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PD-1 and LAG-3: synergistic fostering of T cell exhaustion PD-1 和 LAG-3:协同促进 T 细胞衰竭
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-18 DOI: 10.1038/s41392-024-02000-1
Maike Hofmann, Robert Thimme, Wolfgang W. Schamel
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引用次数: 0
Correction: The JAK-STAT pathway: from structural biology to cytokine engineering 更正:JAK-STAT 通路:从结构生物学到细胞因子工程学
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-17 DOI: 10.1038/s41392-024-01975-1
You Lv, Jianxun Qi, Jeffrey J. Babon, Longxing Cao, Guohuang Fan, Jiajia Lang, Jin Zhang, Pengbing Mi, Bostjan Kobe, Faming Wang

Correction to: Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-024-01934-w, published online 21 August 2024

Correction to:信号转导与靶向治疗 https://doi.org/10.1038/s41392-024-01934-w,2024 年 8 月 21 日在线发表
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引用次数: 0
Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα–TRAF3–TAK1–MAPK axis 通过抑制 TNFα-TRAF3-TAK1-MAPK 轴,特异性敲除 ADAM17 可减轻多柔比星诱导的心肌病
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-16 DOI: 10.1038/s41392-024-01977-z
Lin Xie, Fei Xue, Cheng Cheng, Wenhai Sui, Jie Zhang, Linlin Meng, Yue Lu, Wenjing Xiong, Peili Bu, Feng Xu, Xiao Yu, Bo Xi, Lin Zhong, Jianmin Yang, Cheng Zhang, Yun Zhang

The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.

多柔比星诱发心肌病的发病机制仍不清楚。本研究旨在验证我们的假设,即 ADAM17 会加重多柔比星诱导的心肌细胞凋亡,而抑制 ADAM17 可改善多柔比星诱导的心肌病。给 C57BL/6J 小鼠腹腔注射累积剂量的多柔比星诱发心肌病。生成心肌细胞特异性ADAM17基因敲除(A17α-MHCKO)和ADAM17过表达(AAV9-oeA17)小鼠。此外,还对不同小鼠组的心脏组织进行了 RNA 测序,并对接受不同处理的新生大鼠心肌细胞(NRCMs)进行了体外实验。在 A17fl/fl 和 A17α-MHCKO 小鼠中构建了小鼠肿瘤模型。此外,还生成了心肌细胞特异性 TRAF3 敲除小鼠和 TRAF3 表达小鼠。在多柔比星处理的小鼠心脏和 NRCMs 中,ADAM17 的表达和活性明显上调。与 A17fl/fl 小鼠相比,A17α-MHCKO 小鼠表现出更少的由多柔比星诱导的心肌细胞凋亡,而且心肌细胞 ADAM17 的缺乏并不影响多柔比星的抗肿瘤作用。相反,与 AAV9-oeNC 小鼠相比,AAV9-oeA17 小鼠在接受多柔比星治疗后,心肌细胞凋亡明显加剧。从机制上看,多柔比星增强了转录因子C/EBPβ的表达,导致心肌细胞中ADAM17的表达和活性增加,从而增强了TNF-α的脱落并上调了TRAF3的表达。TRAF3 的增加促进了 TAK1 的自身磷酸化,从而激活了 MAPKs 通路,导致心肌细胞凋亡。ADAM17 通过上调 TRAF3/TAK1/MAPKs 信号,对多柔比星诱导的心肌细胞凋亡、心脏重塑和功能障碍起到正向调节作用。因此,以 ADAM17/TRAF3/TAK1/MAPKs 信号为靶点有望治疗多柔比星诱导的心脏毒性。
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引用次数: 0
Integrate and conquer: pan-cancer proteogenomics uncovers cancer vulnerabilities and therapeutic opportunities 整合与征服:泛癌症蛋白质组学揭示癌症弱点和治疗机会
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-15 DOI: 10.1038/s41392-024-02009-6
Debomita Chakraborty, Rossana Romero, Krishnaraj Rajalingam

In a recent article published in Cell by Savage et al., the authors developed a computational workflow for integrating multi-omics data from readily available public online databases to provide novel insights into the proteogenomic landscape of several types of cancers and reveal new druggable targets for drug development or repurposing.1

最近,Savage 等人在《细胞》(Cell)杂志上发表了一篇文章,作者开发了一种计算工作流程,用于整合来自现成公共在线数据库的多组学数据,从而对几种癌症的蛋白质基因组状况有了新的认识,并揭示了新的药物开发或再利用靶点。
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引用次数: 0
A breath of fresh air: targeted non-viral in vivo gene correction in the mammalian lung 新鲜空气:哺乳动物肺部的定向非病毒体内基因校正
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 DOI: 10.1038/s41392-024-01994-y
Jixin Liu, Dirk Grimm

In a recent study published in Science,1 Sun and colleagues showcase the power and potential of lung SORT LNPs, i.e., lipid nanoparticles that upon systemic delivery in mice specifically and efficiently target cells in the lung, most likely facilitated by their binding to plasma vitronectin and uptake via the vitronectin receptor. Most remarkably, when engineered to deliver a base editor, peripheral injection of SORT LNPs enabled highly efficient gene correction in lung stem cells, whole lung and trachea in a mouse model of cystic fibrosis, illustrating the enormous promise of this novel technology for human patients suffering from this devastating disease (Fig. 1).

Fig. 1
figure 1

Lipid nanoparticles (LNPs) bind to vitronectin, which facilitates their uptake by vitronectin receptors (VtnR) in the lungs. The figure illustrates the efficiency of gene editing in various lung cell types and the restoration of CFTR function. This figure was created with BioRender

Full size image
在最近发表于《科学》(Science)1 的一项研究中,Sun 及其同事展示了肺部 SORT LNPs 的威力和潜力,即脂质纳米粒子在小鼠体内全身注射后可特异性地高效靶向肺部细胞,这很可能是由于它们与血浆玻璃连蛋白结合并通过玻璃连蛋白受体被吸收。最引人注目的是,当设计用于递送碱基编辑器时,外周注射 SORT LNPs 能在囊性纤维化小鼠模型的肺干细胞、全肺和气管中实现高效的基因校正,这说明了这种新型技术在人类这种毁灭性疾病患者身上的巨大前景(图 1)。该图说明了基因编辑在各种肺细胞类型中的效率以及 CFTR 功能的恢复情况。本图使用 BioRenderFull size 图像创建
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引用次数: 0
Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects 人类疾病中的铁稳态和铁变态反应:机制和治疗前景
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 DOI: 10.1038/s41392-024-01969-z
Qin Ru, Yusheng Li, Lin Chen, Yuxiang Wu, Junxia Min, Fudi Wang

Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.

铁是人体内不可或缺的矿物质,参与多种生理过程,因此维持铁的平衡对整体健康至关重要。铁过量和缺铁都会导致各种失调和人类疾病。铁中毒(Ferroptosis)是一种依赖于铁的细胞死亡形式,其特点是脂质的广泛过氧化。与其他类型的经典非程序性细胞死亡不同,铁变态反应主要与铁代谢紊乱、脂质过氧化和抗氧化系统失衡有关。铁变态反应通过转录、翻译和翻译后修饰进行调控,这些都会影响细胞对铁变态反应的敏感性。过去十多年来,许多疾病的病因都与铁蛋白沉积有关,包括癌症、代谢紊乱、自身免疫性疾病、中枢神经系统疾病、心血管疾病和肌肉骨骼疾病。与铁突变相关的蛋白质已成为许多目前无法治愈的重大人类疾病的诱人靶标,一些铁突变调节剂已在临床试验中显示出治疗效果,但其临床潜力还需要进一步验证。因此,深入分析铁蛋白沉积及其在人类疾病中的潜在分子机制可能会为临床预防和治疗提供更多策略。在这篇综述中,我们讨论了体内铁平衡的生理意义、嗜铁细胞增多症对人类疾病的病因和发展的潜在作用,以及支持将嗜铁细胞增多症作为靶向治疗方法的证据。重要的是,我们评估了最近的潜在治疗靶点和有希望的干预措施,为未来针对人类疾病的靶向治疗提供指导。
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引用次数: 0
Therapeutic interfering particles against HIV: molecular parasites reducing viremia 针对艾滋病毒的治疗干扰颗粒:减少病毒血症的分子寄生虫
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 DOI: 10.1038/s41392-024-02001-0
Henning Gruell, Stanley Odidika, Philipp Schommers

In a recent article in Science, Leon Weinberger and colleagues report on successful proof-of-concept studies of a novel strategy to control HIV-1 infection by using interfering viral particles.1 This approach radically differs from small-molecule antiretroviral drugs that can prevent disease progression and transmission by inhibiting viral replication but require life-long use.

莱昂-温伯格及其同事最近在《科学》(Science)杂志上发表文章,报告了一种利用干扰病毒颗粒控制 HIV-1 感染的新策略的概念验证研究取得成功。
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引用次数: 0
Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy 用于胰腺癌协同治疗的载药链烷共轭细菌
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-14 DOI: 10.1038/s41392-024-01973-3
Yu Xiao, Tao Pan, Wuren Da, Yuanding Liu, Shuangya Chen, Daiquan Chen, Keying Liu, Yihan Zheng, Daolong Xie, Yuan Gao, Haiyan Xu, Yang Sun, Weihong Tan

Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer’s specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer’s targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.

胰腺癌是死亡率最高的恶性肿瘤之一,目前缺乏有效的治疗药物。作为核酸药物的一种形式,色聚体-药物共轭物(ApDC)在癌症治疗中显示出巨大的潜力。然而,核酸类药物在体内的不稳定性以及胰腺癌的无血管性和致密基质限制了其应用。幸运的是,VNP20009 是一种转基因鼠伤寒沙门氏菌菌株,它偏好厌氧环境,但具有毒性且缺乏特异性,有可能成为 ApDC 的递送载体。在这里,我们提出了一种协同治疗方法,通过简单的一步点击化学反应将 ApDC 与 VNP20009 连接,将细菌的穿透能力与 ApDC 的靶向性和毒性作用结合起来。利用这种策略,细菌通过厌氧趋化作用特异性地靶向胰腺癌,随后在aptamer的特异性结合作用下粘附到肿瘤细胞上。结果表明,与游离药物组相比,这种方法可将 ApDC 的血清稳定性延长至 48 小时,并提高了药物在肿瘤部位的浓度。此外,适配体与癌细胞的靶向结合使肿瘤部位的细菌定植增加了两倍,导致肿瘤细胞死亡和 T 细胞浸润增加。值得注意的是,通过整合化疗和免疫疗法,治疗效果显著增强,在各种动物模型中显示出一致的结果。总之,这种策略利用了细菌和 ApDC 的优势,从而为胰腺癌治疗提供了一种有效的协同策略。
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引用次数: 0
Multi-stage mechanisms of tumor metastasis and therapeutic strategies. 肿瘤转移的多阶段机制和治疗策略。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-11 DOI: 10.1038/s41392-024-01955-5
Zaoqu Liu, Jingqi Chen, Yuqing Ren, Shutong Liu, Yuhao Ba, Anning Zuo, Peng Luo, Quan Cheng, Hui Xu, Xinwei Han

The cascade of metastasis in tumor cells, exhibiting organ-specific tendencies, may occur at numerous phases of the disease and progress under intense evolutionary pressures. Organ-specific metastasis relies on the formation of pre-metastatic niche (PMN), with diverse cell types and complex cell interactions contributing to this concept, adding a new dimension to the traditional metastasis cascade. Prior to metastatic dissemination, as orchestrators of PMN formation, primary tumor-derived extracellular vesicles prepare a fertile microenvironment for the settlement and colonization of circulating tumor cells at distant secondary sites, significantly impacting cancer progression and outcomes. Obviously, solely intervening in cancer metastatic sites passively after macrometastasis is often insufficient. Early prediction of metastasis and holistic, macro-level control represent the future directions in cancer therapy. This review emphasizes the dynamic and intricate systematic alterations that occur as cancer progresses, illustrates the immunological landscape of organ-specific PMN creation, and deepens understanding of treatment modalities pertinent to metastasis, thereby identifying some prognostic and predictive biomarkers favorable to early predict the occurrence of metastasis and design appropriate treatment combinations.

肿瘤细胞的级联转移表现出器官特异性倾向,可能发生在疾病的多个阶段,并在强大的进化压力下进展。器官特异性转移依赖于转移前生态位(PMN)的形成,多种细胞类型和复杂的细胞相互作用促成了这一概念,为传统的转移级联增添了新的维度。在转移扩散之前,作为 PMN 形成的协调者,原发肿瘤衍生的细胞外囊泡为循环肿瘤细胞在远处的继发部位定居和定植准备了肥沃的微环境,从而对癌症的进展和预后产生重大影响。显然,仅在大转移后被动干预癌症转移部位往往是不够的。癌症转移的早期预测和整体宏观调控是癌症治疗的未来方向。本综述强调了癌症进展过程中发生的动态和复杂的系统性改变,阐述了器官特异性 PMN 生成的免疫学格局,并加深了对转移相关治疗模式的理解,从而确定了一些有利于早期预测转移发生和设计适当治疗组合的预后和预测性生物标志物。
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引用次数: 0
Late onset Alzheimer’s disease: modeling disease hallmarks via in vitro 3D iNeuron cultures 晚发性阿尔茨海默病:通过体外三维 iNeuron 培养模拟疾病特征
IF 39.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-10 DOI: 10.1038/s41392-024-01999-7
Giacomo Masserdotti
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引用次数: 0
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Signal Transduction and Targeted Therapy
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