng Wang, Chad E Bennett, Christopher C Coss","doi":"10.1124/jpet.123.001874","DOIUrl":"https://doi.org/10.1124/jpet.123.001874","url":null,"abstract":"<p><p>Estrogen receptors (ERs) are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of ERβ is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating ERα is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine ERs. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single-dose intravenous and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the meta-carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK-293 cells expressing murine ERs revealed species-specific differences in the ER subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. SIGNIFICANCE STATEMENT: This study investigates para- and meta-substituted carborane analogs targeting estrogen receptors (ERs), revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse ortholog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100001"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074897","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":"New potential ligand-receptor axis involved in tissue repair as therapeutic targets in progressive multiple sclerosis.","authors":"Eugenio Antonio Carrera Silva, Jorge Correale, Carla Rothlin, Juan Manuel Ortiz Wilczyñski","doi":"10.1124/jpet.124.002254","DOIUrl":"https://doi.org/10.1124/jpet.124.002254","url":null,"abstract":"<p><p>Progressive multiple sclerosis (MS) represents the worsening phase of the disease, characterized by increasing neurodegeneration and disability and mainly refractory to current treatments. Finding therapeutic options remains challenging partially not only because of the lack of understanding of pathogenic mechanisms but also because the early dogma was centered on neuroinflammation, overshadowing the critical role of the tissue repair process. The tissue repair target should start early in disease development, and therapeutic strategies for progressive MS should combine anti-inflammatory and neuroprotective aspects. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, has shed light on some ligand receptor pairs, such as growth-arrest-specific 6 (GAS6)/protein tyrosine kinase receptor (TYRO3) and protein S (PROS1)/AXL receptor tyrosine kinase (AXL), required to dampen inflammation, promote tissue repair, and engage remyelination. Understanding the role of these proteins in the early stages of MS is a critical step toward preventing or stopping neurodegeneration. Herein, we will discuss the receptor/ligand pairs that might be targetable for therapeutic intervention in progressive MS. SIGNIFICANCE STATEMENT: The aim for progressive multiple sclerosis treatment should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. Targeting the TYRO3, AXL, and MER tyrosine kinase receptor (TAM) signaling axis, particularly as growth-arrest-specific 6/TYRO3 and protein S/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients in the early stages of progressive multiple sclerosis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100029"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074746","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 protective effect of amitriptyline on experimental colitis through inhibiting TLR-4/MD-2 signaling pathway.","authors":"Chengcheng Zeng, Qingqing Zhu, Wu Peng, Chen Huang, Huiting Chen, Hongli Huang, Yongjian Zhou, Chong Zhao","doi":"10.1124/jpet.124.002207","DOIUrl":"https://doi.org/10.1124/jpet.124.002207","url":null,"abstract":"<p><p>Amitriptyline, a pleiotropic tricyclic antidepressant, possesses antioxidant and anti-inflammatory properties. Despite its diverse benefits, the specific effects of amitriptyline on inflammatory bowel disease (IBD) are not yet well defined. To explore this, we used a dextran sulfate sodium (DSS)-induced colitis model to examine the anti-inflammatory effects of amitriptyline and the underlying mechanisms by which it operates. Our research revealed that amitriptyline is effective in alleviating several pathological manifestations associated with colitis. This includes improving body weight retention, reducing disease activity index, lessening of colon length shortening, and repairing of colonic mucosal damage. Treatment with amitriptyline significantly protected mucosal injury by preserving the population of goblet cells and increasing the expression of tight junction proteins. Furthermore, we observed that amitriptyline effectively countered immune cell infiltration, specifically neutrophils and macrophages, while simultaneously lowering the levels of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, and IL-6. Additionally, RNA sequencing analysis pointed to the potential involvement of the Toll-like receptor (TLR) pathway in the anticolitic effects induced by amitriptyline. Subsequent Western blot analysis indicated that amitriptyline significantly inhibited the TLR-4-mediated nuclear factor (NF)-κB signaling pathway. To bolster our findings, in vitro studies demonstrated that amitriptyline downregulated the TLR-4/NF-κB/mitogen-activated protein kinase signaling cascades in mouse macrophages stimulated with lipopolysaccharide. Further molecular investigations revealed that amitriptyline was able to suppress the elevated expression of myeloid differentiation factor 2 that lipopolysaccharide stimulation typically induces. In summary, our findings suggest that amitriptyline effectively mitigates DSS-induced colitis in mice through the inhibition of TLR-4/myeloid differentiation 2 pathway signaling, indicating its potential repurposing for IBD treatment. SIGNIFICANCE STATEMENT: The potential of using amitriptyline in treating inflammatory bowel disease appears promising, leveraging its established safety and dosing profile as an antidepressant. The study results show that amitriptyline can alleviate pathological symptoms, inflammation, and intestinal mucosal damage in mice with colitis induced by DSS. The protective effect observed appears to be linked to the inhibition of TLR-4/myeloid differentiation 2 signaling pathway. By exploring novel applications for existing medications, we can optimize amitriptyline's efficacy and broaden its impact in both medical and commercial contexts.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100024"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074901","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":"Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.","authors":"Yiheng Zhang, Chih-Jen Yang, Alexander R Melrose, Jiaqing Pang, Kirrali Schofield, Serena D Song, Iván Parra-Izquierdo, Tony J Zheng, Joseph P Lyssikatos, Stefan D Gross, Joseph J Shatzel, Owen J T McCarty, Joseph E Aslan","doi":"10.1124/jpet.124.002104","DOIUrl":"https://doi.org/10.1124/jpet.124.002104","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo. Our study included standard-of-care agents (eg, imatinib and nilotinib) and second-generation ABL inhibitors, including ponatinib and bosutinib, designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (eg, asciminib and GNF-2) and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo. Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. SIGNIFICANCE STATEMENT: This study examines the effects of clinically relevant small molecule breakpoint cluster region (BCR)-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (eg, imatinib, ponatinib) with well characterized effects on platelet function, to discern potential antiplatelet and other effects of BCR-ABL TKIs and inform clinical safety.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100020"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074752","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":"Evaluation of systemic and brain pharmacokinetic parameters for repurposing metformin using intravenous bolus administration.","authors":"Sejal Sharma, Yong Zhang, Dhavalkumar Patel, Khondker Ayesha Akter, Sounak Bagchi, Ali Ehsan Sifat, Ehsan Nozohouri, Yeseul Ahn, Vardan T Karamyan, Ulrich Bickel, Thomas J Abbruscato","doi":"10.1124/jpet.124.002152","DOIUrl":"https://doi.org/10.1124/jpet.124.002152","url":null,"abstract":"<p><p>Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence of established systemic and brain pharmacokinetic (PK) parameters at relevant preclinical doses presents a significant knowledge gap. This study highlights these PK parameters and the importance of using pharmacologically relevant preclinical doses to study pharmacodynamics in stroke and related neurodegenerative diseases. A liquid chromatography with tandem mass spectrometry method to measure metformin levels in plasma, brain, and cerebrospinal fluid was developed and validated. In vitro assays examined brain tissue binding and metabolic stability. Intravenous bolus administration of metformin to C57BL6 mice covered a low- to high-dose range maintaining pharmacological relevance. Quantification of metformin in the brain was used to assess brain PK parameters, such as unidirectional blood-to-brain constant (K_in) and unbound brain-to-plasma ratio (K_{p, uu, brain}). Metformin exhibited no binding in the mouse plasma and brain and remained metabolically stable. It rapidly entered the brain, reaching detectable levels in as little as 5 minutes. A K_in value of 1.87 ± 0.27 μL/g/min was obtained. As the dose increased, K_{p, uu, brain} showed decreased value, implying saturation, but this did not affect an increase in absolute brain concentrations. Metformin was quantifiable in the cerebrospinal fluid at 30 minutes but decreased over time, with concentrations lower than those in the brain across all doses. Our findings emphasize the importance of metformin dose selection based on PK parameters for preclinical pharmacological studies. We anticipate further investigations focusing on PKs and pharmacodynamics in disease conditions, such as stroke. SIGNIFICANCE STATEMENT: The study establishes crucial pharmacokinetic parameters of metformin for treating ischemic stroke and neurodegenerative diseases, addressing a significant knowledge gap. It further emphasizes the importance of selecting pharmacologically relevant preclinical doses. The findings highlight metformin's rapid brain entry, minimal binding, and metabolic stability. The necessity of considering pharmacokinetic parameters in preclinical studies provides a foundation for future investigations into metformin's efficacy for neurodegenerative disease(s).</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100013"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074667","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":"VERU-111, an orally available tubulin inhibitor, suppresses ovarian tumor growth and metastasis.","authors":"Shelby Waddell, Guannan Zhao, Ziping Liu, Hao Chen, Wenjing Zhang, Yaohong Wang, Duane D Miller, Junming Yue, Wei Li","doi":"10.1124/jpet.124.002298","DOIUrl":"https://doi.org/10.1124/jpet.124.002298","url":null,"abstract":"<p><p>Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, and well tolerated and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and ultimately apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment of ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo, VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. SIGNIFICANCE STATEMENT: VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo antitumor and antimetastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100006"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074914","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":"Zero-length crosslinking: A breakthrough approach for evaluating target engagement in α-synuclein immunotherapy.","authors":"Jean-Christophe Rochet, Wenzhu Qi, Deniz Kirik","doi":"10.1016/j.jpet.2024.100036","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100036","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100036"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074918","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 targeting of full-length interleukin-33 protein levels with cell-permeable decoy peptides attenuates fibrosis in the bleomycin model in vivo.","authors":"Sergei P Atamas, Virginia Lockatell, Nevins W Todd, John C Papadimitriou, Violeta Rus, Katerina N Lugkey, Stefanie N Vogel, Vladimir Y Toshchakov, Irina G Luzina","doi":"10.1124/jpet.123.002050","DOIUrl":"https://doi.org/10.1124/jpet.123.002050","url":null,"abstract":"<p><p>Interleukin (IL)-33 has been shown to centrally regulate, among other processes, inflammation and fibrosis. Both intracellular full-length (FLIL33) precursor and extracellular mature cytokine (MIL33) forms exert such regulation, albeit differentially. Drug development efforts to target the IL-33 pathway have focused mostly on MIL33 and its specific cell-surface receptor, ST2, with limited attempts to negotiate the pathophysiological contributions from FLIL33. Furthermore, even a successful strategy for targeting MIL33 effects would arguably benefit from a simultaneous attenuation of the levels of FLIL33, which remains the continuous source of MIL33 supply. We therefore sought to develop an approach to depleting FLIL33 protein levels. We previously reported that the steady-state levels of FLIL33 are controlled in part through its proteasomal degradation and that such regulation can be mapped to a segment in the N-terminal portion of FLIL33. We hypothesized that disruption of this regulation would lead to a decrease in FLIL33 levels, thus inducing a beneficial therapeutic effect in an IL-33-dependent pathology. To test this hypothesis, we designed and tested cell-permeable decoy peptides, which mimic the target N-terminal FLIL33 region. We argued that such mimic peptides would compete with FLIL33 for the components of the native FLIL33 production and maintenance molecular machinery. Administered in the therapeutic regimen to bleomycin-challenged mice, the tested cell-permeable decoy peptides alleviated the overall severity of the disease by restoring body weight loss and attenuating accumulation of collagen in the lungs. This proof-of-principle study lays the foundation for future work toward the development of this prospective therapeutic approach. SIGNIFICANCE STATEMENT: An antifibrotic therapeutic approach is proposed and preclinically tested in mice in vivo based on targeting the full-length IL-33 precursor protein. Peptide fusion constructs consisted of a cell-permeable sequence fused with a sequence mimicking an N-terminal segment of IL-33 precursor that is responsible for this protein's stability. Systemic administration of such peptides to mice in either the acute intratracheal or chronic systemic bleomycin challenge models leads to a decrease in the bleomycin-induced elevations of pulmonary IL-33 and collagen.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100008"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074910","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}