Acta Pharmacologica Sinica最新文献

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Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage. 小胶质细胞STING激活促进实验性脑出血小鼠的神经炎症和病理改变。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-08 DOI: 10.1038/s41401-025-01540-8
Yu-Xiao Xue, Yi-Jun Chen, Mei-Zhen Qin, Fan-Fan Shang, Yi-Ting Lu, Yu-Hao Sun, Liu-Guan Bian, Ao Zhang, Yang Yu, Chun-Yong Ding
{"title":"Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage.","authors":"Yu-Xiao Xue, Yi-Jun Chen, Mei-Zhen Qin, Fan-Fan Shang, Yi-Ting Lu, Yu-Hao Sun, Liu-Guan Bian, Ao Zhang, Yang Yu, Chun-Yong Ding","doi":"10.1038/s41401-025-01540-8","DOIUrl":"https://doi.org/10.1038/s41401-025-01540-8","url":null,"abstract":"<p><p>Neuroinflammation, a significant contributor to secondary brain injury, plays a critical role in the pathological process and prognosis of intracerebral haemorrhage (ICH). Thus, developing interventions to mitigate secondary neuroimmune deterioration is of paramount importance. Currently, no effective immunomodulatory drugs are available for ICH. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a recently identified innate immune-sensing pathway primarily expressed in microglia within the central nervous system (CNS) that has been implicated in the pathophysiology of various neurological diseases. In this study we investigated the role of cGAS-STING pathway in ICH. A collagenase model of ICH was established in mice. Brain tissues were collected on D1 or D3 post-ICH. We observed a significant increase in double-stranded (dsDNA) levels and activation of the cGAS-STING pathway in the perihaematomal region of ICH mice. Administration of a blood brain barrier-permeable STING antagonist H151 (10 mg/kg, i.p.) significantly decreased cell apoptosis, alleviated hematoma growth, and improved motor impairments in ICH mice, accompanied by inhibiting the STING pathway in microglia, reducing production/release of the cGAS-STING pathway downstream inflammatory factors, NLRP3 inflammasome activation and gasdermin D (GSDMD)-induced microglial pyroptosis. Microglial Sting conditional knockout significantly mitigated ICH-induced neuroinflammatory responses, pathological damage and motor dysfunction. These results suggest that the microglial STING pathway promotes brain pathological damage and behavioural defects in ICH mice by activating the NLRP3 inflammasome and microglial pyroptosis. The STING pathway may serve as a potential therapeutic target for ICH-induced secondary brain injury.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of indoles as potential endogenous ligands of ERRγ and their modulation on drug binding. 吲哚作为潜在内源性ERRγ配体的鉴定及其对药物结合的调节。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-08 DOI: 10.1038/s41401-025-01550-6
Yuan-Yuan Shuai, Hong-Yang Zhang, Rui Chen, Bai-Ling Wang, Ping Ding, Yan Dong, Ming-Ze Sun, Xi-Shan Wu, Yong Xu, Yan Zhang, Jin-Song Liu, Na Wang, Ting-Ting Xu
{"title":"Identification of indoles as potential endogenous ligands of ERRγ and their modulation on drug binding.","authors":"Yuan-Yuan Shuai, Hong-Yang Zhang, Rui Chen, Bai-Ling Wang, Ping Ding, Yan Dong, Ming-Ze Sun, Xi-Shan Wu, Yong Xu, Yan Zhang, Jin-Song Liu, Na Wang, Ting-Ting Xu","doi":"10.1038/s41401-025-01550-6","DOIUrl":"https://doi.org/10.1038/s41401-025-01550-6","url":null,"abstract":"<p><p>Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor in the ERR subfamily that plays a crucial role in regulating energy metabolism. To date, no endogenous ligand has been identified for ERRγ, posing a challenge for developing targeted therapeutics. Here, we identified that indole and skatole produced by the gut microbiota are potential endogenous ligands of ERRγ using biochemical, cellular, structural, and computational approaches. Indole and skatole increased ERRγ thermostability and directly bound to the ligand-binding domain (LBD) with a K<sub>d</sub> of approximately 1-2 μM but had no significant effect or weak inhibitory activity on the transcriptional efficiency. However, RNA sequencing revealed that ERRγ could coregulate several lipid metabolism- and immune-related genes with indole, suggesting a role for ERRγ in the indole pathway. Interestingly, indole and skatole differentially attenuated the activities of ERRγ ligands: they both neutralized the agonistic activity of GSK4716, while indole reduced the antagonistic activity of 4-hydroxytamoxifen (4OHT) and GSK5182, and skatole affected the agonistic activity of endocrine disruptor bisphenol A (BPA). We further screened additional indole metabolites and analogs, resolved the complex structures of ERRγ-LBD with these compounds, and conducted molecular dynamics simulations to determine their binding site and elucidate their binding mechanisms. This study identified potential endogenous ligands of ERRγ, suggesting a novel link between the energy metabolism regulation and the indole pathway. Our findings highlight the need to consider endogenous ligands when designing and optimizing ERRγ-targeted drugs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities. 以邻近诱导方式靶向神经退行性疾病相关蛋白聚集。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-07 DOI: 10.1038/s41401-025-01538-2
Rui-Xin Ge, Miao Chen, Qing-Chao Li, Min Liu, Jun Zhou, Song-Bo Xie
{"title":"Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities.","authors":"Rui-Xin Ge, Miao Chen, Qing-Chao Li, Min Liu, Jun Zhou, Song-Bo Xie","doi":"10.1038/s41401-025-01538-2","DOIUrl":"10.1038/s41401-025-01538-2","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunction and anatomical changes caused by neuron loss and gliosis, ultimately leading to severe declines in brain function. While these disorders arise from a variety of pathological mechanisms, a common molecular feature is the accumulation of misfolded proteins, which occurs both inside and outside neurons. For example, Alzheimer's disease (AD) is defined by extracellular β-amyloid plaques and intracellular tau neurofibrillary tangles. These pathological protein aggregates are often resistant to traditional small molecule drugs. Recent advances in proximity-inducing chimeras such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras (LYTACs), autophagy-targeted chimeras (AUTOTACs), dephosphorylation-targeting chimeras (DEPTACs) and ribonuclease-targeting chimeras (RIBOTACs) offer promising strategies to eliminate pathological proteins or mRNAs through intracellular degradation pathways. These innovative approaches open avenues for developing new therapies for NDDs. In this review we summarize the regulatory mechanisms of protein aggregation, highlight the advancements in proximity-inducing modalities for NDDs, and discuss the current challenges and future directions in therapeutic development.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Direct inhibition of the TXNIP-NLRP3-GSDMD pathway reduces pyroptosis in colonocytes and alleviates ulcerative colitis in mice by the small compound PEITC. 小化合物PEITC直接抑制TXNIP-NLRP3-GSDMD通路可减少小鼠结肠细胞的焦亡并减轻溃疡性结肠炎。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-07 DOI: 10.1038/s41401-025-01549-z
Jie Wang, Cui Zhang, Jia Qin, Ning An, Mei Bai, Rong-Hui Du, Yan Shen, Xu-Dong Wu, Jing-Cai Cheng, Xue-Feng Wu, Qiang Xu
{"title":"Direct inhibition of the TXNIP-NLRP3-GSDMD pathway reduces pyroptosis in colonocytes and alleviates ulcerative colitis in mice by the small compound PEITC.","authors":"Jie Wang, Cui Zhang, Jia Qin, Ning An, Mei Bai, Rong-Hui Du, Yan Shen, Xu-Dong Wu, Jing-Cai Cheng, Xue-Feng Wu, Qiang Xu","doi":"10.1038/s41401-025-01549-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01549-z","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The etiology of UC is multifaceted, and the underlying pathogenesis remains incompletely understood. Pyroptosis, programmed cell death mediated by the gasdermins, is a pivotal driver of UC pathology due to its dual role in epithelial barrier disruption and inflammatory amplification. We previously showed that phenethyl isothiocyanate (PEITC), an isothiocyanate derived from cruciferous vegetables, alleviated acute liver injury in mice by suppressing hepatocyte pyroptosis. In this study we evaluated the therapeutic potential of PEITC in the treatment of UC and the underlying mechanisms. UC mouse models were established by administration of 2.5% (w/v) dextran sulfate sodium (DSS) daily for 7 days. PEITC (5, 10, or 20 mg·kg<sup>-1</sup>·d<sup>-1</sup>, i.g.) was given 2 days before the start of modeling, and the dosing lasted for a total of 10 days. We showed that during the progression of DSS-induced UC, the pyroptosis pathway was activated accompanied by elevated expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), as well as the activation of caspase-1, gasdermin D (GSDMD) and interleukin-1β (IL-1β). Treatment with PEITC dose-dependently reduced TXNIP and NLRP3 expression while inhibiting the cleavage of proteins associated with the pyroptosis pathway such as caspase-1, GSDMD, and IL-1β. We confirmed the inhibitory effect of PEITC on colonocyte pyroptosis in an in vitro model established in HT29 cells, where PEITC (0.2, 1, 5 µM) dose-dependently inhibited TXNIP and NLRP3 expression and the activation of pro-caspase-1, GSDMD and pro-IL-1β. We revealed that PEITC is directly bound to TXNIP and disrupted the interaction between TXNIP and NLRP3, leading to diminished cellular inflammation and oxidative stress levels. In conclusion, this study demonstrates that PEITC disrupts the interaction of TXNIP and NLRP3 by binding to TXNIP, inhibits NLRP3 activation and colonocyte pyroptosis, and thus effectively alleviates UC symptoms in mice. This study offers novel drug targets along with potential therapeutic candidates for the clinical prevention and treatment of UC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Calycosin synergizes with methotrexate in the treatment of Sjögren's disease by targeting BATF in T follicular helper cells. 毛囊酶与甲氨蝶呤协同作用,通过靶向T滤泡辅助细胞中的BATF治疗Sjögren病。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-03 DOI: 10.1038/s41401-025-01536-4
Su-Lan Yu, Mei-Ling Wu, Philip Hei Li, Ya-Cun Chen, Jing Xie, Xiao-Yu Xu, Dan-Bao Ma, Yun Feng, Jian-Gang Shen, Xiang Lin
{"title":"Calycosin synergizes with methotrexate in the treatment of Sjögren's disease by targeting BATF in T follicular helper cells.","authors":"Su-Lan Yu, Mei-Ling Wu, Philip Hei Li, Ya-Cun Chen, Jing Xie, Xiao-Yu Xu, Dan-Bao Ma, Yun Feng, Jian-Gang Shen, Xiang Lin","doi":"10.1038/s41401-025-01536-4","DOIUrl":"10.1038/s41401-025-01536-4","url":null,"abstract":"<p><p>T follicular helper (Tfh) cells are crucially involved in the pathogenesis of autoimmune disorders, including Sjögren's disease (SjD, also known as Sjögren's syndrome), by promoting effector B cell responses and autoantibodies production. However, targeting Tfh cells remains challenging. In this study, we identified that calycosin (Caly), a natural flavonoid, effectively suppressed pathogenic Tfh cell responses, although it did not affect the plasmacytic differentiation of B cells. Under Tfh polarization conditions, Caly rapidly bound to the master transcription factor, BATF, in both human and murine CD4<sup>+</sup> T cells and thus potently disrupted BATF-mediated Maf gene transcription. Methotrexate (MTX), a first-line medication in the treatment of autoimmune disorders, mainly suppresses B cell responses but fails to target Tfh cells. In a mouse model of experimental Sjögren's syndrome (ESS) that we previously established, MTX synergized with Caly in attenuating the disease pathology and autoantibodies in ESS mice with chronic inflammation, with signs of disease remission. This immunomodulatory function was also validated in peripheral blood mononuclear cells from patients with SjD. Thus, Caly may serve as a novel inhibitor of BATF in suppressing Tfh-cell-mediated humoral autoimmunity and elicit a synergistic effect in combination with B-cell-targeting strategies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The PIWI-interacting RNA CRAPIR alleviates myocardial ischemia‒reperfusion injury by reducing p53-mediated apoptosis via binding to SRSF1. piwi相互作用RNA CRAPIR通过与SRSF1结合减少p53介导的细胞凋亡,从而减轻心肌缺血再灌注损伤。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-03 DOI: 10.1038/s41401-025-01534-6
Hong Yan, Han Li, Dao-Hong Yin, Zi-Zhen Zhang, Qian-Yun Zhang, Zhong-Yu Ren, Yu Hu, Gui-Yang Zheng, Yu Liu, Wen-Ya Ma, Yi-Ning Liu, Xiu-Xiu Wang, Ben-Zhi Cai, Hong-Yang Chen
{"title":"The PIWI-interacting RNA CRAPIR alleviates myocardial ischemia‒reperfusion injury by reducing p53-mediated apoptosis via binding to SRSF1.","authors":"Hong Yan, Han Li, Dao-Hong Yin, Zi-Zhen Zhang, Qian-Yun Zhang, Zhong-Yu Ren, Yu Hu, Gui-Yang Zheng, Yu Liu, Wen-Ya Ma, Yi-Ning Liu, Xiu-Xiu Wang, Ben-Zhi Cai, Hong-Yang Chen","doi":"10.1038/s41401-025-01534-6","DOIUrl":"10.1038/s41401-025-01534-6","url":null,"abstract":"<p><p>Ischemia-reperfusion (I/R) injury refers to the secondary damage that occurs when blood flow is restored to heart tissues and organs following a period of prolonged ischemia. This damage is exacerbated primarily through mechanisms such as oxidative stress, inflammatory responses and apoptosis, all of which can severely impact patient prognosis. PIWI-interacting RNAs (piRNAs) represent a novel class of small noncoding RNAs that play pivotal roles in regulating gene expression and cellular functions. However, the precise role and underlying mechanisms of piRNAs in I/R injury remain poorly understood. In this study, we investigated the role and molecular mechanisms of a cardiac regeneration-associated PIWI-interacting RNA (CRAPIR), previously identified by our team, in I/R injury. An I/R injury model was established in adult male mice. The protein levels of cleaved caspase-3, Bax, Bcl2 and p53 were assessed using Western blotting, and cardiomyocyte apoptosis was detected via TUNEL staining. Our study revealed that, in I/R-damaged heart tissues and hypoxia‒reoxygenation (H/R)-induced cardiomyocyte models, CRAPIR was upregulated 24 h after I/R and H/R but was markedly downregulated at 72 h after I/R injury and 48 h after H/R injury. In the I/R mouse model, agomir-mediated overexpression of CRAPIR alleviated heart dysfunction and reduced cardiomyocyte apoptosis caused by I/R injury. Conversely, CRAPIR knockdown via an antagomir exacerbated I/R-induced cardiac dysfunction and increased the number of apoptotic cardiomyocytes. Mechanistically, CRAPIR interacts with serine/arginine-rich splicing factor 1 (SRSF1), triggering the upregulation of murine double minute 2 (MDM2) expression. The increased MDM2 promoted p53 ubiquitination, leading to reduced p53 levels. Furthermore, silencing SRSF1 or MDM2 attenuated the protective effect of CRAPIR against cardiomyocyte apoptosis following H/R injury. These findings suggest that CRAPIR serves as a critical regulator of I/R injury via the SRSF1/MDM2/p53 signaling pathway.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural basis of the multiple ligand binding mechanisms of the P2X1 receptor. P2X1受体多配体结合机制的结构基础。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-02 DOI: 10.1038/s41401-025-01512-y
Yu-Ting Qiang, Peng-Peng Wu, Xin Liu, Li Peng, Li-Ke Zhao, Ya-Ting Chen, Zhao-Bing Gao, Qiang Zhao, Kun Chen
{"title":"Structural basis of the multiple ligand binding mechanisms of the P2X1 receptor.","authors":"Yu-Ting Qiang, Peng-Peng Wu, Xin Liu, Li Peng, Li-Ke Zhao, Ya-Ting Chen, Zhao-Bing Gao, Qiang Zhao, Kun Chen","doi":"10.1038/s41401-025-01512-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01512-y","url":null,"abstract":"<p><p>As important modulators of human purinergic signaling, P2X1 receptors form homotrimers to transport calcium, regulating multiple physiological processes, and are long regarded as promising therapeutic targets for male contraception and inflammation. However, the development of drugs that target the P2X1 receptor, such as the antagonist NF449, is greatly hindered by the unclear molecular mechanism of ligand binding modes and receptor activation. Here, we report the structures of the P2X1 receptor in complex with the endogenous agonist ATP or the competitive antagonist NF449. The P2X1 receptor displays distinct conformational features when bound to different types of compounds. Despite coupling to the agonist ATP, the receptor adopts a desensitized conformation that arrests the ions in the transmembrane (TM) domain, aligning with the nature of the high desensitization rates of the P2X1 receptor within the P2X family. Interestingly, the antagonist NF449 not only occupies the orthosteric pocket of ATP but also interacts with the dorsal fin, left flipper, and head domains, suggesting a unique binding mode to perform both orthosteric and allosteric mechanisms of NF449 inhibition. Intriguingly, a novel lipid binding site adjacent to the TM helices and lower body of P2X1, which is critical for receptor activation, is identified. Further functional assay results and structural alignments reveal the high conservation of this lipid binding site in P2X receptors, indicating important modulatory roles upon lipid binding. Taken together, these findings greatly increase our understanding of the ligand binding modes and multiple modulatory mechanisms of the P2X1 receptor and shed light on the further development of P2X1-selective antagonists.Keywords: Structural biology; Ligand binding mode; Ion channel; Purinergic P2X1 receptor.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy. IMPDH 抑制剂能上调癌细胞中的 PD-L1 而不影响免疫检查点抑制剂的疗效。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-26 DOI: 10.1038/s41401-024-01411-8
Ming-Ming Zheng, Jia-Yi Li, Hong-Jie Guo, Jie Zhang, Long-Sheng Wang, Ke-Fan Jiang, Hong-Hai Wu, Qiao-Jun He, Ling Ding, Bo Yang
{"title":"IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy.","authors":"Ming-Ming Zheng, Jia-Yi Li, Hong-Jie Guo, Jie Zhang, Long-Sheng Wang, Ke-Fan Jiang, Hong-Hai Wu, Qiao-Jun He, Ling Ding, Bo Yang","doi":"10.1038/s41401-024-01411-8","DOIUrl":"10.1038/s41401-024-01411-8","url":null,"abstract":"<p><p>Tumor cells are characterized by rapid proliferation. In order to provide purines for DNA and RNA synthesis, inosine 5'-monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo guanosine biosynthesis, is highly expressed in tumor cells. In this study we investigated whether IMPDH was involved in cancer immunoregulation. We revealed that the IMPDH inhibitors AVN944, MPA or ribavirin concentration-dependently upregulated PD-L1 expression in non-small cell lung cancer cell line NCI-H292. This effect was reproduced in other non-small cell lung cancer cell lines H460, H1299 and HCC827, colon cancer cell lines HT29, RKO and HCT116, as well as kidney cancer cell line Huh7. In NCI-H292 cells, we clarified that IMPDH inhibitors increased CD274 mRNA levels by enhancing CD274 mRNA stability. IMPDH inhibitors improved the affinity of the ARE-binding protein HuR for CD274 mRNA, thereby stabilizing CD274 mRNA. Guanosine supplementation abolished the IMPDH inhibitor-induced increase in PD-L1 expression. In CT26 and EMT6 tumor models used for ICIs based studies, we showed that despite its immunosuppressive properties, the IMPDH inhibitor mycophenolate mofetil did not reduce the clinical response of checkpoint inhibitors, representing an important clinical observation given that this class of drugs is approved for use in multiple diseases. We conclude that PD-L1 induction contributes to the immunosuppressive effect of IMPDH inhibitors. Furthermore, the IMPDH inhibitor mycophenolate mofetil does not antagonize immune checkpoint blockade.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1058-1067"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724568","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}
引用次数: 0
Differential regulation of pruritic sensation and emotion by cannabinoid type 1 receptors on mPFC glutamatergic and GABAergic neurons. 大麻素1型受体对mPFC谷氨酸能神经元和gaba能神经元的瘙痒感觉和情绪的差异调节。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-12-11 DOI: 10.1038/s41401-024-01426-1
Ou-Yang Zhanmu, Yang Yang, Bin Feng, Hong-Yang Wang, Hao Li, Hui-Juan Zhou, Wen-Qiang Ge, Ke-Xing Wan, Sui-Xi Wang, Kai-Ling Zhang, Hong Zhang, Lei Pei, Hui-Lin Pan, Qing Tian, Man Li
{"title":"Differential regulation of pruritic sensation and emotion by cannabinoid type 1 receptors on mPFC glutamatergic and GABAergic neurons.","authors":"Ou-Yang Zhanmu, Yang Yang, Bin Feng, Hong-Yang Wang, Hao Li, Hui-Juan Zhou, Wen-Qiang Ge, Ke-Xing Wan, Sui-Xi Wang, Kai-Ling Zhang, Hong Zhang, Lei Pei, Hui-Lin Pan, Qing Tian, Man Li","doi":"10.1038/s41401-024-01426-1","DOIUrl":"10.1038/s41401-024-01426-1","url":null,"abstract":"<p><p>Itch causes a strong urge to scratch and induces negative emotions, such as aversion and anxiety. Antihistamine medications are key in the clinical management of pruritus, but their therapeutic efficacy in controlling moderate and severe itching remains limited. The neural circuits in the brain that process itching and itch-induced aversion and anxiety remain unclear so far. Human brain imaging suggests that the medial prefrontal cortex (mPFC) is involved in processing the emotional and motivational components of itching. In this study, we investigated the mechanisms by which glutamatergic and GABAergic neurons in mPFC differentially regulated pruritic sensation and emotion through cannabinoid type 1 receptors (CB1Rs). Chloroquinoline (CQ)-induced acute and calcipotriol (MC903)-induced chronic itch models were established. Fiberoptic calcium imaging was used to detect the activity of the two types of neurons in response to itching. The CB1R antagonist AM251 (0.5 mg in 200 nL) was microinjected into the mPFC through the implanted cannula. We showed that chemogenetic activation of glutamatergic neurons and inhibition of GABAergic neurons in the mPFC reduced scratching and chronic itch-induced anxiety. GABAergic, but not glutamatergic, neurons were involved in acute itch-induced aversion. CB1Rs on glutamatergic and GABAergic neurons modulated chronic itch-induced scratching and anxiety in divergent manners. However, CB1Rs did not affect acute itch-induced scratching. CB1Rs on GABAergic, but not glutamatergic, neurons regulated acute itch-induced aversion. These results may guide the development of therapeutic strategies targeting CB1Rs to treat itch-induced sensory and emotional responses.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"904-921"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811910","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}
引用次数: 0
Poria cocos: traditional uses, triterpenoid components and their renoprotective pharmacology. 茯苓:传统用途、三萜类成分及其肾脏保护药理学。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-10-31 DOI: 10.1038/s41401-024-01404-7
Zhi-Yuan Guo, Xin Wu, Shui-Juan Zhang, Jian-Hua Yang, Hua Miao, Ying-Yong Zhao
{"title":"Poria cocos: traditional uses, triterpenoid components and their renoprotective pharmacology.","authors":"Zhi-Yuan Guo, Xin Wu, Shui-Juan Zhang, Jian-Hua Yang, Hua Miao, Ying-Yong Zhao","doi":"10.1038/s41401-024-01404-7","DOIUrl":"10.1038/s41401-024-01404-7","url":null,"abstract":"<p><p>Poria cocos and its surface layer of Poria cocos (Schw.) Wolf (Polyporaceae), are used in traditional Chinese medicine for its diuretic and renoprotective effects. Phytochemical studies have shown that lanostane and 3,4-seco-lanostane tetracyclic triterpenoids are the main components of P. cocos and its surface layer. Accumulating evidence shows that triterpenoid components in P. cocos and its surface layer contribute to their renoprotective effect. The surface layer of P. cocos showed a stronger diuretic effect than P. cocos. The ethanol extract of the surface layer and its components improved acute kidney injury, acute kidney injury-to-chronic kidney disease transition and chronic kidney disease such as diabetic kidney disease, nephrotic syndrome and tubulointerstitial nephropathy, and protected against renal fibrosis. It has been elucidated that P. cocos and its surface layer exert a diuretic effect and improve kidney diseases through a variety of molecular mechanisms such as aberrant pathways TGF-β1/Smad, Wnt/β-catenin, IκB/NF-κB and Keap1/Nrf2 signaling as well as the activation of renin-angiotensin system, matrix metalloproteinases, aryl hydrocarbon receptor and endogenous metabolites. These studies further confirm the renoprotective effect of P. cocos and its surface layer and provide a beneficial basis to its clinical use in traditional medicine.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"836-851"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556869","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}
引用次数: 0
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