Acta Pharmacologica Sinica最新文献

{"title":"ROS-induced degradation of hERG potassium channels contributes to aripiprazole-induced prolongation of the QTc interval.","authors":"Yu-Hong Cao, Xiao-Chen Wang, Hong-Kun Wang, Zong-Kuai Yang, Dan-Dan Liu, Yang Yang, Rong Kuang, Ping Liang","doi":"10.1038/s41401-025-01648-x","DOIUrl":"https://doi.org/10.1038/s41401-025-01648-x","url":null,"abstract":"<p><p>As antipsychotic administration often persists for a lifetime, antipsychotic-induced cardiotoxicity (AIC) becomes a significant and potentially life-threatening side effect. Owing to the lack of an appropriate human cardiomyocyte experimental model, current research on AIC is primarily based on clinical case reports. In this study, we generated human iPSC-derived cardiomyocytes (iPSC-CMs) and characterized the cardiotoxicity of 6 antipsychotics (clozapine, haloperidol, quetiapine, olanzapine, risperidone, and aripiprazole) used in clinical practice. Multielectrode array analysis revealed that all 6 antipsychotics, when used within their respective clinical plasma concentration (CPC) ranges, were likely to cause a significantly prolonged field potential duration (FPD) in iPSC-CMs. Moreover, administration of the third-generation antipsychotic aripiprazole (10 mg/kg, i.g.) led to marked QT interval prolongation in beagle dogs. We demonstrated that aripiprazole administration resulted in mitochondrial damage and oxidative stress, which accelerated protein degradation of human ether-à-go-go-related gene (hERG) channels, generating a rapid delayed rectifying potassium current (I_Kr) through the proteasome pathway, ultimately leading to FPD prolongation. Scavenging reactive oxygen species or suppressing the ubiquitin‒proteasome pathway (UPP) significantly restored hERG channel function and rescued the prolonged FPD phenotype in aripiprazole-treated iPSC-CMs. Our results suggest that caution should be taken when aripiprazole is prescribed to high-risk patients with preexisting comorbidities. Manipulation of excessive oxidative stress or suppression of the UPP may offer novel therapeutic strategies for mitigating aripiprazole-induced proarrhythmic risk.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205284","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}

{"title":"Targeting the interactions between neutrophils and microglia: a novel strategy for anti-inflammatory treatment of stroke.","authors":"Long-Rui Wang, Zi-Yuan Zhao, Zhao-Wei Li, Yin-Ru Jiang, Wen-Jing Sun, Guan-Hua Du, Rui-Li Shi, Ling-Lei Kong","doi":"10.1038/s41401-025-01662-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01662-z","url":null,"abstract":"<p><p>Stroke is the second leading cause of mortality and the leading cause of adult disability worldwide. Neuroinflammation is a crucial mechanism that regulates the pathogenesis and prognosis of stroke and involves both peripheral and intracerebral immune cells. Neutrophils and microglia are the primary immune cells that mediate neuroinflammation and play bidirectional roles after stroke. Significant interactions between neutrophils and microglia exist. Microglia regulate the activation, infiltration, as well as formation of neutrophil extracellular traps (NETs), whereas neutrophils regulate the polarization and phagocytic activity of microglia. In this review, we summarize the bidirectional roles of neutrophils and microglia in stroke with an emphasis on the interactions between neutrophils and microglia, as well as the associated signaling pathways and targets involved. We further introduce potential stroke treatment drugs that regulate the interactions between neutrophils and microglia, including anti-inflammatory drugs and natural products. We propose that, according to the different ischemic times and cell activation states, regulating the interactions between neutrophils and microglia through relevant targets and signaling pathways may be an ideal strategy for the anti-inflammatory treatment of stroke, potentially improving treatment and prognosis of stroke. This review summarizes the bidirectional roles of neutrophils and microglia in stroke, respectively, focusing on the interactions and signaling pathways between neutrophils and microglia, as well as potential therapeutic targets and drugs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205293","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}

{"title":"Ursolic acid derivative UA312 ameliorates ionizing radiation-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish via targeting chrna3 and grik5.","authors":"Fei-Fei Xu, Yue Shang, Hui-Qiang Wei, Wei-Ying Zhang, Li-Xing Wang, Tong Hu, Shu-Qin Zhang, Yan-Li Li, Hai-Hua Shang, Wen-Bin Hou, Wen-Feng Gou, Sai-Jun Fan, Yi-Liang Li","doi":"10.1038/s41401-025-01564-0","DOIUrl":"10.1038/s41401-025-01564-0","url":null,"abstract":"<p><p>The biological damage caused by ionizing radiation (IR) depends not only on the time and doses of exposure to tissue components but also on the developmental state of the cells. Currently, amifostine is the only radiation-protective agent used for clinical indications related to radiation therapy, but this compound has multiple drawbacks including high toxicity, short half-life and no protective effect on the nervous system. Ursolic acid (UA), a natural pentacyclic triterpenoid that exhibits multiple protective effects including anti-inflammatory, anticarcinogenic, and antioxidant effects. Due to its poor solubility and bioavailability, UA is mostly administered with liposomes. In this study we investigated the impact of UA312, an optimized derivative of UA, on radiation-induced developmental toxicity in zebrafish embryos and larvae. Embryo and larvae survival were observed at 4, 24, 48, and 72 hpf. UA312 was administered at 3 hpf, while embryos were irradiated with 6 Gy of γ-irradiation (dose rate: 0.88 Gy/min) at 4 hpf, then the embryos were moved to a fresh buffer. We determined that 40 µM of UA312 was a safe concentration for zebrafish embryos and larvae. We found that treatment with UA312 (40 µM) restored IR-induced early developmental dysplasia of the zebrafish embryos and larvae. Transcriptomic analysis revealed that exposure to IR inhibited multiple pathways related to neurodevelopment and cardiomyocyte function in zebrafish, which were validated by assessing abnormal cardiac morphology, variations in neurotransmitter levels and alterations in locomotor behavior; and that UA312 treatment ameliorated these alterations. We demonstrated that UA312 treatment significantly reversed the related signaling pathways by targeting chrna3 and grik5. In conclusion, this study identified a promising radioprotective drug, UA312, which alleviates IR-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish by targeting chrna3 and grik5. UA312 may be developed as a novel radioprotective agent against acute IR damage in humans.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2677-2692"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968558","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":"HDAC inhibitor GCJ-490A modulates tumor microenvironment and synergizes with PD-1 antibody against breast and lung cancers in syngeneic murine models.","authors":"Wen-Xin Zhang, Ting He, Kun Fang, Ying-Lei Gao, Yi-Ming Sun, Fa-Jun Nan, Jian Ding, Yi Chen, Yan-Fen Fang","doi":"10.1038/s41401-025-01646-z","DOIUrl":"https://doi.org/10.1038/s41401-025-01646-z","url":null,"abstract":"<p><p>Histone deacetylases (HDAC) inhibition represents one of the few validated strategies in epigenetic cancer therapies, demonstrating significant clinical efficacy in T-cell lymphomas and multiple myeloma, yet exhibiting limited efficacy against solid tumors. GCJ-490A is a novel HDAC inhibitor discovered by medicinal chemists in our institute, which exhibits potent in vitro and in vivo anticancer activity. In this study, we investigated the effects of GCJ-490A on the tumor microenvironment and its potential in synergy with PD-1 antibody in anti-tumor therapy. In syngeneic murine models of breast (EMT6) and lung (LL/2) cancers, we demonstrated that GCJ-490A alone and in combination with PD-1 antibody inhibited tumor growth by regulating T cells and tumor-associated macrophages (TAMs). Specifically, GCJ-490A significantly enhanced T-cell proliferation and cytotoxicity, evidenced by the increased expression of Ki67, CD107a and Granzyme B, and modulated TAMs towards a pro-inflammatory M1 phenotype, while reducing the M2 population. In addition, GCJ-490A upregulated PD-1 on T cells and PD-L1 on myeloid-derived suppressor cells (MDSCs) and TAMs, potentially enhancing PD-1 blockade efficacy. However, the anti-tumor efficacy was less pronounced in LL/2 tumors than in EMT6 tumors, which might be related to the increased infiltration of MDSCs in LL/2 tumors. GCJ-490A promoted MDSCs migration into the tumor by promoting the secretion of CXCL7 from LL/2 cells. In conclusion, GCJ-490A exerts its anti-tumor efficacy by reprogramming the tumor immune microenvironment in EMT6 and LL/2 tumor models, which is augmented when combined with anti-PD-1. However, CXCL7-mediated tumor-type-dependent recruitment of MDSCs by GCJ-490A may limit its therapeutic efficacy, and inhibition of the CXCL7/CXCR1/2 pathway might offer new strategies to address this challenge.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205313","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}

{"title":"JMC14: a novel dual PI3Kδ/CSF1R inhibitor with potent antitumor activity in hematological and solid tumors.","authors":"Xi Zhang, Pu Sun, Yi Wang, Lan Xu, Hui-Yu Li, Lin-Jiang Tong, Cun Tan, Jian Ding, Chun-Hao Yang, Ling-Hua Meng","doi":"10.1038/s41401-025-01575-x","DOIUrl":"10.1038/s41401-025-01575-x","url":null,"abstract":"<p><p>PI3Kδ, predominantly expressed in immune cells and markedly dysregulated in B-cell malignancies, emerges as a promising and well-validated therapeutic target in hematologic cancers. Meanwhile, CSF1R regulates the formation and polarization of tumor-associated macrophages (TAMs), facilitating immune suppression and tumor progression in various solid tumors. Although targeting PI3Kδ or CSF1R has shown promise, the clinical application is often constrained by off-target effects, toxicity, and limited efficacy, particularly in solid malignancies. In this study, we identified JMC14, a novel dual inhibitor targeting PI3Kδ and CSF1R with a distinct structure and favorable selectivity among human kinome, yielding IC₅₀ values of 12 nM against PI3Kδ and 143 nM against CSF1R, respectively. JMC14 preferentially inhibited PI3Kδ-mediated signaling at the cellular level and exhibited robust antiproliferative activity across 10 lines of diffuse large B-cell lymphoma (DLBCL) cells, outperforming the approved PI3Kδ inhibitor idelalisib. Notably, its efficacy negatively correlated with the PI3Kα expression among the cell lines tested, suggesting a compensatory pathway mediated by PI3Kα. Daily oral administration of JMC14 (10, 30, or 100 mg/kg, for 21 days) dose-dependently suppressed tumor progression in xenografts derived from TMD8 cells and DLBCL patients, accompanied by good tolerance. Additionally, M-NFS-60 myeloid leukemia cells, which are dependent on the CSF-1-CSF1R axis for survival and proliferation, were effectively inhibited by JMC14 both in vitro and in vivo, further validating its inhibitory activity targeting CSF1R. Furthermore, JMC14 demonstrated potent antitumor activity in murine triple-negative breast cancer (TNBC), which was associated with its activity to reshape the immune microenvironment by reducing M2-like TAMs, enhancing CD8⁺ T cell infiltration. Collectively, these findings establish JMC14 as a potent dual PI3Kδ/CSF1R inhibitor with remarkable efficacy against both hematologic and solid malignancies with hyperactivation of PI3Kδ and/or CSF1R, highlighting the potential of JMC14 as a useful probe to dissect the interaction of PI3Kδ and CSF1R in tumor progression and immune reprogramming.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2808-2819"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100976","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":"CD200R blockade enhances anti-tumor immunity by unleashing NK and CD8⁺ T cells in tumor.","authors":"Zheng-Feng Zhang, Yu Zhang, Ya-Wen Chen, Guo-Shuai Cao, Xiao-Dong Zheng, Rui Sun, Hui Peng, Zhi-Gang Tian, Hao-Yu Sun","doi":"10.1038/s41401-025-01556-0","DOIUrl":"10.1038/s41401-025-01556-0","url":null,"abstract":"<p><p>Immune checkpoint inhibitors have revolutionized cancer therapy, but a large proportion of patients do not respond well to current checkpoint immunotherapies. CD200R (also known as OX2R) is a transmembrane glycoprotein of the immunoglobulin superfamily that is mainly expressed on myeloid and lymphoid-derived immunocompetent cells such as myeloid cells, natural killer (NK), and CD8⁺ T cells. In this study, we investigated the therapeutic potential and cellular mechanisms of targeting CD200R in tumor immunotherapy. We established 4 subcutaneous tumor mouse models using MC38 (colon cancer), MCA205 (fibrosarcoma), LLC (lung cancer), and EO771 (mammary cancer) cell lines. We found that CD200R was highly expressed on tumor-infiltrating NK and CD8⁺ T cells with exhausted phenotypes in the four subcutaneous tumor mouse models. Either genetic ablation or antibody blockade of CD200R retarded tumor growth and prolonged the survival of tumor-bearing mice by preventing or reversing exhaustion of both NK cells and CD8⁺ T cells. The combined therapy of CD200R antibody with anti-PD-1/anti-PD-L1 synergistically inhibited tumor growth. By depletion of NK or/and CD8⁺ T cells, we demonstrated that both cell types contributed to the anti-tumor efficacy of CD200R blockade in tumor-bearing mice. Further, the blockade of human CD200R significantly enhanced human NK cell function and inhibited human tumor growth in PBMC-reconstituted xenograft mice. Our results demonstrate that CD200R is a potential immune checkpoint molecule that can suppress the tumoricidal activities of NK and CD8⁺ T cells, and could thus be exploited as a therapeutic target in the future.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2835-2848"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952683","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":"Generating potent and persistent antitumor immunity via affinity-tuned CAR-T cells targeting mesothelin.","authors":"Ya-Li Yue, Jun-Jun Liu, Hang Ma, Zhi-di Pan, Lei Wang, Jia-Wei Zhang, Shu-Sheng Wang, Yue-Qing Xie, Hua Jiang, Yan-Lin Bian, Ming-Yuan Wu, Yun-Sheng Yuan, Bao-Hong Zhang, Xiao-Dong Xiao, Jian-Wei Zhu","doi":"10.1038/s41401-025-01572-0","DOIUrl":"10.1038/s41401-025-01572-0","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces challenges of insufficient efficacy and a high recurrence rate. Mesothelin (MSLN) is a membrane glycoprotein highly expressed in various solid tumors that has restricted low expression in normal tissues such as the pleura, peritoneum, and pericardium. We previously performed affinity maturation based on the parental antibody M912, and constructed the phage display library. In this study we identified four novel human anti-MSLN antibodies (LP12, HP4-11, HP4-41/LP6, and HP4-44/LP2) with varying degrees of enhanced affinity. These third-generation CARs targeting MSLN were packaged into lentiviral vectors to generate stable CAR-T cells. The CAR-T variants induced robust cytolytic activity, significant cytokine production, and activation-induced clonal proliferation against various MSLN-positive tumors in vitro, and effectively cleared disseminated tumors in mice. A single administration of the CAR-T variant LP12 potently eradicated various types of MSLN-positive solid tumors, achieved long-term persistence in vivo, effectively prevented tumor recurrence, and exhibited no non-specific toxicity. Therefore, optimizing the affinity of antigen-binding domain in CAR represents a promising strategy for advancing the development of safe and effective CAR-T cell therapies. The LP12 CAR-T cells developed in this study have potential applications in patients with MSLN-positive solid tumors. Schematic illustration of the generation and antitumor mechanism of affinity-tuned MSLN-targeted CAR-T cells. The expression plasmids carrying different anti-MSLN CAR genes were packaged into lentiviral vectors. Lentiviral transduction of human CD3⁺ T cells was performed to generate CAR-T cells, which were then expanded. After injection of moderately affinity-tuned MSLN-targeted CAR-T cells into mice, they enter the bloodstream, recognize, and infiltrate the solid tumors. They specifically recognize and bind to MSLN on the surface of tumor cells, and upon activation, release IFN-γ, IL-2, and TNF-α to exert cytolytic activity. Subsequently, they undergo clonal proliferation and primarily differentiate into effector memory CAR-T cells, maintaining long-term antitumor immunity and effectively preventing recurrence.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2849-2862"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951882","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":"Dysfunction of subthalamic dopaminergic circuitry contributes to anxiety- and depression-like behaviors in 6-OHDA lesion-induced hemiparkinsonian mice.","authors":"Jia-Qi Zhang, Shu-Yi Li, Cui Yin, Ying Ji, Xiang Zhang, Dan-Yang Liu, Hang Yang, Yong Niu, Gui-Yun Cui, Chun-Yi Zhou, Cheng Xiao","doi":"10.1038/s41401-025-01570-2","DOIUrl":"10.1038/s41401-025-01570-2","url":null,"abstract":"<p><p>Anxiety and depression are common non-motor symptoms severely affecting the quality of life in patients with Parkinson's disease, but the underlying pathophysiological mechanisms remain elusive. As dopaminergic (DA) system and the subthalamic nucleus (STN) are involved in motor control and emotional processing, we herein investigated the role of DA circuitry in the STN in regulating depression in parkinsonian mice. A hemi-parkinsonian mouse model was established by injection of 6-OHDA into the right medial forebrain bundle (MFB), desipramine (20 mg/kg, i.p.) was injected 30 min before the intracranial injection. Motor function was monitored in open field test and apomorphine-induced contra-lesional rotation and rotarod tests; anxiety- and depression-like behaviors were assessed with the open field test, elevated plus maze, tail suspension test and forced swim test. We found that the hemi-parkinsonian mice displayed motor dysfunction and depression-like behaviors at different time points. Fiber photometry recording revealed that STN neurons were hypersensitive to anxiety- and depression-like stimulation; chemogenetic inhibition of STN neurons mitigated anxiety- and depression-like behaviors. While dopamine release was significantly reduced in the STN of the parkinsonian mice in response to anxiety- and depression-like stimulation, the expression of D1- and D2-like dopamine receptors was time-dependently changed. Intracranial injection of either D1- or D2-like dopamine receptor agonist into the STN mitigated anxiety- and depression-like behaviors in the parkinsonian mice. We conclude that STN DA circuitry may be promising targets to treat anxiety and depression in PD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2622-2636"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957343","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":"A phase III clinical trial of monthly minodronate in the treatment of Chinese postmenopausal women with osteoporosis.","authors":"Hao Zhang, Ya-Nan Huo, Ya-Wei Zhang, Zhi-Feng Cheng, Xiao-Jing Wang, Jun Chen, Qi-Fu Li, Xin-Hua Xiao, Li-Zhen Lan, Xin-Long Ma, Liu-Jun Fu, Xiao-Pan Chen, Ling-Qing Yuan, Fang-Jiang Xu, Li You, Jin-Luo Cheng, Dun Hong, Fei Hua, Li Mao, Guo-Xi Jin, Guan-Feng Yao, Ya-Jun Bing, Gui-Jie Xie, Ying Yang, Jin Xu, Ying Zhang, Wei Zhang, Yue Ding, Guo-Ping Cai, Hui-Min Zhou, Cheng-Yun Liu, Jian-Xiang Zhang, Zhong-Min Zhao, Bu-Jun Zhuang, Xiao Cheng, Zhen-Lin Zhang","doi":"10.1038/s41401-025-01661-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01661-0","url":null,"abstract":"<p><p>To date, monthly oral bisphosphonates have not been available in China. In this randomized, double blind, positive-controlled, multicenter phase III clinical trial, we compared the efficacy and safety of monthly minodronate versus weekly alendronate in the treatment of Chinese postmenopausal women with osteoporosis. A total of 548 participants were screened across 31 study centers, of which 330 participants were randomized into two groups: the experimental group (n = 165) received oral minodronate (50 mg/tablet once every four weeks) and alendronate placebo (once weekly), while the positive control group (n = 165) received oral alendronate (70 mg/tablet once weekly) and minodronate placebo (once every four weeks) for a duration of 48 weeks. The bone mineral density (BMD) of the lumbar spine, femoral neck and total hip were measured using dual-energy X-ray absorptiometry (DXA) at baseline and at 24 and 48 weeks. At the end of treatments, the experimental group exhibited a mean increase (SD) in BMD above the baseline at the lumbar spine, femoral neck and total hip of 4.61% (4.613%), 3.04% (4.034%) and 3.40% (3.569%), respectively, compared with those of 4.55% (3.753%), 1.86% (3.592%) and 2.30% (4.838%) in the control group. All improvements from the baseline in the two groups were statistically significant. The monthly minodronate did not cause new safety risks compared with alendronate. This study demonstrates that monthly minodronate administration is non-inferior to weekly alendronate in terms of therapeutic efficacy, while maintaining a comparable safety profile. Furthermore, the monthly dosing schedule of minodronate may significantly enhance medication adherence among osteoporosis patients, potentially improving long-term treatment outcomes.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205070","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}

{"title":"Translin deletion impairs cocaine-induced locomotor sensitization and RGS8 expression in the nucleus accumbens.","authors":"Xiu-Ping Fu, Ren-Kun Wu, Aparna P Shah, Bruce Ladenheim, Jesse Alt, Jean Lud Cadet, Rana Rais, Ramesh Chandra, Xiao-Bo Cen, Jay M Baraban","doi":"10.1038/s41401-025-01565-z","DOIUrl":"10.1038/s41401-025-01565-z","url":null,"abstract":"<p><p>Multiple lines of evidence show that the microRNA system plays a prominent role in regulating behavioral responses to psychostimulants. Suppressing microRNA degradation is an effective strategy for elucidating the impact of these intracellular messengers on cellular function. The translin/trax complex is an RNase that appears to mediate degradation of a small number of microRNAs. In this study we investigated the effect of deleting the translin/trax microRNA-degrading enzyme on cocaine-induced behavioral responses in mice. Wild type and Translin (Tsn) KO mice were injected with cocaine and their open-field locomotor activity was monitored. We found that the locomotor activity in response to repeated (5, 10 and 20 mg/kg, i.p.), but not acute (20 mg/kg, i.p.), cocaine exposure was significantly impaired in Tsn KO mice. We identified several microRNAs (412-5p, 412-3p, 93-3p, 7b-3p, and 204-5p) that were significantly increased in the NAc of Tsn KO mice. As regulator of G-protein signaling 8 (RGS8) is a predicted target gene shared by three of these microRNAs, and expressed in the NAc, we confirmed its reduced expression in this region in Tsn KO mice. Moreover, shRNA-mediated knockdown of RGS8 in the NAc attenuated locomotor sensitization to repeated cocaine administration. Taken together, our results suggest that microRNAs targeted by the translin/trax RNase inhibit cocaine-induced locomotor sensitization, in part, by silencing expression of RGS8.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2637-2648"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960525","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}