BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Ruoxin Tu,Yining Wang,Ru Xu,Shusheng Wang,Jiabin Cai,Lin Sun,Pengfei Gao
Despite therapeutic advances, hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide. While dihydrotanshinone I (DHT) shows promising anticancer potential, its molecular mechanisms in HCC remain unexplored. Here, we unveil a novel chemokine (C-C Motif) receptor 5(CCR5)-mediated regulatory network targeted by DHT in HCC treatment. This study identifies CCR5 as a crucial survival factor in HCC, uncovers a novel CCR5-Nuclear factor erythroid 2-related factor 2(NRF2) regulatory axis, and reveals a dual-targeting mechanism of DHT through direct CCR5 inhibition and Reactive oxygen species(ROS)-dependent cell death induction, validating its therapeutic efficacy by disrupting redox homeostasis. This study uncovers a novel CCR5-ROS-NRF2 signaling axis in HCC and establishes DHT as a promising therapeutic agent through its unique targeting mechanism. These findings provide new insights into HCC pathogenesis and present an innovative therapeutic strategy for HCC treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Pengcheng Zhang,Yaxin Wang,Yigang Xu,Xueping Li,Xuya Yu,Yi Li,Dunwan Zhu,Fang Luo,Wen Li,Xu Jin
The dysregulation of the microglia-neuron axis plays a pivotal role in the pathogenesis of cognitive dysfunction following traumatic brain injury (TBI). The C–C chemokine receptor 5 (CCR5), markedly upregulated on both microglia and neurons post-injury, serves as a crucial mediator in the neuroinflammatory response and consequent neurological deficits. However, the therapeutic application of CCR5 antagonists in TBI is impeded by the delivery barriers presented by the blood-brain barrier (BBB) and their limited neuron-targeting efficacy. In this study, we introduce a novel nasal-to-brain delivery nanoplatform designed to facilitate the efficient brain delivery of DAPTA, a peptide antagonist of CCR5, aiming to inhibit CCR5 signaling and improving cognitive function following TBI. Biocompatible chitosan nanocarriers grafted with cell-penetrating peptide (TAT) and neuron-binding lactoferrin (Lf) were initially fabricated, demonstrating substantial DAPTA loading capacity, active mucosal and neural transportation, and enhanced neuron-targeting capabilities. The dual-engineered nanodrugs (DA@LT NPs) effectively penetrated the trigeminal and olfactory nerves, significantly enhancing the transport of DAPTA into the brain following intranasal delivery. In a TBI-induced mouse model, DA@LT NPs markedly alleviated the neuroinflammatory response, promoted M2 microglia polarization, protected neurons from pyroptosis, and improved both motor and cognitive functions of animals. The non-invasive intranasal delivery of the therapeutic CCR5 peptide antagonist using these mucus-penetrating and neuron-targeting nanoformulations presents a promising intervention for ameliorating neurological inflammation and cognitive impairments associated with TBI.
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
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2023
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IF 3.9
Yan Nan,Wang Zhengdong,Li Zhou,Zheng Yang,Chang Nan,Xu Kangjie,Wang Qian,Duan Xiaoxu
This study aimed to examine the immuntoxic effects of arsenic in the nervous system. Our results showed that arsenic increased corticocerebral and hippocampal weights ( p < 0.05). Morris water maze tests revealed that arsenic significantly increased the time spent in latency to platform on the fourth day in 50 mg/L arsenic exposure and the fifth day in 25 and 50 mg/L arsenic exposure, as well as reduced the path length in target quadrant, time spent in target quadrant, and crossing times of the platform ( p < 0.05). Hematoxylin–eosin staining showed that the vacuolated degeneration and pyknosis was found in the cerebral cortex and hippocampus of arsenic-treated mice. The mRNA levels of corticocerebral and hippocampal brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were decreased in the 50 mg/L arsenic-treated group ( p < 0.05). In addition, immunofluorescence staining showed that 25 and 50 mg/L arsenic all increased the expression of CD11b and glial fibrillary acidic protein (GFAP) in the cerebral cortex and hippocampus ( p < 0.05). Arsenic markedly raised antigen-presenting molecule MHCII and CD40 mRNA levels in the cerebral cortex and hippocampus and upregulated the cell chemokine receptor 5 (CCR5) and CCR7 mRNA levels in the cerebral cortex at the 50 mg/L arsenic group, and increased the CCR7 mRNA levels in the hippocampus at the 25 and 50 mg/L arsenic groups ( p < 0.05). Arsenic activated the nucleotide-binding domain-like receptor protein-3 (NLRP3) inflammasome, and enhanced its upstream promoter NF-κB protein level and downstream regulators IL-18 mRNA levels. Collectively, these results provide new evidences for the neuro-immune toxicity of arsenic. Graphical abstract
研究领域:
神经毒理学
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免疫毒理学
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神经科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Ling Tang,Liyuan Wang,Feng Jin,Yuehan Hao,Tianming Zhao,Wenxu Zheng,Zhiyi He
Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.
研究领域:
神经科学
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分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Gut Microbes
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2024
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IF 12.2
Fangfang Chen,Songhe Guo,Yiqiu Li,Yongfan Lu,Le Liu,Shengxin Chen,Jun An,Ge Zhang
The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1+ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1+PD-L1+ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1+PD-L1+ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1+PD-L1+ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression.
研究领域:
肿瘤学
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免疫学
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微生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2021
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IF 9.776
Yudi Deng,Zhijie Jiang,Yincheng Jin,Jianan Qiao,Shan Yang,Hui Xiong,Jing Yao
Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Möbius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4 + and CD8 + T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.
研究领域:
肿瘤学
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纳米技术
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药理学
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免疫学
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癌症生物学
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DOI
PubMed
高影响因子
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