Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-18DOI: 10.1016/j.xcrm.2025.101944
Subhamoy Chakraborty, Utsav Sen, Kedwin Ventura, Vrinda Jethalia, Charles Coleman, Subhasree Sridhar, Avisek Banerjee, Hilal Ozakinci, Yazhini Mahendravarman, Konrad Snioch, Elisa de Stanchina, Misty D Shields, Lewis E Tomalin, Deniz Demircioglu, Theresa A Boyle, Anna Tocheva, Dan Hasson, Triparna Sen
{"title":"Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer.","authors":"Subhamoy Chakraborty, Utsav Sen, Kedwin Ventura, Vrinda Jethalia, Charles Coleman, Subhasree Sridhar, Avisek Banerjee, Hilal Ozakinci, Yazhini Mahendravarman, Konrad Snioch, Elisa de Stanchina, Misty D Shields, Lewis E Tomalin, Deniz Demircioglu, Theresa A Boyle, Anna Tocheva, Dan Hasson, Triparna Sen","doi":"10.1016/j.xcrm.2025.101944","DOIUrl":"10.1016/j.xcrm.2025.101944","url":null,"abstract":"","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101944"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.","authors":"Xuqing Shen, Yueyue Chen, Yingying Tang, Ping Lu, Mingzhu Liu, Tiebo Mao, Yawen Weng, Feier Yu, Yimei Liu, Yujie Tang, Liwei Wang, Ningning Niu, Jing Xue","doi":"10.1016/j.xcrm.2025.101928","DOIUrl":"10.1016/j.xcrm.2025.101928","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101928"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advanced image-identified extranodal extension of retropharyngeal lymph nodes in the refinement of N classification for nasopharyngeal carcinoma.","authors":"Wei Jiang, Gao-Yuan Wang, Guan-Jie Qin, Wu-Qi Zhang, Xiao-Dong Zhu, Ya-Qian Han, Feng Lei, Liang-Fang Shen, Kun-Yu Yang, Chun-Yan Cui, Ling-Long Tang, Yan-Ping Mao, Lei Chen, Rui Guo, Ling Li, Zheng Wu, Gui-Qiong Xu, Qin Zhou, Jing Huang, Shao-Hui Huang, Ji-Bin Li, Li-Zhi Liu, Jun Ma, Xiao-Jing Du","doi":"10.1016/j.xcrm.2025.101942","DOIUrl":"10.1016/j.xcrm.2025.101942","url":null,"abstract":"<p><p>Advanced extranodal extension (ENE) in cervical lymph nodes (CLNs) increases the risk of distant metastasis in nasopharyngeal carcinoma (NPC). The 9th NPC staging system classifies N1/N2 patients with advanced CLN ENE as N3 due to similar outcomes. However, the prognostic impact of advanced ENE in retropharyngeal lymph nodes (RLNs) remains unclear. In this study of 4,485 patients with non-metastatic NPC, N1/N2 patients with advanced RLN ENE demonstrate better 5-year overall survival (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.38-0.93; HR: 0.57, 95% CI: 0.32-1.00) and failure-free survival (HR: 0.63, 95% CI: 0.44-0.92; HR: 0.52, 95% CI: 0.31-0.86) than N3 patients. Advanced RLN ENE shows a positive correlation with other RLN-related anatomical factors and is not identified as an independent prognostic factor. External validation in 3,849 patients from five centers supports these findings. Based on this evidence, upgrading advanced RLN ENE to N3 is not advised.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101942"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-11DOI: 10.1016/j.xcrm.2025.101946
Antonio Santos-Peral, Magdalena Zaucha, Elena Nikolova, Ekin Yaman, Barbara Puzek, Elena Winheim, Sebastian Goresch, Magdalena K Scheck, Lisa Lehmann, Frank Dahlstroem, Hadi Karimzadeh, Julia Thorn-Seshold, Shenzhi Jia, Fabian Luppa, Michael Pritsch, Julia Butt, Camila Metz-Zumaran, Giovanna Barba-Spaeth, Stefan Endres, Sarah Kim-Hellmuth, Tim Waterboer, Anne B Krug, Simon Rothenfusser
{"title":"Basal T cell activation predicts yellow fever vaccine response independently of cytomegalovirus infection and sex-related immune variations.","authors":"Antonio Santos-Peral, Magdalena Zaucha, Elena Nikolova, Ekin Yaman, Barbara Puzek, Elena Winheim, Sebastian Goresch, Magdalena K Scheck, Lisa Lehmann, Frank Dahlstroem, Hadi Karimzadeh, Julia Thorn-Seshold, Shenzhi Jia, Fabian Luppa, Michael Pritsch, Julia Butt, Camila Metz-Zumaran, Giovanna Barba-Spaeth, Stefan Endres, Sarah Kim-Hellmuth, Tim Waterboer, Anne B Krug, Simon Rothenfusser","doi":"10.1016/j.xcrm.2025.101946","DOIUrl":"10.1016/j.xcrm.2025.101946","url":null,"abstract":"<p><p>The live-attenuated yellow fever 17D (YF17D) vaccine is a model of acute viral infection that induces long-lasting protective immunity. Among immunocompetent adults, responses to YF17D vary significantly. To understand the sources of this variability, we investigate the influence of sex, age, human leukocyte antigen (HLA) type, and 20 prior infections on basal immune parameters and the cellular and antibody response to YF17D in 250 healthy young individuals. Multivariate regression found that sex and cytomegalovirus (CMV) infection significantly contribute to baseline immune variation but do not affect vaccine responses except for reduced YF17D-specific CD8<sup>+</sup> frequencies in CMV-infected males. However, the abundance at baseline of non-specific cytokine-expressing T helper cells in circulation is associated with stronger vaccine responses, a state that smoking favors. Additionally, an elevated baseline level of interferon-stimulated CXCL10 is linked to poorer vaccination outcomes. Altogether, YF17D reactivity is conditioned by the baseline immune status independent of sex and CMV-related variations.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101946"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-11DOI: 10.1016/j.xcrm.2025.101970
Elham Adabi, Filippos T Charitidis, Frederic B Thalheimer, Mar Guaza-Lasheras, Colin Clarke, Christian J Buchholz
{"title":"Enhanced conversion of T cells into CAR T cells by modulation of the MAPK/ERK pathway.","authors":"Elham Adabi, Filippos T Charitidis, Frederic B Thalheimer, Mar Guaza-Lasheras, Colin Clarke, Christian J Buchholz","doi":"10.1016/j.xcrm.2025.101970","DOIUrl":"10.1016/j.xcrm.2025.101970","url":null,"abstract":"<p><p>Delivery of chimeric antigen receptors (CARs) to T cells is usually mediated by lentiviral vectors (LVs), which can have broad tropism or be T cell targeted. To better understand the molecular events during CAR T cell generation, T cell transduction with four different LVs is followed by single-cell multi-omics analysis, distinguishing between transduced T cells and T cells with vector signal but no CAR. We find that only a fraction of the T cells that encounter vectors convert into CAR T cells. Single-cell transcriptome data reveal that interferon-stimulated genes are upregulated in non-transduced cells, whereas extracellular signal-regulated kinase (ERK)2 phosphatases are upregulated in CAR T cells. This expression pattern is evident in CAR T cells from healthy donors and patients. The role of the mitogen-activated protein kinase (MAPK)/ERK pathway in CAR T cell generation is confirmed by chemical inhibitors. These data provide molecular insights into T cell transduction with implications for improving CAR T cell generation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101970"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"MFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1.","authors":"Wenhui Wang, Jiming Chen, Shibo Wang, Xinhai Sun, Jie Yang, Pengfei Yu, Guinv Hu, Jiang Wang, Jing Zhang, Shuya Qiao, Jianli Wang, Gensheng Zhang, Yuzhou He, Huajun Feng, Zhijian Cai","doi":"10.1016/j.xcrm.2024.101922","DOIUrl":"10.1016/j.xcrm.2024.101922","url":null,"abstract":"<p><p>Anti-PD-1 therapy, effective in patients with various advanced tumors, still encounters the challenge of insensitivity in most patients. Here, we demonstrate that PD-L1 on tumor cell-derived extracellular vesicles (TEVs) is critical for anti-PD-1 therapy resistance. Reducing endogenous and transferring exogenous TEVs abrogates and induces anti-PD-1 therapy resistance, respectively. Notably, PD-L1 is sorted onto TEVs via the endosomal sorting complex required for transport after ubiquitination by UBE4A and gradually upregulated on TEVs with tumor progression. During progression, increased MFGE8 from tumor cells promotes self α<sub>v</sub> integrin signaling activation, enabling themselves to upregulate UBE4A, thereby increasing PD-L1 on TEVs and enhancing their immunosuppressive abilities. Translationally, anti-MFGE8-neutralizing antibodies effectively downregulate UBE4A and TEV PD-L1, thereby negating anti-PD-1 therapy resistance. Furthermore, serum MFGE8 and PD-L1<sup>+</sup> EV levels of tumor patients correlate positively, and high levels of both indicate poor prognosis after anti-PD-1 therapy. Thus, MFGE8 is a promising target for overcoming resistance and predicting responsiveness to anti-PD-1 therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101922"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-01-22DOI: 10.1016/j.xcrm.2024.101924
Hang Zhang, Fan Yang, Ying Xu, Shen Zhao, Yi-Zhou Jiang, Zhi-Ming Shao, Yi Xiao
{"title":"Multimodal integration using a machine learning approach facilitates risk stratification in HR+/HER2- breast cancer.","authors":"Hang Zhang, Fan Yang, Ying Xu, Shen Zhao, Yi-Zhou Jiang, Zhi-Ming Shao, Yi Xiao","doi":"10.1016/j.xcrm.2024.101924","DOIUrl":"10.1016/j.xcrm.2024.101924","url":null,"abstract":"<p><p>Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common type of breast cancer, with continuous recurrence remaining an important clinical issue. Current relapse predictive models in HR+/HER2- breast cancer patients still have limitations. The integration of multidimensional data represents a promising alternative for predicting relapse. In this study, we leverage our multi-omics cohort comprising 579 HR+/HER2- breast cancer patients (200 patients with complete data across 7 modalities) and develop a machine-learning-based model, namely CIMPTGV, which integrates clinical information, immunohistochemistry, metabolomics, pathomics, transcriptomics, genomics, and copy number variations to predict recurrence risk of HR+/HER2- breast cancer. This model achieves concordance indices (C-indices) of 0.871 and 0.869 in the train and test sets, respectively. The risk population predicted by the CIMPTGV model encompasses those identified by single-modality models. Feature analysis reveals that synergistic and complementary effects exist in different modalities. Simultaneously, we develop a simplified model with a mean area under the curve (AUC) of 0.840, presenting a useful approach for clinical applications.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101924"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"First-in-human phase 1 study of an orally bioavailable vascular-disrupting agent DX1002 in patients with advanced solid tumors.","authors":"Xiao-Li Wei, Hao-Xiang Wu, Dan-Yun Ruan, Feng Wang, Li Xu, Yu-Hong Li, Yu-Xiang Ma, Zhi-Qiang Wang, Yun-Peng Yang, Liang-Wei Tang, Bao-Lin Chen, Zhi-Quan Yong, Rui-Hua Xu, Hong-Yun Zhao","doi":"10.1016/j.xcrm.2025.101969","DOIUrl":"10.1016/j.xcrm.2025.101969","url":null,"abstract":"<p><p>DX1002 is an oral vascular-disrupting agent and exhibits promising results in preclinical studies, leading to tumor vasculature destruction and xenografted tumor necrosis in various animal models. In the phase 1 trial, 17 patients with solid tumors receive DX1002 ranging from 50 to 1,100 mg. The maximum tolerated dose and recommended phase 2 dose of DX1002 are determined as 600 mg once daily. The most common treatment-related adverse events are nausea (23.5%), vomiting (17.6%), and fatigue (11.8%). All patients are evaluable for anti-tumor response, 12 of which achieve stable disease as best response. One patient with non-small cell lung cancer achieves a stable disease duration of 6.5 months. The median time to progression (TTP) is 2.70 months (95% confidence interval [CI], 0.90-4.60). Interestingly, reduced blood perfusion is observed by contrast-enhanced ultrasound in a patient with colon cancer. In conclusion, DX1002 is well tolerated and exhibits preliminary anti-tumor efficacy in patients with solid tumors. This study was registered at chictr.org.cn (ChiCTR2400080298).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101969"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neoadjuvant immunotherapy with or without chemotherapy in locally advanced oral squamous cell carcinoma: Randomized, two-arm, phase 2 trial.","authors":"Hai-Ming Liu, Xue-Peng Xiong, Zi-Li Yu, Zhe Shao, Gai-Li Chen, Yu-Tong Liu, Xin-Xin Wang, Qiu-Yun Fu, Xiao-Xia Cheng, Jing Li, Jia-Li Zhang, Bo Li, Hong-Yun Gong, Ya-Hua Zhong, Wei Zhang, Jun Jia, Bing Liu, Gang Chen","doi":"10.1016/j.xcrm.2025.101930","DOIUrl":"10.1016/j.xcrm.2025.101930","url":null,"abstract":"<p><p>Patients with locally advanced oral squamous cell carcinoma (OSCC) have poor outcomes with standard care. Neoadjuvant therapy is shown to be effective for these patients. In the randomized, two-arm, phase 2, non-comparative trial, we investigate the efficacy and safety of the neoadjuvant programmed cell death 1 (PD-1) inhibitor camrelizumab with or without docetaxel-cisplatin-5-fluorouracil (TPF) chemotherapy in patients with resectable locally advanced OSCC. Patients with stage III-IVA OSCC receive neoadjuvant therapy with three cycles of camrelizumab (arm Cam) with or without two cycles of TPF chemotherapy (arm Cam+TPF), followed by surgery and adjuvant therapy. Major pathological response (MPR) is achieved in both arm Cam (5/34, 14.7%) and arm Cam+TPF (26/34, 76.4%). With a median follow-up of 32 months, the 2-year event-free survival (EFS) rate of arm Cam and Cam+TPF is 52.9% and 91.2%, respectively. This work demonstrates feasibility and safety for immunochemotherapy in the neoadjuvant setting for OSCC. This study was registered at ClinicalTrials.gov (NCT04649476).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101930"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-02-18Epub Date: 2025-02-05DOI: 10.1016/j.xcrm.2025.101936
Stephanie E Simonds, Jack T Pryor, Brian Y H Lam, Georgina K Dowsett, Tomris Mustafa, Astrid Munder, Kayla Elysee, Eglantine Balland, Lachlan O Cowley, Giles S H Yeo, Andrew Lawrence, David C Spanswick, Michael A Cowley
{"title":"The metabolic and cardiovascular effects of amphetamine are partially mediated by the central melanocortin system.","authors":"Stephanie E Simonds, Jack T Pryor, Brian Y H Lam, Georgina K Dowsett, Tomris Mustafa, Astrid Munder, Kayla Elysee, Eglantine Balland, Lachlan O Cowley, Giles S H Yeo, Andrew Lawrence, David C Spanswick, Michael A Cowley","doi":"10.1016/j.xcrm.2025.101936","DOIUrl":"10.1016/j.xcrm.2025.101936","url":null,"abstract":"<p><p>Amphetamine (AMPH) exerts metabolic and cardiovascular effects. The central melanocortin system is a key regulator of both metabolic and cardiovascular functions. Here, we show that the melanocortin system partially mediates AMPH-induced anorexia, energy expenditure, tachycardia, and hypertension. AMPH increased α-melanocyte stimulating hormone (αMSH) secretion from the hypothalamus, elevated blood pressure and heart rate (HR), increased brown adipose tissue (BAT) thermogenesis, and reduced both food intake (FI) and body weight (BW). In melanocortin 4 receptor-deficient (MC4R knockout [KO]) mice, metabolic and cardiovascular effects of AMPH were significantly attenuated. Antagonism of serotonergic and noradrenergic neurotransmitter systems attenuated AMPH-induced αMSH secretion as well as AMPH-induced metabolic and cardiovascular effects. We propose that AMPH increases serotonergic activation of proopiomelanocortin (POMC) neurons and reduces the noradrenergic inhibition of POMC neurons, thereby disinhibiting them. Together, these presynaptic mechanisms result in increased POMC activity, increased αMSH secretion, and increased activation of MC4R pathways that regulate both the metabolic and cardiovascular systems.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101936"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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