Pharmacological research最新文献

Blockade of the CLCF1-CNTFR axis enhances the efficacy of GPC3 CAR-T cell therapy in hepatocellular carcinoma. 阻断CLCF1-CNTFR轴可增强GPC3 CAR-T细胞治疗肝癌的疗效。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-06 DOI: 10.1016/j.phrs.2026.108209

Hao Zhang, Qiuzhong Pan, Tong Xiang, Lili Huang, Haoran Zhong, Xinyi Yang, Yingzi Li, Jun Luo, Hao Chen, Yan Tang, Qijing Wang, Jia He, Song Gao, Chaopin Yang, Jianchuan Xia

{"title":"Blockade of the CLCF1-CNTFR axis enhances the efficacy of GPC3 CAR-T cell therapy in hepatocellular carcinoma.","authors":"Hao Zhang, Qiuzhong Pan, Tong Xiang, Lili Huang, Haoran Zhong, Xinyi Yang, Yingzi Li, Jun Luo, Hao Chen, Yan Tang, Qijing Wang, Jia He, Song Gao, Chaopin Yang, Jianchuan Xia","doi":"10.1016/j.phrs.2026.108209","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.108209","url":null,"abstract":"Hepatocellular carcinoma (HCC) exhibits a profoundly immunosuppressive tumor microenvironment (TME) that limits the efficacy of immune checkpoint blockade and CAR-T cell therapy. In this study, we identified cardiotrophin-like cytokine factor 1 (CLCF1) as significantly upregulated in HCC and associated with poor prognosis and reduced response to immunotherapy. Accordingly, we engineered a GPC3-targeted CAR-T cell capable of self-secreting a soluble engineered CNTFR (eCNTFR) to locally neutralize CLCF1 within the TME. Compared with conventional GPC3 CAR-T cells, eCNTFR-armored GPC3 CAR-T cells exhibited enhanced cytotoxicity, increased cytokine production, improved functional persistence, and superior antitumor efficacy in vitro and in xenograft models. Mechanistically, eCNTFR-mediated blockade of the CLCF1-CNTFR axis suppressed STAT3 signaling and TGF-β production, thereby inhibiting tumor growth, stemness, and the formation of an immunosuppressive TME. These findings establish CLCF1 as a key tumor-promoting and immunosuppressive mediator in HCC and support eCNTFR-armored CAR-T cells as a promising therapeutic strategy for HCC immunotherapy.","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108209"},"PeriodicalIF":10.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Tubular TNFSF4/OX40L promotes fibrotic transition following acute kidney injury via activating GSK-3α. 肾小管TNFSF4/OX40L通过激活GSK-3α促进急性肾损伤后的纤维化转变。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-06 DOI: 10.1016/j.phrs.2026.108230

Kexin Yang, Lei Zhang, Ziyi Xiong, Yingying Lu, Shumin Zhang, Yifei Liu, Lei Zhang, Juan Cai, Chengyuan Tang, Yu Liu, Tuo Deng, Lin Sun, Fuyou Liu, Shaobin Duan, Li Xiao

{"title":"Tubular TNFSF4/OX40L promotes fibrotic transition following acute kidney injury via activating GSK-3α.","authors":"Kexin Yang, Lei Zhang, Ziyi Xiong, Yingying Lu, Shumin Zhang, Yifei Liu, Lei Zhang, Juan Cai, Chengyuan Tang, Yu Liu, Tuo Deng, Lin Sun, Fuyou Liu, Shaobin Duan, Li Xiao","doi":"10.1016/j.phrs.2026.108230","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.108230","url":null,"abstract":"Acute kidney injury (AKI) often progresses to chronic kidney disease (CKD) characterized by renal fibrosis, yet the regulatory mechanisms driving this transition remain elusive. Here, it is demonstrated that tumor necrosis factor superfamily member 4 (TNFSF4/OX40L) significantly upregulates in proximal tubular cells (PTCs) from patients with CKD and in murine models of AKI-CKD transition induced by unilateral ischemia-reperfusion injury (uIRI) or repeated low-dose cisplatin. Elevated TNFSF4 levels correlates positively with the severity of tubulointerstitial injury and negatively with estimated glomerular filtration rate. Functionally, proximal tubule-specific deletion of Tnfsf4 markedly ameliorates tubular damage, renal inflammation and interstitial fibrosis in both AKI-CKD models. Furthermore, anti-TNFSF4 monoclonal antibody exerts its therapeutic effects in AKI-CKD mice suffering from uIRI. Conversely, overexpression of TNFSF4 exacerbates pro-fibrotic responses in PTCs under TGF-β1 or chronic hypoxia conditions. Mechanistically, immunoprecipitation-mass spectrometry identifies an interaction between TNFSF4 and glycogen synthase kinase-3α (GSK-3α). TNFSF4 blocks synaptotagmin-like protein 4 (SYTL4)-mediated ubiquitination of GSK-3α, prolongs its half-life, and sustains profibrotic signaling, effects reversed by GSK-3α knockdown. Collectively, these results uncover a previously unrecognized TNFSF4-GSK-3α axis as a key proximal tubule-intrinsic driver of AKI-CKD progression, and propose targeting this pathway as a promising therapeutic strategy to mitigate renal fibrosis and halt AKI-CKD transition.","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108230"},"PeriodicalIF":10.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Unlocking healthy aging through gut microbial tryptophan metabolism. 通过肠道微生物色氨酸代谢解锁健康衰老。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-05 DOI: 10.1016/j.phrs.2026.108229

Lianbin Xu, Teresa G Valencak, Luzhen Wang, Xiaowen Wang, Xiuli Li, Hui-Zeng Sun

引用次数: 0

Montelukast activates β4-containing BK channels and emerges as a pharmacological tool to reduce hippocampal excitability. 孟鲁司特激活含有β4的BK通道，成为降低海马兴奋性的药理学工具。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-05 DOI: 10.1016/j.phrs.2026.108233

Federico Orsi, Juliana Monat, Nicolás Enrique, Verónica Milesi, Karen Castillo, Jesica Raingo, Pedro Martín

{"title":"Montelukast activates β4-containing BK channels and emerges as a pharmacological tool to reduce hippocampal excitability.","authors":"Federico Orsi, Juliana Monat, Nicolás Enrique, Verónica Milesi, Karen Castillo, Jesica Raingo, Pedro Martín","doi":"10.1016/j.phrs.2026.108233","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.108233","url":null,"abstract":"Large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels are critical regulators of neuronal excitability and have been implicated in multiple epileptic syndromes. Their functional diversity arises from the co-assembly of pore-forming α-subunits with auxiliary β subunits, among which β4 is highly expressed in distinct regions of the central nervous system, including hippocampal Dentate Gyrus Granule Cells (DGGCs). Here, we identify montelukast (MTK), a clinically approved cysteinyl-leukotriene receptor antagonist, as a direct activator of BK channels, with markedly enhanced efficacy in the presence of the β1 and β4 subunits. MTK acts at submicromolar concentrations and facilitates channel opening by altering the energetics of the pore domain, independent of voltage-sensor activation or Ca²⁺ binding to the cytosolic gating ring. In mouse hippocampal slices, MTK reduces intrinsic excitability of DGGCs by decreasing input resistance and enhancing the afterhyperpolarization, effects fully reversed by the BK channel blocker paxilline. Experiments using physiological DGGCs action potential voltage waveforms confirm that MTK enhances subthreshold and evoked BK currents in α/β4 channels as selective targets. Altogether, our findings suggest that MTK, beyond its known anti-inflammatory properties, may modulate neural excitability through direct BK channel activation, offering a novel therapeutic strategy for seizure suppression.","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108233"},"PeriodicalIF":10.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Corrigendum to “Transplanted human striatal progenitors exhibit functional integration and modulate host circuitry in a Huntington’s disease animal model” [Pharmacol. Res. 219 (2025) 107905] “移植的人类纹状体祖细胞在亨廷顿病动物模型中表现出功能整合和调节宿主电路”的勘误表[Pharmacol]。Res. 219(2025) 107905]。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-01 Epub Date: 2026-04-04 DOI: 10.1016/j.phrs.2026.108182

Linda Scaramuzza , Marta Ribodino , Christian Cassarino , Marta Morrocchi , Gabriela B. Gomez Gonzalez , Roberta Parolisi , Edoardo Sozzi , Giacomo Turrini , Valentina Cerrato , Paola Conforti , Eriola Hoxha , Riccardo Tognato , Greta Galeotti , Chiara Cordiglieri , Maria Cristina Crosti , Stefano Zucca , Martina Lorenzati , Serena Bovetti , Paolo Spaiardi , Claudio de’Sperati , Annalisa Buffo

引用次数: 0

Corrigendum to “The role of cannabinoid ligands in neurodegenerative diseases: Emerging anti-inflammatory, immunomodulation and disease-modifying perspectives” [Pharmacol. Res. 227 (2026) 108185] “大麻素配体在神经退行性疾病中的作用：新兴的抗炎、免疫调节和疾病改善观点”的勘误表[Pharmacol]。[Res. 227(2026) 108185]。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-01 Epub Date: 2026-04-23 DOI: 10.1016/j.phrs.2026.108206

Gabriela Mantovani Baldasso , Rodrigo Sebben Paes , Artur Graeff Moreira , Sofia Gallo Salvadori , Christian Limberger , Fiorentina Roviezzo , Raffaele Capasso , Rafael Cypriano Dutra

引用次数: 0

Editorial: Sixty years from THC: Landscape and perspectives on the pharmacology of cannabinoids 社论：六十年的THC：大麻素药理学的景观和观点。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-01 Epub Date: 2026-03-24 DOI: 10.1016/j.phrs.2026.108173

Luigia Cristino, Fabricio A. Moreira, Uwe Grether

引用次数: 0

Corrigendum to “Mitochondrial dysfunction and immunoinflammatory remodeling in heart failure: Emerging role of conceptualizationthe mtDNA–cGAS/STING axis and therapeutic opportunities” [Pharmacol. Res. 227 (2026) 108195] “心力衰竭的线粒体功能障碍和免疫炎症重塑：概念化mtDNA-cGAS/STING轴和治疗机会的新兴作用”的勘误表[Pharmacol]。Res. 227(2026) 108195]。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-05-01 Epub Date: 2026-04-21 DOI: 10.1016/j.phrs.2026.108200

Xi Zhang , Xiangchen Xia , Yanmin Zhang , Xiaomin Liu , Xiaoyu Wei , Shichuan Chen , Yuchen Song , Yicheng Chen , Jianzhong Pang , Qiang Xu , Fuyun Jia

引用次数: 0

Retraction notice to "PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells" [Pharmacol. Res. 70 (2013) 90-101]. 关于“PIM1激酶抑制剂诱导非小细胞肺癌细胞放射增敏”的撤回通知[Pharmacol]。Res. 70(2013) 90-101]。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-04-29 DOI: 10.1016/j.phrs.2026.108165

Wanyeon Kim, HyeSook Youn, TaeWoo Kwon, JiHoon Kang, EunGi Kim, Beomseok Son, Hee Jung Yang, Youngmi Jung, BuHyun Youn

引用次数: 0

Nuclear receptors in metabolism and diseases: mechanistic and therapeutic insights. 代谢和疾病中的核受体：机制和治疗的见解。

IF 10.5 2区医学

Pharmacological research Pub Date : 2026-04-22 DOI: 10.1016/j.phrs.2026.108207

Huichang Bi

引用次数: 0