BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
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2021
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IF 3.77
O.Yu. Selyutina,P.A. Kononova,V.E. Koshman,E.A. Shelepova,M. Gholam Azad,R. Afroz,M. Dharmasivam,Paul V. Bernhardt,N.E. Polyakov,D.R. Richardson
Background Iron (Fe)-induced oxidative stress leads to reactive oxygen species that damage biomembranes, with this mechanism being involved in the activity of some anti-cancer chemotherapeutics. Methods Herein, we compared the effect of the ligand, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), or the potential ligand, Emodin, on Fe-catalyzed lipid peroxidation in cell membrane models (micelles and bicelles). These studies were performed in the presence of hydrogen peroxide (H 2 O 2 ) and the absence or presence of ascorbate. Results In the absence of ascorbate, Fe(II)/Emodin mixtures incubated with H 2 O 2 demonstrated slight pro-oxidant properties on micelles versus Fe(II) alone, while the Fe(III)-Dp44mT complex exhibited marked antioxidant properties. Examining more physiologically relevant phospholipid-containing bicelles, the Fe(II)- and Fe(III)-Dp44mT complexes demonstrated antioxidant activity without ascorbate. Upon adding ascorbate, there was a significant increase in the peroxidation of micelles and bicelles in the presence of unchelated Fe(II) and H 2 O 2 . The addition of ascorbate to Fe(III)-Dp44mT substantially increased the peroxidation of micelles and bicelles, with the Fe(III)-Dp44mT complex being reduced by ascorbate to the Fe(II) state, explaining the increased reactivity. Electron paramagnetic resonance spectroscopy demonstrated ascorbyl radical anion generation after mixing ascorbate and Emodin, with signal intensity being enhanced by H 2 O 2 . This finding suggested Emodin semiquinone radical formation that could play a role in its reactivity via ascorbate-driven redox cycling. Examining cultured melanoma cells in vitro , ascorbate at pharmacological levels enhanced the anti-proliferative activity of Dp44mT and Emodin. Conclusions and general significance Ascorbate-driven redox cycling of Dp44mT and Emodin promotes their anti-proliferative activity.
研究领域:
生物化学
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药理学
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Xiaowei Chai,Yuanying Jiang,Hui Lu,Xin Huang
Introduction: Candidiasis, mainly caused by Candida albicans, poses a serious threat to human health. The escalating drug resistance in C. albicans and the limited antifungal options highlight the critical need for novel therapeutic strategies.Methods: We evaluated 12 machine learning models on a self-constructed dataset with known anti-C. albicans activity. Based on their performance, the optimal model was selected to screen our separate in-house compound library with unknown anti-C. albicans activity for potential antifungal agents. The anti-C. albicans activity of the selected compounds was confirmed through in vitro drug susceptibility assays, hyphal growth assays, and biofilm formation assays. Through transcriptomics, proteomics, iron rescue experiments, CTC staining, JC-1 staining, DAPI staining, molecular docking, and molecular dynamics simulations, we elucidated the mechanism underlying the anti-C. albicans activity of the compound.Result: Among the evaluated machine learning models, the best predictive model was an ensemble learning model constructed from Random Forests and Categorical Boosting using soft voting. It predicts that Dp44mT exhibits potent anti-C. albicans activity. The in vitro tests further verified this finding that Dp44mT can inhibit planktonic growth, hyphal formation, and biofilm formation of C. albicans. Mechanistically, Dp44mT exerts antifungal activity by disrupting cellular iron homeostasis, leading to a collapse of mitochondrial membrane potential and ultimately causing apoptosis.Conclusion: This study presents a practical approach for predicting the antifungal activity of com-pounds using machine learning models and provides new insights into the development of antifungal compounds by disrupting iron homeostasis in C. albicans.
研究领域:
医学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Zixu Wang,Shanshan Xiang,Yihe Qiu,Fangying Yu,Sufen Li,Shufen Zhang,Guangtao Song,Yichong Xu,Tingting Meng,Hong Yuan,Fuqiang Hu
Cellular iron is inseparably related with the proper functionalities of mitochondria for its potential to readily donate and accept electrons. Though promising, the available endeavors of iron chelation antitumor therapies have tended to be adjuvant therapies. Herein, we conceptualized and fabricated an “iron-phagy” nanoparticle (Dp44mT@HTH) capable of inducing the absolute devastation of mitochondria via inhibiting the autophagy-removal of impaired ones for promoting cancer cell death. The Dp44mT@HTH with hyaluronic acid (HA) as hydrophilic shell can specifically target the highly expressed CD44 receptors on the surface of 4T1 tumor cells. After internalization and lysosomal escape, the nanoparticle disassembles in response to the reactive oxygen species (ROS), subsequently releasing the iron chelator Dp44mT and autophagy-inhibitory drug hydroxychloroquine (HCQ). Dp44mT can then seize cellular Fe 2+ to trigger mitochondrial dysfunction via respiratory chain disturbance, while HCQ not only lessens Fe 2+ intake, but also impedes fusions of autophagosomes and lysosomes. Consequentially, Dp44mT@HTH induces irreversible mitochondrial impairments, in this respect creating a substantial toxic stack state that induces apoptosis and cell death. Initiating from the perspective of endogenous substances, this strategy illuminates the promise of iron depletion therapy via irreversible mitochondrial damage induction for anticancer treatment.
研究领域:
肿瘤学
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纳米医学
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细胞生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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