Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies.","authors":"Ahmed M Elshazly, Aya A Elzahed, David A Gewirtz","doi":"10.1124/jpet.123.002048","DOIUrl":"10.1124/jpet.123.002048","url":null,"abstract":"<p><p>The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2 and, more recently, also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains their clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy. Autophagy is an inherent cellular mechanism whereby cytoplasmic components are selectively degraded to maintain cellular homeostasis via the generation of energy and metabolic intermediates. Although the cytoprotective form of autophagy is thought to predominate, other forms of autophagy have also been identified in response to chemotherapeutic agents in various tumor models; these include cytotoxic, cytostatic, and nonprotective functional forms of autophagy. In this review, we provide an overview of the autophagic machinery induced in response to HER2-targeted monoclonal antibodies, with a focus on trastuzumab and trastuzumab-emtansine, in an effort to determine whether autophagy targeting or modulation could be translated clinically to increase their effectiveness and/or overcome the development of resistance. SIGNIFICANCE STATEMENT: This manuscript is one in a series of papers that interrogate the role(s) of the autophagy induced in response to antineoplastic agents in various cancer models. This series of papers was developed in an effort to establish whether autophagy targeting or modulation is likely to be an effective adjuvant strategy to increase the efficacy of cancer chemotherapeutic agents. This review explores the relationship between the autophagic machinery and HER2-targeted therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100007"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074645","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":"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}

{"title":"Innovation through imitation: IL-33 decoys show promise in pulmonary fibrosis.","authors":"Maya E Kotas, Erin D Gordon","doi":"10.1016/j.jpet.2024.100035","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100035","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100035"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074646","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 in overcoming enzalutamide resistance in castration-resistant prostate cancer.","authors":"Kendall Simpson, Derek B Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu","doi":"10.1124/jpet.124.002424","DOIUrl":"10.1124/jpet.124.002424","url":null,"abstract":"<p><p>Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100034"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074654","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":"Quantification of cinpanemab (BIIB054) binding to α-synuclein in cerebrospinal fluid of phase 1 single ascending dose samples.","authors":"YuTing Liu, Minhua Yang, Kyle Fraser, Danielle Graham, Paul H Weinreb, Andreas Weihofen, Warren D Hirst, Jesse M Cedarbaum, Blake Pepinsky","doi":"10.1124/jpet.124.002199","DOIUrl":"10.1124/jpet.124.002199","url":null,"abstract":"<p><p>Through its pathological and genetic association with Parkinson disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Although published studies from some immunotherapy trials have demonstrated engagement in plasma, none has shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system. Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low-affinity binding to monomeric forms. The avidity-driven binding, low drug concentration, and the very low α-syn levels, plus its heterogeneous nature in cerebrospinal fluid (CSF), made it impossible to measure drug-target interactions by conventional assays. Here we overcame these challenges by using zero-length crosslinking to stabilize the BIIB054-α-syn complexes and then quantified the crosslinked complexes using a Meso Scale Discovery electrochemiluminescence assay. CSF samples from healthy volunteers (HVs, n = 46) and individuals with PD (PD, n = 18) from study 228HV101 (phase 1 clinical trial of BIIB054) demonstrated dose- and time-dependent binding of cinpanemab to α-syn with measurable complexes detected at doses ≥15 mg/kg. Complex formation displayed a direct positive correlation to drug concentration (Spearman rank correlation = 0.8295 [HV], 0.8032 [PD] P < .0001 [HV, PD]). The observed binding of cinpanemab to α-syn in CSF is consistent with its low intrinsic affinity for α-syn monomer and provides evidence that the drug is behaving with expected binding dynamics in the central nervous system compartment. SIGNIFICANCE STATEMENT: A zero-length crosslinking method with Meso Scale Discovery detection was developed to enable quantification of cinpanemab-α-synuclein (α-syn) complexes in clinical cerebrospinal fluid samples by preventing signal loss caused by their rapid dissociation. Observed dose- and time-dependent binding was consistent with cinpanemab's affinity for α-syn and provided confidence the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the central nervous system.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100003"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074831","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":"Interrogating a compound library in search of an inhibitor for TREM-like transcript-1 to fibrinogen binding.","authors":"Andrea Acsiniuc, Barbara Manfredi, Javier Menéndez-Pérez, Siobhan Branfield, A Valance Washington","doi":"10.1124/jpet.124.002086","DOIUrl":"10.1124/jpet.124.002086","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) remains one of the leading causes of death worldwide. Aberrant platelet function mediates fibrin(ogen)-rich thrombi that lead to occlusive thrombi associated with mortality. The receptor, TREM-like transcript-1 (TLT-1), stored in the platelet α-granules and released upon platelet activation, binds fibrinogen and von Willebrand factor. Once it is released from platelets, TLT-1 is a potential therapeutic target to prevent the thrombosis associated with CVD. Here we designed an assay to screen a compound library of small molecules inhibitors. Human embryonic kidney (HEK)-293 cells stably transfected with a full-length human treml-1 construct were used to screen library of 800 compounds, for inhibition of TLT-1 to fibrinogen binding in an attachment assay using crystal violet staining. The possible cytotoxicity of the best compounds was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide MTT and calcein AM staining assays. We demonstrated that the addition of TLT-1 to HEK-293 cells increases cell adhesion by more than 2-fold. We identified ∼80 compounds that inhibit binding by more than 80%. We further tested the top compounds and confirmed that reduction of hTLT-1 to fibrinogen bound in the top compounds was not caused by cytotoxicity, as per colorimetric and fluorescent viability assays. Four compounds were identified as potential small molecule inhibitors, one of which, BM-8372, demonstrated significant effect in platelet aggregation and spreading assays. SIGNIFICANCE STATEMENT: Triggering receptor expressed in myeloid cells-like transcript-1 (TLT-1) is a key platelet receptor that binds fibrinogen and mediates clot formation. The developed assay successfully screened 800 small molecules, pinpointing ∼80 potent inhibitors that reduce TLT-1 binding by over 80%. Importantly, the study rigorously rules out cytotoxicity concerns, affirming the therapeutic potential of the identified compounds. By elucidating TLT-1's role and presenting promising inhibitors, this research offers a significant stride toward developing novel strategies to combat cardiovascular disease-related thrombosis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100009"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074650","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":"Mechanisms and management of thrombosis in cancer: Focus on gastrointestinal malignancies.","authors":"Simone Monegatti, Nicola Martinelli, Simonetta Friso, Henri M H Spronk, Hugo Ten Cate","doi":"10.1124/jpet.124.002203","DOIUrl":"10.1124/jpet.124.002203","url":null,"abstract":"<p><p>Cancer patients have an increased risk of venous thromboembolism, which is their second cause of death after disease progression itself. Several thrombotic risk factors coexist in cancer patients, including the ability of both cancer and tumoral microenvironment's cells to directly or indirectly activate platelets and the enzymes of the coagulation cascade, resulting in a hypercoagulable state of blood. This narrative review gives an overview of the main mechanisms leading to venous thromboembolism in cancer patients, including the role that platelets and the clotting proteins may have in tumor growth and metastasis. Of note, the hemostatic balance is altered in cancer patients who may, next to a thrombosis tendency, also have an increased risk of bleeding. To highlight the complexity and the precariousness of the hemostatic balance of these patients, we discuss 2 specific gastrointestinal malignancies: hepatocellular carcinoma, which is frequently associated with liver cirrhosis, a condition that causes profound alterations of hemostasis, and colorectal cancer, which is characterized by a fragile mucosa that is prone to bleeding. Understanding the molecular mechanisms of cancer-associated thrombosis may give a unique opportunity to develop new innovative drugs, acting differently on distinct pathways and potentially allowing to reduce the risk of bleeding related to antithrombotic therapies. SIGNIFICANCE STATEMENT: The topic is significant because understanding the molecular mechanisms leading to cancer-associated thrombosis and bleeding, focusing on gastrointestinal malignancies, enables the development of more rationale and innovative antithrombotic strategies for cancer-associated thrombosis. Eventually, this will support an improved and patient-tailored antithrombotic management in vulnerable oncologic patients.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100018"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074652","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":"Discovery of aurovertin B as a potent metastasis inhibitor against triple-negative breast cancer: Elucidating the complex role of the ATF3-DUSP1 axis.","authors":"Jian-Jun Shen, Xi Yang, Meng Yu, Qing-Cui Li, Ru-Yu Wang, Wen-Yan Yu, Jia-Li Zhang, Yi-Li Chen, Wen-Ting Zhu, Jia Li, Zha-Jun Zhan, Rui Wu","doi":"10.1124/jpet.124.002264","DOIUrl":"10.1124/jpet.124.002264","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is characterized by high mortality rates, primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937, and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of dual-specificity phosphatase 1 (DUSP1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified activating transcription factor 3 (ATF3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the metastatic mechanisms of TNBC. SIGNIFICANCE STATEMENT: This study constructs a high-throughput phenotypic screening system utilizing epithelial-mesenchymal transition marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100005"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074717","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":"Inhibiting p38α MAPK signaling: A balancing act in treating inflammation.","authors":"Isabelle Kwan, Raisa Karim, Markus A Seeliger","doi":"10.1016/j.jpet.2024.100039","DOIUrl":"10.1016/j.jpet.2024.100039","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"100039"},"PeriodicalIF":3.1,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449411","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":"Restraint stress exacerbates indomethacin-induced gastric antral ulcers by gastroparesis via activation of corticotropin-releasing factor 2 receptors in refed mice.","authors":"Hiroshi Satoh, Yasutada Akiba, Tetsuro Urushidani, Jonathan D Kaunitz","doi":"10.1016/j.jpet.2024.103381","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.103381","url":null,"abstract":"<p><p>We examined the effects of stress on the indomethacin (IND)-induced gastric antral ulcer formation in refed mice. Male mice underwent refeeding of diet for 2 hours after a fast for 22 hours, followed by IND injection; the lesion index was measured 24 hours later. Mice also underwent a defined diet for 2 hours following a fast for 22 hours, and the stomachs were collected 1.5 hours later. We then measured the volume and the bile acid concentrations of the gastric contents. Mice underwent restraint stress (RS) in a cylindrical plastic tube for 60 minutes, or treatment with corticotropin-releasing factor (CRF), following refeeding of diet for 2 hours. We then examined the effects of RS and CRF on the lesion index, gastric emptying, and duodenogastric bile reflux. The effects of receptor antagonists for CRF₂ (astressin-2B), CRF₁, 5-hydroxytriptamine 3 (ondansetron), dopamine 2 (haloperidol), and cholecystokinin 1 (lorglumide) on the effects of RS or CRF were examined. IND (10 mg/kg, s.c.) induced pronounced lesions in the antrum. RS and CRF (30 μg/kg, i.p.) increased the severity of the antral lesions accompanied by an increase in gastric volume and concentration of bile acids. These effects of RS and peripheral CRF were significantly inhibited by pretreatment with astressin-2B, ondansetron, haloperidol, and lorglumide, but not by the CRF₁ receptor antagonist. This study suggests that RS increases the severity of IND-induced gastric antral ulcers associated with gastroparesis and enhanced bile reflux via activation of peripheral CRF₂, 5-hydroxytriptamine 3, and cholecystokinin 1 receptors with central dopamine 2 receptor, but not by CRF₁ receptor. SIGNIFICANCE STATEMENT: Restraint stress worsens nonsteroidal anti-inflammatory drugs-induced antral ulcers due to inhibition of gastric motility and increase in bile reflux via activation of peripheral corticotropin-releasing factor 2, 5-hydroxytriptamine 3, and cholecystokinin 1 receptors with central dopamine 2 receptor. Our study predicts that gastroparesis induced by antimotility drugs, stress, functional dyspepsia, Parkinson disease, diabetes mellitus, and other conditions worsens, and gastroprokinetic agents prevent the severity of nonsteroidal anti-inflammatory drugs-induced gastric antral ulcers.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103381"},"PeriodicalIF":3.1,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449451","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}