FEBS Open Bio最新文献_第2页

Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance. 长期接触胰岛素可能会引起表观遗传学改变，导致胰岛素抵抗。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-10-29 DOI: 10.1002/2211-5463.13891

Shehnaz Bano, Shyam More, Dattatray S Mongad, Abdul Khalique, Dhiraj P Dhotre, Manoj K Bhat, Vasudevan Seshadri

{"title":"Prolonged exposure to insulin might cause epigenetic alteration leading to insulin resistance.","authors":"Shehnaz Bano, Shyam More, Dattatray S Mongad, Abdul Khalique, Dhiraj P Dhotre, Manoj K Bhat, Vasudevan Seshadri","doi":"10.1002/2211-5463.13891","DOIUrl":"10.1002/2211-5463.13891","url":null,"abstract":"Glucose homeostasis is maintained by insulin. Insulin resistance is caused by multiple factors including hereditary factors and diet. The molecular mechanism underlying insulin resistance (IR) is not completely understood. Hyperinsulinemia often precedes insulin resistance and Type 2 diabetes. We had previously shown that prolonged exposure of insulin-responsive cells to insulin in the absence of high levels of glucose led to insulin resistance. In the present study, we show that the underlying cause for the impaired insulin signalling is the defective PI3K/AKT pathway. The observed insulin resistance is likely due to epigenetic alterations, as it can be maintained for several generations even when insulin is not provided, and epigenetic modifiers can reverse it. We also show that liver cell line (BRL-3A) developed impaired insulin signalling upon prolonged exposure to insulin in the absence of high levels of glucose. Transcriptomic analysis of the insulin-sensitive and resistance cells uncover altered signalling networks involved in chromatin remodelling, Rho GTPases, and ubiquitination. Furthermore, trimethylation of histone H3 at lysine 4 (H3K4me3) is increased in insulin-resistant cells. We extended these studies to mice, and show that mice injected with low doses of insulin when fasting develop insulin resistance with impaired glucose tolerance and increased HOMA-IR index. Altogether, these findings suggest that dysregulated synthesis of insulin in the absence of glucose stimulus could lead to epigenetic alterations that may ultimately result in insulin resistance.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"81-93"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proximity-dependent biotinylation reveals an interaction between ubiquitin-specific peptidase 46 and centrosome-related proteins. 接近依赖性生物素化揭示了泛素特异性肽酶 46 与中心体相关蛋白之间的相互作用。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-10-31 DOI: 10.1002/2211-5463.13918

Kazuma Yoshioka, Reiko Nakagawa, Chi Lieu Kim Nguyen, Hayate Suzuki, Kiyohiro Ishigaki, Seiya Mizuno, Tsukasa Okiyoneda, Shizufumi Ebihara, Kazuya Murata

{"title":"Proximity-dependent biotinylation reveals an interaction between ubiquitin-specific peptidase 46 and centrosome-related proteins.","authors":"Kazuma Yoshioka, Reiko Nakagawa, Chi Lieu Kim Nguyen, Hayate Suzuki, Kiyohiro Ishigaki, Seiya Mizuno, Tsukasa Okiyoneda, Shizufumi Ebihara, Kazuya Murata","doi":"10.1002/2211-5463.13918","DOIUrl":"10.1002/2211-5463.13918","url":null,"abstract":"Protein ubiquitination extensively modulates protein functions and controls various biological processes, such as protein degradation, signal transduction, transcription, and DNA repair. Ubiquitination is a reversible post-translational modification, and deubiquitinating enzymes cleave ubiquitin from proteins. Ubiquitin-specific peptidase 46 (USP46), a deubiquitinase, is highly expressed in the brain and regulates neural functions. Deleting lysine 92 (ΔK92) in USP46 reduces murine depression-like behavior in the tail suspension test. However, the molecular basis for USP46's role in regulating neural function has not yet been fully understood. Here we employed a proximity-dependent biotinylation approach to characterize the USP46 protein interaction partners. Using homology-independent targeted integration (HITI), a genome editing technique, we established knockin cell lines that stably express USP46 wildtype- or ΔK92-biotin ligase fusion protein. We identified 286 candidate interaction partners, including well-known binding partners of USP46. Although there were no obvious differences in the interactome of USP46 between wildtype and ΔK92, a gene ontology analysis revealed that centrosome-related proteins were significantly enriched in the proximal proteins of USP46. Several centrosome-related proteins were bound to USP46 in Neuro2a cells, but their protein expression levels were not affected in the brains of USP46-deficient mice. These results uncover a potential relationship between USP46 and centrosome regulation independently of protein stabilization.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"151-164"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In the Limelight: Education. 焦点：教育。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 DOI: 10.1002/2211-5463.13954

引用次数: 0

DDX3 participates in miRNA biogenesis and RNA interference through translational control of PACT and interaction with AGO2. DDX3 通过对 PACT 的翻译控制以及与 AGO2 的相互作用，参与 miRNA 的生物发生和 RNA 干扰。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-11-14 DOI: 10.1002/2211-5463.13920

Ming-Chih Lai, Yen-Ling Yu, Chiao-Nung Chen, Jau-Song Yu, Hsin-Yuan Hung, Shih-Peng Chan

{"title":"DDX3 participates in miRNA biogenesis and RNA interference through translational control of PACT and interaction with AGO2.","authors":"Ming-Chih Lai, Yen-Ling Yu, Chiao-Nung Chen, Jau-Song Yu, Hsin-Yuan Hung, Shih-Peng Chan","doi":"10.1002/2211-5463.13920","DOIUrl":"10.1002/2211-5463.13920","url":null,"abstract":"DDX3 is a DEAD-box RNA helicase that plays multiple roles in RNA metabolism, including translation. We previously reported that DDX3 is required for translation of PACT, a binding partner of Dicer, suggesting a role for DDX3 in microRNA (miRNA) biogenesis and RNA interference (RNAi). Emerging evidence suggests that DDX3 plays a vital role in tumorigenesis and cancer progression, however, its underlying mechanism is still not fully understood. Here, we showed that the control of PACT by DDX3 is conserved in human cells and Caenorhabditis elegans. Using a miRNA microarray, we found that DDX3 regulates the expression of a small subset of cancer-related miRNAs. These oncogenic miRNAs were down-regulated by knockdown of DDX3 or PACT and up-regulated by overexpression of DDX3 or PACT in HEK293T cells. Similar results were obtained in human cancer HCT116 and HeLa cells. Dual luciferase reporter assay showed that DDX3 and PACT are required for short hairpin RNA (shRNA)-induced RNAi. We also performed co-immunoprecipitation to confirm the interaction between DDX3 and AGO2, a significant component of the RNA-induced silencing complex, supporting a role for DDX3 in the RNAi pathway. We further examined the effects of DDX3 and PACT on cell proliferation, and stable overexpression of DDX3 in HEK293 cells results in loss of contact inhibition of cell growth. Hence, we propose that DDX3 may participate in cancer development by regulating the RNAi pathway.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"180-195"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

tVNS alters inflammatory response in adult VPA-induced mouse model of autism: evidence for sexual dimorphism. tVNS 可改变 VPA 诱导的成年自闭症小鼠模型的炎症反应：性双态性的证据。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-10-14 DOI: 10.1002/2211-5463.13889

Hale Gök Dağıdır, Neslihan Bukan, Meltem Bahcelioglu, Ayşen Çalıkuşu, Ece Alim, Saadet Özen Dizakar, Elif Topa, Hayrunnisa Bolay

{"title":"tVNS alters inflammatory response in adult VPA-induced mouse model of autism: evidence for sexual dimorphism.","authors":"Hale Gök Dağıdır, Neslihan Bukan, Meltem Bahcelioglu, Ayşen Çalıkuşu, Ece Alim, Saadet Özen Dizakar, Elif Topa, Hayrunnisa Bolay","doi":"10.1002/2211-5463.13889","DOIUrl":"10.1002/2211-5463.13889","url":null,"abstract":"Autism is a neurodevelopmental disorder with limited treatment alternatives and which incidence is increasing. Some research suggests that vagus nerve simulation might lead to the reduction of certain symptom. Therefore, we aimed to examine the effect of bilateral transcutaneous auricular vagus nerve stimulation (tVNS) on the inflammatory response in an adult valproic acid (VPA) induced mouse (C57BL6) model of autism for the first time. The autism model was induced by oral VPA administration (600 mg·kg-1) to C57BL/6 pregnant mice on E12.5 days. The study included three groups: the VPA Transcutaneous Auricular Stimulation Group (VPA + tVNS), the VPA Control Group (VPA + sham), and the Healthy Control Group (Control + sham). Each group included 16 mice (8 M/8 F). Our results show that serum IL-1β and IL-6 levels were significantly higher in male VPA-exposed mice than controls. However, IL-1β was significantly lower, and IL-6, TNF- α, and IL-22 were not different in female VPA-exposed mice compared to the control group. Brain NLRP3 levels were significantly higher in both sexes in the VPA autism model (P < 0.05). tVNS application increased brain NLRP3 levels in both sexes and reduced serum IL-1β levels in male mice. We conclude that cytokine dysregulation is associated with the VPA-induced adult autism model, and the inflammatory response is more pronounced in male mice. tVNS application altered the inflammatory response and increased brain NLPR3 levels in both sexes. Further studies are needed to understand the beneficial or detrimental role of the inflammatory response in autism and its sexual dimorphism.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"69-80"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Assessment IS learning: developing a student-centred approach for assessment in Higher Education. 评估即学习：在高等教育中开发以学生为中心的评估方法。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-11-01 DOI: 10.1002/2211-5463.13921

Stephen Rutherford, Connie Pritchard, Nigel Francis

{"title":"Assessment IS learning: developing a student-centred approach for assessment in Higher Education.","authors":"Stephen Rutherford, Connie Pritchard, Nigel Francis","doi":"10.1002/2211-5463.13921","DOIUrl":"10.1002/2211-5463.13921","url":null,"abstract":"Assessment and the associated feedback from those assessments are powerful factors in the development of students' learning. We have seen a shift within the Higher Education sector to conceptualise assessment as being more than summative assessment 'of' learning. Instead, there has been a greater emphasis on assessment 'as' learning, or assessment 'for' learning, through the enhanced use of formative assessments. Centralising assessment within the learning process highlights that assessment IS learning and cannot be separated from other elements of the learning process. In particular, assessment has a vital role to play in the development of students' self-regulated learning skills and the development of independence in learners. However, for assessments to effectively support learning, they need to be meaningful, engaging, well-integrated into the learning activities and 'student-focused'. Placing student skills development and personal development at the centre of assessment design has the potential to empower students through assessment. This review focuses on the potential of assessment to support student learning and development, using the 'Equity, Agency, Transparency' ('EAT') framework as a lens for effective assessment and feedback practices. We suggest ways in which we can make our assessment and feedback practices more inclusive, meaningful and authentic to the students' learning needs.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"21-34"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chorein deficiency promotes ferroptosis. 胆囊素缺乏会促进铁蛋白沉积。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-11-08 DOI: 10.1002/2211-5463.13870

Yoshiaki Nishizawa, Hitoshi Sakimoto, Omi Nagata, Natsuki Sasaki, Yuka Urata, Kaoru Arai, Hanae Hiwatashi, Izumi Yokoyama, Shosei Kishida, Akira Sano, Masayuki Nakamura

{"title":"Chorein deficiency promotes ferroptosis.","authors":"Yoshiaki Nishizawa, Hitoshi Sakimoto, Omi Nagata, Natsuki Sasaki, Yuka Urata, Kaoru Arai, Hanae Hiwatashi, Izumi Yokoyama, Shosei Kishida, Akira Sano, Masayuki Nakamura","doi":"10.1002/2211-5463.13870","DOIUrl":"10.1002/2211-5463.13870","url":null,"abstract":"Ferroptosis is a type of programmed cell death owed to an intracellular accumulation of iron resulting in the generation reactive oxygen species, which in turn can cause peroxidation of plasma membrane lipids and ultimately result in cell death. We investigated the potential involvement of VPS13A deficiency in ferroptosis. The VPS13A gene encodes for chorein, and its deficiency is a molecular cause of chorea-acanthocytosis (ChAc), a Huntington-like disease with neurodegeneration in the striatum. In our previous study, we found male infertility characterized by increased malondialdehyde staining of the spermatozoa in the testes of the ChAc model mice. Thus, in this study we performed metabolome analysis of sperm extracted from the epididymis of the ChAc model mice, which revealed decreased cystine levels, suggesting an association between chorein deficiency and ferroptosis. We then investigated the role of chorein in ferroptosis using VPS13A knockdown (VPS13A-KD) HEK293 cells. We found that VPS13A-KD cells displayed a significantly diminished resistance to tert-Butyl hydroperoxide (tBHP)-induced lipid peroxidation and cell death compared to control cells, which could be rescued by treatment with ferrostatin-1. Moreover, VPS13A-KD cells showed Fe(II) accumulation, suggesting an impaired capacity for divalent iron removal. In the cytosolic fraction of VPS13A-KD cells, the protein level of glutathione peroxidase 4 (GPX4) was significantly reduced, suggesting that dysfunction of chorein impairs GPX4 transport, thereby facilitating ferroptosis. These results suggest that ferroptosis may contribute to neurodegeneration in ChAc caused by loss of chorein function.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"58-68"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lysine deacetylase inhibitors have low selectivity in cells and exhibit predominantly off-target effects. 赖氨酸去乙酰化酶抑制剂在细胞中的选择性较低，主要表现为脱靶效应。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-10-31 DOI: 10.1002/2211-5463.13896

Kiara E Bornes, Marcus A Moody, Thomas M Huckaba, Megan C Benz, Emily C McConnell, Maryam Foroozesh, Van H Barnes, Bridgette M Collins-Burow, Matthew E Burow, Terry J Watt, Tasha B Toro

{"title":"Lysine deacetylase inhibitors have low selectivity in cells and exhibit predominantly off-target effects.","authors":"Kiara E Bornes, Marcus A Moody, Thomas M Huckaba, Megan C Benz, Emily C McConnell, Maryam Foroozesh, Van H Barnes, Bridgette M Collins-Burow, Matthew E Burow, Terry J Watt, Tasha B Toro","doi":"10.1002/2211-5463.13896","DOIUrl":"10.1002/2211-5463.13896","url":null,"abstract":"Lysine deacetylases (KDACs or HDACs) are metal-dependent enzymes that regulate lysine acetylation, a post-translational modification that is present on thousands of human proteins, essential for many cellular processes, and often misregulated in diseases. The selective inhibition of KDACs would allow for understanding of the biological roles of individual KDACs and therapeutic targeting of individual enzymes. Recent studies have suggested that purportedly specific KDAC inhibitors have significant off-target binding, but the biological consequences of off-target binding were not evaluated. We compared the effects of treatment with two of the reportedly most KDAC-selective inhibitors, Tubastatin A and PCI-34051, in HT1080 cells in which the endogenous KDAC6 or KDAC8 gene has been mutated to inactivate enzyme catalysis while retaining enzyme expression. Genetic inactivation results in much stronger deacetylation defects on known targets compared to inhibitor treatment. Gene expression analysis revealed that both inhibitors have extensive and extensively overlapping off-target effects in cells, even at low inhibitor doses. Furthermore, Tubastatin A treatment led to increased histone acetylation, while inactivation of KDAC6 or KDAC8 did not. Genetic inactivation of KDAC6, but not KDAC8, impaired tumor formation in a xenograft model system, in contrast to previous reports with KDAC inhibitors suggesting the reverse. We conclude that the majority of observed biological effects of treatment with KDAC inhibitors are due to off-target effects rather than the intended KDAC inhibition. Developing a truly specific KDAC6 inhibitor could be a promising therapeutic avenue, but it is imperative to develop new inhibitors that selectively mimic genetic inactivation of individual KDACs.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"94-107"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-inflammatory properties of ophioglonin derived from the fern Ophioglossum vulgatum L. via inactivating NF-κB and MAPK signaling pathways. 从蕨类植物 Ophioglossum vulgatum L. 中提取的 Ophioglonin 通过使 NF-κB 和 MAPK 信号通路失活而具有抗炎特性。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-10-25 DOI: 10.1002/2211-5463.13914

Xiaoqing Zhu, Cheng Tian, Dan Yao, Siqi Li, Junjiang Lv, Yongwen Chen, Xiaoyong Huang

{"title":"Anti-inflammatory properties of ophioglonin derived from the fern Ophioglossum vulgatum L. via inactivating NF-κB and MAPK signaling pathways.","authors":"Xiaoqing Zhu, Cheng Tian, Dan Yao, Siqi Li, Junjiang Lv, Yongwen Chen, Xiaoyong Huang","doi":"10.1002/2211-5463.13914","DOIUrl":"10.1002/2211-5463.13914","url":null,"abstract":"Medicinal plants contain bioactive compounds that have therapeutic effects on human health. Ophioglossum vulgatum L. is a representative species of the fern genus Ophioglossum that has anti-inflammatory properties as recognized in folk medicine. Herein, we performed a nitric oxide (NO) assay-guided screening in RAW264.7 cells to investigate the active components of the plant. We found that ophioglonin (OPN), a characteristic homoflavonoid of the genus Ophioglossum, is one of the bioactive components. Therefore, we performed a comparative analysis of the isolated compounds and found that OPN has effects similar to those of isolated dihydroquercetin and luteolin at the concentrations tested. The antioxidant and anti-inflammatory activities of OPN were extensively validated using lipopolysaccharide -stimulated RAW264.7 cells, mouse bone marrow-derived macrophages (BMDMs), and peritoneal exudate macrophages (PEMs). In vivo experiments with a carrageenan-induced mouse paw edema model further confirmed the anti-inflammatory effect of OPN. Additionally, we found that OPN and Ophioglossum vulgatum extracts inhibit the activation of signal transducers, NF-ĸB p65, IĸBα, ERK, p38, and JNK, consistent with the findings of pathway enrichment analysis. This work reinforces the anti-inflammatory properties of Ophioglossum vulgatum and indicates that OPN is a promising therapeutic agent for inflammation-associated disorders. Further clinical evaluations, including clinical trials, would be beneficial to validate the anti-inflammatory properties of OPN.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"122-139"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unique pharmacological properties of etrasimod among S1P receptor modulators. 在 S1P 受体调节剂中，依曲莫德具有独特的药理特性。

IF 2.8 4区生物学

FEBS Open Bio Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1002/2211-5463.13907

Ibragim Gaidarov, H Kiyomi Komori, Dariusz T Stepniak, Karin Bruinsma, Huong Dang, Xiaohua Chen, Todd Anthony, Joel Gatlin, Lisa Karimi-Naser, Anh-Tuan Ton, Tim Indersmitten, Paul E Miller, Andre Ghetti, Najah Abi-Gerges, David Unett, Hussien Al-Shamma, Christopher J Rabbat, Catherine Crosby, John W Adams

{"title":"Unique pharmacological properties of etrasimod among S1P receptor modulators.","authors":"Ibragim Gaidarov, H Kiyomi Komori, Dariusz T Stepniak, Karin Bruinsma, Huong Dang, Xiaohua Chen, Todd Anthony, Joel Gatlin, Lisa Karimi-Naser, Anh-Tuan Ton, Tim Indersmitten, Paul E Miller, Andre Ghetti, Najah Abi-Gerges, David Unett, Hussien Al-Shamma, Christopher J Rabbat, Catherine Crosby, John W Adams","doi":"10.1002/2211-5463.13907","DOIUrl":"10.1002/2211-5463.13907","url":null,"abstract":"Etrasimod (ADP334) is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of immune-mediated inflammatory diseases. Interaction between S1P and its five receptor subtypes (S1P1-S1P5) plays a role in several physiologic systems, including the cardiovascular and immune systems. Since differences in S1PR binding and downstream intracellular signaling could contribute to distinct profiles of drug efficacy and safety, we directly compared the S1P1-5 selectivity profile of etrasimod to three marketed S1PR modulators: fingolimod, ozanimod, and siponimod. Using both heterologous expression systems and human umbilical vein endothelial cells that spontaneously express S1P1, we profiled key S1P1 downstream signaling pathways and found that etrasimod had similar potency to the other tested S1PR modulators in promoting β-arrestin recruitment and S1P1 internalization. However, etrasimod was notably less potent than other S1PR modulators in assays measuring S1P1-mediated G protein activation (GTPγS binding and cAMP inhibition). Relatively lower potency of etrasimod in inducing G protein signaling corresponded to significantly diminished activation of human cardiac G protein-coupled inwardly rectifying potassium channels when compared to ozanimod. Together with pharmacokinetic properties, this pharmacologic profile of etrasimod may contribute to the positive benefit risk profile of etrasimod observed during the phase III ELEVATE UC 52 and ELEVATE UC 12 trials in patients with moderately to severely active ulcerative colitis.","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"108-121"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0