Acta Pharmacologica Sinica最新文献

{"title":"Correction: Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis.","authors":"Wei Wang, Xiao-Kang Chen, Lu Zhou, Feng Wang, Yan-Ji He, Bing-Jun Lu, Ze-Gang Hu, Zhu-Xin Li, Xue-Wei Xia, Wei Eric Wang, Chun-Yu Zeng, Liang-Peng Li","doi":"10.1038/s41401-024-01447-w","DOIUrl":"10.1038/s41401-024-01447-w","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1494"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790875","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":"Visceral adipose tissue-derived extracellular vesicles promote stress susceptibility in obese mice via miR-140-5p.","authors":"Hao Wang, Li Zhang, Wan-Yue Yang, Xiao-Yi Ji, An-Qi Gao, Yi-Hong Wei, Xin Ding, Yue Kang, Jian-Hua Ding, Yi Fan, Ming Lu, Gang Hu","doi":"10.1038/s41401-025-01484-z","DOIUrl":"10.1038/s41401-025-01484-z","url":null,"abstract":"<p><p>Obesity increases the risk of depression. Evidence shows that peripheral inflammation, glycemic dysregulation, and hyperactivity within the hypothalamic-pituitary-adrenal axis are implicated in both obesity and depression. In this study we investigated the impact of visceral adipose tissue (VAT), a crucial characteristic of obesity, on stress susceptibility in obese mice. Age-matched mice were fed with chow diet (CD) or high-fat diet (HFD), respectively, for 12 weeks. CD mice were deprived of VAT and received transplantation of VAT from HFD mice (TransHFD) or CD mice (TransCD). Extracellular vesicles (EVs) were prepared from VAT of CD or HFD mice, and intravenously injected (100 μg, 4 times in 2 weeks) in naïve mice or injected into hippocampus (5 μg, 4 times in 2 weeks) through implanted bilateral cannula. Depression-like behaviors were assessed 14 days after transplantation. We showed that HFD mice exhibited significantly higher body weight gain and impaired insulin and glucose tolerance, accompanied by increased stress susceptibility. Transplantation of VAT or VAT-derived EVs from HFD mice caused synaptic damage and promoted stress susceptibility in recipient mice. Through inhibiting miRNA biogenesis in the VAT and miRNA sequencing analysis, we demonstrated that miR-140-5p was significantly upregulated in both VAT-EVs and hippocampus of HFD mice. Overexpression of hippocampal miR-140-5p in naïve mice not only facilitated acute stress-induced depression-like behaviors, but also decreased hippocampal CREB-BDNF signaling cascade and synaptic plasticity. Conversely, knockdown of miR-140-5p in the VAT, VAT-EVs or hippocampus of HFD mice protected against acute stress, reducing stress susceptibility that were mediated via CREB-BDNF pathway. In summary, VAT-EVs or the cargo miRNAs in obese mice promote synaptic damage and stress susceptibility, providing potential therapeutic targets for metabolism-related affective disorders.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1221-1235"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389837","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":"Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2.","authors":"Cai-Ling Tang, Yuan-Qing Li, Xi-Kun Du, Xiao-Xia Fang, Yi-Man Guang, Pei-Zhuo Li, Shuang Chen, Sheng-Yu Xue, Jia-Min Yu, Xiao-Yi Liu, Yi-Pan Luo, Lan-Xin Zhou, Cheng Luo, Huan Xiong, Zhong-Jie Liang, Hong Ding","doi":"10.1038/s41401-024-01452-z","DOIUrl":"10.1038/s41401-024-01452-z","url":null,"abstract":"<p><p>The bromodomain (BRD) represents a highly conserved structural module that provides BRD proteins with fundamental functionality in modulating protein-protein interactions involved in diverse biological processes such as chromatin-mediated gene transcription, DNA recombination, replication and repair. Consequently, dysregulation of BRD proteins has been implicated in the pathogenesis of numerous human diseases. In recent years, considerable scientific endeavors have focused on unraveling the molecular mechanisms underlying BRDs and developing inhibitors that target these domains. While these inhibitors compete for binding with the acetylated lysine binding site of BRDs, achieving inhibition of BRD proteins via competitive pocket binding has proven challenging due to the conserved nature of these pockets. To address this limitation, the present study employed dynamic simulations for a comprehensive analysis, leading to the identification of a non-conserved pocket in CECR2 for achieving BRD family inhibition through allosteric modulation. Subsequently, the compound BAY 11-7085 was proven capable of covalently binding to C494 of this pocket after covalent docking and biological verification in vitro. The allosteric inhibition strategy of CECR2 was further verified by the structurally optimized compound LC-CE-7, which is an allosteric covalent CECR2 inhibitor with anti-cancer effects in MDA-MB-231 cells.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1476-1491"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998100","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":"Electrophysiological characterization of human KCNT1 channel modulators and the therapeutic potential of hydroquinine and tipepidine in KCNT1 mutation-associated epilepsy mouse model.","authors":"Qing Guo, Jun Gan, En-Ze Wang, Yu-Ming Wei, Jie Xu, Yun Xu, Fei-Fei Zhang, Meng Cui, Meng-Xing Jia, Ming-Jian Kong, Qiong-Yao Tang, Zhe Zhang","doi":"10.1038/s41401-024-01457-8","DOIUrl":"10.1038/s41401-024-01457-8","url":null,"abstract":"<p><p>Patients suffering epilepsy caused by the gain-of-function mutants of the hKCNT1 potassium channels are drug refractory. In this study, we cloned a novel human KCNT1B channel isoform using the brain cDNA library and conducted patch-clamp and molecular docking analyses to characterize the pharmacological properties of the hKCNT1B channel using thirteen drugs. Among cinchona alkaloids, we found that hydroquinine exerted the strongest blocking effect on the hKCNT1B channel, especially the F313L mutant. In addition, we confirmed the antitussive drug tipepidine was also a potent inhibitor of the hKCNT1B channel. Subsequently, we proved that these two drugs produced an excellent therapeutic effect on the epileptic model of KCNT1 Y777H mutant male mice; thus, both could be ready-to-use anti-epileptic drugs. On the other hand, we demonstrated that the activation of the KCNT1 channel by loxapine and clozapine was through interacting with pore domain residues to reverse the run-down of the KCNT1 channel. Taken together, our results provide new insights into the mechanism of the modulators in regulating the KCNT1 channel activity as well as important candidates for clinical tests in the treatment of KCNT1 mutant-associated epilepsy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1190-1204"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051293","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":"Peptidoglycan isolated from the fruit of Lycium barbarum alleviates liver fibrosis in mice by regulating the TGF-β/Smad7 signaling and gut microbiota.","authors":"Ying-Min Nie, Wan-Qi Zhou, Ting Niu, Meng-Fei Mao, Yu-Xue Zhan, Yun Li, Kai-Ping Wang, Mei-Xia Li, Kan Ding","doi":"10.1038/s41401-024-01454-x","DOIUrl":"10.1038/s41401-024-01454-x","url":null,"abstract":"<p><p>The hepatoprotective effect of the fruit of Lycium barbarum has been documented in China over millennia. Lycium barbarum polysaccharides (LBPs) were the first macromolecules reported to mitigate liver fibrosis in carbon tetrachloride (CCl₄)-treated mice. Herein, a neutral peptidoglycan, named as LBPW, was extracted from the fruit of Lycium barbarum. In this study, we investigated the hepatoprotective mechanisms of LBPW. CCl₄-induced liver fibrosis mice were administered LBPW (50, 100, 200 mg ·kg^-1 ·d^-1, i.p.) or (100, 200, 300 mg· kg^-1 ·d^-1, i.g.) for 6 weeks. We showed that either i.p. or i.g. administration of LBPW dose-dependently attenuated liver damage and fibrosis in CCl₄-treated mice. Pharmacokinetic analysis showed that cyanine 5.5 amine (Cy5.5)-labeled LBPW (Cy5.5-LBPW) could be detected in the liver through i.p. and i.g. administration with i.g.-administered Cy5.5-LBPW mainly accumulating in the intestine. In TGF-β1-stimulated LX-2 cells as well as in the liver of CCl₄-treated mice, we demonstrated that LBPW significantly upregulated Smad7, a negative regulator of TGF-β/Smad signaling, to retard the activation of hepatic stellate cells (HSCs) and prevent liver fibrosis. On the other hand, LBPW significantly boosted the abundance of Akkermansia muciniphila (A. muciniphila) and fortified gut barrier function. We demonstrated that A. muciniphila might be responsible for the efficacy of LBPW since decreasing the abundance of this bacterium by antibiotics (Abs) blocked the effectiveness of LBPW. Overall, our results show that LBPW may exert the hepatoprotective effect via rebalancing TGF-β/Smad7 signaling and propagating gut commensal A. muciniphila, suggesting that LBPW could be leading components to be developed as new drug candidates or nutraceuticals against liver fibrosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1329-1344"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998267","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":"Therapeutic potential and pharmacological mechanisms of Traditional Chinese Medicine in gout treatment.","authors":"Jing-Wen Guo, Guo-Qiang Lin, Xin-Yi Tang, Jia-Ying Yao, Chen-Guo Feng, Jian-Ping Zuo, Shi-Jun He","doi":"10.1038/s41401-024-01459-6","DOIUrl":"10.1038/s41401-024-01459-6","url":null,"abstract":"<p><p>Gout is a systemic metabolic disorder caused by elevated uric acid (UA) levels, affecting over 1% of the population. The most common complication of gout is gouty arthritis (GA), characterized by swelling, pain or tenderness in peripheral joints or bursae, which can lead to the formation of tophi. At present, western medicines like colchicine, febuxostat and allopurinol are the primary treatment strategy to alleviate pain and prevent flare-ups in patients with GA, but they have significant side effects and increased mortality risks. Traditional Chinese medicine (TCM) has been utilized for thousands of years for the prevention and treatment of GA, demonstrating effective control over serum UA (SUA) levels with fewer side effects. Herein we summarized a total of 541 studies published from 2000 to 2023 in sources including PubMed, Web of Science, the Cochrane Library and Embase, highlighting the therapeutic potential of TCM in treating gout and GA, particularly in combination with modern medical strategies. This review focuses on TCM formulas, Chinese herbal extracts, and active compounds derived from TCM, providing an overview of recent clinical application and the pharmacological research based on animal models and cellular systems. Particularly, the current review categorized the clinical and experimental evidence into the strategies for improving hyperuricemia, decreasing the sudden onset of acute GA and retarding chronic GA progression, supplied further coherent reference and enlightenment for clinicians, investigators of natural product chemistry, researchers in TCM and pharmacology. We hope this article will inspire the development of novel formulas and molecular entities for the treatment of gout and GA.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1156-1176"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998272","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":"Editorial Expression of Concern: The combination of baicalin and baicalein enhances apoptosis via the ERK/p38 MAPK pathway in human breast cancer cells.","authors":"Qian-Mei Zhou, Song Wang, Hui Zhang, Yi-Yu Lu, Xiu-Feng Wang, Yoshiharu Motoo, Shi-Bing Su","doi":"10.1038/s41401-024-01430-5","DOIUrl":"10.1038/s41401-024-01430-5","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1492"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714853","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":"Retraction Note: Physcion, a naturally occurring anthraquinone derivative, induces apoptosis and autophagy in human nasopharyngeal carcinoma.","authors":"Ming-Jie Pang, Zhun Yang, Xing-Lin Zhang, Zhao-Fang Liu, Jun Fan, Hong-Ying Zhang","doi":"10.1038/s41401-024-01433-2","DOIUrl":"10.1038/s41401-024-01433-2","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1493"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765428","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":"Endothelial Gsα deficiency promotes ferroptosis and exacerbates atherosclerosis in apolipoprotein E-deficient mice via the inhibition of NRF2 signaling.","authors":"Li-Fan He, Lei Wang, Jing-Wei Li, Xiao Xiong, Xiao-Lin Yue, Pei-Dong Yuan, Han-Lin Lu, Jian-Gang Gao, Fang-Pu Yu, Min Chen, Lee S Weinstein, Jian-Min Yang, Cheng Zhang, Xiaoteng Qin, Wencheng Zhang","doi":"10.1038/s41401-024-01446-x","DOIUrl":"10.1038/s41401-024-01446-x","url":null,"abstract":"<p><p>The importance of ferroptosis in the occurrence and progression of atherosclerosis is gradually being recognized. The stimulatory G protein α subunit (Gsα) plays a crucial role in the physiology of endothelial cells (ECs). Our previous study showed that endothelial Gsα could regulate angiogenesis and preserve endothelial permeability. In this study, we investigated whether endothelial Gsα contributed to atherosclerosis through ferroptosis and oxidative stress. We generated endothelial Gsα-specific knockout mice in apolipoprotein E-deficient (ApoE^-/-) background (ApoE^-/-Gsα^ECKO), and found that the mice exhibited aggravated atherosclerotic lesions and signs of ferroptosis compared with their wild-type littermates (ApoE^-/-Gsα^fl/fl). In human aortic endothelial cells (HAECs), overexpression of Gsα reduced lipid peroxidation and ferroptosis, whereas Gsα knockdown exacerbated oxidative stress and ferroptosis. Further, Gsα overexpression in HAECs increased the expression of antioxidant genes nuclear factor erythroid 2-related 2 (NRF2) and its downstream genes. Gsα regulated the expression of NRF2 through CCCTC-binding factor (CTCF). In conclusion, this study has revealed that Gsα acts as a defense factor against endothelial ferroptosis and is a potential target for the treatment of atherosclerosis and associated ischemic heart disease. A model depicting the increase in the endothelial Gsα protein level in response to atherosclerotic stimuli. Gsα regulates NRF2 expression through cAMP/Epac/CTCF-mediated transcription and inhibits ferroptosis. Endothelial Gsα deficiency alleviates antioxidative stress and exacerbates atherosclerosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1289-1302"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976957","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":"Activation of MST1 protects filtration barrier integrity of diabetic kidney disease in mice through restoring the tight junctions of glomerular endothelial cells.","authors":"Ting-Ting Yang, Ying Liu, Yu-Ting Shao, Lin Li, Dan-Dan Pan, Tao Wang, Zhen-Zhou Jiang, Bao-Jing Li, Si-Tong Qian, Meng Yan, Xia Zhu, Cai Heng, Jun-Jie Liu, Qian Lu, Xiao-Xing Yin","doi":"10.1038/s41401-024-01421-6","DOIUrl":"10.1038/s41401-024-01421-6","url":null,"abstract":"<p><p>As a pathological feature of diabetic kidney disease (DKD), dysregulated glomerular filtration barrier function could lead to the increased levels of proteinuria. The integrity of tight junctions (TJs) of glomerular endothelial cells (GECs) is a guarantee of physiological function of glomerular filtration barrier. Mammalian sterile 20-like kinase (MST1) is a key regulatory protein in the blood-brain barrier (BBB), and it regulates the expression of TJs-related proteins in cerebral vascular endothelial cells. Our previous study showed that MST1 was involved in renal tubulointerstitial fibrosis of DKD. In the present study we investigated the role of MST1 in barrier function of GECs of DKD, and explored its regulatory mechanisms. In kidney tissue section of DKD patients and db/db mice, and high glucose (HG)-cultured mouse glomerular endothelial cells (mGECs), we showed that MST1 was inactivated in the GECs of DKD accompanied by disrupted glomerular endothelial barrier. In db/db mice and HG-cultured mGECs, knockdown of MST1 increased proteinuria levels, and disrupted glomerular endothelial barrier through decreasing TJs-related proteins, whereas MST1 overexpression restored glomerular endothelial barrier through regaining TJs-related proteins. In db/db mice and HG-cultured mGECs, we demonstrated that MST1 inhibition induced TJs's disruption of GECs via activating YAP1/TEAD signaling. Verteporfin (an inhibitor of YAP1-TEAD interaction) and PY-60 (a YAP1 agonist) were used to verify the role of YAP1/TEAD signaling in the regulation effect of MST1 on barrier function of mGECs. In conclusion, MST1 activation recovers glomerular endothelial barrier of DKD by regaining TJs-related proteins via inhibiting YAP1/TEAD signaling. This study highlights the multiple regulation of MST1 activation on kidney injury.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1345-1360"},"PeriodicalIF":6.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790873","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}