撰文丨王聪 编辑丨王多鱼 排版丨水成文 最近几年，以 司美格鲁肽 为代表的 GLP-1 类药物几乎无处不在，它们帮助了许多人安全的控制糖尿病和减肥，此外，这类药物还能降低心血管疾病风险、治疗 睡眠呼吸暂停、骨关节炎，甚至还有助于戒烟戒酒、缓解阿尔茨海默病等疾病。 GLP-1 类药物的畅销，并非一朝一夕。从发现 GLP-1 激素，解析其作用机制，再开发为糖尿病和肥胖的治疗药物，这一旅程漫长而曲折，跨越了 40 多年时 间，涉及学术界和制药行业的数百名研究人员，而诺贝尔奖至多授予 3 人，如果今年的诺贝尔生理学或医学奖奖授予 GLP-1 的发现和相关药物开发，谁值得获 奖？ 对 GLP-1 的结构和功能的早期认识是基于 Joel Habener、 Jens Juul Holst、 Svetlana Mojsov 、 Dan Drucker 几人的研究，而诺和诺德的研究人员 Lotte Bjerre Knudsen 开发了基于 GLP-1 的药物利拉鲁肽和司美格鲁肽。 如果 GLP-1 研究获得诺贝尔奖的认可，那么获奖者大概率是从这 5 人中产生。而在去年，"诺奖风向标"之一的拉斯克奖授予了其中 3 人 —— Jo ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 在人体神经系统中，数十亿个神经元相互协作，形成复杂的神经网络，以高时空分辨率执行多种神经生理活动。神经元膜上的各种离子通道介导离子 跨膜运输的动态和顺序过程，并严格调控神经递质释放和信号转导等生理功能。离子运输异常可导致瘫痪、癫痫和先天性痛觉缺失等神经疾病。 目前，这些疾病的临床治疗通常通过刺激生物离子通道来恢复正常的离子运输，包括药物治疗和物理神经调节。然而，小分子药物由于离子通道结构 相似，往往缺乏亚型特异性，并且代谢迅速，限制了治疗的精准度和效果。侵入性的物理神经调节方法，例如皮质内刺激 （ICS） 和脑深部刺激 （DBS） ，具有高时空精度，但需要植入电极，存在感染和术后并发症的风险。包括经颅直流电刺激 （tDCS） 和经颅磁刺激 （TMS） 在内的非侵 入性方法缺乏通道级定位，导致作用机制不明确且治疗范围有限。 作为一种革命性技术， 光遗传学 通过基因表达光敏蛋白并用可见光刺激实现通道特异性神经调控。然而，其临床应用受到不可预测的基因毒性和可 见光组织穿透力有限的安全风险的限制。因此，迫切需要探索具有分子级精度的非基因神经调节策略，以动态调节神经元治疗神经疾病 ...

Core Viewpoint - The article discusses a groundbreaking study that utilizes optogenetics to discover compounds that can selectively modulate the Integrated Stress Response (ISR), which has therapeutic potential for various diseases including viral infections, cancer, and neurodegenerative disorders [2][4]. Group 1: Research Overview - The research was published in the journal Cell by a team from the Broad Institute, led by Professor James Collins, and included Felix Wong and Maxwell Wilson [3]. - The study developed an optogenetics platform for drug discovery, enabling the identification of compounds that can selectively eliminate cells with high ISR under various stress conditions [4][14]. Group 2: Methodology and Findings - The research team utilized double-stranded RNA-dependent protein kinase R (PKR) as a key sensor for ISR activation, simulating natural activation during viral infections [7]. - A high-throughput screening of 370,830 compounds was conducted, identifying those that enhance cell death without cytotoxicity across different cell types and stressors [7][14]. - The identified compounds were shown to upregulate Activating Transcription Factor 4 (ATF4), increasing cellular sensitivity to stress and apoptosis, with GCN2 identified as a molecular target [8]. Group 3: Antiviral Activity - The compounds demonstrated broad-spectrum antiviral activity, with one compound significantly reducing viral load in a mouse model of herpes simplex virus infection [9][14]. - Structure-activity relationship and toxicology studies highlighted opportunities for optimizing therapeutic effects [9]. Group 4: Significance of the Study - The study showcases a novel optogenetics approach for drug discovery and introduces ISR enhancers with potential therapeutic applications [10].

Core Viewpoint - The study indicates that optogenetic vagal nerve stimulation (VNS) can alleviate heart failure (HF) by limiting the generation of monocyte-derived inflammatory CCRL2+ macrophages [2][3][4]. Summary by Sections Mechanism of Action - The research demonstrates that VNS reduces the proportion of CCRL2+ macrophages, which are derived from myeloid monocytes and exhibit unique tumor necrosis factor alpha (TNF-α) cytokine responses, hypertrophic, and fibrotic characteristics [4]. - The elimination of CCRL2+ macrophages can prevent cardiac remodeling and heart failure [4]. Key Findings - The study confirms a positive correlation between CCRL2+ macrophages and TNF-α responsive proteins in the human heart with cardiac remodeling and dysfunction [5]. - Activation of the α7 nicotinic acetylcholine receptor (α7nAChR) plays a crucial role in the cardiac protective effects mediated by VNS, as it inhibits the response of CCRL2+ macrophages to TNF-α by increasing the expression of the transcription factor NRF2 [4][5]. Therapeutic Implications - Overall, the results suggest that the vagus nerve-immune axis can regulate heart failure and represents a promising therapeutic target [6].