作者: Zha, Huiyan ; Xie, Yaochen ; Zhu, Difeng ; Wang, Jiajia ; Weng, Qinjie ; He, Qiaojun ; Wang, Jincheng ; Hu, Yuming ; Gong, Shuchen ; Yang, Chen ; Lv, Shuying ; Li, Guilin ; Wang, Lingkun ; Ping, Li

Acetaminophen (APAP) is a widely used analgesic and antipyretic medicine. It is frequently employed to alleviate pain and mitigate fever-related symptoms, but it can cause liver injury or even liver failure when overdosed. Isorhapontigenin, a compound derived from Chinese herbs and grapes, has been demonstrated to exhibit antioxidant and anti-inflammatory effects. This study focused on evaluating the effect of isorhapontigenin in alleviating APAP-induced liver injury. In the study, a single intraperitoneal administration of APAP was employed to induce liver injury, and isorhapontigenin was given orally 3 days before or 1 h after APAP administration. The results revealed that isorhapontigenin significantly mitigated liver injury by effectively inhibiting APAP-induced apoptosis, oxidative stress, and inflammation. Furthermore, transcriptomic RNA sequencing of liver tissues indicated that isorhapontigenin probably protected against APAP-induced liver injury by promoting fatty acid oxidation. Pharmacological experiments also demonstrated that isorhapontigenin treatment led to a significant reduction in triglyceride accumulation, increased ATP levels and direct fatty acid oxidation activity, as well as enhanced expression of proteins associated with fatty acid oxidation, including PPAR-α, PGC-1α, and CPT-1A. Moreover, the protective effects of isorhapontigenin against APAP-induced liver injury were abolished by a CPT-1A inhibitor, etomoxir. Notably, we found that combining isorhapontigenin with NAC (N-acetyl-L-cysteine) resulted in a more significant alleviation of APAP-induced liver injury compared to NAC alone. In conclusion, our study indicates that isorhapontigenin is a potential therapeutic strategy that works by regulating fatty acid oxidation to alleviate APAP-induced liver injury.

2025-01-01·BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

Extracellular matrix stiffness facilitates neurite outgrowth by reprogramming the fatty acid oxidation-dependent macrophage polarization

Article

作者: Wang, Congwei ; Zhang, Zhengguo ; Liu, Zhaoyang ; Wang, Shan ; Fan, Zhongyu ; Chu, Xu ; Chen, Yazhou

The extracellular matrix (ECM) is involved in various of pathophysiology processes, such as wound healing and neurogenesis. During tissue injury, the recruited bone marrow-derived monocytes in the impaired site undergo functional and phenotypic changes and participate in the initiation, maintenance, and resolution phases of tissue repair. However, the effects of ECM stiffness on monocyte differentiation and function remain largely unknown. Herein, we developed a gelatin-hydroxyphenylpropionic acid-based hydrogel with different substrate stiffnesses by varying hydrogen peroxide concentrations, which demonstrated good biocompatibility. Furthermore, the high substrate stiffness hydrogel could polarize macrophage into immunosuppressive phenotype with increased expression of interleukin 10, transforming growth factor β, CD206, and CD163. Twenty three differentially expressed metabolites were identified in stiff hydrogel-cultured macrophages in comparison with soft hydrogel cultured macrophages via metabolite analysis. In addition, 4-hydroxybenzoic acid was the most upregulated metabolite, which could confer protection against neuronal and acute inflammation. Mechanistically, the high substrate stiffness induced macrophage immunosuppressive differentiation by upregulating the expression of the fatty acid oxidation (FAO)-related proteins peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-δ. Consistently, the FAO inhibitor etomoxir reversed the high substrate stiffness mediated macrophage immunosuppressive polarization and neurite outgrowth. Therefore, the alteration in macrophage phenotype induced by increased substrate stiffness can promote tissue repair in clinical applications.

2024-12-06·JOURNAL OF PROTEOME RESEARCH

Antitumoral Activity and Metabolic Signatures of Dichloroacetate, 6-Aminonicotinamide and Etomoxir in Breast-Tumor-Educated Macrophages

Article

作者: Duarte, Iola F. ; Dias, Ana S. ; Helguero, Luisa ; Almeida, Catarina R.

Pharmacological targeting of metabolic pathways represents an appealing strategy to selectively kill cancer cells while promoting antitumor functions of stromal cells. In this study, we assessed the effectiveness of 13 metabolic drugs (MDs) in steering in vitro generated breast tumor-educated macrophages (TEMs) toward an antitumoral phenotype. For that, the production of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α), two important regulators of tumor progression, was evaluated. Notably, dichloroacetate (DCA), 6-aminonicotinamide (6-AN), and etomoxir decreased VEGF production and enhanced TNF-α release. Hence, we further clarified their impact on TEM metabolism using an untargeted NMR-based metabolomics approach. DCA downregulated glycolysis and enhanced the utilization of extracellular substrates like lactate while reconfiguring lipid metabolism. Several DCA-induced changes significantly correlated with heightened TNF-α production in response to pro-inflammatory stimulation. The inhibition of the pentose phosphate pathway by 6-AN was accompanied by enhanced glutaminolysis, which correlated with a decreased level of VEGF production. In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.

项与乙莫克舍相关的新闻（医药）

2024-04-08

·奇点网

这些加油站可不是什么好东西

*仅供医学专业人士阅读参考就在上个月，奇点糕专门唠了两回癌细胞和肿瘤相关成纤维细胞（CAFs）狼狈为奸、沆瀣一气的故事，没想到假期刚过就看到了续集，而且又是来自中国学者的研究登上顶级期刊，好，先鼓掌~上海交通大学医学院附属仁济医院薛婧团队与同济大学、西安交通大学等高校研究者合作，在Cancer Cell期刊发表的最新研究成果显示：存在甲基转移酶SETD2缺失的胰腺癌细胞会发生表观遗传失调，调控一部分CAFs分化为脂质含量更丰富的表型（特征为高表达转运体ABCA8a），而这些CAFs“上供”的脂质就会被癌细胞利用，以增强自身侵袭能力[1]。论文核心内容总结此前薛婧团队开展的研究已经显示，SETD2缺失会使癌细胞发生上皮-间质转化（EMT），增强自身转移能力，还可导致肿瘤微环境中的中性粒细胞帮癌细胞实现免疫逃逸[2-3]，可以说是为祸不浅；本次研究则从能量代谢和肿瘤间质的角度，来探索SETD2缺失的影响。研究者们首先借助基因集富集分析（GSEA）发现，SETD2突变或低表达，与胰腺导管腺癌（PDAC）及多种实体瘤中，氧化磷酸化（OXPHOS）相关基因表达的显著富集高度相关，说明SETD2缺失会导致癌细胞的代谢重塑；通过细胞、小鼠和类器官实验，研究者们又证实由SETD2缺失导致的癌细胞线粒体氧化磷酸化水平上升，对促进肿瘤进展有关键作用。那么问题来了，被癌细胞线粒体氧化磷酸化消耗的底物是什么，它们又来自哪里呢？研究者们用小分子抑制剂分别打击了癌细胞对葡萄糖、谷氨酰胺和脂肪酸的代谢，发现CPT-1抑制剂Etomoxir打压脂肪酸代谢，带来的抑癌作用最为明显，说明癌细胞更倾向于在SETD2缺失时代谢脂质，但胰腺本身并不是富集脂质的器官，那脂肪酸肯定别有出处。在小鼠SETD2缺失肿瘤中，研究者们找到了一大批外形酷似脂肪细胞、富含脂质（Lipid-laden）的细胞，并通过免疫荧光染色证实，它们大多存在CAFs的多个特征性标志物，所以本质上还是CAFs；单细胞RNA测序则显示，这类CAFs构成了有鲜明特征的亚群（主要特征为ABCA8a+FAP+），转录组学特征也与脂质代谢有关。SETD2缺失肿瘤中富含脂质的CAFs当然了，这类CAFs变得“油腻”肯定是癌细胞背后操控的结果：CellphoneDB细胞相互作用分析显示，富含脂质的CAFs内存在明显的BMP信号活跃，其中BMP2信号为旁分泌性，来自空间分布上与CAFs相当接近的癌细胞，且BMP2信号会直接调控CAFs储存脂质的能力，将其沉默可显著减少CAFs内储存的脂质，同时显著延缓肿瘤生长。癌细胞来源的BMP2信号让CAFs变“油腻”进一步实验显示，富含脂质的CAFs主要会通过高表达的ABCA8a转运蛋白，将长链脂肪酸转运给癌细胞；而癌细胞则会发生转录组学重编程，SETD2缺失使组蛋白H3K27Ac发生异位堆积（ectopic deposition），进而调节BMP2等众多基因的表达，这一方面导致了前面提到的CAFs变油腻，另一方面也使癌细胞能够具有加速氧化磷酸化消耗脂质的能力。总而言之，CAFs帮助癌细胞的罪证又多了一条，宁可让自己变油腻都要促癌，这样的癌症帮凶按说必须得出重拳打击才行，不过针对胰腺癌细胞的氧化磷酸化进行精准干预，可能是更有可行性的治疗策略呢。参考文献：[1]Niu N, Shen X, Wang Z, et al. Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer[J]. Cancer Cell, 2024.[2]Niu N, Lu P, Yang Y, et al. Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia–mesenchymal transition during pancreatic carcinogenesis[J]. Gut, 2020, 69(4): 715-726.[3]Niu N, Shen X, Zhang L, et al. Tumor Cell‐Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis[J]. Advanced Science, 2023, 10(2): 2202937.本文作者丨谭硕

2023-12-26

·生物谷

Nat Commun｜复旦大学顾建英/陈勇/周宇红：解析肢端型黑色素瘤淋巴结转移的时空进化机制

肢端型黑色素瘤(AM)是我国最常见的黑色素瘤亚型，相较于欧美常见的皮肤亚型，AM有着截然不同的肿瘤微环境及基因组突变特征，患者从传统的PD-1单抗及靶向治疗中获益有限。淋巴结是AM早期播散的重要路径，淋巴结转移严重影响AM患者预后，并对评估手术方案及选择术后辅助治疗策略至关重要。近年来已有研究从单细胞转录组测序的角度解析了AM原发灶和淋巴结转移灶之间的肿瘤微环境的差异，但针对AM淋巴结转移阴性/阳性患者的原发灶之间的肿瘤微环境的差异却鲜有报道。AM在淋巴结转移过程中原发灶的肿瘤细胞如何发生自身重塑以及驯化免疫、间质细胞以实现早期播散，是一个亟待解决的关键科学问题。2023年12月8日，复旦大学附属中山医院顾建英、周宇红教授团队与附属肿瘤医院陈勇教授团队合作，于期刊Nature Communications发表题为“Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses”的研究成果，解析了AM淋巴结转移的免疫代谢时空进化机制。该研究通过对AM淋巴结转移阴性/阳性患者的原发灶进行单细胞联合空间转录组测序分析，绘制了其时空进化图谱。研究团队发现淋巴结转移阳性的AM表现出高度的肿瘤异质性、抑制性免疫微环境和复杂的细胞间通讯。在AM发生淋巴结转移之初，原发病灶微环境中的肿瘤、免疫和间质细胞已发生促进淋巴结转移的表型转换。在肿瘤细胞层面，AM淋巴结转移需要肿瘤细胞发生表征为脂肪酸氧化的代谢重塑，这一过程依赖于MYC+肿瘤细胞中的关键转录因子MITF。体内实验证明局部给于Etomoxir(脂肪酸氧化抑制剂)处理，可以通过靶向脂肪酸氧化途径阻止MITF介导的AM淋巴结转移。在免疫细胞层面，淋巴结转移阳性的AM微环境表征为FGFBP2+NKT细胞等免疫效应细胞的显著减少和CXCL13+CD8T细胞等耗竭性免疫细胞的显著增多。在间质细胞层面，淋巴结转移阳性的AM中具有较多的由成纤维细胞与内皮细胞形成龛样结构，通过促进血管新生介导AM淋巴结转移。图1. 该研究的图文摘要复旦大学附属中山医院整形外科顾建英教授、肿瘤内科周宇红教授、附属肿瘤医院骨软组织外科陈勇教授为本文的共同通讯作者。卫传元助理研究员、孙伟主治医师和沈康杰博士为本文的共同第一作者。注：文中插图源于 Nature Communications原文链接：https://doi.org/10.1038/s41467-023-43980-y本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

2022-07-06

·生物谷

北京大学钟超团队发现PD-1信号通过调节LTi细胞功能促进肠道稳态

PD-1/PD-L1 抑制剂目前已被 FDA 批准应用于包括恶性黑色素瘤、非小细胞肺癌、肝癌、胃癌、头颈癌等二十余种癌症的治疗，较传统治疗取得较好效果。 PD-1/PD-L1 抑制剂目前已被 FDA 批准应用于包括恶性黑色素瘤、非小细胞肺癌、肝癌、胃癌、头颈癌等二十余种癌症的治疗，较传统治疗取得较好效果。然而，PD-1/PD-L1 阻断，往往伴随免疫相关副作用（immune-related adverse events，irAEs），严重者导致免疫治疗中断。肠炎作为 PD-1/PD-L1 抑制剂治疗过程中的常见 irAEs，其发生机制至今尚不清楚。因此，深入探讨 PD-1 信号对肠道稳态的调控作用，有利于对 PD-1 抑制剂肿瘤治疗过程中副反应的防护。 2022年7月4日，北京大学钟超课题组在 Nature 子刊 Nature Metabolism 在线发表了题为：该研究发现，PD-1 信号通过限制淋巴组织诱导细胞（Lymphoid tissue inducer，简称LTi）活化过程中脂肪酸氧化促进其免疫效应功能，从而维持肠道稳态，缓解肠道炎症。首先，研究者发现 PD-1 基因（PDCD1）缺失会导致小鼠肠道菌群紊乱、肠炎易感，重复了肿瘤免疫治疗中 PD-1 抑制剂引起肠炎发生的临床现象。LTi 是富集于哺乳动物肠道的一群天然免疫细胞，通过分泌效应细胞因子 IL-22 对维持肠道稳态具有重要作用。研究团队发现 PD-1 分子在结肠 LTi 细胞上高水平表达，然而，其信号是否对 LTi 的功能存在调控作用仍未见报道。利用 LTi 细胞 PDCD1 缺失的条件性敲除小鼠，研究团队证明 PD-1 信号通过促进 LTi 细胞分泌 IL-22，对维持肠道稳态、减缓肠炎发生具有重要作用。机制上，研究团队利用单细胞测序（scRNA-seq）、细胞能量代谢检测等技术，发现LTi细胞活化过程中会发生脂合成及糖代谢增强的代谢重编程，而 PD-1 信号缺失导致活化 LTi 细胞脂肪酸氧化（FAO）水平异常增高，进而抑制其 IL-22 的表达。据此，研究团队利用 Etomoxir 等 FAO 抑制剂或通过构建 LTi 细胞 FAO 限速酶 Cpt1 的条件性敲除小鼠，均有效恢复了 PD-1 信号缺失 LTi 中的 IL-22 表达。单细胞测序分析LTi细胞活化过程的代谢重塑总而言之，该研究揭示了 PD-1 信号调控肠道 LTi 细胞活化过程中的代谢重编程，从而促进其发挥免疫效应功能，维持肠道稳态。同时，该研究也为 PD-1 抑制剂治疗过程中出现的肠炎副反应提供了一种可能的解释，为针对性治疗提供了参考策略。

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适应症	最高研发状态	国家/地区	公司	日期
多发性硬化症	临床2期	-	Meta-IQ	-
视神经炎	临床2期	-	Meta-IQ	-
胶质母细胞瘤	临床前	美国	Numiera Therapeutics, Inc.	2024-11-01
低级神经胶质瘤	临床前	美国	Numiera Therapeutics, Inc.	2024-11-01