Acta Pharmacologica Sinica最新文献

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Calycosin synergizes with methotrexate in the treatment of Sjögren's disease by targeting BATF in T follicular helper cells.
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.
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.
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
Progressive noradrenergic degeneration and motor cortical dysfunction in Parkinson's disease. 帕金森病的进行性去甲肾上腺素能退化和运动皮质功能障碍。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-26 DOI: 10.1038/s41401-024-01428-z
Wei Zhou, Hong-Yuan Chu
{"title":"Progressive noradrenergic degeneration and motor cortical dysfunction in Parkinson's disease.","authors":"Wei Zhou, Hong-Yuan Chu","doi":"10.1038/s41401-024-01428-z","DOIUrl":"10.1038/s41401-024-01428-z","url":null,"abstract":"<p><p>The locus coeruleus norepinephrine (LC-NE) system plays an important role in regulating brain function, and its neuronal loss has been well-documented in Parkinson's disease (PD). The LC-NE neurodegeneration is believed to underlie various nonmotor symptoms in people with PD, including neuropsychiatric deficits, sleep disruptions, and cognitive impairments. Of particular interest, LC-NE neurons send intensive axonal projections to the motor regions of the cerebral cortex. However, how NE depletion in the motor cortex contributes to PD pathophysiology remains poorly understood. In addition, recent studies provided increasing mechanistic insights into secondary changes in the cerebral cortex as LC-NE degenerates, which might involve its interaction with dopaminergic signaling during the chronic course of the disease. In the present article, we briefly discuss clinical and preclinical studies that support the critical roles of LC-NE neurodegeneration and motor cortical dysfunction in both motor and nonmotor deficits in Parkinsonian states. We focus our discussion on the potential impact of LC-NE neurodegeneration on motor cortical function and the subsequent symptom manifestation. Last, we propose future research directions that can advance our understanding of cortical pathophysiology in PD by integrating noradrenergic degeneration.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"829-835"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724569","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
The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer. 新型BCL-2/BCL-XL抑制剂APG-1252介导的GSDME裂解增强了HER2靶向疗法对HER2阳性胃癌的抗肿瘤疗效。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-26 DOI: 10.1038/s41401-024-01414-5
Qiu-Yun Luo, Jing Yang, Tian Di, Zeng-Fei Xia, Lin Zhang, Wen-Tao Pan, Shan Shi, Li-Qiong Yang, Jian Sun, Miao-Zhen Qiu, Da-Jun Yang
{"title":"The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer.","authors":"Qiu-Yun Luo, Jing Yang, Tian Di, Zeng-Fei Xia, Lin Zhang, Wen-Tao Pan, Shan Shi, Li-Qiong Yang, Jian Sun, Miao-Zhen Qiu, Da-Jun Yang","doi":"10.1038/s41401-024-01414-5","DOIUrl":"10.1038/s41401-024-01414-5","url":null,"abstract":"<p><p>HER2-positive gastric cancer has a poor prognosis, with a high incidence of drug resistance and a lack of effective treatments for drug-resistant patients. The exploration of the mechanism of resistance to HER2-targeted therapy in HER2-positive gastric cancer and the identification of effective strategies to reverse it are urgently needed. In this study, we found that HER2-targeted agents upregulated the expression of GSDME and that the overexpression of GSDME attenuated the sensitivity of HER2-targeted agents. Furthermore, we observed that the BCL-2/BCL-XL inhibitor APG-1252 plus lapatinib promoted GSDME-mediated pyroptosis and exhibited remarkable antitumor activity both in vitro and in vivo. Mechanistically, APG-1252 combined with lapatinib synergistically induced GSDME-mediated pyroptosis in HER2-positive gastric cancer by activating caspase-dependent pathways and blocking the phospho-AKT/GSK-3β/MCL-1 signaling pathway. Our data indicated that the combination of lapatinib and APG-1252 had a synergistic antitumor effect on HER2-positive gastric cancer through the induction of caspase-3/GSDME-mediated apoptosis and pyroptosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1082-1096"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724571","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
Neuropeptide-mediated activation of astrocytes improves stress resilience in mice by modulating cortical neural synapses. 神经肽介导的星形胶质细胞激活通过调节皮质神经突触改善小鼠的应激恢复能力。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-12-06 DOI: 10.1038/s41401-024-01420-7
Jing Cui, Xiao-Ran Wang, Jie Yu, Bo-Rui Zhang, Ya-Fei Shi, Kwok-Fai So, Li Zhang, Ji-An Wei
{"title":"Neuropeptide-mediated activation of astrocytes improves stress resilience in mice by modulating cortical neural synapses.","authors":"Jing Cui, Xiao-Ran Wang, Jie Yu, Bo-Rui Zhang, Ya-Fei Shi, Kwok-Fai So, Li Zhang, Ji-An Wei","doi":"10.1038/s41401-024-01420-7","DOIUrl":"10.1038/s41401-024-01420-7","url":null,"abstract":"<p><p>Astrocytes are known to modulate synaptogenesis or neuronal activities, thus participating in mental functions. It has been shown that astrocytes are involved in the antidepressant mechanism. In this study we investigated the potential hormonal mediator governing the astrocyte-neuron interplay for stress-coping behaviors. Mice were subjected to chronic restraint stress (CRS) for 14 days, and then brain tissue was harvested for analyses. We found that the expression of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor PAC1 was significantly decreased in astrocytes of the prelimbic (PrL) cortex. By conducting a combination of genetics, in vivo imaging and behavioral assays we demonstrated that PAC1 in cortical astrocytes was necessary for maintaining normal resilience of mice against chronic environmental stress like restraint stress. Furthermore, we showed the enhancement of de novo cortical spine formation and synaptic activity under PACAP-mediated astrocytic activation possibly via the ATP release. The molecular mechanisms suggested that the vesicle homeostasis mediated by PACAP-PAC1 axis in astrocytes was involved in regulating synaptic functions. This study identifies a previously unrecognized route by which neuropeptide modulates cortical functions via local regulation of astrocytes.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"867-879"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790876","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
A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia. 一种新的膜联蛋白二聚体靶向星形胶质细胞的小胶质吞噬,以保护脑缺血后的脑血屏障。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-12-11 DOI: 10.1038/s41401-024-01432-3
Wei Tang, Rong Cheng, Meng-Yue Gao, Min-Jin Hu, Lu Zhang, Qiang Wang, Xin-Yu Li, Wei Yan, Xiao-Ying Wang, Hai-Mei Yang, Jian Cheng, Zi-Chun Hua
{"title":"A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia.","authors":"Wei Tang, Rong Cheng, Meng-Yue Gao, Min-Jin Hu, Lu Zhang, Qiang Wang, Xin-Yu Li, Wei Yan, Xiao-Ying Wang, Hai-Mei Yang, Jian Cheng, Zi-Chun Hua","doi":"10.1038/s41401-024-01432-3","DOIUrl":"10.1038/s41401-024-01432-3","url":null,"abstract":"<p><p>Despite the vital role of astrocytes in preserving blood-brain barrier (BBB) integrity, their therapeutic potential as targets in ischemic stroke-induced barrier disruption remains underexplored. We previously reported externalization of phosphatidylserine (PS) on astrocytic membranes concurrent with the emergence of PS externalization in neurons. PS externalization of astrocytes induced microglial phagocytosis of astrocytes, resulting in reduced astrocyte-vascular coupling and subsequent BBB breakdown. Annexin A5 (ANXA5) belongs to the superfamily of calcium (Ca<sup>2+</sup>)- and phospholipid-binding proteins. Here, we report two X-ray structures of human ANXA5, including monomeric ANXA5 (1.42 Å) and dimeric ANXA5 (1.80 Å). Through the combination of molecular docking and functional analysis, we explored the mechanism of action of ANXA5 in stroke treatment. In addition, we observed a clear increase in therapeutic efficacy corresponding to the increased affinity of ANXA5 for PS. In summary, the phagocytosis of PS-externalized astrocytes by microglia has emerged as a critical mechanism driving BBB breakdown after ischemia. Our findings offer valuable structural insight into ANXA5 as an innovative pharmacological target for safeguarding blood-brain barrier integrity after cerebral ischemia. These insights may facilitate the development of novel PS-targeting medications aimed at achieving enhanced efficacy with minimal side effects.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"852-866"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811849","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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