首页 > 最新文献

Pharmacological research最新文献

英文 中文
Suppression of ZEB1 by Ethyl caffeate attenuates renal fibrosis via switching glycolytic reprogramming 咖啡酸乙酯抑制 ZEB1 可通过切换糖酵解重编程减轻肾脏纤维化。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-11 DOI: 10.1016/j.phrs.2024.107407
Renal fibrosis (RF) is a common endpoint of various chronic kidney diseases, leading to functional impairment and ultimately progressing to end-stage renal failure. Glycolytic reprogramming plays a critical role in the pathogenesis of fibrosis, which maybe a potential therapeutic target for treating renal fibrosis. Here, we revealed the novel role of ZEB1 in renal fibrosis, and whether targeting ZEB1 is the underlying mechanism for the anti-fibrotic effects of ethyl caffeate (EC) to regulate the glycolytic process. Treatment of EC attenuated the renal fibrosis and inhibited ZEB1 expression in vivo and in vitro, reducing the upregulated expression of glycolytic enzymes (HK2, PKM2, PFKP) and key metabolites (lactic acid, pyruvate). ZEB1 overexpression promoted the renal fibrosis and glycolysis, whereas knockout of ZEB1 apparently attenuated renal fibrosis in vivo and in vitro. EC interacted with ZEB1 to modulate the glycolytic enzymes for suppressing the elevated glycolytic reprogramming during renal fibrosis. In summary, our study reveals that ZEB1 plays an important role in regulating glycolytic reprogramming during the renal tubular epithelial cell fibrosis, suggesting inhibition of ZEB1 may be a potential strategy for treating renal fibrosis. Additionally, EC is a potential new drug candidate for the treatment of renal fibrosis and CKD.
肾脏纤维化(RF)是各种慢性肾脏疾病的常见终点,会导致功能损害并最终发展为终末期肾衰竭。糖酵解重编程在肾脏纤维化的发病机制中起着关键作用,这也许是治疗肾脏纤维化的潜在治疗靶点。在这里,我们揭示了ZEB1在肾脏纤维化中的新作用,以及靶向ZEB1是否是咖啡酸乙酯(EC)调节糖酵解过程从而发挥抗纤维化作用的潜在机制。咖啡酸乙酯能减轻肾脏纤维化,抑制体内和体外ZEB1的表达,减少糖酵解酶(HK2、PKM2、PFKP)和关键代谢产物(乳酸、丙酮酸)的上调表达。ZEB1 过表达会促进肾脏纤维化和糖酵解,而敲除 ZEB1 则会明显减轻体内和体外的肾脏纤维化。EC与ZEB1相互作用,调节糖酵解酶,从而抑制肾脏纤维化过程中升高的糖酵解重编程。总之,我们的研究揭示了 ZEB1 在肾小管上皮细胞纤维化过程中调节糖酵解重编程的重要作用,这表明抑制 ZEB1 可能是治疗肾纤维化的一种潜在策略。此外,EC还是治疗肾脏纤维化和慢性肾脏病的潜在候选新药。
{"title":"Suppression of ZEB1 by Ethyl caffeate attenuates renal fibrosis via switching glycolytic reprogramming","authors":"","doi":"10.1016/j.phrs.2024.107407","DOIUrl":"10.1016/j.phrs.2024.107407","url":null,"abstract":"<div><div>Renal fibrosis (RF) is a common endpoint of various chronic kidney diseases, leading to functional impairment and ultimately progressing to end-stage renal failure. Glycolytic reprogramming plays a critical role in the pathogenesis of fibrosis, which maybe a potential therapeutic target for treating renal fibrosis. Here, we revealed the novel role of ZEB1 in renal fibrosis, and whether targeting ZEB1 is the underlying mechanism for the anti-fibrotic effects of ethyl caffeate (EC) to regulate the glycolytic process. Treatment of EC attenuated the renal fibrosis and inhibited ZEB1 expression <em>in vivo</em> and <em>in vitro</em>, reducing the upregulated expression of glycolytic enzymes (HK2, PKM2, PFKP) and key metabolites (lactic acid, pyruvate). ZEB1 overexpression promoted the renal fibrosis and glycolysis, whereas knockout of ZEB1 apparently attenuated renal fibrosis <em>in vivo</em> and <em>in vitro</em>. EC interacted with ZEB1 to modulate the glycolytic enzymes for suppressing the elevated glycolytic reprogramming during renal fibrosis. In summary, our study reveals that ZEB1 plays an important role in regulating glycolytic reprogramming during the renal tubular epithelial cell fibrosis, suggesting inhibition of ZEB1 may be a potential strategy for treating renal fibrosis. Additionally, EC is a potential new drug candidate for the treatment of renal fibrosis and CKD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003529/pdfft?md5=a00d2024b82c8f4b29e0a5aa3d9980a5&pid=1-s2.0-S1043661824003529-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Gut-vascular axis and postbiotics: The need for clear definitions and further research 肠道-血管轴和益生菌后:需要明确定义和进一步研究
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-11 DOI: 10.1016/j.phrs.2024.107405
{"title":"Gut-vascular axis and postbiotics: The need for clear definitions and further research","authors":"","doi":"10.1016/j.phrs.2024.107405","DOIUrl":"10.1016/j.phrs.2024.107405","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003505/pdfft?md5=e0f3d76c0e00564bf2cb781dd7738823&pid=1-s2.0-S1043661824003505-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Development of dual GPBAR1 agonist and RORγt inverse agonist for the treatment of inflammatory bowel diseases 开发用于治疗炎症性肠病的 GPBAR1 双激动剂和 RORγt 反向激动剂
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-10 DOI: 10.1016/j.phrs.2024.107403

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through in vitro and in vivo experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects in vivo were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In in vitro, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1-/-, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.

包括克罗恩病和溃疡性结肠炎在内的炎症性肠病(IBD)是以免疫反应失调和持续炎症为特征的慢性疾病。最新研究表明,胆汁酸受体(尤其是 GPBAR1)和转录因子 RORγt 在调节肠道炎症中发挥着关键作用。本研究评估了 PBT002(一种 GPBAR1 双激动剂和 RORγt 反向激动剂)在 IBD 模型中的治疗潜力。我们通过体外和体内实验评估了 PBT002 的作用。从水疱中提取的巨噬细胞和 T 淋巴细胞暴露于 PBT002,以评估其免疫调节活性。在 TNBS、DSS 或 DSS + IL-23 诱导的小鼠结肠炎模型中,也使用了 Gpbar1 基因敲除的雄性小鼠,对其体内的有益效果进行了评估。PBT002 对 GPBAR1 的 EC50 值为 1.2 µM,对 RORγt 的 IC50 值为 2.8 µM。在体外,PBT002 可调节巨噬细胞向抗炎 M2 表型极化,减少 Th17 细胞标记物,同时增加 Treg 标记物。在 TNBS 诱导的结肠炎模型中,PBT002 可减少体重下降、CDAI 和结肠损伤,同时调节细胞因子基因的表达,使其趋于抗炎。在 GPBAR1-/- 中,PBT002 的抗炎作用减弱,这表明它部分依赖于 GPBAR1。RNA 测序显示 PBT002 对炎症通路有明显的调节作用。在 DSS+IL-23 诱导的结肠炎中,PBT002 可减轻疾病恶化,降低促炎细胞因子水平和免疫细胞浸润。总之,PBT002 是一种 GPBAR1 激动剂和 RORγt 反向激动剂,它能调节先天性免疫反应和适应性免疫反应,从而减轻 IBD 模型中的炎症和疾病严重程度。
{"title":"Development of dual GPBAR1 agonist and RORγt inverse agonist for the treatment of inflammatory bowel diseases","authors":"","doi":"10.1016/j.phrs.2024.107403","DOIUrl":"10.1016/j.phrs.2024.107403","url":null,"abstract":"<div><p>Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through <em>in vitro</em> and <em>in vivo</em> experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects <em>in vivo</em> were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In <em>in vitro</em>, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1<sup>-/-</sup>, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003487/pdfft?md5=28b5877642e9d0f3d4ba6b3924eacde3&pid=1-s2.0-S1043661824003487-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142229113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Age-related macular degeneration (AMD) is a detrimental eye disease, and the most common cause of visual loss in many countries around the world 老年黄斑变性(AMD)是一种有害的眼病,也是世界上许多国家最常见的视力丧失原因。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-10 DOI: 10.1016/j.phrs.2024.107402
{"title":"Age-related macular degeneration (AMD) is a detrimental eye disease, and the most common cause of visual loss in many countries around the world","authors":"","doi":"10.1016/j.phrs.2024.107402","DOIUrl":"10.1016/j.phrs.2024.107402","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003475/pdfft?md5=21918934b5613bd64bd2bae3f4a8ce06&pid=1-s2.0-S1043661824003475-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Glucagon-like peptide-1 receptor agonists and risk of gastrointestinal cancers: A systematic review and meta-analysis of randomized controlled trials 胰高血糖素样肽-1 受体激动剂与胃肠道癌症风险:随机对照试验的系统回顾和荟萃分析
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-07 DOI: 10.1016/j.phrs.2024.107401

Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used for glucose lowering and weight-loss. However, their association with gastrointestinal cancer remains uncertain. This meta-analysis assesses the risk of gastrointestinal cancer in patients treated with GLP-1 RAs.

Methods

We searched Medline/PubMed, Embase, and Scopus databases from inception to November 15, 2023, for randomized controlled trials (RCTs) with at least 24 weeks of safety follow-up. Pooled risk ratios (RRs) were calculated using fixed- and random-effect models. Risk of bias was assessed using the revised Cochrane risk-of-bias tool, and certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.

Results

We included 90 RCTs with 124,791 participants, with an average follow-up of 3.1 years per participant. No significant association was found between GLP-1 RAs and the risk of any gastrointestinal cancer (RRrandom=0.99, 95 % CI: 0.86−1.13), or site-specific gastrointestinal cancers including biliary tract (RR=0.98, 0.54−1.78), colorectal (RR=1.13, 0.92−1.39), gallbladder (RR=1.32, 0.43−4.00), gastric (RR=0.88, 0.58−1.33), hepatic (RR=0.79, 0.51−1.21), oesophageal (RR=0.70, 0.38−1.28), pancreatic (RR=1.05, 0.77−1.43), and small intestine cancer (RR=0.78, 0.20−3.04). The corresponding absolute risk differences excluded important impacts on risk. Additional analyses, limited to placebo-controlled trials, high-dose studies, or those with a follow-up duration of ≥5 years, confirmed these findings. Risk of bias was generally low and the certainty of evidence was high for all outcomes.

Conclusions

This meta-analysis found no significant impact of GLP-1 RAs on gastrointestinal cancer risk. Long-term safety monitoring of these agents remains important.

Systematic review registration

CRD42023476762.

背景胰高血糖素样肽-1 受体激动剂(GLP-1 RAs)常用于降糖和减肥。然而,它们与胃肠道癌症的关系仍不确定。本荟萃分析评估了接受 GLP-1 RAs 治疗的患者罹患胃肠道癌症的风险。方法我们检索了 Medline/PubMed、Embase 和 Scopus 数据库中从开始到 2023 年 11 月 15 日至少有 24 周安全随访的随机对照试验 (RCT)。采用固定效应和随机效应模型计算汇总风险比 (RR)。采用修订版 Cochrane 偏倚风险工具评估偏倚风险,采用建议评估、发展和评价分级(GRADE)框架确定证据的确定性。没有发现 GLP-1 RAs 与任何胃肠道癌症(RRrandom=0.99,95 % CI:0.86-1.13)或特定部位胃肠道癌症(包括胆道癌(RR=0.98,0.54-1.78)、结直肠癌(RR=1.13,0.92-1.39)、胆囊癌(RR=1.32,0.43-4.00)、胃癌(RR=0.88,0.58-1.33)、肝癌(RR=0.79,0.51-1.21)、食道癌(RR=0.70,0.38-1.28)、胰腺癌(RR=1.05,0.77-1.43)和小肠癌(RR=0.78,0.20-3.04)。相应的绝对风险差异排除了对风险的重要影响。仅限于安慰剂对照试验、高剂量研究或随访时间≥5年的其他分析证实了这些发现。结论这项荟萃分析发现,GLP-1 RAs 对胃肠道癌症风险没有显著影响。对这些药物进行长期安全监测仍然非常重要。
{"title":"Glucagon-like peptide-1 receptor agonists and risk of gastrointestinal cancers: A systematic review and meta-analysis of randomized controlled trials","authors":"","doi":"10.1016/j.phrs.2024.107401","DOIUrl":"10.1016/j.phrs.2024.107401","url":null,"abstract":"<div><h3>Background</h3><p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used for glucose lowering and weight-loss. However, their association with gastrointestinal cancer remains uncertain. This meta-analysis assesses the risk of gastrointestinal cancer in patients treated with GLP-1 RAs.</p></div><div><h3>Methods</h3><p>We searched Medline/PubMed, Embase, and Scopus databases from inception to November 15, 2023, for randomized controlled trials (RCTs) with at least 24 weeks of safety follow-up. Pooled risk ratios (RRs) were calculated using fixed- and random-effect models. Risk of bias was assessed using the revised Cochrane risk-of-bias tool, and certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.</p></div><div><h3>Results</h3><p>We included 90 RCTs with 124,791 participants, with an average follow-up of 3.1 years per participant. No significant association was found between GLP-1 RAs and the risk of any gastrointestinal cancer (RR<sub>random</sub>=0.99, 95 % CI: 0.86−1.13), or site-specific gastrointestinal cancers including biliary tract (RR=0.98, 0.54−1.78), colorectal (RR=1.13, 0.92−1.39), gallbladder (RR=1.32, 0.43−4.00), gastric (RR=0.88, 0.58−1.33), hepatic (RR=0.79, 0.51−1.21), oesophageal (RR=0.70, 0.38−1.28), pancreatic (RR=1.05, 0.77−1.43), and small intestine cancer (RR=0.78, 0.20−3.04). The corresponding absolute risk differences excluded important impacts on risk. Additional analyses, limited to placebo-controlled trials, high-dose studies, or those with a follow-up duration of ≥5 years, confirmed these findings. Risk of bias was generally low and the certainty of evidence was high for all outcomes.</p></div><div><h3>Conclusions</h3><p>This meta-analysis found no significant impact of GLP-1 RAs on gastrointestinal cancer risk. Long-term safety monitoring of these agents remains important.</p></div><div><h3>Systematic review registration</h3><p>CRD42023476762.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003463/pdfft?md5=b09020c3cbb46c26ef9172af7132514f&pid=1-s2.0-S1043661824003463-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Janus effect of colloidal self-assembly on the biological response of amphiphilic drugs 胶体自组装对两亲药物生物反应的杰纳斯效应
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-07 DOI: 10.1016/j.phrs.2024.107400

In aqueous environment amphiphilic molecules organize themselves into supramolecular structures deeply affecting the chemo-physical properties. Supramolecular assemby is also crucial in the pharmaceutical development of bioactive lipophilic molecules whose attitude to self-aggregate is a recognized factor affecting the in vivo pharmacokinetic, but can also play a crucial role in the interaction with the biological targets in in vitro tests. In aqueous solution, amphiphilic drugs exist in a complex equilibrium involving free monomers, oligomers and larger supramolecular aggregates held together by noncovalent bonds. In this review we focus our attention on the dual effect of drugs self-assembly, which can both reduce the availability of active compounds and create multivalent scaffolds, potentially improving binding affinity and avidity to cellular targets. We examine the effect of aggregation on different classes of amphiphatic molecules with significant biological activities, such as immunomodulatory, anti-tumor, antiviral, and antibiotic.

Our purpose is to provide a comprehensive overview of how supramolecular chemistry influences the pharmacological and biological responses of amphiphilic molecules, emphasizing the need to consider these effects in early-stage drug development and in vitro testing. By elucidating these phenomena, this review aims to offer insights into optimizing drug design and formulation to overcome challenges posed by self-aggregation.

在水环境中,两亲性分子会自行组织成超分子结构,从而对化学物理性质产生深刻影响。超分子组装也是生物活性亲脂分子药物开发的关键,其自我聚集的态度是公认的影响体内药代动力学的因素,但在体外试验中也会在与生物靶标的相互作用中发挥关键作用。在水溶液中,两亲性药物处于一种复杂的平衡状态,包括自由单体、低聚物和由非共价键结合在一起的较大的超分子聚集体。在这篇综述中,我们将重点关注药物自组装的双重效应,它既能减少活性化合物的可用性,又能创造多价支架,从而有可能提高与细胞靶点的结合亲和力和热敏性。我们的目的是全面概述超分子化学如何影响两亲分子的药理和生物反应,强调在早期药物开发和体外测试中考虑这些效应的必要性。通过阐明这些现象,本综述旨在为优化药物设计和配方提供见解,以克服自聚集带来的挑战。
{"title":"The Janus effect of colloidal self-assembly on the biological response of amphiphilic drugs","authors":"","doi":"10.1016/j.phrs.2024.107400","DOIUrl":"10.1016/j.phrs.2024.107400","url":null,"abstract":"<div><p>In aqueous environment amphiphilic molecules organize themselves into supramolecular structures deeply affecting the chemo-physical properties. Supramolecular assemby is also crucial in the pharmaceutical development of bioactive lipophilic molecules whose attitude to self-aggregate is a recognized factor affecting the <em>in vivo</em> pharmacokinetic, but can also play a crucial role in the interaction with the biological targets in <em>in vitro</em> tests. In aqueous solution, amphiphilic drugs exist in a complex equilibrium involving free monomers, oligomers and larger supramolecular aggregates held together by noncovalent bonds. In this review we focus our attention on the dual effect of drugs self-assembly, which can both reduce the availability of active compounds and create multivalent scaffolds, potentially improving binding affinity and avidity to cellular targets. We examine the effect of aggregation on different classes of amphiphatic molecules with significant biological activities, such as immunomodulatory, anti-tumor, antiviral, and antibiotic.</p><p>Our purpose is to provide a comprehensive overview of how supramolecular chemistry influences the pharmacological and biological responses of amphiphilic molecules, emphasizing the need to consider these effects in early-stage drug development and <em>in vitro</em> testing. By elucidating these phenomena, this review aims to offer insights into optimizing drug design and formulation to overcome challenges posed by self-aggregation.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003451/pdfft?md5=58af0853ab6e131116a929bfa8905410&pid=1-s2.0-S1043661824003451-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142164241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Novel hypothalamic pathways for metabolic effects of spexin 丝氨酸代谢效应的新型下丘脑途径。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-07 DOI: 10.1016/j.phrs.2024.107399

One of the main underlying etiologies of type 2 diabetes (T2DM) is insulin resistance, which is most frequently caused by obesity. Notably, the deregulation of adipokine secretion from visceral adiposity has been identified as a crucial characteristic of type 2 diabetes and obesity. Spexin is an adipokine that is released by many different tissues, including white adipocytes and the glandular stomach, and is negatively connected with the state of energy storage. This peptide acts through GALR2/3 receptors to control a wide range of metabolic processes, including inflammation, browning, lipolysis, energy expenditure, and eating behavior. Specifically, spexin can enter the hypothalamus and regulate the hypothalamic melanocortin system, which in turn balances energy expenditure and food intake. This review examines recent advances and the underlying mechanisms of spexin in obesity and T2DM. In particular, we address a range of topics from basic research to clinical findings, such as an analysis of the possible function of spexin in the hypothalamic melanocortin response, which involves reducing energy intake and increasing energy expenditure while also enhancing insulin sensitivity and glucose tolerance. Gaining more insight into the mechanisms that underlie the spexin system's control over energy metabolism and homeostasis may facilitate the development of innovative treatment approaches that focus on combating obesity and diabetes.

2 型糖尿病(T2DM)的主要病因之一是胰岛素抵抗,而胰岛素抵抗最常见的原因是肥胖。值得注意的是,内脏脂肪分泌脂肪因子的失调已被确定为 2 型糖尿病和肥胖症的一个重要特征。Spexin 是一种由包括白色脂肪细胞和腺胃在内的许多不同组织释放的脂肪因子,与能量储存状态呈负相关。这种肽通过 GALR2/3 受体发挥作用,控制一系列新陈代谢过程,包括炎症、褐变、脂肪分解、能量消耗和进食行为。具体来说,spexin 可进入下丘脑并调节下丘脑黑皮质素系统,进而平衡能量消耗和食物摄入。本综述探讨了肥胖症和 T2DM 中 spexin 的最新研究进展和内在机制。我们特别探讨了从基础研究到临床发现的一系列主题,例如分析了spexin在下丘脑黑皮质素反应中可能发挥的功能,这包括减少能量摄入和增加能量消耗,同时还能增强胰岛素敏感性和葡萄糖耐量。更深入地了解spexin系统控制能量代谢和平衡的机制,可能有助于开发创新的治疗方法,重点防治肥胖症和糖尿病。
{"title":"Novel hypothalamic pathways for metabolic effects of spexin","authors":"","doi":"10.1016/j.phrs.2024.107399","DOIUrl":"10.1016/j.phrs.2024.107399","url":null,"abstract":"<div><p>One of the main underlying etiologies of type 2 diabetes (T2DM) is insulin resistance, which is most frequently caused by obesity. Notably, the deregulation of adipokine secretion from visceral adiposity has been identified as a crucial characteristic of type 2 diabetes and obesity. Spexin is an adipokine that is released by many different tissues, including white adipocytes and the glandular stomach, and is negatively connected with the state of energy storage. This peptide acts through GALR2/3 receptors to control a wide range of metabolic processes, including inflammation, browning, lipolysis, energy expenditure, and eating behavior. Specifically, spexin can enter the hypothalamus and regulate the hypothalamic melanocortin system, which in turn balances energy expenditure and food intake. This review examines recent advances and the underlying mechanisms of spexin in obesity and T2DM. In particular, we address a range of topics from basic research to clinical findings, such as an analysis of the possible function of spexin in the hypothalamic melanocortin response, which involves reducing energy intake and increasing energy expenditure while also enhancing insulin sensitivity and glucose tolerance. Gaining more insight into the mechanisms that underlie the spexin system's control over energy metabolism and homeostasis may facilitate the development of innovative treatment approaches that focus on combating obesity and diabetes.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S104366182400344X/pdfft?md5=0b2bcdbceb718b2eb7916cef31f47eb8&pid=1-s2.0-S104366182400344X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Multi-omics analysis of gut-brain axis reveals novel microbial and neurotransmitter signatures in patients with arteriosclerotic cerebral small vessel disease 对肠道-大脑轴的多指标分析揭示了动脉硬化性脑小血管疾病患者体内新的微生物和神经递质特征
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-06 DOI: 10.1016/j.phrs.2024.107385

Arteriosclerotic cerebral small vessel disease (aCSVD) is a major cause of stroke and dementia. Although its underlying pathogenesis remains poorly understood, both inflammaging and gut microbiota dysbiosis have been hypothesized to play significant roles. This study investigated the role of gut microbiota in the pathogenesis of aCSVD through a comparative analysis of the gut microbiome and metabolome between CSVD patients and healthy controls. The results showed that patients with aCSVD exhibited a marked reduction in potentially beneficial bacterial species, such as Faecalibacterium prausnitzli and Roseburia intestinalis, alongside an increase in taxa from Bacteroides and Proteobacteria. Integrated metagenomic and metabolomic analyses revealed that alterations in microbial metabolic pathways, including LPS biosynthesis and phenylalanine-tyrosine metabolism, were associated with the status of aCSVD. Our findings indicated that microbial LPS biosynthesis and phenylalanine-tyrosine metabolism potentially influenced the symptoms and progression of aCSVD via pro-inflammatory effect and modulation of systemic neurotransmitters, respectively. These results imply that gut microbiota characteristics may serve as indicators for early detection of aCSVD and as potential gut-directed therapeutic intervention target.

动脉硬化性脑小血管病(aCSVD)是导致中风和痴呆的主要原因。尽管人们对其潜在的发病机制仍知之甚少,但炎症和肠道微生物群失调被认为在其中发挥了重要作用。本研究通过对比分析 CSVD 患者和健康对照组的肠道微生物组和代谢组,研究了肠道微生物组在 aCSVD 发病机制中的作用。结果显示,aCSVD 患者体内潜在的有益细菌种类明显减少,如Faecalibacterium prausnitzli和Roseburia intestinalis,同时乳杆菌和变形菌类群增加。综合元基因组学和代谢组学分析表明,微生物代谢途径(包括 LPS 生物合成和苯丙氨酸-酪氨酸代谢)的改变与 aCSVD 的状况有关。我们的研究结果表明,微生物的LPS生物合成和苯丙氨酸-酪氨酸代谢可能会分别通过促炎作用和调节全身神经递质来影响心血管疾病的症状和进展。这些结果表明,肠道微生物群特征可作为早期检测心血管缺血性疾病的指标和潜在的肠道定向治疗干预目标。
{"title":"Multi-omics analysis of gut-brain axis reveals novel microbial and neurotransmitter signatures in patients with arteriosclerotic cerebral small vessel disease","authors":"","doi":"10.1016/j.phrs.2024.107385","DOIUrl":"10.1016/j.phrs.2024.107385","url":null,"abstract":"<div><p>Arteriosclerotic cerebral small vessel disease (aCSVD) is a major cause of stroke and dementia. Although its underlying pathogenesis remains poorly understood, both inflammaging and gut microbiota dysbiosis have been hypothesized to play significant roles. This study investigated the role of gut microbiota in the pathogenesis of aCSVD through a comparative analysis of the gut microbiome and metabolome between CSVD patients and healthy controls. The results showed that patients with aCSVD exhibited a marked reduction in potentially beneficial bacterial species, such as <em>Faecalibacterium prausnitzli</em> and <em>Roseburia intestinalis</em>, alongside an increase in taxa from Bacteroides and Proteobacteria. Integrated metagenomic and metabolomic analyses revealed that alterations in microbial metabolic pathways, including LPS biosynthesis and phenylalanine-tyrosine metabolism, were associated with the status of aCSVD. Our findings indicated that microbial LPS biosynthesis and phenylalanine-tyrosine metabolism potentially influenced the symptoms and progression of aCSVD via pro-inflammatory effect and modulation of systemic neurotransmitters, respectively. These results imply that gut microbiota characteristics may serve as indicators for early detection of aCSVD and as potential gut-directed therapeutic intervention target.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S104366182400330X/pdfft?md5=cc30885785018985ee6a86be93a5eb59&pid=1-s2.0-S104366182400330X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The bioenergetics of traumatic brain injury and its long-term impact for brain plasticity and function 创伤性脑损伤的生物能及其对大脑可塑性和功能的长期影响。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-05 DOI: 10.1016/j.phrs.2024.107389

Mitochondria provide the energy to keep cells alive and functioning and they have the capacity to influence highly complex molecular events. Mitochondria are essential to maintain cellular energy homeostasis that determines the course of neurological disorders, including traumatic brain injury (TBI). Various aspects of mitochondria metabolism such as autophagy can have long-term consequences for brain function and plasticity. In turn, mitochondria bioenergetics can impinge on molecular events associated with epigenetic modifications of DNA, which can extend cellular memory for a long time. Mitochondrial dysfunction leads to pathological manifestations such as oxidative stress, inflammation, and calcium imbalance that threaten brain plasticity and function. Hence, targeting mitochondrial function may have great potential to lessen the outcomes of TBI.

线粒体为细胞的存活和运作提供能量,并有能力影响高度复杂的分子事件。线粒体对维持细胞能量平衡至关重要,而能量平衡决定着神经系统疾病(包括创伤性脑损伤)的病程。线粒体新陈代谢的各个方面(如自噬)会对大脑功能和可塑性产生长期影响。反过来,线粒体生物能又会影响与 DNA 表观遗传修饰相关的分子事件,从而将细胞记忆延长很长时间。线粒体功能障碍会导致氧化应激、炎症和钙失衡等病理表现,威胁大脑的可塑性和功能。因此,以线粒体功能为靶点可能具有减轻创伤性脑损伤后果的巨大潜力。
{"title":"The bioenergetics of traumatic brain injury and its long-term impact for brain plasticity and function","authors":"","doi":"10.1016/j.phrs.2024.107389","DOIUrl":"10.1016/j.phrs.2024.107389","url":null,"abstract":"<div><p>Mitochondria provide the energy to keep cells alive and functioning and they have the capacity to influence highly complex molecular events. Mitochondria are essential to maintain cellular energy homeostasis that determines the course of neurological disorders, including traumatic brain injury (TBI). Various aspects of mitochondria metabolism such as autophagy can have long-term consequences for brain function and plasticity. In turn, mitochondria bioenergetics can impinge on molecular events associated with epigenetic modifications of DNA, which can extend cellular memory for a long time. Mitochondrial dysfunction leads to pathological manifestations such as oxidative stress, inflammation, and calcium imbalance that threaten brain plasticity and function. Hence, targeting mitochondrial function may have great potential to lessen the outcomes of TBI.</p></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003347/pdfft?md5=363d1b4d55eed5fe951f506efffd6ece&pid=1-s2.0-S1043661824003347-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Corrigendum to “GPR37 promotes cancer growth by binding to CDK6 and represents a new theranostic target in lung adenocarcinoma”[Pharmacol. Res. 183 (2022) 106389] 更正:"GPR37 通过与 CDK6 结合促进癌症生长,是肺腺癌的新治疗靶点"[《药理学研究》183 (2022) 106389]。
IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-05 DOI: 10.1016/j.phrs.2024.107391
{"title":"Corrigendum to “GPR37 promotes cancer growth by binding to CDK6 and represents a new theranostic target in lung adenocarcinoma”[Pharmacol. Res. 183 (2022) 106389]","authors":"","doi":"10.1016/j.phrs.2024.107391","DOIUrl":"10.1016/j.phrs.2024.107391","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":null,"pages":null},"PeriodicalIF":9.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1043661824003360/pdfft?md5=4e04df07c67f973d9d849d4605780f77&pid=1-s2.0-S1043661824003360-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
期刊
Pharmacological research
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1