Chinese Journal of Integrative Medicine
·
2026
·
IF 3.1
Wang Ya-fen,Yue Shi-jun,Li Jia-yao,Meng Si-tong,Zheng Min,Zhang Yu-fang,Gu Ying,Hou Bin,Biao Ya-ning
Objective To explore the molecular mechanism of Xuefu Zhuyu Decoction (XFZYD) against myocardial fibrosis. Methods The active components of XFZYD were identified by high performance liquid chromatography (HPLC). Network pharmacology, molecular docking, and affinity dot-mass spectrometry (AD-MS) were used to predict and validate the binding interaction between XFZYD components and copper transporter 1 (CTR1). Sixty male Kunming mice were randomly divided into 6 groups using a random number table. Control, isoproterenol hydrochloride (ISO), captopril, low-, medium-, and high-dose XFZYD (5.69, 11.38, and 22.76 g/kg) groups, with 10 mice in each group. Except the control group, mice received daily subcutaneous injection of ISO (10 mg/kg) for 28 d to induce myocardial fibrosis, concurrently treated with respective drugs by gavage. Cardiac function was assessed by echocardiography (ECG) and electrocardiography (UCG). Serum myocardial injury markers and transforming growth factor beta 1 (TGF-β 1) were measured by a biochemical analyzer and enzyme-linked Immunosorbent assay (ELISA). Pathological changes and collagen deposition was observed using HE, Masson and sirius red staining methods. Copper content in cardiac tissue was determined by inductively coupled plasma mass spectrometry (ICP-MS), and protein expressions of collagen I, III, alpha-smooth muscle actin (α-SMA), lysyl oxidase (LOX), CTR1, copper chaperone for superoxide dismutase (CCS), and cytochrome c oxidase 17 (COX17) were detected by Western blot, immunohistochemistry, and immunofluorescence. In vitro , TGF-β 1 (5 ng/mL)-stimulated NIH-3T3 fibroblasts were treated with XFZYD (60 mg/L), with or without CuCl 2 (20 µ mol/L) or SLC31A1 overexpression for 24 h, and the same indicators were evaluated. Results HPLC identified 7 major components in XFZYD. Network pharmacology revealed that XFZYD targets copper metabolism related genes. Molecular docking showed strong binding affinities between the 7 compounds and CTR1, and AD-MS confirmed direct binding of paeoniflorin and amygdalin to CTR1. In vivo , XFZYD could ameliorate the collagen deposition, cardiac dysfunction, and elevated levels of collagen I/III, α-SMA, LOX, and copper content exhibited in ISO-induced myocardial fibrosis mice ( P <0.05 or P <0.01). In vitro , XFZYD had the effects of suppressing copper overload and the upregulation of LOX, collagen I/III, and α-SMA in TGF β 1 stimulated NIH-3T3 fibroblasts, whereas co-treatment with CuCl 2 exacerbates these fibrotic responses and attenuates the protective effect of XFZYD ( P <0.05 or P <0.01). XFZYD had the effect of partially reversing the enhanced copper accumulation, LOX activation, and collagen deposition induced by SLC31A1 (CTR1) overexpression in TGF β 1 stimulated fibroblasts, and SLC31A1 overexpression reduces its efficacy ( P <0.05 or P <0.01). Conclusions XFZYD exerted a protective effect against ISO-induced myocardial fibrosis. The mechanism may be related to regulating the CTR1–copper–LOX axis, thereby reducing excessive collagen deposition and cross-linking in cardiac fibroblasts.
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DOI
PubMed
高影响因子
Redox Biology
·
2023
·
IF 11.4
Dingbang Huang,Lixuan Chen,Qiuyi Ji,Yang Xiang,Qin Zhou,Kaiju Chen,Xiaoshun Zhang,Fei Zou,Xingmei Zhang,Zaihua Zhao,Tao Wang,Gang Zheng,Xiaojing Meng
Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ 1-42 -treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ 1-42 , and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ 1-42 -treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.
研究领域:
神经科学
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毒理学
·
神经退行性疾病
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DOI
PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2021
·Vol. 413
·期 5
·1353-1361
·
IF 4.157
Sun Qi-Xuan,Wei Xing,Zhang Shang-Qing,Chen Ming-Li,Yang Ting,Yu Yong-Liang,Wang Jian-Hua
Copper transporter 1 (CTR1) is a transport protein involved in copper and cisplatin uptake. The visualization of cellular CTR1 migration and its redistribution is highly important in copper/cisplatin exposure/transport. However, to the best of our knowledge, this is a highly challenging task. Herein, a dual-mode imaging strategy for CTR1 is developed by hyphenating confocal laser scanning microscopy (CLSM) and laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) with a fluorescent/elemental bifunctional tag conjugated with anti-CTR1 antibody. The tag consists of rhodamine B and zirconium metal-organic frameworks (Zr-MOF) for CLSM fluorescence imaging and LA-ICPMS element imaging for a same group of HepG2 cells in a designated visual zone. This dual-mode imaging strategy facilitates visualization of CTR1 migration and meanwhile provides information of CTR1 redistribution in HepG2 cells by uptake of divalent copper or cisplatin. The present dual-mode imaging strategy provides in-depth information for the elucidation of CTR1 involved biological processes.
Graphical abstract
研究领域:
生物学
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生物化学
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分析化学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
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