Acta Pharmaceutica Sinica. B最新文献_第9页

Dual alarmin-receptor-specific targeting peptide systems for treatment of sepsis 用于治疗脓毒症的双重警戒素-受体特异性靶向肽系统

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-19 DOI: 10.1016/j.apsb.2024.08.015

Seok-Jun Mun, Euni Cho, Woo Jin Gil, Seong Jae Kim, Hyo Keun Kim, Yu Seong Ham, Chul-Su Yang

{"title":"Dual alarmin-receptor-specific targeting peptide systems for treatment of sepsis","authors":"Seok-Jun Mun, Euni Cho, Woo Jin Gil, Seong Jae Kim, Hyo Keun Kim, Yu Seong Ham, Chul-Su Yang","doi":"10.1016/j.apsb.2024.08.015","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.015","url":null,"abstract":"The pathophysiology of sepsis is characterized by a systemic inflammatory response to infection; however, the cytokine blockade that targets a specific early inflammatory mediator, such as tumor necrosis factor, has shown disappointing results in clinical trials. During sepsis, excessive endotoxins are internalized into the cytoplasm of immune cells, resulting in dysregulated pyroptotic cell death, which induces the leakage of late mediator alarmins such as HMGB1 and PTX3. As late mediators of lethal sepsis, overwhelming amounts of alarmins bind to high-affinity TLR4/MD2 and low-affinity RAGE receptors, thereby amplifying inflammation during early-stage sepsis. In this study, we developed a novel alarmin/receptor-targeting system using a TLR4/MD2/RAGE-blocking peptide (TMR peptide) derived from the HMGB1/PTX3-receptors interacting motifs. The TMR peptide successfully attenuated HMGB1/PTX3- and LPS-mediated inflammatory cytokine production by impairing its interactions with TLR4 and RAGE. Moreover, we developed TMR peptide-conjugated liposomes (TMR-Lipo) to improve the peptide pharmacokinetics. In combination therapy, moderately antibiotic-loaded TMR-Lipo demonstrated a significant therapeutic effect in a mouse model of cecal ligation- and puncture-induced sepsis. The identification of these peptides will pave the way for the development of novel pharmacological tools for sepsis therapy.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"23 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186914","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 role of the microbiota–gut–brain axis in methamphetamine-induced neurotoxicity: Disruption of microbial composition and short-chain fatty acid metabolism 微生物群-肠-脑轴在甲基苯丙胺诱导的神经毒性中的作用：微生物组成和短链脂肪酸代谢紊乱

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-14 DOI: 10.1016/j.apsb.2024.08.012

Lijian Chen, Kaikai Zhang, Jiali Liu, Xiuwen Li, Yi Liu, Hongsheng Ma, Jianzheng Yang, Jiahao Li, Long Chen, Clare Hsu, Jiahao Zeng, Xiaoli Xie, Qi Wang

{"title":"The role of the microbiota–gut–brain axis in methamphetamine-induced neurotoxicity: Disruption of microbial composition and short-chain fatty acid metabolism","authors":"Lijian Chen, Kaikai Zhang, Jiali Liu, Xiuwen Li, Yi Liu, Hongsheng Ma, Jianzheng Yang, Jiahao Li, Long Chen, Clare Hsu, Jiahao Zeng, Xiaoli Xie, Qi Wang","doi":"10.1016/j.apsb.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.012","url":null,"abstract":"Methamphetamine (METH) abuse is associated with significant neurotoxicity, high addiction potential, and behavioral abnormalities. Recent studies have identified a connection between the gut microbiota and METH-induced neurotoxicity and behavioral disorders. However, the underlying causal mechanisms linking the gut microbiota to METH pathophysiology remain largely unexplored. In this study, we employed fecal microbiota transplantation (FMT) and antibiotic (Abx) intervention to manipulate the gut microbiota in mice administered METH. Furthermore, we supplemented METH-treated mice with short-chain fatty acids (SCFAs) and pioglitazone (Pio) to determine the protective effects on gut microbiota metabolism. Finally, we assessed the underlying mechanisms of the gut–brain neural circuit in vagotomized mice. Our data provide compelling evidence that modulation of the gut microbiome through FMT or microbiome knockdown by Abx plays a crucial role in METH-induced neurotoxicity, behavioral disorders, gut microbiota disturbances, and intestinal barrier impairment. Furthermore, our findings highlight a novel prevention strategy for mitigating the risks to both the nervous and intestinal systems caused by METH, which involves supplementation with SCFAs or Pio.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"34 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186911","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

Sunlenca® (Lenacapavir): A first-in-class, long-acting HIV-1 capsid inhibitor for treating highly multidrug-resistant HIV-1 infection Sunlenca®（来那卡韦）：治疗高度耐多药 HIV-1 感染的一流长效 HIV-1 外壳抑制剂

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-14 DOI: 10.1016/j.apsb.2024.08.009

Chunhua Ma, Junbiao Chang, Bin Yu

引用次数: 0

Cell carriers change the in vivo fate of nanoparticles 细胞载体改变纳米粒子的体内命运

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-14 DOI: 10.1016/j.apsb.2024.08.011

Xiaotong Li, Jianhua He, Wei He

引用次数: 0

Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria 纳米工程线粒体可通过替代功能障碍线粒体治疗眼部线粒体疾病

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-13 DOI: 10.1016/j.apsb.2024.08.007

Yi Wang, Nahui Liu, Lifan Hu, Jingsong Yang, Mengmeng Han, Tianjiao Zhou, Lei Xing, Hulin Jiang

{"title":"Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria","authors":"Yi Wang, Nahui Liu, Lifan Hu, Jingsong Yang, Mengmeng Han, Tianjiao Zhou, Lei Xing, Hulin Jiang","doi":"10.1016/j.apsb.2024.08.007","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.007","url":null,"abstract":"Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing it. Herein, mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"7 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186915","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

Real-time platelet P2Y12 receptor occupancy as a promising pharmacodynamics biomarker for bridging the gap between PK/PD of clopidogrel therapy 实时血小板 P2Y12 受体占据率是一种很有前景的药效学生物标记物，可弥合氯吡格雷治疗的 PK/PD 差距

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-13 DOI: 10.1016/j.apsb.2024.08.008

Haipeng Li, Yueming Gu, Yumeng Zhao, Aiyun Xu, Dong Sun, Jingkai Gu

{"title":"Real-time platelet P2Y12 receptor occupancy as a promising pharmacodynamics biomarker for bridging the gap between PK/PD of clopidogrel therapy","authors":"Haipeng Li, Yueming Gu, Yumeng Zhao, Aiyun Xu, Dong Sun, Jingkai Gu","doi":"10.1016/j.apsb.2024.08.008","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.008","url":null,"abstract":"Clopidogrel effectively inhibits platelet aggregation in response to ADP by irreversibly binding to the platelet P2Y receptor through its active metabolite. However, the observed discrepancies between the pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel present substantial challenges in individualizing of antiplatelet therapy. To address these challenges, a robust liquid chromatography–tandem mass spectrometry method has been developed to facilitate the real-time assessment of platelet P2Y receptor occupancy. This method has been validated in animal models, providing a reliable link between individual PK profiles and PD effects. Target receptor occupancy offers a comprehensive overview of interindividual variations in clopidogrel metabolism, regulation of P2Y receptor expression, and platelet turnover. Moreover, it directly correlates with the inhibitory effect on platelet aggregation. The levels of platelet P2Y occupancy accurately reflect the extent of clinical factors influencing the PD of clopidogrel, including dosage, drug–drug interactions (DDI), and type 2 diabetes mellitus (T2DM). As a normalized metric, platelet P2Y occupancy not only serves potential as a diagnostic tool for personalized clopidogrel therapy but also aids in elucidating the role of the P2Y signaling pathway in cases of abnormal on-treatment platelet reactivity.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186941","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

Immunometabolic rewiring in macrophages for periodontitis treatment via nanoquercetin-mediated leverage of glycolysis and OXPHOS 通过纳米槲皮素介导的糖酵解和 OXPHOS杠杆作用，重构巨噬细胞的免疫代谢线路，从而治疗牙周炎

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-12 DOI: 10.1016/j.apsb.2024.07.008

Yi Zhang, Junyu Shi, Jie Zhu, Xinxin Ding, Jianxu Wei, Xue Jiang, Yijie Yang, Xiaomeng Zhang, Yongzhuo Huang, Hongchang Lai

{"title":"Immunometabolic rewiring in macrophages for periodontitis treatment via nanoquercetin-mediated leverage of glycolysis and OXPHOS","authors":"Yi Zhang, Junyu Shi, Jie Zhu, Xinxin Ding, Jianxu Wei, Xue Jiang, Yijie Yang, Xiaomeng Zhang, Yongzhuo Huang, Hongchang Lai","doi":"10.1016/j.apsb.2024.07.008","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.07.008","url":null,"abstract":"Periodontitis is a chronic inflammatory disease marked by a dysregulated immune microenvironment, posing formidable challenges for effective treatment. The disease is characterized by an altered glucose metabolism in macrophages, specifically an increase in aerobic glycolysis, which is linked to heightened inflammatory responses. This suggests that targeting macrophage metabolism could offer a new therapeutic avenue. In this study, we develop an immunometabolic intervention using quercetin (Q) encapsulated in bioadhesive mesoporous polydopamine (Q@MPDA) to treat periodontitis. Our results demonstrate that Q@MPDA can reprogram inflammatory macrophages to an anti-inflammatory phenotype (, from-M1-to-M2 repolarization). In a murine periodontitis model, locally administered Q@MPDA reduced the presence of inflammatory macrophages, and decreased the levels of inflammatory cytokines (IL-1 and TNF-) and reactive oxygen species (ROS) in the periodontium. Consequently, it alleviated periodontitis symptoms, reduced alveolar bone loss, and promoted tissue repair. Furthermore, our study revealed that Q@MPDA could inhibit the glycolysis of inflammatory macrophages while enhancing oxidative phosphorylation (OXPHOS), facilitating the shift from M1 to M2 macrophage subtype. Our findings suggest that Q@MPDA is a promising treatment for periodontitis immunometabolic rewiring.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"33 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186919","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

GPR17 modulates anxiety-like behaviors via basolateral amygdala to ventral hippocampal CA1 glutamatergic projection GPR17 通过杏仁核基底外侧到海马 CA1 腹侧的谷氨酸能投射调节焦虑样行为

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-10 DOI: 10.1016/j.apsb.2024.08.005

Ruizhe Nie, Xinting Zhou, Jiaru Fu, Shanshan Hu, Qilu Zhang, Weikai Jiang, Yizi Yan, Xian Cao, Danhua Yuan, Yan Long, Hao Hong, Susu Tang

{"title":"GPR17 modulates anxiety-like behaviors via basolateral amygdala to ventral hippocampal CA1 glutamatergic projection","authors":"Ruizhe Nie, Xinting Zhou, Jiaru Fu, Shanshan Hu, Qilu Zhang, Weikai Jiang, Yizi Yan, Xian Cao, Danhua Yuan, Yan Long, Hao Hong, Susu Tang","doi":"10.1016/j.apsb.2024.08.005","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.005","url":null,"abstract":"Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, electrophysiology recordings, fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"5 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186922","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

Future prospects in clinical translation of inorganic nanoparticles 无机纳米粒子临床转化的未来前景

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-08 DOI: 10.1016/j.apsb.2024.08.001

Ke Xu, Ying Liu, Chunying Chen

引用次数: 0

Novel benzothiazole derivatives target the Gac/Rsm two-component system as antibacterial synergists against Pseudomonas aeruginosa infections 以 Gac/Rsm 双组分系统为靶点的新型苯并噻唑衍生物是铜绿假单胞菌感染的抗菌增效剂

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-08-08 DOI: 10.1016/j.apsb.2024.08.002

Jun Liu, Wenfu Wu, Jiayi Hu, Siyu Zhao, Yiqun Chang, Qiuxian Chen, Yujie Li, Jie Tang, Zhenmeng Zhang, Xiao Wu, Shumeng Jiao, Haichuan Xiao, Qiang Zhang, Jiarui Du, Jianfu Zhao, Kaihe Ye, Meiyan Huang, Jun Xu, Haibo Zhou, Junxia Zheng, Pinghua Sun

{"title":"Novel benzothiazole derivatives target the Gac/Rsm two-component system as antibacterial synergists against Pseudomonas aeruginosa infections","authors":"Jun Liu, Wenfu Wu, Jiayi Hu, Siyu Zhao, Yiqun Chang, Qiuxian Chen, Yujie Li, Jie Tang, Zhenmeng Zhang, Xiao Wu, Shumeng Jiao, Haichuan Xiao, Qiang Zhang, Jiarui Du, Jianfu Zhao, Kaihe Ye, Meiyan Huang, Jun Xu, Haibo Zhou, Junxia Zheng, Pinghua Sun","doi":"10.1016/j.apsb.2024.08.002","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.002","url":null,"abstract":"The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, (IC = 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations . In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating -derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that significantly augmented the antibacterial effects of three widely used antibiotics—tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)—compared with single-dose antibiotic treatments for infection . The findings of this study suggest the potential of as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"10 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186923","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