TOXICOLOGY
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2021
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IF 4.221
Aijing Bi,Zhen Guo,Guocui Yang,Youfang Huang,Zhimin Yin,Lan Luo
Cadmium (Cd) is a highly toxic environmental pollutant, leading to the occurrence and development of multiple neurological diseases. γ-glutamylcysteine (γ-GC) is a dipeptide formed by the condensation of l -glutamic acid and l -cysteine, which has antioxidant, anti-inflammatory, and chelating properties. The purpose of this study is to investigate the effect of γ-GC on Cd-induced apoptosis in PC12 cells. PC12 cells were pretreated with or without γ-GC (2 mM or 4 mM) for 2 h and exposed to Cd (10 μM) for 12 h, and survival, apoptosis, and oxidative stress of PC12 cells were detected after different treatments. The results showed that γ-GC significantly inhibited cell viability reduction, apoptosis, and depolarization of mitochondrial transmembrane potential in Cd-treated PC12 cells, as indicated by CCK-8 assay, flow cytometry, TUNEL staining, and JC-1 detection. Western blot showed that γ-GC down-regulated the ratio of Bax/Bcl-2 and the protein levels of cytosolic cytopigment c, cleaved-caspase-9, cleaved-caspase-3, and cleaved-PARP. Mechanistically, γ-GC suppressed Cd-induced ROS production, MDA accumulation, and GSH depletion, and increased the activity of antioxidant enzymes. Cd-induced activation of MAPK and PI3K/Akt signaling pathways were inhibited by γ-GC treatment, while sustained phosphorylation of JNK, p38, or Akt reversed anti-apoptotic effects of γ-GC. These results suggested that γ-GC inhibited Cd-induced apoptosis in PC12 cells through decreasing oxidative stress and inhibiting the activation of MAPK and PI3K/Akt signaling pathways. γ-GC could be used as a potential protective agent against Cd neurotoxicity.
研究领域:
神经毒理学
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细胞生物学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
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2024
·Vol. 17
·期 3
·291
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IF 4.3
Nannan Kang,Jun Ma,Yuling Hu,Rongrong Di,Lei Wang,Xuanling Zhang,Yisheng Lai,Yu Liu
Background: Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells need MTH1 for survival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. Methods: MA−24 was screened by malachite green colorimetric assay for MTH1 inhibitors and the kinetic characteristics of MA−24 were assessed. The features of MA−24’s binding with MTH1 were ascertained through molecular docking, and the cytotoxic activity of MA−24 was validated in vitro and in vivo. Target engagement assays, comet assay, and Western blot confirmed the intracellular target and mechanism of MA−24. Results: MA−24 shows potent antitumor bioactivity both in vitro and in vivo. MA−24 competitively inhibited the MTH1 and further induced DNA strand breaks, leading to increased apoptosis of cancer cells depending on the upregulation of the cleaved-caspase 3–cleaved-PARP axis. In particular, MA−24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). Conclusions: MA−24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great potential for the further development MA−24 as an anti-cancer drug.
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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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
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2017
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IF 2.936
En-Xia Wang,Bo-Yang Zou,Lei Shi,Lin-Ying Du,Yan-Yan Zhu,Ya-Meng Jiang,Xiao-Dong Ma,Xiao-Hui Kang,Chang-Yuan Wang,Yu-Hong Zhen,Li-Dan Sun
Aims To investigate the antitumor effects of 7- O -geranylquercetin (GQ), a novel O -alkylated derivative of quercetin, against non-small cell lung cancer (NSCLC) cell lines A549 and NCI-H1975 and the corresponding mechanisms. Main methods Cell viability was assessed using MTT assay. The expression of proteins involved in apoptosis and autophagy was measured using western blotting. Besides, apoptosis was determined with DAPI staining, Annexin V-PI staining and transmission electron microscopy (TEM) assay, and autophagy was observed with TEM assay. Cell cycle and reactive oxygen species (ROS) level were detected using flow cytometry. Key findings GQ inhibited viability of A549 and NCI-H1975 cells in a dose- and time-dependent manner without apparent cytotoxicity to normal human lung fibroblast cells. GQ down-regulated the expression of apoptosis-related proteins pro-caspase 3 and Bcl-2, and up-regulated the expression of cleaved-PARP and Bax in A549 and NCI-H1975 cells. Meanwhile, GQ-induced cell apoptosis could be attenuated by caspase inhibitor Z-VAD-FMK. Besides, GQ induced autophagosome formation in A549 and NCI-H1975 cells, promoted the expression of autophagy-related proteins LC3-II and Beclin 1, and suppressed the expression of p62. Autophagy inhibition with chloroquine or Beclin 1 siRNA could effectively inhibit GQ-induced apoptosis. Furthermore, GQ treatment increased the generation of ROS, and ROS inhibitor N -acetylcysteine could reverse GQ-induced autophagy and apoptosis. Taken together, GQ could induce apoptosis and autophagy via ROS generation in A549 and NCI-H1975 cells, and GQ-induced autophagy contributed to apoptosis. Significance Our findings highlight that GQ is a promising anticancer agent for the treatment of lung cancer.
研究领域:
肿瘤学
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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
危险品化学品经营许可证（带存储）