Acta Pharmaceutica Sinica. B最新文献

{"title":"Disrupting calcium homeostasis and glycometabolism in engineered lipid-based pharmaceuticals propel cancer immunogenic death","authors":"Qiuxia Peng ,&nbsp;Xiaolong Li ,&nbsp;Chao Fang ,&nbsp;Chunyan Zhu ,&nbsp;Taixia Wang ,&nbsp;Binxu Yin ,&nbsp;Xiulin Dong ,&nbsp;Huaijuan Guo ,&nbsp;Yang Liu ,&nbsp;Kun Zhang","doi":"10.1016/j.apsb.2024.12.018","DOIUrl":"10.1016/j.apsb.2024.12.018","url":null,"abstract":"<div><div>Homeostasis and energy and substance metabolism reprogramming shape various tumor microenvironment to sustain cancer stemness, self-plasticity and treatment resistance. Aiming at them, a lipid-based pharmaceutical loaded with CaO₂ and glucose oxidase (GOx) (LipoCaO₂/GOx, LCG) has been obtained to disrupt calcium homeostasis and interfere with glycometabolism. The loaded GOx can decompose glucose into H₂O₂ and gluconic acid, thus competing with anaerobic glycolysis to hamper lactic acid (LA) secretion. The obtained gluconic acid further deprives CaO₂ to produce H₂O₂ and release Ca²⁺, disrupting Ca²⁺ homeostasis, which synergizes with GOx-mediated glycometabolism interference to deplete glutathione (GSH) and yield reactive oxygen species (ROS). Systematical experiments reveal that these sequential multifaceted events unlocked by Ca²⁺ homeostasis disruption and glycometabolism interference, ROS production and LA inhibition, successfully enhance cancer immunogenic deaths of breast cancer cells, hamper regulatory T cells (Tregs) infiltration and promote CD8⁺ T recruitment, which receives a considerably-inhibited outcome against breast cancer progression. Collectively, this calcium homeostasis disruption glycometabolism interference strategy effectively combines ion interference therapy with starvation therapy to eventually evoke an effective anti-tumor immune environment, which represents in the field of biomedical research.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1255-1267"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776899","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":"Parkin inhibits iron overload-induced cardiomyocyte ferroptosis by ubiquitinating ACSL4 and modulating PUFA-phospholipids metabolism","authors":"Dandan Xiao ,&nbsp;Wenguang Chang ,&nbsp;Xiang Ao ,&nbsp;Lin Ye ,&nbsp;Weiwei Wu ,&nbsp;Lin Song ,&nbsp;Xiaosu Yuan ,&nbsp;Luxin Feng ,&nbsp;Peiyan Wang ,&nbsp;Yu Wang ,&nbsp;Yi Jia ,&nbsp;Xiaopeng Tang ,&nbsp;Jianxun Wang","doi":"10.1016/j.apsb.2024.12.027","DOIUrl":"10.1016/j.apsb.2024.12.027","url":null,"abstract":"<div><div>Iron overload is strongly associated with heart disease. Ferroptosis is a new form of regulated cell death indicated in cardiac ischemia–reperfusion (I/R) injury. However, the specific molecular mechanism of myocardial injury caused by iron overload in the heart is still unclear, and the involvement of ferroptosis in iron overload-induced myocardial injury is not fully understood. In this study, we observed that ferroptosis participated in developing of iron overload and I/R-induced cardiomyopathy. Mechanistically, we discovered that Parkin inhibited iron overload-induced ferroptosis in cardiomyocytes by promoting the ubiquitination of long-chain acyl-CoA synthetase 4 (ACSL4), a crucial protein involved in ferroptosis-related lipid metabolism pathways. Additionally, we identified <em>p53</em> as a transcription factor that transcriptionally suppressed Parkin expression in iron-overloaded cardiomyocytes, thereby regulating iron overload-induced ferroptosis. In animal studies, cardiac-specific Parkin knockout mice (<em>Myh6-CreER</em>^<em>T2</em><em>/Parkin</em>^{<em>fl/fl</em>}) fed a high-iron diet presented more severe myocardial damage, and the high iron levels exacerbated myocardial I/R injury. However, the ferroptosis inhibitor Fer-1 significantly suppressed iron overload-induced ferroptosis and myocardial I/R injury. Moreover, Parkin effectively protected against impaired mitochondrial function and prevented iron overload-induced mitochondrial lipid peroxidation. These findings unveil a novel regulatory pathway involving p53–Parkin–ACSL4 in heart disease by inhibiting of ferroptosis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1589-1607"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776326","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":"eIF3a function in immunity and protection against severe sepsis by regulating B cell quantity and function through m6A modification","authors":"Qianying Ouyang ,&nbsp;Jiajia Cui ,&nbsp;Yang Wang ,&nbsp;Ke Liu ,&nbsp;Yan Zhan ,&nbsp;Wei Zhuo ,&nbsp;Juan Chen ,&nbsp;Honghao Zhou ,&nbsp;Chenhui Luo ,&nbsp;Jianming Xia ,&nbsp;Liansheng Wang ,&nbsp;Chengxian Guo ,&nbsp;Jianting Zhang ,&nbsp;Zhaoqian Liu ,&nbsp;Jiye Yin","doi":"10.1016/j.apsb.2025.02.005","DOIUrl":"10.1016/j.apsb.2025.02.005","url":null,"abstract":"<div><div>eIF3a is a <em>N</em>⁶-methyladenosine (m⁶A) reader that regulates mRNA translation by recognizing m⁶A modifications of these mRNAs. It has been suggested that eIF3a may play an important role in regulating translation initiation <em>via</em> m⁶A during infection when canonical cap-dependent initiation is inhibited. However, the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation <em>in vivo</em>. In this study, we investigated the <em>in vivo</em> function of eIF3a using <em>eIF3a</em> knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage, which contributed to severe sepsis induced by Lipopolysaccharide (LPS). Ectopic eIF3a overexpression in the <em>eIF3a</em> knockdown mice rescued mice from LPS-induced severe sepsis. We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m⁶A modification of mRNAs. These findings unveil a novel mechanism underlying sepsis, implicating the pivotal role of B cells in this complex disease process regulated by eIF3a. Furthermore, eIF3a may be used to develop a potential strategy for treating sepsis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1571-1588"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776327","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":"BRD4 regulates m6A of ESPL1 mRNA via interaction with ALKBH5 to modulate breast cancer progression","authors":"Haisheng Zhang ,&nbsp;Linlin Lu ,&nbsp;Cheng Yi ,&nbsp;Tao Jiang ,&nbsp;Yunqing Lu ,&nbsp;Xianyuan Yang ,&nbsp;Ke Zhong ,&nbsp;Jiawang Zhou ,&nbsp;Jiexin Li ,&nbsp;Guoyou Xie ,&nbsp;Zhuojia Chen ,&nbsp;Zongpei Jiang ,&nbsp;Gholamreza Asadikaram ,&nbsp;Yanxi Peng ,&nbsp;Dan Zhou ,&nbsp;Hongsheng Wang","doi":"10.1016/j.apsb.2024.12.037","DOIUrl":"10.1016/j.apsb.2024.12.037","url":null,"abstract":"<div><div>The interaction between m⁶A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m⁶A levels and suppresses the malignancy of breast cancer (BC) cells <em>via</em> increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 <em>via</em> enhanced binding between its 3′ untranslated regions (3′UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between <em>ESPL1</em> mRNA and m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of <em>ESPL1</em> mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1552-1570"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776328","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":"Lycorine hydrochloride directly targets UBA1 to suppress cellular senescence","authors":"Jiaqing Yang ,&nbsp;Junhao Xu ,&nbsp;Ziheng Qiu ,&nbsp;Zhiyong Mao ,&nbsp;Xiaojun Xu ,&nbsp;Ying Jiang ,&nbsp;Guizhu Wu","doi":"10.1016/j.apsb.2025.01.026","DOIUrl":"10.1016/j.apsb.2025.01.026","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1696-1699"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776704","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":"Monocytes in the brain–heart crosstalk control sleep under myocardial infarction","authors":"Meng Mao ,&nbsp;Hailong Bing ,&nbsp;Jianping Ye ,&nbsp;Zhengyuan Xia ,&nbsp;Qinjun Chu","doi":"10.1016/j.apsb.2025.01.025","DOIUrl":"10.1016/j.apsb.2025.01.025","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1700-1702"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776703","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":"Evaluation of the efficacy and mechanisms of azvudine in elderly patients with malignant tumors complicated by COVID-19","authors":"Ranran Sun ,&nbsp;Yihang Song ,&nbsp;Zhe Li ,&nbsp;Daming Wang,&nbsp;Zujiang Yu","doi":"10.1016/j.apsb.2025.03.036","DOIUrl":"10.1016/j.apsb.2025.03.036","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1712-1714"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776384","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":"Parabacteroides distasonis promotes liver regeneration by increasing β-hydroxybutyric acid (BHB) production and BHB-driven STAT3 signals","authors":"Manlan Guo ,&nbsp;Xiaowen Jiang ,&nbsp;Hui Ouyang ,&nbsp;Xianglong Zhang ,&nbsp;Shuaishuai Zhang ,&nbsp;Peng Wang ,&nbsp;Guofang Bi ,&nbsp;Ting Wu ,&nbsp;Wenhong Zhou ,&nbsp;Fengting Liang ,&nbsp;Xiao Yang ,&nbsp;Shicheng Fan ,&nbsp;Jian-hong Fang ,&nbsp;Peng Chen ,&nbsp;Huichang Bi","doi":"10.1016/j.apsb.2025.01.024","DOIUrl":"10.1016/j.apsb.2025.01.024","url":null,"abstract":"<div><div>The liver regenerative capacity is crucial for patients with end-stage liver disease following partial hepatectomy (PHx). The specific bacteria and mechanisms regulating liver regeneration post-PHx remain unclear. This study demonstrated dynamic changes in the abundance of <em>Parabacteroides distasonis</em> (<em>P. distasonis</em>) post-PHx, correlating with hepatocyte proliferation. Treatment with live <em>P. distasonis</em> significantly promoted hepatocyte proliferation and liver regeneration after PHx. Targeted metabolomics revealed a significant positive correlation between <em>P. distasonis</em> and <em>β</em>-hydroxybutyric acid (BHB), as well as hyodeoxycholic acid and 3-hydroxyphenylacetic acid in the gut after PHx. Notably, treatment with BHB, but not hyodeoxycholic acid or 3-hydroxyphenylacetic acid, significantly promoted hepatocyte proliferation and liver regeneration in mice after PHx. Moreover, STAT3 inhibitor Stattic attenuated the promotive effects of BHB on cell proliferation and liver regeneration both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, <em>P. distasonis</em> upregulated the expression of fatty acid oxidation-related proteins, and increased BHB levels in the liver, and then BHB activated the STAT3 signaling pathway to promote liver regeneration. This study, for the first time, identifies the involvement of <em>P. distasonis</em> and its associated metabolite BHB in promoting liver regeneration after PHx, providing new insights for considering <em>P. distasonis</em> and BHB as potential strategies for promoting hepatic regeneration.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1430-1446"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776841","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 retrospective cohort study of the efficacy and safety of oral azvudine versus nirmatrelvir/ritonavir in elderly hospitalized COVID-19 patients aged over 60 years","authors":"Bo Yu ,&nbsp;Haiyu Wang ,&nbsp;Guangming Li ,&nbsp;Junyi Sun ,&nbsp;Hong Luo ,&nbsp;Mengzhao Yang ,&nbsp;Yanyang Zhang ,&nbsp;Ruihan Liu ,&nbsp;Ming Cheng ,&nbsp;Shixi Zhang ,&nbsp;Guotao Li ,&nbsp;Ling Wang ,&nbsp;Guowu Qian ,&nbsp;Donghua Zhang ,&nbsp;Silin Li ,&nbsp;Quancheng Kan ,&nbsp;Jiandong Jiang ,&nbsp;Zhigang Ren","doi":"10.1016/j.apsb.2024.12.032","DOIUrl":"10.1016/j.apsb.2024.12.032","url":null,"abstract":"<div><div>Azvudine and nirmatrelvir/ritonavir (Paxlovid) are recommended for COVID-19 treatment in China, but their safety and efficacy in the elderly population are not fully known. In this multicenter, retrospective, cohort study, we identified 5131 elderly hospitalized COVID-19 patients from 32,864 COVID-19 patients admitted to nine hospitals in Henan Province, China, from December 5, 2022, to January 31, 2023. The primary outcome was all-cause death, and the secondary outcome was composite disease progression. Propensity score matching (PSM) was performed to control for confounding factors, including demographics, vaccination status, comorbidities, and laboratory tests. After 2:1 PSM, 1786 elderly patients receiving azvudine and 893 elderly patients receiving Paxlovid were included. Kaplan–Meier and Cox regression analyses revealed that compared with Paxlovid group, azvudine could significantly reduce the risk of all-cause death (log-rank <em>P</em> = 0.002; HR: 0.71, 95% CI: 0.573–0.883, <em>P</em> = 0.002), but there was no difference in composite disease progression (log-rank <em>P</em> = 0.52; HR: 1.05, 95% CI: 0.877–1.260, <em>P</em> = 0.588). Four sensitivity analyses verified the robustness of above results. Subgroup analysis suggested that a greater benefit of azvudine over Paxlovid was observed in elderly patients with primary malignant tumors (<em>P</em> for interaction = 0.005, HR: 0.32, 95% CI: 0.18−0.57) compared to patients without primary malignant tumors. Safety analysis revealed that azvudine treatment had a lower incidence of adverse events and higher lymphocyte levels than Paxlovid treatment. In conclusion, azvudine treatment is not inferior to Paxlovid treatment in terms of all-cause death, composite disease progression and adverse events in elderly hospitalized COVID-19 patients.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1333-1343"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776903","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 synthetic peptide, derived from neurotoxin GsMTx4, acts as a non-opioid analgesic to alleviate mechanical and neuropathic pain through the TRPV4 channel","authors":"ShaoXi Ke ,&nbsp;Ping Dong ,&nbsp;Yi Mei ,&nbsp;JiaQi Wang ,&nbsp;Mingxi Tang ,&nbsp;Wanxin Su ,&nbsp;JingJing Wang ,&nbsp;Chen Chen ,&nbsp;Xiaohui Wang ,&nbsp;JunWei Ji ,&nbsp;XinRan Zhuang ,&nbsp;ShuangShuang Yang ,&nbsp;Yun Zhang ,&nbsp;Linda M. Boland ,&nbsp;Meng Cui ,&nbsp;Masahiro Sokabe ,&nbsp;Zhe Zhang ,&nbsp;QiongYao Tang","doi":"10.1016/j.apsb.2024.12.028","DOIUrl":"10.1016/j.apsb.2024.12.028","url":null,"abstract":"<div><div>Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an <em>μ</em>-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of <em>Trpv4</em> knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 3","pages":"Pages 1447-1462"},"PeriodicalIF":14.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776322","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}