Spectrochim Acta A Mol Biomol SpectroscPMID:40450799
摘要：设计、合成了一种基于甘氨酰-L-苯丙氨酸肽的席夫碱（HL）荧光探针，并使用各种分析技术对其进行了表征。研究了该席夫碱对不同金属离子的化学传感能力。该化学传感器探针对锌离子和铝离子表现出高选择性和高灵敏度，检测限分别为1.63×10⁻⁶ M和1.25×10⁻⁶ M。Job曲线分析和贝内西-希尔德布兰德关系清楚地表明，荧光探针与金属离子之间的化学计量比为1:1，锌离子的表观结合常数为1.02×10⁵ M，铝离子的表观结合常数为2.39×10⁵ M。在依次交替添加铝离子或锌离子以及乙二胺四乙酸（EDTA）的四个循环中，HL的发射强度保持可逆，证明了有效的“关-开-关”荧光响应。化合物HL代表了一个可调系统，该系统包含一个或门（OR）和一个与非门（INHIBIT）逻辑门，有两组不同的输入：（i）锌（IN1）和铝（IN2），以及（ii）锌/铝（IN1）和EDTA（IN2），以荧光发射作为输出。此外，使用锌（IN1）、铝（IN2）和EDTA（IN3）作为输入实现了一个蕴含逻辑门。此外，该探针在很宽的pH范围内对实际水样中的锌和铝进行定量检测显示出优异的潜力。使用密度泛函理论（DFT）计算确定了化合物（HL、HL-Zn和HL-Al）的优化分子几何结构和最高占据分子轨道-最低未占据分子轨道（HOMO-LUMO）能隙。
Eur J Med ChemPMID:40815902
摘要：引入了SS-、RR-、SR-和RR/SS构型的1,3-二乙基-4,5-二苯基-4,5-二氢-1H-咪唑-2-亚基作为新型基于咪唑啉的N-杂环卡宾（NHC）配体，用于设计具有抗肿瘤活性的（NHC）金（I）配合物（卤代（NHC）金（I）配合物：氯代（5a-d）、溴代（6a-d）、碘代（7a-d）；SS,SS-、RR,RR-、SR,SR-和RR,SS构型的[(NHC)Au(I)]配合物：8a-d）。SS构型配合物5a-7a的X射线结构显示苯环呈双赤道排列，且柱状结构受到干扰，金-金距离增加（>5.6 Å）。SR构型迫使苯环处于NHC平面上方的顺斜位置，仅允许形成分离的二聚体（5c-7c）。对于[(NHC)Au(I)]配合物8c，在晶体中观察到单分子。空间和动态条件减少了溶液中配体的重排，从而提高了稳定性。这些配合物在卵巢癌细胞（A2780wt（野生型）、A2780cis（顺铂耐药））中显示出比乳腺癌细胞（MDA-MB-231、MCF-7）更高的生长抑制作用，并克服了A2780细胞中的顺铂耐药性（在A2780wt中的作用 = A2780cis）。氯代和溴代（NHC）金（I）配合物产生了相当的效果，因为存在快速的Br/Cl交换（6a-d → 5a-d）。碘代（NHC）金（I）配合物7a-d更具活性，这是由于部分降解为8a-d。后者是本研究中细胞毒性最大的化合物。NHC配体的构型不影响配合物的细胞毒性。对映体和非对映体表现出相同的抗代谢作用。以5a-d和8a-d为例，研究了细胞摄取情况。在孵育30分钟内，A2780wt和MDA-MB-231细胞中的金含量达到最大值。在对应于抗增殖作用的半数最大抑制浓度（IC）值的浓度下（5a-d：20 μM，8a-d：5 μM），5b、5c和5d在A2780wt细胞中诱导的金含量几乎相同，比5a低30-50%。[(NHC)Au(I)]配合物的积累趋势为8d < 8a < 8b < 8c。此外，5a-d抑制了A2780wt细胞中的环氧合酶-1（COX-1）和硫氧还蛋白还原酶（TrxR），并上调了谷胱甘肽（GSH）水平。相反，8a-d没有降低COX-1和TrxR活性，但导致GSH适度下调。GSH水平没有因谷胱甘肽二硫化物（GSSG）而降低，表明8a-d影响GSH的形成。© 2017爱思唯尔公司。保留所有权利。
Eur J Med ChemPMID:40812066
摘要：赖氨酸特异性去甲基化酶1（LSD1）在癌症中经常过度表达，通过去除致癌组蛋白标记H3K4me1/2和H3K9me1/2来驱动肿瘤进展，使其成为一个引人注目的治疗靶点。自发现以来，抑制LSD1可抑制癌细胞增殖、侵袭和迁移，促使抑制剂得到广泛开发。反苯环丙胺衍生物是最有效的抑制剂类别，其IC值在亚微摩尔至纳摩尔范围内。临床评估的候选药物如TCP、ORY-1001和INCB059872；单独或联合给药；通过结合其FAD辅因子不可逆地抑制LSD1。本综述系统地分析了所有报道的基于反苯环丙胺的LSD1抑制剂，阐明了它们的构效关系（SAR）、合成策略、作用机制见解和抗癌概况。重点介绍了增强效力和选择性的关键SAR修饰。总的来说，这些抑制剂显示出显著的治疗前景。我们进一步讨论了优化LSD1靶向癌症治疗的挑战（如选择性、耐药性）、机遇和未来方向。
Eur J Med ChemPMID:40886680
摘要：成纤维细胞活化蛋白（FAP）几乎仅在癌症相关基质细胞上表达，这使其成为正电子发射断层扫描（PET）肿瘤成像的一个有前景的靶点。虽然镓或铝[F]F标记的FAP抑制剂（FAPIs）已得到详细表征，但含有共价结合F标记的FAPIs的潜在优势在很大程度上仍不为人知。本研究的目的是通过比较两种含有共价结合F标记的FAPIs和基于螯合剂的放射性配体铝[F]F-FAPI-42来填补这一空白。F标记的FAPIs通过直接（6-[F]F-FAPI）或间接（[F]AFA-FAPI）放射性氟化或通过铝[F]F螯合方法（铝[F]F-FAPI-42）制备，其放射性示踪剂的活性产率为11-57%，摩尔活性为5-170 GBq/μmol。细胞摄取研究表明，与HT1080-WT细胞相比，所有三种候选物在HT1080-FAP中的积累显著更高。6-[F]F-FAPI和铝[F]F-FAPI-42在接种了这两种细胞系的小鼠和患有皮下DSL-6A/C1肿瘤的大鼠中显示出相当的FAP选择性和肿瘤摄取，而对于[F]AFA-FAPI未观察到体内FAP选择性。在皮下肿瘤模型中，铝[F]F-FAPI-42表现出较低的肝胆排泄和从FAP阴性组织中更快的清除。相比之下，在脑内U87胶质瘤肿瘤模型中，6-[F]F-FAPI显示出更高的肿瘤摄取和更好的肿瘤滞留。与已确立的胶质瘤示踪剂[F]FET相比，两种靶向FAP的示踪剂对脑内肿瘤的可视化肿瘤与背景比值高出两倍以上。总之，虽然基于螯合剂的放射性配体铝[F]F-FAPI-42非常适合外周肿瘤的可视化，但具有共价结合F标记的6-[F]F-FAPI在脑肿瘤成像方面显示出更有利的特性。
Eur J Med ChemPMID:40803165
摘要：Pin1是一种磷酸化依赖性肽脯氨酰异构酶，它特异性识别并催化pSer/Thr-Pro基序的顺反异构化。它在细胞周期调控、信号转导和肿瘤发生中起着关键作用。由于其在多种癌症类型中过表达，Pin1已成为开发抗癌药物的一个有前景的靶点。然而，Pin1相对浅而平的表面给传统小分子抑制剂设计带来了重大挑战。为了克服这些限制，我们采用了基于X射线晶体学的片段筛选策略，并从一个精心策划的片段库中鉴定出约50种Pin1-片段复合物结构。系统的结构分析揭示了几个可成药的结合热点，包括特征明确的催化中心（位点1）和催化残基Cys113附近的一个相邻区域（位点2）。这两个位点都支持与多种片段支架的稳定结合。值得注意的是，几个片段在多个位点表现出协同结合，突出了它们作为多功能抑制剂设计支架的潜力。此外，一部分片段对Cys113具有反应性，其共价结合模式通过晶体学和质谱分析得到证实。酶抑制试验进一步证明，几个片段在溶液中有效抑制Pin1活性，验证了它们作为先导化合物的潜力。总之，本研究通过结构驱动的片段筛选方法系统地绘制了Pin1上的功能性结合口袋，扩展了其可成药范围，并确定了关键结构特征和片段化学类型，以指导选择性、明确的Pin1抑制剂的开发。
Eur J Med ChemPMID:40812069
摘要：刚地弓形虫是一种专性细胞内寄生虫，全球约三分之一的人口受到感染，这使得弓形虫病成为一个重大的公共卫生问题。目前的治疗方法——通常是乙胺嘧啶和磺胺嘧啶联合使用——仅限于感染的急性期，而且常常会引起过敏反应和严重的副作用。海生喹啉类化合物（MQs）是一类最初从海洋微生物中分离出来的化合物，已显示出有前景的药理学特性，包括在体外和体内模型中均具有抗刚地弓形虫活性。为满足对更有效、更安全疗法的需求，本研究调查了新型合成MQ衍生物对该寄生虫的抑制作用。合成了17种带有吲哚基团并入海生喹啉骨架的MQs。评估了所有化合物对细胞内刚地弓形虫速殖子（RH株）的半数最大有效浓度（EC）以及对人包皮成纤维细胞（HFFs）的半数最大细胞毒性浓度（CC）。计算了选择性指数（SI = CC/EC）。两种衍生物表现出出色的选择性，SI值分别为516和751，同时在计算机辅助的药物代谢及药物动力学性质预测方面具有良好特性，包括高胃肠道吸收、血脑屏障通透性以及无预测毒性。这些发现支持了基于吲哚的MQs作为治疗弓形虫病进一步临床前开发的有前景候选药物的潜力。
Spectrochim Acta A Mol Biomol SpectroscPMID:40446716
摘要：类胡萝卜素是一大类化学物质，其中某些类胡萝卜素已显示出改变人类代谢途径的能力。番茄红素就是一种用于癌症预防和治疗的类胡萝卜素。尽管如此，类胡萝卜素对脑癌细胞代谢和单个细胞器功能的确切影响仍不清楚。在本研究中，我们建议使用拉曼光谱和成像技术在单细胞水平分析类胡萝卜素代谢。本文旨在探索三种具有代表性的类胡萝卜素化合物，以更好地了解它们的总体作用及其对脑癌细胞的影响。因此，利用拉曼技术，我们分析了未添加以及添加了藏红花素、岩藻黄质和叶黄素的星形细胞瘤细胞（CRL-1718细胞系）。我们的拉曼研究表明，在实施类胡萝卜素后癌细胞的代谢会发生改变。我们发现类胡萝卜素会影响脂质含量（基于1444 cm处谱带的强度）和单个细胞内细胞色素c的氧化还原状态（基于1583 cm处谱带的强度）。
Eur J Med ChemPMID:40848519
摘要：B细胞淋巴瘤-2（Bcl-2）家族作为细胞死亡的三方开关，通过蛋白质-蛋白质相互作用，精确调节内在凋亡途径以响应各种细胞信号应激。作为关键且独特的成员，髓样细胞白血病-1（Mcl-1）对于内在凋亡途径中线粒体功能的调节至关重要。Mcl-1在众多血液系统恶性肿瘤以及实体瘤中过度表达，与肿瘤发展、预后不良和化疗耐药密切相关。因此，它是癌症治疗中一个有前景的治疗靶点。2018年，我们综述了2012年至2017年小分子Mcl-1抑制剂的研究进展。本综述旨在总结小分子Mcl-1抑制剂（根据其核心骨架）或降解剂作为有前景的抗癌药物（2018年至今）的最新研究进展。此外，还提供了大多数化合物相应的构效关系（SARs）。此外，还阐明了一些强效化合物与Mcl-1蛋白复合物的共晶体结构。本综述有望为从事开发更有效的靶向Mcl-1小分子抑制剂或降解剂的药物化学家提供有价值的见解。
Eur J Med ChemPMID:40884958
摘要：Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), plays a pivotal role in epigenetic regulation by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to transcriptional repression of target genes. Dysregulation of EZH2 has been implicated in various cancers, including lymphomas, prostate, and breast cancers, by promoting oncogenic transformation and tumor progression. Targeting EZH2 has been regarded as a promising strategy for cancer therapy. Over the past decade, significant progress has been made in the development of EZH2 inhibitors and degraders, several of which have been approved or are undergoing various clinical trials. These agents function by competing with the cofactor S-adenosyl-l-methionine (SAM) at the active site within the SET domain of EZH2, thereby preventing the methylation of H3K27 and reactivating silenced tumor suppressor genes. In addition, next-generation strategies, including dual EZH1/EZH2 inhibitors, PROTAC-based degraders, and combination regimens with immunotherapy or hormonal therapy, are being actively explored to enhance therapeutic benefit and overcome resistance mechanisms that limit monotherapy efficacy. This review provides an overview of the current landscape of EZH2-targeted therapies since 2020 and future directions for optimizing their application.
Eur J Med ChemPMID:40882436
摘要：Since the outbreak of SARS-CoV-2 in recent years, our society has become more aware that zoonotic diseases pose a real threat. Therefore, the demand for small molecules that target host proteins, essential for viral entry and replication, has increased as an interesting strategy for the development of antiviral agents, as these agents may be effective against several different pathogens. NAK kinases is one such potential target family because they are involved in a variety of cellular functions, hijacked by viruses to invade host cells, such as clathrin-mediated endocytosis. A large number of different inhibitors have already been reported targeting NAK kinases, but there are still no compounds that selectively target AAK1 over other NAK family members, in particular the closely related family member BIKE. Here, we developed a series of pyrazolo[1,5-a]pyrimidine-based macrocyclic NAK inhibitors, starting from the acyclic AAK1 inhibitor LP-935509. Through a structure-guided activity relationship study within the NAK family, we identified potent AAK1 inhibitors 16, 18 and 27, which show promising selectivity within the NAK family. The inhibitors showed a potent inhibition of the phosphorylation of the AP-2 complex and the antiviral activity of the compounds was evaluated against various RNA viruses.
Eur J Med ChemPMID:40882438
摘要：Chronic pain has become a major factor affecting the quality of human life. Nav1.7 is a subtype of neuronal voltage-gated sodium channel. Its mutation is closely related to pain syndrome. By inhibiting the function of Nav1.7, it can effectively relieve pain. As a result, it has been extensively researched as a hot target for pain management. In this manuscript, a series of new arylsulfonamide compounds based on Nav1.7 were designed and synthesized. The biological properties of these compounds were assessed through various experiments, including in vitro and in vivo evaluations, microsomal stability, selectivity, hERG and pharmacokinetic studies. Compound 50 was found to show favorable microsomal stability, in vivo safety, high selectivity and a low potential risk of cardiotoxicity. Further in vivo studies showed that compound 50 had a faster onset of action and better analgesic efficacy in several pain models than positive control. In addition, molecular docking results showed that compound 50 formed 2 hydrogen bonds and π-π stacking interactions with amino acid residues in the lipid exposed pocket of Nav1.7. These results suggested that compound 50 might be a potent candidate for the treatment of neuropathic pain.
Eur J Med ChemPMID:40848518
摘要：Lugdunin, a newly discovered antibiotic with a unique structure, emerged during a decade-long antibiotic discovery void and is considered a promising lead for combating drug-resistant bacteria. However, its narrow spectrum targeting only Gram-positive bacteria and its structural limitations have hindered its development and clinical application. Herein, inspired by our previous combinatorial modification strategies for lugdunin, we designed and synthesized a series of multi-cationic lugdunin derivatives using a biphenylmethyl modification on the tryptophan indole structure combined with multi-cationic amino acid mutations, aiming to expand its antimicrobial spectrum. Our results showed that the optimized derivative, Lug-15, exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria, including Escherichia coli and Pseudomonas aeruginosa. Lug-15 rapidly kills bacteria primarily through membrane disruption and had a very low propensity to induce bacterial resistance. Additionally, it demonstrated low hemolytic toxicity and significant therapeutic potential in various infection models, including keratitis caused by MRSA and P. aeruginosa, MRSA-induced pneumonia, thigh muscle infection, and wound infection, indicating Lug-15's broad-spectrum therapeutic potential. Therefore, this study overcomes the historical limitation of prior SAR attempts and offers a new lead for combating drug-resistant bacteria.
Eur J Med ChemPMID:40884960
摘要：The ABCG2 transporter is an efflux pump that can transport various anticancer drugs and is strongly associated with multidrug resistance (MDR) in cancer. A promising strategy to combat MDR mediated by this transporter is through functional inhibition. However, there are currently no potent selective ABCG2 inhibitors in clinical trials. Chalcone, a privileged scaffold, can be easily synthesized to produce a wide array of derivatives with diverse biological applications. Notably, chalcone derivatives have been identified as inhibitors of ABC transporters, including ABCG2. In this study, we synthesized and evaluated a series of twenty chalcone derivatives as potential ABCG2 inhibitors. Out of these, ten compounds were found to completely inhibit ABCG2 transport activity. Among them, compounds 10, 19, and 20 demonstrated particularly high potency, with EC values (compound concentrations giving a half-maximal inhibition) of 0.34, 0.83, and 0.94 μM, respectively. These three promising chalcone derivatives selectively inhibited ABCG2, enhanced the binding of the 5D3 conformational antibody, and exhibited low cytotoxicity, with estimated IG values (compound concentrations giving a half-maximal cell viability) exceeding 50 μM. The therapeutic ratio (TR), calculated as the ratio of IG to EC values, revealed that 10 had a TR greater than 147, nearly 3-fold higher than those of 19 (greater than 60) and 20 (greater than 53). Modeling studies, while biased towards the conformation of the selected starting compound, successfully reproduced relevant interactions with residues Phe439 and Asn436, which are consistent with ABCG2 inhibition. Finally, 10 was shown to chemosensitize cell lines that overexpress ABCG2, effectively overcoming the MDR phenotype mediated by this transporter.
Spectrochim Acta A Mol Biomol SpectroscPMID:40446719
摘要：Drug repositioning and reuse is a cost-effective strategy for the development of new drugs, and drug co-crystal is a fast and effective technical means. Acetylsalicylic acid is a BCS II drug, which has the limitations of high permeability and low solubility, and the safety and efficacy of the drug have been greatly affected. Co-crystallization with other forming agents is considered to be a promising technical means, which can not only increase the solubility, but also improve the dissolution rate and stability. In this paper, the cocrystal of acetylsalicylic acid and arginine was prepared by grinding method. The physical and chemical characterization of the raw material, the mixture and the obtained cocrystal was carried out by XRD, terahertz spectroscopy (THz-TDS) and Raman spectroscopy (Raman). The obvious difference was observed on the characteristic peaks of the cocrystal, which proved the formation of the cocrystal. Understanding the basic properties of lattice vibration during the eutectic process is challenging, yet it can be accomplished through theoretical calculations. By employing density-functional theory (DFT) calculations, the molecular configurations and vibration spectra of the two drug cocrystals can be obtained, enabling a deeper understanding of the vibration modes of drug molecules in the low-frequency range. Moreover, this study demonstrates the sensitivity of terahertz time-domain spectroscopy (TDS) technology in detecting intermolecular hydrogen-bond interactions in drug cocrystals. When comparing cocrystal molecules with active pharmaceutical ingredient (API) molecules, it is found that cocrystals possess better binding energy, driven by intermolecular hydrogen bonds and dispersion forces.
Eur J Med ChemPMID:40839918
摘要：Blocking the membrane fusion function mediated by the S2 subunit 6-helix bundle (6-HB) structure is an effective strategy for treating coronavirus infections. However, the 6-HB structure of infectious bronchitis virus (IBV) remains unclear, hindering the development of targeted drugs. In this study, we predicted the 6-HB structure of IBV via in silico and designed an antiviral peptide HR2P based on this structure. This peptide, derived from a conserved HR2 domain identified via amino acid sequence alignment of 511 IBV strains, disrupted IBV-mediated intercellular membrane fusion. The inhibition results demonstrated that HR2P had broad-spectrum inhibitory activity against different IBV strains representing four dominant genotypes in vitro, reducing viral proliferation and replication by 100- to 1000-fold. Notably, the most potent suppression was observed against the IBV Sczy3 strain of the predominant GI-19 genotype. Meanwhile, in vivo treatment with HR2P effectively mitigated IBV infection and reduced horizontal transmission capacity, as evidenced by reduced morbidity and mortality in IBV-infected chickens and alleviated tracheal and kidney damage. Early administration of HR2P showed superior suppression efficacy. Therefore, the HR2P peptide demonstrates potential as a targeted therapeutic agent against IBV, offering a foundation for IBV prevention strategies.
Eur J Med ChemPMID:40839916
摘要：The diterpene andrographolide, a nature-derived product, exerts a wide range of pharmacological effects, including anti-inflammatory, antiviral, immunostimulatory, and anticancer activities, due to its ability to target multiple pathways. In this study, some andrographolide derivatives of an enlarged decalin structure with a seven-membered ring or an isoxazole-fused decalin structure were designed, synthesized, and evaluated for their activity against cancer cell growth and angiogenesis. Among them, compound AGW-11 (designated as compound 8) showed potent and broad-spectrum anticancer activity and anti-angiogenic activity in vitro. Mechanistically, 8 was found to effectively suppress the phosphorylation of EGFR and ERK½ and induce 4T1 cell apoptosis in a gradient concentration-dependent manner; while 8 inhibited angiogenesis by reduction of HUVEC proliferation, tube formation and cell invasion, and decreased VEGFR2 kinase activity and lowered VEGFR2 and ERK1/2 phosphorylation. The results from in vivo anti-4T1 tumor-bearing mouse model showed that treatment with 8 significantly suppressed tumor growth and decreased the probability of lung tumor metastasis, as previously reported AGS-30 (2). Consistent with the in vitro results, the in vivo data demonstrated that the anti-angiogenic and anti-tumor effects of 8 in a mouse xenograft model. Treatment with 8 effectively inhibited expressions of Ki67, CD31 and VEGF in tumors, suggesting that 8 inhibits tumor angiogenesis. Meanwhile, the apoptotic factor cleaved caspase 3 was elevated that tumor cells was induced to death after treatment with 8. These findings will facilitate our andrographolide-related drug discovery efforts.
Eur J Med ChemPMID:40812065
摘要：The rampant overuse of antibiotics has triggered widespread bacterial resistance, further exacerbated by biofilm-forming pathogens and non-mutating persisters, necessitating urgent development of novel antibiotics. Here, a series of bis-pyridinium cationic amphiphilic antimicrobial small molecules were designed and synthesized. Structure-activity relationships indicated that the hydrophobic tail chain length is crucial for the antibacterial activity. In vitro bioassay demonstrated that compound 3g exerted potent antibacterial activity (MIC = 1 μg/mL and MIC = 2 μg/mL) while also exhibiting low hemolytic activity (HC > 1000 μg/mL), capability for rapid and complete bacterial sterilization, a longer post-antibiotic effect (PAE), and hardly induce bacterial resistance. Encouragingly, when 3g was used to combat persisters and biofilms in vitro, it demonstrated powerful bactericidal effects. Mechanistic studies indicated that 3g exerted its antimicrobial action through related membrane activity and was associated with membrane components phosphatidylglycerol (PG) and cardiolipin (CL), inducing content leakage, and ultimately causing bacterial death. Notably, 3g demonstrates superior in vivo antibacterial activity compared to vancomycin. Overall, these findings deliver important insights into the development of amphiphilic antimicrobial peptide mimics while validating the potential of 3g as an effective antimicrobial.
Eur J Med ChemPMID:40882439
摘要：随着抗菌药物耐药性的不断上升以及传统疗法的持续失败，开发针对耐甲氧西林金黄色葡萄球菌（MRSA）的创新药物对于有效的临床治疗至关重要。在此，设计了一种源自哈尔满的新型二甲基季铵盐5b，它表现出强大的抗MRSA活性，包括对临床菌株（MIC = 0.25 - 0.5μg/mL）具有快速杀菌模式、缓慢获得耐药性、良好的稳定性以及低细胞毒性和溶血毒性。此外，化合物5b在小鼠皮肤感染模型中显示出有效的治疗效果，与万古霉素相比具有竞争力。机制研究表明，化合物5b通过减少细胞外多糖抑制生物膜形成，通过与肽聚糖和脂磷壁酸（LTA）结合破坏细胞壁的结构和功能，通过与磷脂酰乙醇胺（PE）相互作用靶向细胞膜，伴随去极化、通透性改变和完整性破坏。特别是，化合物5b可进一步降低细胞内代谢活性，通过增加活性氧（ROS）水平、降低谷胱甘肽（GSH）和超氧化物歧化酶（SOD）活性来破坏氧化还原平衡。此外，化合物5b可通过自发过程以熵和焓驱动的方式与DNA结合。总体而言，这项工作提供了一个突出的抗MRSA先导候选物，通过多靶点机制来应对耐药感染。
Int ImmunopharmacolPMID:40976054
摘要：目的：细胞焦亡与痛风的急性发作和自发缓解有关，但其具体调控机制尚不清楚。本研究旨在探讨X连锁DEAD盒解旋酶3（DDX3X）作为影响细胞焦亡的枢纽分子在调节痛风性炎症中的潜在作用。 方法：采用生物信息学分析来鉴定细胞焦亡和痛风相关基因及其潜在联系。用尿酸钠晶体刺激巨噬细胞（THP-1）（0、3、6、9、12小时）以构建痛风性炎症模型。检测DDX3X、白细胞介素-1β（IL-1β）和经典细胞焦亡途径分子。通过免疫荧光评估活性氧（ROS）水平以及DDX3X与NLRP3的共定位。为了确定DDX3X对细胞焦亡和痛风性炎症的影响，在敲低和过表达DDX3X后，通过蛋白质印迹法检测细胞焦亡关键基因和IL-1β。 结果：生物信息学证实细胞焦亡参与痛风，并鉴定出9个痛风-焦亡相关基因（Gout-PRGs）。对这9个Gout-PRGs的相关性分析表明，DDX3X与NLRP3密切相关。验证表明痛风患者外周血单个核细胞（PBMCs）中DDX3X表达升高。在体外痛风性炎症模型中，经典细胞焦亡途径分子和DDX3X的表达均呈现明显的非线性特征，并且与ROS积累和IL-1β表达呈平行趋势。免疫荧光结果显示DDX3X与NLRP3有明显的共定位。在氧化应激的早期（3小时）和晚期（9小时）敲低和过表达DDX3X后，NLRP3、IL-1β和细胞焦亡分子均呈现特征性变化。 结论：DDX3X可通过激活NLRP3炎性小体和介导巨噬细胞焦亡来调节痛风性炎症。
Int ImmunopharmacolPMID:41037851
摘要：背景：黄芪多糖（APS）已被证明可减轻肌肉萎缩。本研究探讨了APS对D-半乳糖（D-gal）诱导的C2C12成肌细胞线粒体自噬的影响及其潜在机制。 方法：使用CCK-8法评估C2C12成肌细胞的细胞活力。为进一步阐明APS的作用，我们评估了有无O-连接N-乙酰葡糖胺转移酶（OGT）时C2C12成肌细胞的骨骼肌细胞直径和线粒体自噬。采用肌球蛋白重链（MyHC）免疫荧光染色和蛋白质免疫印迹分析。进行免疫共沉淀（Co-IP）实验和免疫荧光染色以检测OGT与PTEN诱导的假定激酶1（PINK1）之间的相互作用。在体内，用D-半乳糖处理雄性C57BL/6 J小鼠以诱导肌肉减少症，并给予APS以评估其对肌肉功能和线粒体健康的影响。 结果：APS通过OGT诱导O-连接N-乙酰葡糖胺化促进体外线粒体自噬。敲低OGT显著削弱了APS的保护作用。OGT通过S425位点用O-连接N-乙酰葡糖胺修饰PINK1。在体内，APS治疗显著改善了D-半乳糖诱导的肌肉减少症小鼠的握力和肌肉质量。组织学分析显示腓肠肌纤维横截面积增加，蛋白质免疫印迹分析显示肌肉组织中LC3II、PINK1和帕金蛋白的表达增强。 结论：总体而言，APS促进OGT介导的O-连接N-乙酰葡糖胺化以稳定PINK1，从而促进体外D-半乳糖处理的C2C12成肌细胞中的线粒体自噬。在体内，APS改善了肌肉减少症小鼠模型的肌肉功能和线粒体健康。这些发现表明APS可能作为肌肉萎缩及相关病症的潜在治疗剂。
Int ImmunopharmacolPMID:40987022
摘要：背景：单独进行自然杀伤（NK）细胞或T细胞的过继性转移需要较长的准备时间。我们开发了一种快速共培养系统，包括细胞因子诱导的记忆样NK（CIML NK）细胞和活化T细胞（Ac-T），以及肿瘤穿透肽iRGD。 方法：将外周血单个核细胞（PBMC）用白细胞介素（IL）-12/15/18预处理16小时，然后洗涤以诱导记忆NK表型。通过慢病毒转导产生K562-CD48-41BBL-mbIL-21细胞，并用作饲养细胞，从PBMC中扩增和激活NK细胞7天。在第7天，加入抗CD3单克隆抗体（OKT3）和抗CD28单克隆抗体（CD28.2），并过夜洗涤24小时。将iRGD修饰的CIML NK&Ac-T细胞（CIML NK&Ac-T-iRGD）的体外（细胞毒性、细胞因子）和体内（肿瘤抑制、生存）功能与未添加CD3/CD28的CIML NK&T-iRGD进行比较。 结果：我们建立了一个包含NK细胞和T细胞的一周快速共培养系统。该系统显著增加了细胞因子分泌，并对胃癌细胞系表现出强大的体外细胞毒性，在胃癌异种移植模型中显著抑制肿瘤生长并延长生存期。值得注意的是，iRGD修饰的CIML NK&Ac-T细胞比CIML NK&T细胞显示出更好的疗效。 结论：我们的数据表明，用于过继性细胞转移的iRGD修饰的CIML NK&Ac-T细胞快速共培养系统在胃癌中显示出强大的抗肿瘤作用。这种方法省时且节省成本，与传统NK细胞疗法相比具有更广泛的临床应用潜力。
《柳叶刀-公共卫生》最新综述揭示中国成人睡眠危机：平均睡眠时长微增，但失眠率飙升至近50%，导致高达6280亿美元经济损失。文章深度拆解睡眠健康“中国悖论”，分析生物、生活方式、社会及环境多重风险因素，并探讨国家层面的应对策略及面临的挑战，呼吁从社会文化、公众认知和医疗体系等多维度发力，偿还万亿级“睡眠赤字”，实现“睡得久更要睡得聪明”。
本文揭示了减肥后，体重的下降并不等同于免疫系统完全恢复。脂肪组织中的免疫细胞可能保留“肥胖记忆”，影响代谢健康和反弹风险。文章探讨了运动、节食、药物和手术等减肥方式对脂肪组织免疫代谢的重塑作用，强调了理解“肥胖记忆”对未来肥胖治疗的重要性。
本文通过对英国CPRD数据的“试验模拟”，验证了ACEi和ARB在心血管保护方面等效的经典结论。更重要的是，研究发现该结论在被传统临床试验“忽略”的75岁以上老年人、女性和慢性肾脏病患者中依然成立，为精准医疗提供了更广泛的循证依据，展现了真实世界数据在扩展药物适用范围方面的巨大潜力。
MedSegX突破通用医疗AI“贪多嚼不烂”困境，通过结构化数据库MedSegDB和专家混合网络ConMoAE，实现精准、泛化、高效的医疗影像分割，并在2D/3D任务、已知/未知场景及模糊指令下超越现有SOTA，赋能临床应用。
Nature Medicine重磅研究发现“健康肥胖”基因密码，揭示266个“解耦”基因变异，将肥胖精细划分为8种遗传亚型。这些基因能让脂肪增加但代谢健康，为肥胖精准治疗提供新方向。
哈佛34年追踪研究揭示，地中海饮食对高风险APOE4纯合子携带者预防痴呆的保护作用最为显著，且通过调节特定代谢物实现。研究发现APOE4纯合子有独特的代谢指纹，地中海饮食能精准纠正其脂质代谢失调。孟德尔随机化证实4-GBA、类胡萝卜素和谷氨酰胺对痴呆有因果保护作用，为精准干预提供靶点。
Nature Medicine重磅研究：iAorta AI系统能在普通平扫CT中精准识别急性主动脉综合征，缩短诊断时间，弥补医生经验差距，为患者抢夺宝贵的救治机会，挽救生命。
本文深入探讨骨质疏松的分子发病机制，揭示基因、衰老、免疫、氧化应激及肠道菌群等多重因素的复杂交织。并分析西医治疗、中医药和干细胞、AI等前沿疗法，为骨质疏松的防治提供多角度、综合性的新思路。
挑战“安芬森法则”！折叠转换蛋白能根据环境刺激彻底重塑结构，扮演多重生物功能，存在于细菌到人类。本文探讨其能量景观、进化机制及AlphaFold为何受挫，揭示生命复杂性。
一项涵盖22万名患者的“伞形评价”显示，加速康复外科（ERAS）显著缩短脊柱手术住院时间、降低医疗成本和并发症，且不增加再入院风险，开启脊柱康复新时代。
研究揭示晚期前列腺癌在不同种族患者（特别是非裔和欧裔美国男性）中存在显著的基因组和转录组差异，体现在MYC通路激活、免疫信号抑制、以及TMPRSS2:ERG基因融合频率不同，尽管临床预后相似。这强调了精准医疗中种族多样性的重要性。
研究揭示，即使尿钙水平正常，肾脏内部仍可能因Claudin-2蛋白缺陷引发钙质异常积聚，导致肾结石形成，挑战传统认知。
Zotero 插件
