BACKGROUND:Lung cancer is one of the deadliest cancers world-wide and immunotherapy has been considered as a promising therapeutic strategy. Previously, our study found that tannins in Phyllanthus emblica L. (PTF) could inhibit the growth of tumor by activating the immune response in liver cancer, and also exhibited a cytotoxicity on human lung cancer cells A549, H460, H1703 in vitro.OBJECTIVE:To explore whether PTF inhibited the growth of lung cancer through its immune-regulating function and to clarify underlying mechanisms.METHODS:The induction of immunogenic cell death (ICD) were characterized by calreticulin exposure, extracellular ATP secretion, and High Mobility Group Box 1(HMGB1) release both in vivo using LLC-derived xenograft tumor model and in vitro using both mouse LLC and human A549 cancer cells.RESULTS:PTF inhibited lung cancer cells growth and tumorigenesis in vivo/vitro and promoted anti-tumor immune responses. We further found that PTF could induce ICD, which then activated Type I interferon responses and CXCL9/10-mediated chemotaxis. Mechanistically, PTF induced the formation of intracellular protein aggregates and following activation of PERK/ATF4/CHOP-dependent endoplasmic reticulum stress-related ICD. Moreover, PTF improved the antitumor efficacy of cisplatin by inducing ICD both in vitro and in vivo. Finally, we screened out 5 components from PTF, including gallocatechin, gallic acid, methyl gallate, ethyl gallate and ellagic acid, which could induce ICD in vitro and might be considered as the potential antitumor pharmacodynamic substances.CONCLUSION:In conclusion, PTF inhibits the growth of lung cancer by triggering ICD and remodeling the tumor microenvironment, suggesting that PTF may have promising prospects as an adjacent immunotherapy for cancers.

Correction for ‘ Moringa oleifera leaf polysaccharides exert anti-lung cancer effects upon targeting TLR4 to reverse the tumor-associated macrophage phenotype and promote T-cell infiltration’ by Shukai Wang et al. , Food Funct. , 2023, 14 , 4607–4620, https://doi.org/10.1039/D2FO03685A.

目的 筛选余甘子鞣质调控巨噬细胞极化的活性部位,探讨其调控巨噬细胞极化的主要化学成分和作用机制.方法 采用CCK-8细胞增殖实验检测细胞活力;荧光定量PCR(qPCR)检测M2巨噬细胞标志物Arg-1、CD206、TNF-αmRNA表达水平以筛选有效部位;UPLC-Q-Exactive-MS/MS 表征其化学成分.利用 SwissADME 和 SwissTargetPrediction数据库筛选活性成分并获取其对应靶点,与GEO数据库中筛选的M1-M2型巨噬细胞差异基因取交集,运用Cytoscape3.7.2软件绘制"药物成分-潜在靶点"网络图,并在STRING数据库进行蛋白互作关系分析,并进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析.结果 基于体外巨噬细胞极化模型,发现余甘子鞣质20％甲醇洗脱部位可显著抑制M2巨噬细胞标志物Arg-1和CD206mRNA的表达,升高M1巨噬细胞标志物TNF-αmRNA的表达(P＜0.001),且活性明显强于其他洗脱部位.通过比对余甘子糅质与20％甲醇洗脱部位UPLC-MS总离子流图,鉴定出20％甲醇洗脱部位中化学成分29个,筛选出有效成分11个,对应靶点94个,药物-巨噬细胞相关交集靶点37个;KEGG富集分析结果显示,余甘子糅质20％甲醇洗脱部位调控巨噬细胞极化相关靶点主要为HIF-1信号通路、PI3K-Akt信号通路、NF-kappaB信号通路等,涉及有机物的反应、对含氧化合物的反应、对化学刺激的细胞反应等显著相关生物过程.结论 本研究基于巨噬细胞极化模型筛选出余甘子鞣质中调控巨噬细胞极化的主要活性部位,借助网络药理学初步证明了余甘子鞣质20％甲醇洗脱部位可以多成分、多靶点、多通路共同调控巨噬细胞极化,为进一步阐明余甘子鞣质调控巨噬细胞极化的药效物质和作用机制提供依据.

Tumor-associated macrophages (TAMs) participate in tumorigenesis, growth, invasion as well as metastasis by facilitating an immunosuppressive tumor microenvironment. Reversing the pro-tumoral M2 phenotype of TAMs has become a hot spot in advancing cancer immunotherapy. In the current study, the content of Moringa oleifera leaf polysaccharides (MOLP) was determined and characterized, along with the anti-cancer mechanism of MOLP studied in a Lewis lung cancer (LLC) tumor-bearing mouse model and bone marrow-derived macrophages. The monosaccharide composition and gel permeation chromatography analyses show that MOLP are mainly composed of galactose, glucose, and arabinose, with approximately 17.35 kDa average molecular weight (Mw). In vivo studies demonstrate that MOLP convert TAMs from the immunosuppressive M2 phenotype to the antitumor M1 phenotype, thus inducing CXCL9 and CXCL10 expression and increasing T-cell infiltration in the tumor. Furthermore, macrophage depletion and T cell suppression demonstrated that the tumor suppressive effect of MOLP was reliant on reprogramming macrophage polarization and T cell infiltration. In vitro studies revealed that MOLP could induce the phenotypic switch from M2 macrophages to M1 by targeting TLR4. The current study highlights that MOLP are promising anticancer plant-derived polysaccharides with potential in modulating the immune microenvironment and have a bright application prospect in the immunotherapy of lung cancer.

The aim of this study is to evaluate the anti-hyperuricemia effect and clarify the possible mechanisms of flavonoids and phenolics of MOL (MOL-FP) in mice. Hyperuricemia mice were generated via intraperitoneal (i.p.) administration of potassium oxonate (PO) and oral gavage (p.o.) of hypoxanthine (HX). Serum uric acid (UA), weight, serum XO activity, hepatic XO activity, urea nitrogen (BUN), creatinine (CRE), serum AST level, serum ALT level, mRNA expression of renal urate-anion transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), organic anion transporters 3 (OAT3), and ATP-binding cassette transporter G2 (ABCG2) were determined. The molecular docking was conducted using AutoDock Vina 1.2.0 to screen potential XO inhibitors in MOL-FP. Serum metabolomics was established to collect the metabolic profiles of mice and explore the metabolic changes that occurred after MOL-FP treatment. MOL-FP could notably reduce the serum UA level of hyperuricemia mice by inhibiting XO activity and regulating renal urate transporters. Molecular docking studies indicated that 5-p-coumaroylquinic acid, 3-p-coumaroylquinic acid, and catechin could be potential XO inhibitors. Besides, MOL-FP prevented the pathological process of hyperuricemia by regulating biomarkers associated with purine metabolism, amino acid metabolism, and lipid metabolism.

目的 建立不同产地辣木Mforingaoleifera叶药材和黄酮部位UPLC-Q-Exactive Orbitrap-MS指纹图谱和多成分定量方法,并进行化学计量学分析,为辣木叶药材和黄酮部位的质量控制提供参考.方法 采用UPLC-Q-Exactive Orbitrap-MS检测并结合"中药色谱指纹图谱相似度评价系统(2012A版)"建立15个不同批次辣木叶药材和黄酮部位(S1～S15)指纹图谱,并进行相似度评价和共有峰指认,测定3个黄酮类成分异牡荆素、异槲皮苷、紫云英苷含量.采用聚类分析(hierarchical clustering analysis,HCA)、主成分分析(principal component analysis,PCA)、正交偏最小二乘法-判别分析(orthogonal partial least-squares discrimination analysis,OPLS-DA)等化学计量学分析方法对15批不同产地辣木叶药材质量和黄酮部位进行评价.结果 15批不同产地辣木叶药材标定了 17个共有峰,指认出其中14个共有峰;辣木叶黄酮部位标定和指认出10个共有峰.15批不同产地辣木叶和黄酮部位的相似度和HCA分析聚为4类,且HCA结果与相似度评价结果基本相一致;PCA、OPLS-DA分析聚为3类.15批药材中异牡荆素、异槲皮苷、紫云英苷的含量分别为0.06％～0.19％、0.27％～0.79％、0.08％～0.23％;黄酮部位中含量分别为0.53％～3.53％、6.49％～14.36％、2.05％～4.66％.结论 建立了专属性强、灵敏度高的不同产地辣木叶药材和辣木叶黄酮部位的定性定量方法,为辣木叶药材和辣木叶黄酮部位综合评价提供依据.