Acta Pharmacologica Sinica最新文献

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Tetrandrine augments melanoma cell immunogenicity via dual inhibition of autophagic flux and proteasomal activity enhancing MHC-I presentation. 粉防己碱通过双重抑制自噬通量和增强MHC-I呈递的蛋白酶体活性来增强黑色素瘤细胞的免疫原性。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-02-27 DOI: 10.1038/s41401-025-01507-9
Li-Na He, Yu-Jiao Liu, Jun-Bo Jiang, Ding-Ye Wang, Yu-Ling Li, Shi-Ji Zeng, Zi Guo, Pei-Yan Yao, Zi-Chang Lin, Si-Xian Lv, Xiao-Yi Liu, Wei Guo, Fang Liu, Biao-Yan Du, Ting-Xiu Zhao, Jian-Yong Xiao, Ya-Fei Shi, Kun Wang
{"title":"Tetrandrine augments melanoma cell immunogenicity via dual inhibition of autophagic flux and proteasomal activity enhancing MHC-I presentation.","authors":"Li-Na He, Yu-Jiao Liu, Jun-Bo Jiang, Ding-Ye Wang, Yu-Ling Li, Shi-Ji Zeng, Zi Guo, Pei-Yan Yao, Zi-Chang Lin, Si-Xian Lv, Xiao-Yi Liu, Wei Guo, Fang Liu, Biao-Yan Du, Ting-Xiu Zhao, Jian-Yong Xiao, Ya-Fei Shi, Kun Wang","doi":"10.1038/s41401-025-01507-9","DOIUrl":"10.1038/s41401-025-01507-9","url":null,"abstract":"<p><p>MHC-I-mediated antigen presentation is pivotal in antitumor immunity, enabling the recognition and destruction of tumor cells by CD8<sup>+</sup> T cells. Both the proteasome and autophagy serve as essential cellular degradation mechanisms that regulate the stability and functionality of MHC-I molecules. In melanoma, modulating the pathways that affect MHC-I antigen presentation is pivotal and can profoundly influence the therapeutic outcomes of immunotherapy. Our initial effort of this study was a screening process to identify natural compounds capable of amplifying MHC-I surface expression on B16 melanoma cells. Utilizing flow cytometry with fluorescently tagged antibodies, we identified tetrandrine (Tet), a bisbenzylisoquinoline alkaloid derived from the root of Stephania tetrandra, as a potent enhancer of MHC-I-mediated antigen presentation in B16 melanoma cells. We demonstrate that tetrandrine (2.5, 5, 7.5 μM) dose-dependently upregulates both surface and total MHC-I protein levels in B16 or A375 melanoma cells by simultaneously inhibiting autophagy and proteasomal activity, two key pathways involved in MHC-I degradation. This dual inhibition stabilizes MHC-I molecules, leading to enhanced tumor antigen presentation and improved recognition by CD8<sup>+</sup> T cells. In co-culture systems, tetrandrine treatment increased CD8<sup>+</sup> T cell activation and cytotoxicity against melanoma cells, evidenced by elevated IFN-γ secretion and increased tumor cell apoptosis. Administration of tetrandrine (50 mg·kg<sup>-1</sup>·d<sup>-1</sup>, i.g., for 15 days) significantly suppressed melanoma growth in mouse models accompanied by increased CD8<sup>+</sup> T cell infiltration and activation within the tumor microenvironment. Notably, tetrandrine synergized with anti-PD-1 immune checkpoint therapy, leading to enhanced tumor growth inhibition compared to either treatment alone. We revealed that tetrandrine (7.5 μM) blocked the lysosomal calcium efflux channel TPC2, disrupting lysosomal calcium homeostasis, thus impairing lysosomal acidification and proteasomal activity, thereby stabilizing MHC-I molecules and promoting antigen presentation. These results highlight tetrandrine's unique mechanism of action in enhancing MHC-I-mediated antigen presentation through dual inhibition of autophagic flux and proteasomal degradation. This study underscores tetrandrine's potential as a novel immunomodulatory agent to boost CD8<sup>+</sup> T cell-mediated tumor cell eradication and enhance the efficacy of immune checkpoint therapies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2056-2072"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522401","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
FGF21, a modulator of astrocyte reactivity, protects against ischemic brain injury through anti-inflammatory and neurotrophic pathways. FGF21是一种星形胶质细胞反应性调节剂,可通过抗炎和神经营养途径预防缺血性脑损伤。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-02-28 DOI: 10.1038/s41401-024-01462-x
Dong-Xue Wang, Wen-Ting Huang, Jun-Feng Shi, Fei Liu, Wen-Yi Jiang, Ke-Yang Chen, Shu-Yang Zhang, Xiao-Kun Li, Li Lin
{"title":"FGF21, a modulator of astrocyte reactivity, protects against ischemic brain injury through anti-inflammatory and neurotrophic pathways.","authors":"Dong-Xue Wang, Wen-Ting Huang, Jun-Feng Shi, Fei Liu, Wen-Yi Jiang, Ke-Yang Chen, Shu-Yang Zhang, Xiao-Kun Li, Li Lin","doi":"10.1038/s41401-024-01462-x","DOIUrl":"10.1038/s41401-024-01462-x","url":null,"abstract":"<p><p>Ischemic stroke is a frequent cause of mortality and disability, and astrocyte reactivity is closely associated with injury outcomes. Fibroblast growth factor 21 (FGF21), an endogenous regulator, has been shown to perform pleiotropic functions in central nervous system (CNS) disorders. However, studies on neurological diseases have paid little attention to the effects and detailed mechanisms of FGF21 in astrocytes. Here, we found elevated serum levels of FGF21 in stroke patients and transient middle cerebral artery occlusion (tMCAO) mice. In the peri-infarct cortex, microglia and astrocytes serve as sources of FGF21 in addition to neurons. MRI and neurobehavioral assessments of wild-type (WT) and FGF21<sup>-/-</sup> tMCAO model mice revealed a deteriorated consequence of the loss of FGF21, with exacerbated brain infarction and neurological deficits. Additionally, combined with the pharmacological treatment of WT mice with recombinant human FGF21 (rhFGF21) after tMCAO, FGF21 was identified to suppress astrocytic activation and astrocyte-mediated inflammatory responses after brain ischemia and participated in controlling the infiltration of peripheral inflammatory cells (including macrophages, neutrophils, monocytes, and T cells) by modulating chemokines expression (such as Ccl3, Cxcl1, and Cxcl2) in astrocytes. Furthermore, rhFGF21 was shown to boost the production of neurotrophic factors (BDNF and NGF) in astrocytes, and by which rescued neuronal survival and promoted synaptic protein expression (postsynaptic density protein-95 (PSD-95), synaptotagmin 1 (SYT1), and synaptophysin) in neurons after ischemic injury. Overall, our findings implicate that FGF21 acts as a suppressor of astrocyte activation, and exerts anti-inflammatory and neurotrophic effects after ischemic brain injury through its action on astrocytes, offering an alternative therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1834-1851"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530896","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
Gracillin suppresses cancer progression through inducing Merlin/LATS protein-protein interaction and activating Hippo signaling pathway. 格拉西林通过诱导Merlin/LATS蛋白相互作用和激活Hippo信号通路抑制癌症进展。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-03-07 DOI: 10.1038/s41401-025-01514-w
Jin-Xuan Su, Hai-Xia Zhou, Zhi-Jing Zhang, Xiao-Feng Zhou, Qiu-Ming Zou, Si-Jia Li, Xiao-Song Zhuang, Jian-Qin Lai, Si-Yu Yang, Kai Cui, Yong-Qi Liu, Rui-Jie Yuan, Heng-Xin Pan, Zi-Sheng Li, Han-Yun Tu, Mei Cheng, Yu Yan, Qi Qi, Yu-Bo Zhang
{"title":"Gracillin suppresses cancer progression through inducing Merlin/LATS protein-protein interaction and activating Hippo signaling pathway.","authors":"Jin-Xuan Su, Hai-Xia Zhou, Zhi-Jing Zhang, Xiao-Feng Zhou, Qiu-Ming Zou, Si-Jia Li, Xiao-Song Zhuang, Jian-Qin Lai, Si-Yu Yang, Kai Cui, Yong-Qi Liu, Rui-Jie Yuan, Heng-Xin Pan, Zi-Sheng Li, Han-Yun Tu, Mei Cheng, Yu Yan, Qi Qi, Yu-Bo Zhang","doi":"10.1038/s41401-025-01514-w","DOIUrl":"10.1038/s41401-025-01514-w","url":null,"abstract":"<p><p>Gene therapy, epigenetic therapies, natural compounds targeted therapy, photodynamic therapy, nanoparticles, and precision medicines are becoming available to diagnose and treat cancer. Gracillin, a natural steroidal saponin extracted from herbs, has shown potent efficacy against a range of malignancies. In this study, we investigated the molecular anticancer mechanisms of gracillin. We showed that gracillin dose-dependently suppressed proliferation, migration, and invasion in breast cancer, liver cancer, and glioblastoma cells with IC<sub>50</sub> values around 1 μM, which were associated with MST-independent activation of Hippo signaling pathway and subsequent decreased YAP activity. We demonstrated that gracillin activated the Hippo signaling by inducing Merlin/LATS protein-protein interaction (PPI). A competitive inhibitory peptide (SP) derived from the binding interface of the PPI, disrupted the interaction, abolishing the anticancer activity of gracillin. In nude mice bearing MDA-MB-231, HCCLM3, or U87MG xenograft tumor, administration of gracillin (5, 10 mg·kg<sup>-1</sup>·d<sup>-1</sup>, i.g. for 21 days) dose-dependently suppressed the tumor growth, associated with the induced Merlin/LATS PPI, activated Hippo signaling, as well as decreased YAP activity in tumor tissues. Our data demonstrate that gracillin is an efficacious therapeutic agent for cancer treatment, induction of Merlin/LATS PPI might provide proof-of-concept in developing therapeutic agent for cancer treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2016-2028"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584238","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
Dorsal raphe GABA-ergic neurons regulate the susceptibility to social transfer of pain in mice. 中缝背gaba能神经元调节小鼠对疼痛社会转移的易感性。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-02-26 DOI: 10.1038/s41401-025-01494-x
Lin Ai, Yi Han, Ting Ge, Sha Sha, Xiao-Jing Zhai, Ran Ji, Yu Zhou, Dan-Dan Chen, An Xie, Wen-Xin Zhang, Zhou Wu, Mo-Ruo Zhang, Jun-Xia Yang, An-Kang Hu, Jun-Li Cao, Ling-Zhen Song, Hong-Xing Zhang
{"title":"Dorsal raphe GABA-ergic neurons regulate the susceptibility to social transfer of pain in mice.","authors":"Lin Ai, Yi Han, Ting Ge, Sha Sha, Xiao-Jing Zhai, Ran Ji, Yu Zhou, Dan-Dan Chen, An Xie, Wen-Xin Zhang, Zhou Wu, Mo-Ruo Zhang, Jun-Xia Yang, An-Kang Hu, Jun-Li Cao, Ling-Zhen Song, Hong-Xing Zhang","doi":"10.1038/s41401-025-01494-x","DOIUrl":"10.1038/s41401-025-01494-x","url":null,"abstract":"<p><p>Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1892-1904"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514328","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
Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2. 小脑内上调Rheb(S16H)可改善SCA2小鼠的运动功能障碍。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-03-03 DOI: 10.1038/s41401-025-01504-y
Sehwan Kim, Junwoo Park, Hyemi Eo, Gi Beom Lee, Se Min Park, Minsang Shin, Seung Eun Lee, Youngpyo Nam, Sang Ryong Kim
{"title":"Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2.","authors":"Sehwan Kim, Junwoo Park, Hyemi Eo, Gi Beom Lee, Se Min Park, Minsang Shin, Seung Eun Lee, Youngpyo Nam, Sang Ryong Kim","doi":"10.1038/s41401-025-01504-y","DOIUrl":"10.1038/s41401-025-01504-y","url":null,"abstract":"<p><p>Cerebellar ataxia (CA) is characterized by impaired balance and coordination due to the loss of cerebellar neurons caused by various factors, and effective treatments are currently lacking. Recently, we observed reduced expression of signaling molecules in the mammalian target of rapamycin complex 1 (mTORC1) pathway in the cerebellum of mice with spinocerebellar ataxia type 2 (SCA2) compared with wild-type mice. To investigate the effects of mTORC1 upregulation on motor dysfunction in mice with SCA2, we administered an intracerebellar injection of adeno-associated virus serotype 1 carrying a constitutively active form of Ras homolog enriched in brain [Rheb(S16H)], which is an upstream activator of mTORC1. This treatment led to increased Rheb(S16H) expression in calbindin-D28K-positive Purkinje cells and increased levels of neurotrophic factors. Additionally, Rheb(S16H) upregulation reduced abnormal behaviors and protected Purkinje cells in mice with SCA2. Our findings suggest that upregulating Rheb(S16H) in the cerebellum may be a promising therapeutic strategy for hereditary CA.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1852-1863"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539961","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
Carrimycin exhibited broad spectrum inhibitory activities against coronaviruses replication through down-regulating host factor TMEM41B. 卡里霉素通过下调宿主因子TMEM41B对冠状病毒的复制表现出广谱的抑制作用。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-05-15 DOI: 10.1038/s41401-025-01577-9
Kun Wang, Hui-Qiang Wang, Ge Yang, Shuo Wu, Hai-Yan Yan, Meng-Yuan Wu, Yu-Huan Li, Jian-Dong Jiang
{"title":"Carrimycin exhibited broad spectrum inhibitory activities against coronaviruses replication through down-regulating host factor TMEM41B.","authors":"Kun Wang, Hui-Qiang Wang, Ge Yang, Shuo Wu, Hai-Yan Yan, Meng-Yuan Wu, Yu-Huan Li, Jian-Dong Jiang","doi":"10.1038/s41401-025-01577-9","DOIUrl":"10.1038/s41401-025-01577-9","url":null,"abstract":"<p><p>We previously reported that carrimycin could inhibit pan-coronavirus including HCoV-229E, HCoV-OC43 and SARS-CoV-2. We found that carrimycin targeted the post-entry replicative events in coronavirus infection. Carrimycin could impede the viral protein translation switch from ORF1a to ORF1b by targeting programmed -1 ribosomal frameshifting (-1PRF). Carrimycin could also inhibit the newly synthesized (nascent) viral RNA. In this study we investigated whether carrimycin also inhibited the newly emerged SARS-CoV-2 variants. We showed that carrimycin (1.25-10 µM) dose-dependently inhibited both viral RNA and protein levels in Vero E6 cells. We further demonstrated that carrimycin disrupted the formation of SARS-CoV-2 double membrane vesicles (DMVs), and identified the host transmembrane protein B (TMEM41B) as the key factor involved in this process. Overexpression of TMEM41B increased viral protein levels and mRNA levels, whereas TMEM41B knockdown reduced viral replication including HCoV-229E, HCoV-OC43 and SARS-CoV-2. Moreover, overexpression of TMEM41B partially reversed the inhibitory effect of carrimycin, suggesting that carrimycin indeed exerted antiviral effects through regulation of TMEM41B. We revealed that carrimycin directly bound to TMEM41B and induced its K48 ubiquitination degradation, thereby inhibiting viral replication. These results expand the understanding of carrimycin's antiviral mechanisms, particularly its antiviral activity, and enrich our knowledge about the role of host factors in regulating viral replication.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2006-2015"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075239","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
YY1/HIF-1α/mROS positive-feedback loop exacerbates glomerular mesangial cell proliferation in mouse early diabetic kidney disease. YY1/HIF-1α/mROS正反馈回路促进小鼠早期糖尿病肾病肾小球系膜细胞增殖
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-03-04 DOI: 10.1038/s41401-025-01498-7
Ting-Ting Yang, Yu-Ting Shao, Qian Cheng, Yu-Tian He, Zhen Qiu, Dan-Dan Pan, Huan-Ming Zhang, Zhen-Zhou Jiang, Meng Yan, Chang-Jiang Ying, Bao-Jing Li, Jun-Jie Liu, Si-Tong Qian, Tao Wang, Xiao-Xing Yin, Qian Lu
{"title":"YY1/HIF-1α/mROS positive-feedback loop exacerbates glomerular mesangial cell proliferation in mouse early diabetic kidney disease.","authors":"Ting-Ting Yang, Yu-Ting Shao, Qian Cheng, Yu-Tian He, Zhen Qiu, Dan-Dan Pan, Huan-Ming Zhang, Zhen-Zhou Jiang, Meng Yan, Chang-Jiang Ying, Bao-Jing Li, Jun-Jie Liu, Si-Tong Qian, Tao Wang, Xiao-Xing Yin, Qian Lu","doi":"10.1038/s41401-025-01498-7","DOIUrl":"10.1038/s41401-025-01498-7","url":null,"abstract":"<p><p>Mesangial cells (MCs) are the most active intrinsic cells in the glomerulus. MCs excessively proliferate at the early stage of diabetic kidney disease (DKD), eventually causing glomerular sclerosis and even renal failure; inhibiting glomerular MC proliferation in early DKD is a promising prevention and treatment strategy for early DKD. Our previous study shows that Yin Yang 1 (YY1), a zinc finger protein, is a novel regulator of DKD-induced renal fibrosis. In this study we investigated the role of YY1 in glomerular MC proliferation in DKD in vivo and in vitro. We first showed that YY1 expression levels were significantly increased in the glomerular MCs of DKD patients and db/db mice and in high glucose (HG)-treated SV40-MES13 cells. By using YY1 expression/knockdown plasmids, we confirmed that YY1 contributed to glomerular MC proliferation in vitro. We demonstrated that YY1 upregulated hypoxia-inducible factor-1 alpha (HIF-1α) expression and activity in HG-treated SV40-MES13 cells, leading to overproduction of mROS. Moreover, mROS contributed to positive feedback regulation of YY1/HIF-1α signaling, and the YY1/HIF-1α/mROS positive feedback loop exacerbated glomerular MC proliferation in HG-treated SV40-MES13 cells. In addition, renal-specific YY1 overexpression promoted glomerular MC proliferation in normal mice, whereas renal-specific YY1 knockdown mitigated MC proliferation in early diabetic mice by inactivating HIF-1α/ROS signaling. In conclusion, the YY1/HIF-1α/mROS positive feedback loop might be an attractive therapeutic target for overcoming glomerulosclerosis in early DKD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1974-1989"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555592","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
Costunolide normalizes neuroinflammation and improves neurogenesis deficits in a mouse model of depression through inhibiting microglial Akt/mTOR/NF-κB pathway. 木香内酯通过抑制小胶质细胞Akt/mTOR/NF-κB通路,使小鼠抑郁模型中的神经炎症正常化并改善神经发生缺陷。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-02-26 DOI: 10.1038/s41401-025-01506-w
Shao-Qi Zhang, Qiao Deng, Cheng Tian, Huan-Huan Zhao, Li-Ying Yang, Xin-Wei Cheng, Guo-Ping Wang, Dong Liu
{"title":"Costunolide normalizes neuroinflammation and improves neurogenesis deficits in a mouse model of depression through inhibiting microglial Akt/mTOR/NF-κB pathway.","authors":"Shao-Qi Zhang, Qiao Deng, Cheng Tian, Huan-Huan Zhao, Li-Ying Yang, Xin-Wei Cheng, Guo-Ping Wang, Dong Liu","doi":"10.1038/s41401-025-01506-w","DOIUrl":"10.1038/s41401-025-01506-w","url":null,"abstract":"<p><p>Neuroinflammation is crucial for the pathogenesis of major depression. Preclinical studies have shown the potential of anti-inflammatory agents, specifically costunolide (COS), correlate with antidepressant effects. In this study, we investigated the molecular mechanisms underlying the antidepressant actions of COS. Chronic restraint stress (CRS) was induced in male mice. The mice were treated with either intra-DG injection of COS (5 μM, 1 μL per side) or COS (20 mg/kg, i.p.) for 1 week. We showed that administration of COS through the both routes significantly ameliorated the depressive-like behavior in CRS-exposed mice. Furthermore, administration of COS significantly improved chronic stress-induced adult hippocampal neurogenesis deficits in the mice through attenuating microglia-derived neuroinflammation. We demonstrated that COS (5 μM) exerted anti-neuroinflammatory effects in LPS-treated BV2 cells via inhibiting microglial Akt/mTOR/NF-κB pathway; inactivation of mTOR/NF-κB/IL-1β pathway was required for the pro-neurogenic action of COS in CRS-exposed mice. Our results reveal the antidepressant mechanism of COS that is normalizing neuroinflammation to improve neurogenesis deficits, supporting anti-inflammatory agents as a potential therapeutic strategy for depression.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1864-1876"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514327","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
Author Correction: Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy. 作者更正:四氢小檗碱通过促进phb2介导的线粒体自噬来延缓小鼠心脏衰老。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 DOI: 10.1038/s41401-025-01503-z
Lei Wang, Xue-Qing Tang, Yang Shi, Hui-Min Li, Zi-Yu Meng, Hui Chen, Xiao-Han Li, Yong-Chao Chen, Heng Liu, Yang Hong, Heng-Hui Xu, Ling Liu, Limin Zhao, Wei-Na Han, Xin Liu, Yong Zhang
{"title":"Author Correction: Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.","authors":"Lei Wang, Xue-Qing Tang, Yang Shi, Hui-Min Li, Zi-Yu Meng, Hui Chen, Xiao-Han Li, Yong-Chao Chen, Heng Liu, Yang Hong, Heng-Hui Xu, Ling Liu, Limin Zhao, Wei-Na Han, Xin Liu, Yong Zhang","doi":"10.1038/s41401-025-01503-z","DOIUrl":"10.1038/s41401-025-01503-z","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2073-2074"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539960","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
Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease. 口服FPR2/ALX调节剂调节骨髓细胞活性,改善炎症性肠病的粘膜炎症。
IF 6.9 1区 医学
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-03-11 DOI: 10.1038/s41401-025-01525-7
Wen-Sheng Yang, Qing Liu, Yang Li, Guan-Yi Li, Shi Lin, Jie Li, Lin-Yu Li, Yuan Li, Xi-Lin Ge, Xiao-Zhen Wang, Wei Wu, Jun Yan, Guang-Fei Wang, Qing-Tong Zhou, Qiang Liu, Ming-Wei Wang, Zhi-Ping Li
{"title":"Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease.","authors":"Wen-Sheng Yang, Qing Liu, Yang Li, Guan-Yi Li, Shi Lin, Jie Li, Lin-Yu Li, Yuan Li, Xi-Lin Ge, Xiao-Zhen Wang, Wei Wu, Jun Yan, Guang-Fei Wang, Qing-Tong Zhou, Qiang Liu, Ming-Wei Wang, Zhi-Ping Li","doi":"10.1038/s41401-025-01525-7","DOIUrl":"10.1038/s41401-025-01525-7","url":null,"abstract":"<p><p>Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1-FPR2 in complex with heterotrimeric G<sub>i</sub> to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED<sub>50</sub> values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1958-1973"},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603189","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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