ACS Medicinal Chemistry Letters最新文献

英文中文

Vascular occlusion for optimising the functional improvement in patients with knee osteoarthritis: a randomised controlled trial. 通过血管闭塞优化膝关节骨性关节炎患者的功能改善：随机对照试验。

IF 20.3 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1136/ard-2024-226579

Ewoud Jacobs, Lenka Stroobant, Jan Victor, Dirk Elewaut, Thomas Tampere, Steven Wallaert, Erik Witvrouw, Joke Schuermans, Evi Wezenbeek

Objectives: Knee osteoarthritis (KOA) is a leading cause of global disability with conventional exercise yielding only modest improvements. Here we aimed to investigate the benefits of integrating blood flow restriction (BFR) into traditional exercise programmes to enhance treatment outcomes.

Methods: The Vascular Occlusion for optimizing the Functional Improvement in patients with Knee Osteoarthritis randomised controlled trial enrolled 120 patients with KOA at Ghent University Hospital, randomly assigning them to either a traditional exercise programme or a BFR-enhanced programme over 24 sessions in 12 weeks. Assessments were conducted at baseline, 6 weeks, 12 weeks and 3 months postintervention using linear mixed models with Dunn-Sidak corrections for multiple comparisons. Primary outcome was the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire at 3 months follow-up with knee strength, Pain Catastrophizing Scale questionnaire and functional tests as secondary outcomes. Analysis followed an intention-to-treat approach (NCT04996680).

Results: The BFR group showed greater improvements in KOOS pain subscale (effect size (ES)=0.58; p=0.0009), quadriceps strength (ES=0.81; p<0.0001) and functional tests compared with the control group at 12 weeks. At 3 months follow-up, the BFR group continued to exhibit superior improvements in KOOS pain (ES=0.55; p=0.0008), symptoms (ES=0.59; p=0.0004) and quality of life (QoL) (ES=0.66; p=0.0001) with sustained benefits in secondary outcomes. Drop-out rates were similar in both groups.

Conclusion: Incorporating BFR into traditional exercise programmes significantly enhances short-term and long-term outcomes for patients with KOA demonstrating persistent improvements in pain, symptoms, QoL and functional measures compared with conventional exercise alone. These findings suggest that BFR can provide the metabolic stimulus needed to achieve muscle strength and functional gains with lower mechanical loads. Reduced pain and increased strength support a more active lifestyle, potentially maintaining muscle mass, functionality and QoL even beyond the supervised intervention period.

Trial registration number: NCT04996680.

目标：膝关节骨性关节炎（KOA）是导致全球残疾的主要原因之一，而传统的锻炼方法只能起到一定的改善作用。在此，我们旨在研究将血流限制（BFR）纳入传统锻炼计划对提高治疗效果的益处：血管闭塞优化膝关节骨关节炎患者功能改善随机对照试验在根特大学医院招募了 120 名膝关节骨关节炎患者，将他们随机分配到传统锻炼计划或 BFR 增强计划中，在 12 周内进行 24 次训练。在基线、6周、12周和干预后3个月进行评估，采用线性混合模型，并对多重比较进行邓恩-西达克校正。主要结果是随访3个月时的膝关节损伤和骨关节炎结果评分（KOOS）问卷，次要结果是膝关节力量、疼痛灾难化量表问卷和功能测试。分析采用意向治疗法（NCT04996680）：结果：BFR 组在 KOOS 疼痛分量表（效应大小 (ES)=0.58; p=0.0009）、股四头肌力量（ES=0.81; pConclusion）方面有更大改善：与单独进行传统锻炼相比，在传统锻炼计划中加入阻力训练可显著提高 KOA 患者的短期和长期疗效，在疼痛、症状、生活质量和功能测量方面均有持续改善。这些研究结果表明，BFR 可提供所需的新陈代谢刺激，以较低的机械负荷实现肌肉力量和功能的提高。疼痛的减轻和力量的增强可支持更积极的生活方式，甚至在监督干预期结束后仍能保持肌肉质量、功能和 QoL：NCT04996680.

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引用次数: 0

Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients 抗 PD-1 治疗期间肠道微生物群的纵向分析揭示了黑色素瘤患者反应的稳定微生物特征

IF 30.3 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1016/j.chom.2024.10.006

Angeli D.G. Macandog, Carlotta Catozzi, Mariaelena Capone, Amir Nabinejad, Padma P. Nanaware, Shujing Liu, Smita Vinjamuri, Johanna A. Stunnenberg, Serena Galiè, Maria Giovanna Jodice, Francesca Montani, Federica Armanini, Ester Cassano, Gabriele Madonna, Domenico Mallardo, Benedetta Mazzi, Salvatore Pece, Maria Tagliamonte, Vito Vanella, Massimo Barberis, Luigi Nezi

Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8⁺ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides.

免疫检查点抑制剂（ICIs）可改善晚期黑色素瘤的治疗效果，但许多患者会出现难治性或复发。肠道微生物群调节抗肿瘤反应。然而，不一致的基线预测因素导致了反应的异质性和横断面数据的不足。我们对无法切除的黑色素瘤患者进行了基线和抗PD-1治疗期间的随访，收集粪便和血液样本，调查肠道微生物群和免疫标记物的变化。在 ICI 治疗期间，患者不同的反应与不同的肠道微生物群动态有关。我们通过稳定的微生物群功能筛选出完全应答者，并通过多个外部队列和实验进行验证。我们确定了主要组织相容性复合体 I 类（MHC I 类）限制肽，这些肽来源于拉赫诺斯皮拉科（Lachnospiraceae）鞭毛蛋白相关基因（FLach），是肿瘤相关抗原的结构同源物，在 ICI 治疗前检测到完全应答者中的 FLach 反应性 CD8+ T 细胞，并证明 FLach 肽能提高抗肿瘤免疫力。这些发现凸显了微生物功能的预后价值和仿肿瘤微生物肽的治疗潜力。

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引用次数: 0

Tumor derived cell-free nucleic acid upregulates programmed death-ligand 1 expression in neutrophil via intracellular Toll-like receptor signaling. 肿瘤衍生的无细胞核酸通过细胞内 Toll 样受体信号传导，上调中性粒细胞中程序性死亡配体 1 的表达。

IF 20.1 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1002/cac2.12615

Suguru Saito, Duo-Yao Cao, Tomohiro Shibata, Yan Liu, Aoi Otagiri-Hoshi, Xiaojiang Cui, Kenneth E Bernstein

引用次数: 0

A cross-systems primer for synthetic microbial communities 合成微生物群落的跨系统入门指南

IF 20.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1038/s41564-024-01827-2

Elijah C. Mehlferber, Gontran Arnault, Bishnu Joshi, Laila P. Partida-Martinez, Kathryn A. Patras, Marie Simonin, Britt Koskella

The design and use of synthetic communities, or SynComs, is one of the most promising strategies for disentangling the complex interactions within microbial communities, and between these communities and their hosts. Compared to natural communities, these simplified consortia provide the opportunity to study ecological interactions at tractable scales, as well as facilitating reproducibility and fostering interdisciplinary science. However, the effective implementation of the SynCom approach requires several important considerations regarding the development and application of these model systems. There are also emerging ethical considerations when both designing and deploying SynComs in clinical, agricultural or environmental settings. Here we outline current best practices in developing, implementing and evaluating SynComs across different systems, including a focus on important ethical considerations for SynCom research. Here the authors outline best practices for the development, implementation and evaluation of synthetic microbial communities (or SynComs) across different systems.

合成群落（SynComs）的设计和使用是最有前途的策略之一，可用于揭示微生物群落内部以及这些群落与其宿主之间复杂的相互作用。与自然群落相比，这些简化的联合体为在可控尺度上研究生态相互作用提供了机会，同时也有利于可重复性和促进跨学科科学的发展。然而，要有效实施 SynCom 方法，需要在开发和应用这些模型系统时考虑几个重要因素。在临床、农业或环境环境中设计和部署综合观测系统时，还需要考虑新出现的伦理问题。在此，我们将概述目前在不同系统中开发、实施和评估 SynComs 的最佳实践，包括重点关注 SynCom 研究的重要伦理考虑因素。

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引用次数: 0

Zeolite and metal-organic framework based microporous crystalline materials in adsorption separation of C4 hydrocarbons 基于沸石和金属有机框架的微孔晶体材料在 C4 碳氢化合物吸附分离中的应用

IF 20.3 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1016/j.ccr.2024.216293

Meng Zhao, Xue-Song Gu, Lanlan Sun, Yun Yang, Tong Li

The quest for energy-efficient and environmentally benign methods for separating C4 hydrocarbon mixtures has led to the exploration of porous materials, with zeolites and metal-organic frameworks (MOFs), especially MOFs at the forefront. These materials exhibit tunable pore sizes, diverse chemical functionalities, and the capacity for structural transformation in response to external stimuli, attributes that are highly desirable for separation processes. This review provides an in-depth analysis of the fundamental principles governing the adsorptive separation of C4 hydrocarbons, including thermodynamic, kinetic, molecular sieving, responsive framework separation, and guest conformation-controlled mechanisms. It also examines strategies to enhance the selectivity and stability of porous materials, such as the introduction of open metal sites, functional group modifications, and the engineering of flexible frameworks. The discussion extends to the current limitations and challenges in the industrial application of these materials. By synthesizing recent breakthroughs and identifying pivotal research directions, this review aims to offer a strategic roadmap for future research endeavors.

为了寻求高效节能、对环境无害的 C4 碳氢化合物混合物分离方法，人们开始探索多孔材料，其中沸石和金属有机框架（MOFs），尤其是 MOFs 走在了前列。这些材料具有可调节的孔隙大小、多种化学功能以及在外部刺激下发生结构转变的能力，这些特性都是分离过程非常需要的。本综述深入分析了 C4 碳氢化合物吸附分离的基本原理，包括热力学、动力学、分子筛分、响应框架分离和客体构象控制机制。报告还探讨了提高多孔材料选择性和稳定性的策略，如引入开放金属位点、官能团修饰和柔性框架工程。讨论还延伸到当前这些材料在工业应用中的局限性和挑战。本综述总结了最近的突破并确定了关键的研究方向，旨在为未来的研究工作提供战略路线图。

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引用次数: 0

Community standards and future opportunities for synthetic communities in plant–microbiota research 植物微生物群落研究中的群落标准和合成群落的未来机遇

IF 20.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1038/s41564-024-01833-4

Trent R. Northen, Manuel Kleiner, Marta Torres, Ákos T. Kovács, Mette Haubjerg Nicolaisen, Dorota M. Krzyżanowska, Shilpi Sharma, George Lund, Lars Jelsbak, Oliver Baars, Nikolaj Lunding Kindtler, Kathrin Wippel, Caja Dinesen, Jessica A. Ferrarezi, Malek Marian, Adele Pioppi, Xinming Xu, Tonni Andersen, Niko Geldner, Paul Schulze-Lefert, Julia A. Vorholt, Ruben Garrido-Oter

Harnessing beneficial microorganisms is seen as a promising approach to enhance sustainable agriculture production. Synthetic communities (SynComs) are increasingly being used to study relevant microbial activities and interactions with the plant host. Yet, the lack of community standards limits the efficiency and progress in this important area of research. To address this gap, we recommend three actions: (1) defining reference SynComs; (2) establishing community standards, protocols and benchmark data for constructing and using SynComs; and (3) creating an infrastructure for sharing strains and data. We also outline opportunities to develop SynCom research through technical advances, linking to field studies, and filling taxonomic blind spots to move towards fully representative SynComs. Here the authors discuss the use of synthetic communities, or SynComs, in plant–microbiome research and propose steps to develop community standards that will support future research.

利用有益微生物被视为提高可持续农业生产的一种有前途的方法。合成群落（SynComs）正被越来越多地用于研究相关的微生物活动以及与植物宿主的相互作用。然而，群落标准的缺乏限制了这一重要研究领域的效率和进展。为弥补这一不足，我们建议采取三项行动：(1) 界定参考 SynComs；(2) 建立构建和使用 SynComs 的社区标准、协议和基准数据；(3) 创建共享菌株和数据的基础设施。我们还概述了通过技术进步、与实地研究的联系以及填补分类学盲点来发展 SynCom 研究的机会，以迈向具有充分代表性的 SynCom。

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引用次数: 0

Wnt/GSK-3β mediates posttranslational modifications of FLYWCH1 to regulate intestinal epithelial function and tumorigenesis in the colon. Wnt/GSK-3β 介导 FLYWCH1 翻译后修饰，调节结肠肠上皮功能和肿瘤发生。

IF 20.1 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1002/cac2.12625

Sheema Almozyan, Roya Babaei-Jadidi, Abrar Aljohani, Sepideh Youssefi, William Dalleywater, Prerna Kadam, Bradley Spencer-Dene, Emad Rakha, Mohammad Ilyas, Abdolrahman Shams Nateri

引用次数: 0

Novel Phenylpiperidine Derivatives as QPCT and QPCTL Inhibitors for Treating Cancer or Fibrotic Diseases 作为治疗癌症或纤维化疾病的 QPCT 和 QPCTL 抑制剂的新型苯基哌啶衍生物

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1021/acsmedchemlett.4c0049510.1021/acsmedchemlett.4c00495

Ram W. Sabnis*,

Provided herein are novel phenylpiperidine derivatives as QPCT and QPCTL inhibitors, pharmaceutical compositions, use of such compounds in treating cancer or fibrotic diseases, and processes for preparing such compounds.

本文提供了作为 QPCT 和 QPCTL 抑制剂的新型苯基哌啶衍生物、药物组合物、此类化合物在治疗癌症或纤维化疾病中的用途以及制备此类化合物的工艺。

引用次数: 0

Discovery of PARP1-Sparing Inhibitors for Protein ADP-Ribosylation 发现 PARP1 蛋白质 ADP-核糖基化分离抑制剂

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1021/acsmedchemlett.4c0039510.1021/acsmedchemlett.4c00395

Elisa N. Stephens, Liang-Chieh Chen, Arshad J. Ansari, Kaiyu Shen, Lei Zhang, Steven G. Guillen, Clay C. C. Wang and Yong Zhang*,

Poly-ADP-ribose polymerases (PARPs) that catalyze cellular ADP-ribosylation play important roles in human health. PARP inhibitors have found success in the clinic for cancer treatment. However, isoform-specific inhibitors are needed for improved safety. Here, we report the unexpected discovery of nicotinamide mimics that block non-PARP1-catalyzed ADP-ribosylation at micromolar concentrations. These PARP1-sparing PARP inhibitors represent first-in-class probes for ADP-ribosylation, shedding light on the selective inhibition of PARPs.

聚 ADP 核糖聚合酶（PARPs）能催化细胞 ADP 核糖基化，在人类健康中发挥着重要作用。PARP 抑制剂已成功应用于临床癌症治疗。然而，为了提高安全性，还需要特异的同工酶抑制剂。在这里，我们报告了意外发现的烟酰胺模拟物，它们能在微摩尔浓度下阻断非 PARP1 催化的 ADP-核糖基化。这些PARP1-sparing PARP抑制剂代表了ADP-核糖基化的第一类探针，揭示了PARPs的选择性抑制。

引用次数: 0

Design and reporting of prebiotic and probiotic clinical trials in the context of diet and the gut microbiome 从饮食和肠道微生物组的角度设计和报告益生菌和益生菌临床试验

IF 20.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters

Pub Date : 2024-10-30 DOI: 10.1038/s41564-024-01831-6

Kevin Whelan, Margaret Alexander, Claire Gaiani, Genelle Lunken, Andrew Holmes, Heidi M. Staudacher, Stephan Theis, Maria L. Marco

Diet is a major determinant of the gastrointestinal microbiome composition and function, yet our understanding of how it impacts the efficacy of prebiotics and probiotics is limited. Here we examine current evidence of dietary influence on prebiotic and probiotic efficacy in human studies, including potential mechanisms. We propose that habitual diet be included as a variable in prebiotic and probiotic intervention studies. This recommendation is based on the potential mechanisms via which diet can affect study outcomes, either directly or through the gut microbiome. We consider the challenges and opportunities of dietary assessment in this context. Lastly, we provide recommendations for the design, conduct and reporting of human clinical trials of prebiotics and probiotics (and other biotic interventions) to account for any effect of diet and nutrition. Here the authors make recommendations for the design of clinical trials for prebiotics and probiotics that includes consideration of diet and the gut microbiome.

饮食是胃肠道微生物组组成和功能的主要决定因素，但我们对饮食如何影响益生菌和益生菌功效的了解却很有限。在此，我们研究了目前人类研究中饮食对益生元和益生菌功效影响的证据，包括潜在的机制。我们建议将习惯性饮食作为变量纳入益生菌和益生元干预研究中。这一建议是基于饮食可直接或通过肠道微生物组影响研究结果的潜在机制。在此背景下，我们考虑了膳食评估的挑战和机遇。最后，我们为益生元和益生菌（以及其他生物干预）人体临床试验的设计、实施和报告提供了建议，以考虑膳食和营养的任何影响。

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引用次数: 0

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