BRITISH JOURNAL OF PHARMACOLOGY
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2024
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IF 6.8
Yunfu Shen,You Yang,Zi Wang,Wanjun Lin,Na Feng,Meina Shi,Jiachen Liu,Wenzhe Ma
Background and Purpose Triple-negative breast cancer (TNBC) has a poor prognosis due to limited therapeutic options. Recent studies have shown that TNBC is highly dependent on mitochondrial oxidative phosphorylation. The aim of this study was to investigate the potential of coptisine, a novel compound that inhibits the complex I of the mitochondrial electron transport chain (ETC), as a treatment for TNBC. Experimental Approach In this study, mitochondrial metabolism in TNBC was analysed by bioinformatics. In vitro and in vivo experiments (in mice) were conducted to evaluate the potential of coptisine as an ETC complex I-targeting therapeutic agent and to investigate the molecular mechanisms underlying coptisine-induced mitochondrial dysfunction. The therapeutic effect of coptisine was assessed in TNBC cells and xenograft mouse model. Key Results We demonstrated that mitochondrial ETC I was responsible for this metabolic vulnerability in TNBC. Furthermore, a naturally occurring compound, coptisine, exhibited specific inhibitory activity against this complex I. Treatment with coptisine significantly inhibited mitochondrial functions, reprogrammed cellular metabolism, induced apoptosis and ultimately inhibited the proliferation of TNBC cells. Additionally, coptisine administration induced prominent growth inhibition that was dependent on the presence of a functional complex I in xenograft mouse models. Conclusion and Implications Altogether, these findings suggest the promising potential of coptisine as a potent ETC complex I inhibitor to target the metabolic vulnerability of TNBC. Graphical
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
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2024
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IF 27.4
Wen Li,Qi-Wen Chen,Jin-Xuan Fan,Zi-Yi Han,Wen-Fang Song,Xuan Zeng,Xian-Zheng Zhang
Due to inherent differences in cellular composition and metabolic behavior with host cells, tumor-harbored bacteria can discriminatorily affect tumor immune landscape. However, the mechanisms by which intracellular bacteria affect antigen presentation process between tumor cells and antigen-presenting cells (APCs) are largely unknown. The invasion behavior of attenuated Salmonella VNP20009 (VNP) into tumor cells is investigated and an attempt is made to modulate this behavior by modifying positively charged polymers on the surface of VNP. It is found that non-toxic chitosan oligosaccharide (COS) modified VNP (VNP@COS) bolsters the formation of gap junction between tumor cells and APCs by enhancing the ability of VNP to infect tumor cells. On this basis, a bacterial biohybrid is designed to promote in situ antigen cross-presentation through intracellular bacteria induced gap junction. This bacterial biohybrid also enhances the expression of major histocompatibility complex class I molecules on the surface of tumor cells through the incorporation of Mdivi-1 coupled with VNP@COS. This strategic integration serves to heighten the immunogenic exposure of tumor antigens; while, preserving the cytotoxic potency of T cells. A strategy is proposed to precisely controlling the function and local effects of microorganisms within tumors.
研究领域:
癌症生物学
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免疫学
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生物技术
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
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2024
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IF 6.7
Jia-Yi Zheng,Xiao-Yuan Ji,An-Qi Zhao,Fang-Yuan Sun,Li-Fang Liu,Gui-Zhong Xin
Mitochondrial complex activity controls a multitude of physiological processes by regulating the cellular metabolism. Current methods for evaluating mitochondrial complex activity mainly focus on single metabolic reactions within mitochondria. These methods often require fresh samples in large quantities for mitochondria purification or intact mitochondrial membranes for real-time monitoring. Confronting these limitations, we shifted the analytical perspective toward interactive metabolic networks at the whole-cell level to reflect mitochondrial complex activity. To this end, we compiled a panel of mitochondrial respiratory chain-mapped metabolites (MRCMs), whose perturbations theoretically provide an overall reflection on mitochondrial complex activity. By introducing N-dimethyl-p-phenylenediamine and N-methyl-p-phenylenediamine as a pair of mass spectrometry probes, an ultraperformance liquid chromatography-tandem mass spectrometry method with high sensitivity (LLOQ as low as 0.2 fmol) was developed to obtain accurate quantitative data of MRCMs. Machine learning was then combined to capture the relationship between MRCMs and mitochondrial complex activity. Using Complex I as a proof-of-concept, we identified NADH, alanine, and phosphoenolpyruvate as metabolites associated with Complex I activity based on the whole-cell level. The effectiveness of using their concentrations to reflect Complex I activity was further validated in external data sets. Hence, by capturing the relationship between metabolites and mitochondrial complex activity at the whole-cell level, this study explores a novel analytical paradigm for the interrogation of mitochondrial complex activity, offering a favorable complement to existing methods particularly when sample quantities, type, and treatment timeliness pose challenges. More importantly, it shifts the focus from individual metabolic reactions within mitochondria to a more comprehensive view of an interactive metabolic network, which should serve as a promising direction for future research into the functional architecture between mitochondrial complexes and metabolites.
研究领域:
分析化学
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生物化学
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机器学习
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代谢组学
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线粒体生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2024
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IF 12.8
Weihan Zhang,Shijun Yuan,Zipeng Zhang,Shunli Fu,Shujun Liu,Jinhu Liu,Qingping Ma,Zhenxing Xia,Panpan Gu,Shuying Gao,Zhiyue Zhang,Xinke Zhang,Yongjun Liu,Na Zhang
Tumor cells transmit various immunosuppressive signals and induce a dysfunctional state in T cells, which essentially leads to immune escape and tumor progression. However, developing effective strategies to counteract the domestication of T cells by tumor cells remains a challenge. Here, we prepared pH-responsive lipid nanoparticles (NL/PLDs) co-loaded with PCSK9 shRNA, lonidamine (LND), and low-dose doxorubicin (DOX). NL/PLDs can awaken domesticated T cells function by sending pro-activation, pro-recognition, and pro-killing signals by increasing tumor immunogenicity, increasing the expression of major histocompatibility complex I (MHC-I) on tumor cells, and alleviating the suppression effect of tumor-secreted lactic acid (LA) on the T cell effector function, respectively. In melanoma-bearing mice, NL/PLDs effectively relieved tumor immunosuppressive microenvironment (TIME) and enhanced the antitumor immunity mediated by CD8 + T cells. Furthermore, when combined with aPD-1, NL/PLDs demonstrated strong antitumor effects and increased immunotherapeutic efficacy. This regulatory strategy provides new insights for enhancing immunotherapy by regulating tumor immunosuppressive signals and shows significant potential for clinical tumor treatment.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
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产品关联
DOI
PubMed
高影响因子
Aggregate
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2024
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IF 13.9
Xiaoliu Liang,Hui Liu,Hu Chen,Xuqi Peng,Zhenjie Li,Minglei Teng,Yisheng Peng,Jiwei Li,Linyu Ding,Jingsong Mao,Chengchao Chu,Hongwei Cheng,Gang Liu
The efficacy of transarterial chemoembolization (TACE) has been limited by insufficient embolization and a high incidence of tumor recurrence. Herein, we identified that aberrant metabolic reprogramming and immunosuppression contribute to TACE refractoriness and Rhein, as a potential glycolytic metabolism inhibitor and immunoactivation inducer, was optimized to sensitize tumors to TACE therapy. To achieve efficient embolization, we developed an oil-in-water lipiodol embolic emulsion by stabilizing the self-assembled Rhein nanogel. The assembled Rhein exhibited a nanofiber network, and its integration enhanced the mechanical stability and viscoelasticity of the lipiodol embolic agent. With the synergistic advantages of solid and liquid embolic agents, this carrier-free Pickering emulsion exhibits efficient embolization and sustained drug release in models of unilateral renal artery embolization, rabbit ear tumor embolization, rabbit orthotopic liver cancer, and rat orthotopic liver cancer. Compared to conventional three-way catheter mixing methods, multimodal imaging corroborates a marked enhancement in local drug retention and tumor suppression. Importantly, the incorporation of Rhein-mediated synergistic immunoembolization in this strategy achieved efficient embolization while robustly activating anti-tumor immune responses, including inducing immunogenic cell death, dendritic cell activation, and major histocompatibility complex class I presentation to CD8 + T cells for tumor killing. Together, these findings reveal a novel strategy for the application of self-assembled Rhein nanofiber-stabilized lipiodol emulsion to control metabolic signaling and immunoactivation in TACE.
研究领域:
肿瘤学
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药学
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生物医学工程
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免疫学
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代谢学
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产品关联
DOI
高影响因子
ACS Nano
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2024
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IF 15.8
Shiji Fang,Liyun Zheng,Gao-Feng Shu,Chen Xiaoxiao,Xiaoju Guo,Yiming Ding,Wenjing Yang,Jiale Chen,Zhongwei Zhao,Jianfei Tu,Minjiang Chen,Jian-Song Ji
Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients’ overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
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2024
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IF 14.3
Xietao Ye,Yuping Liu,Liangyin Wei,Yeyang Sun,Xiaoran Zhang,Hong Wang,Hong Guo,Xiaoying Qin,Xiaoqi Li,Ding Qu,Jiege Huo,Yan Chen
Microsatellite-stable colorectal cancer (MSS-CRC) exhibits resistance to programmed cell death protein-1 (PD-1) therapy. Improving the infiltration and tumor recognition of cytotoxic T-lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS-CRC cells is engineered for the co-delivery of ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC, named as Ab@Rg1/Att-ZIF. This system is selectively engulfed by Ly-6C + monocytes during blood circulation and utilizes a “hitchhiking” mechanism to migrate toward the core of MSS-CRC. Ab@Rg1/Att-ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class-I (MHC-I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS-CRC, significantly improving the tumor inhibition of PD-1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation-guided precise drug co-delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD-1 treatment of MSS-CRC.
研究领域:
肿瘤学
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药学
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免疫治疗
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纳米技术
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癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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