American Journal of Cancer Research
·
2023
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IF 5.3
Qi-Tang Huang,Quan-Quan Hu,Zhao-Feng Wen,Yan-Li Li
Since the approval by the Food and Drug Administration (FDA), ferumoxytol and other iron oxide nanoparticles (IONs) have been widely used as iron supplements for patients with iron deficiency. Meanwhile, IONs have also been used as contrast agents in magnetic resonance imaging and as drug carriers. Importantly, IONs have demonstrated a significant inhibitory effect on the growth of tumors, including hematopoietic and lymphoid tumors, such as leukemia. In this study, we further demonstrated the effect of IONs on inhibiting the growth of diffuse large B-cell lymphoma (DLBCL) cells by enhancing ferroptosis-mediated cell death. IONs treatment caused an accumulation of intracellular ferrous iron and the onset of lipid peroxidation in DLBCL cells as well as the suppressed expression of anti-ferroptosis protein Glutathione Peroxidase 4 (GPX4), thereby leading to increased ferroptosis. Mechanistically, IONs increased cellular lipid peroxidation through the generation of ROS via the Fenton reaction and regulating the iron metabolism-related proteins, such as ferroportin (FPN) and transferrin receptor (TFR), which elevated the intracellular labile iron pool (LIP). Hence, our findings suggest the potential therapeutic effect of IONs on the treatment of patients with DLBCL.
研究领域:
肿瘤学
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纳米医学
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血液学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
·
2024
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IF 1.9
Lin Shuai,Cai Hui,Song Xuemei
The objective of this study was to explore the effects and mechanisms of the combination of isobavachalcone (IBC) and doxorubicin (DOX) on the progression of anaplastic thyroid cancer (ATC). Cell viability of 8505C and CAL62 cells was observed by CCK-8 assay. Kits were used to detect the presence of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and cellular iron. Protein expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was detected using western blot, and CD31 was detected through immunofluorescence. Tumor xenograft models of 8505C cells were constructed to observe the effect of IBC and DOX on ATC growth in vivo. The co-administration of IBC and DOX exhibited a synergistic effect of suppressing the growth of 8505C and CAL62 cells. The concurrent use of IBC and DOX resulted in elevated iron, ROS, and MDA levels, while reducing GSH levels and protein expression of SLC7A11 and GPX4. However, the Fer-1 ferroptosis inhibitor effectively counteracted this effect. In vitro and in vivo, the inhibitory effect on ATC cell proliferation and tumor growth was significantly enhanced by the combination of IBC and DOX. The combination of IBC and DOX can inhibit the growth of ATC by activating ferroptosis, and might prove to be a potent chemotherapy protocol for addressing ATC.
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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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
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IF 6.656
Weiqi Cui,Junwei Zhang,Deqiao Wu,Jingxian Zhang,Hui Zhou,Ying Rong,Fanglin Liu,Bo Wei,Xia Xu
Background Pancreatic cancer is one of the most common malignant tumors of the digestive tract. Ponicidin, a tetracyclic diterpenoid active ingredient extracted from the traditional phytomedicine Rubescens, has high safety and great inhibitory effect on the proliferation of a variety of cancer cells, especially malignant tumor cells of the digestive tract. However, the inhibitory effect and mechanism of ponicidin on pancreatic cancer cells is still unclear. Our study aimed to use metabonomics technology to analyze and explore the suppressive effect of ponidicin against pancreatic cancer cells. Methods MTT and flow cytometry were conducted to study the potential effect of ponicidin on SW1990 cells. Secondly, UPLC-MS/MS was used to analyze the small molecule metabolites and relevant differential metabolic pathways induced by ponicidin treatment. Furthermore, through the determination of glutathione peroxidase 4 (GPX4) activity and molecular docking simulation experiments, the effects of intracellular GPX4 activity and GSH/GSSG ratio after ponicidin were evaluated. Finally, the determination of the content of iron ions and malondialdehyde in cells, and the experiment of the effect of ferroptosis inhibitors on cell viability, the effect of ponicidin on the induction of ferroptosis in SW1990 cells was also detected. Results The IC 50 of ponicidin on SW1990 cells was 20 μM, which could significantly induce cell apoptosis and arrest the cells in G 2 /M phase. Metabolomics results showed that the contents of endogenous small molecules such as gamma-glutamylcysteine, 5-oxoproline, glutamic acid, reduced glutathione (GSH), oxidized glutathione (GSSG) and arachidonic acid have changed significantly. Main differential compounds were involved in the gamma-glutamyl cycle and polyunsaturated fatty acid metabolism of pancreatic cancer cell lines. Additionally, ponicidin could covalently bind to GSH in SW1990 cells to form a conjugate Pon-GSH, which further reduced the content of free GSH and GPX4 activity in cells. Notably, ponicidin dose-dependently increased levels of iron ions, malondialdehyde and reactive oxygen species in SW1990 cells, and the ferroptosis inhibitors could significantly block the effects of ponicidin on the proliferation of SW1990 cells. Conclusion Ponicidin could suppress the pancreatic cancer cell proliferation via inducing ferroptosis by inhibiting the gamma-glutamyl cycle and regulating the polyunsaturated fatty acid metabolism in SW1990 cells.
研究领域:
肿瘤学
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药理学
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代谢组学
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细胞生物学
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2025
·Vol. 21
·期 11
·4872-4894
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IF 10
Chen Yuxing,Tao Yong,Huang Qiu,Xu Jingtao,Wang Zhenxin,Zhang Ye,Fu Guangxu,Tan Fuqiang,Feng Keyi,Ou Yunsheng
Osteosarcoma remains a challenging malignancy with poor prognosis, particularly in metastatic cases. This study investigates the therapeutic potential and molecular mechanisms of the Hinokitiol-iron complex (Fe(hino)3) against osteosarcoma. Fe(hino)3 induced dose-dependent cell death in osteosarcoma cell lines (HOS, 143b, and K7M2) through multiple pathways. At moderate doses, Fe(hino)3 triggered ferroptosis by disrupting mitochondrial function, enhancing ROS generation and lipid peroxidation, downregulating GSS and GPX4, and upregulating HO1 and Ferritin expression. At higher doses, Fe(hino)3 activated the NLRC4/Caspase-1/GSDMD pathway, leading to pyroptosis and the release of inflammatory factors. Mechanistically, Fe(hino)3 acted as a dual-mode cell death inducer through iron overload-mediated ferroptosis and NLRC4-dependent pyroptosis while modifying the immunosuppressive tumor microenvironment. In actual clinical application, Fe(hino)3 might be used as an alternative to chemotherapy or other targeted therapies for advanced osteosarcoma at a relatively low dose to improve biosafety and reduce side effects. However, when considering it in combination with immunotherapy for advanced osteosarcoma, a relatively safe high dose is more appropriate due to the pyroptosis-mediated inflammatory response but it still needs to consider the biosafety of combination therapy. These findings provide new insights into the development of Fe(hino)3 dose-dependent therapeutic strategies for advanced osteosarcoma treatment.
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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免疫学
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生物化学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-15
·
IF 14.7
Jiang Jun,Yang Lili,Xie Qianqian,Liu Xi,Jiang Jie,Zhang Jie,Zhang Shuping,Zheng Huizhen,Li Wenjie,Cai Xiaoming,Liu Sijin,Li Ruibin
Ferroptosis is a promising strategy for cancer therapy, with numerous inhibitors of its braking axes under investigation as potential drugs. However, few studies have explored the potential of activating the driving axes to induce ferroptosis. Herein, phosphatidylcholine peroxide decorating liposomes (LIP PCPO ) are synthesized to induce ferroptosis by targeting divalent metal transporter 1 (DMT1). LIP PCPO is found to boost lysosomal Fe 2+ efflux by inducing cysteinylation of lysosomal DMT1, resulting in glutathione peroxidase 4 (GPX4) suppression, glutathione depletion and ferroptosis in breast cancer cells and xenografts. Importantly, LIP PCPO induced ferroptotic cell death is independent of acquired resistance to radiation, chemotherapy, or targeted agents in 11 cancer cell lines. Furthermore, a strong synergistic ferroptosis effect is observed between LIP PCPO and an FDA-approved drug, artesunate, as well as X rays. The formula of LIP PCPO encapsulating artesunate significantly inhibits tumor growth and metastasis and improves the survival rate of breast cancer-bearing female mice. These findings provide a distinct strategy for inducing ferroptosis and highlight the potential of LIP PCPO as a vector to synergize the therapeutic effects of conventional ferroptosis inducers.
研究领域:
癌症生物学
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药理学
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治疗学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
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2025
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IF 11.9
Dan Liu,Hui Yu,Zhicun Liu,Le Wang,Dawo Liu,Xiangyu Cao
Acrolein is a significant high priority hazardous air pollutant. This research explore the relationship of acrolein-induced ferroptosis with the pathogenesis of lung injury by combining cellular, transcriptome, and animal-level studies. The results in vivo and in vitro models indicated that a total of 18,868 differenced lncRNAs and 15,639 differenced mRNAs were obtained after acrolein exposure. After screening, 636 lncRNAs and 214 mRNAs were obviously different of the acrolein injured group with the control group. Differential genes were mainly enriched in the iron ion binding, tissue homeostasis, etc. Among them, lncRNA MIR155HG significantly responded to the toxic effects of acrolein, the knockdown of lncRNA MIR155HG could inhibit miR-155-5p expression, promote CD200R1 expression, and improve cell viability. Furthermore, it effectively inhibited acrolein-induced the activation of ferroptosis pathway in BEAS-2B cells and lung tissue, indicating that lncRNA MIR155HG might be a potential new target for the inhibition of acrolein toxicity. LncRNA-MIR155HG/miR-155-5p/CD200R1 axis played an significant role in the lung injury, and induced ferroptosis by regulating the Nrf2/SLC7A11/GPX4 pathway. This study is the first to reveal that acrolein exposure significantly affected lncRNA and mRNA expression in BEAS-2B cells, and found that lncRNA MIR155HG effectively regulated acrolein-induced ferroptosis pathway, providing novel insights for the treatment of lung injury.
研究领域:
毒理学
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分子生物学
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环境卫生
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呼吸系统疾病
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基因组学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Shiyan Fu,Yong Li,Li Shen,Yonglai Chen,Jingxuan Lu,Yonghong Ran,Yazhen Zhao,Hong Tang,Longfei Tan,Qinyang Lin,Yuhui Hao
Unavoidable damage to normal tissues and tumor microenvironment (TME) resistance make it challenging to eradicate breast carcinoma through radiotherapy. Therefore, it is urgent to develop radiotherapy sensitizers that can effectively reduce radiation doses and reverse the suppressive TME. Here, a novel biomimetic PEGylated Cu 2 WS 4 nanozyme (CWP) with multiple enzymatic activities is synthesized by the sacrificing template method to have physical radiosensitization and biocatalyzer-responsive effects on the TME. Experiment results show that CWP can improve the damage efficiency of radiotherapy on breast cancer cell 4T1 through its large X-ray attenuation coefficient of tungsten and nucleus-penetrating capacity. CWP also exhibit strong Fenton-like reactions that produced abundant ROS and GSH oxidase-like activity decreasing GSH. This destruction of redox balance further promotes the effectiveness of radiotherapy. Transcriptome sequencing reveals that CWP induced ferroptosis by regulating the KEAP1/NRF2/HMOX1/GPX4 molecules. Therefore, owing to its multiple enzymatic activities, high-atomic W elements, nucleus-penetrating, and ferroptosis-inducing capacities, CWP effectively improves the efficiency of radiotherapy for breast carcinoma in vitro and in vivo. Furthermore, CWP-mediated radiosensitization can trigger immunogenic cell death (ICD) to improve the anti-PD-L1 treatments to inhibit the growth of primary and distant tumors effectively. These results indicate that CWP is a multifunctional nano-sensitizers for radiotherapy and immunotherapy.
研究领域:
纳米技术
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肿瘤学
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放射生物学
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免疫治疗
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分子生物学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
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IF 5.7
Hanhan Xie,Ji Yang,Tong Liu,Xinyue Zhang,Shan Zuo,Yingjie Gao,Xi Kuang,Tao Zhang
Lignin is dietary fiber from plant cell walls with multiple biological antioxidant and anti-inflammatory activities. However, whether lignin protects from ulcerative colitis (UC) and underlying mechanisms is unclear. Herein, UC mouse modeling was established with dextran sulfate sodium (DSS) and treatment with lignin for 1 week. Results showed that lignin inhibited the disease activity index (DAI), histological damage, and cell death in UC mice. We also found that lignin reversed the alterations of ferroptotic features in DSS-induced mice and ferroptotic cells, as evidenced by increased expression of GPX4 and 4-HNE and decreased transferrin expression, ameliorating the phenomenon of iron overload, GSH depletion, and ROS and MDA production. Furthermore, the increased expression of NRF2 was observed in IECs under lignin treatment. Also, the upstream regulatory molecule ERK of NRF2 was activated. Further research revealed that lignin can bind GPR37. Meanwhile, lignin was able to alleviate colitis by improving the composition of the intestinal flora in DSS mice and its effect was similar to that of 5-ASA. Taken together, these findings suggest that lignin protects against ferroptosis in UC by combining GPR37 and activating the ERK-NRF2-GPX4 signaling axis, which provides new ideas for clinical intervention in the treatment of UC.
研究领域:
胃肠病学
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药理学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Guangyao Shan,Yunyi Bian,Guangyu Yao,Jiaqi Liang,Haochun Shi,Zhengyang Hu,Zhaolin Zheng,Guoshu Bi,Hong Fan,Cheng Zhan
Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and associated with drug resistance in lung adenocarcinoma (LUAD). It's found that aldehyde dehydrogenase 2 (ALDH2), which is highly mutated in East Asian populations, is correlated with response to chemotherapy in LUAD patients. The rs671 variant knock-in, downregulation, and pharmacological inhibition of ALDH2 render LUAD cells more vulnerable to ferroptosis inducers and platinum-based chemotherapy. ALDH2 inhibits ferroptosis through the detoxification of 4-hydroxynonenal and malondialdehyde, the product of lipid peroxidation, as well as the production of NADH at the same time. Besides, ALDH2 deficiency leads to elevated intracellular pH (pHi), thus inhibiting the ERK/CREB1/GPX4 axis. Interestingly, ALDH2 is also regulated by CREB1, and the ALDH2 enzyme activity was decreased with elevated pHi. What's more, the elevated pHi caused by impaired ALDH2 activity promotes the biosynthesis of lipid droplets to counteract ferroptosis. At last, the effect of ALDH2 on ferroptosis and chemosensitivity is confirmed in patient-derived organoids and xenograft models. Collectively, this study demonstrates that ALDH2 deficiency confers sensitivity to platinum through ferroptosis in LUAD, and targeting ALDH2 is a promising new strategy to enhance the sensitivity of platinum-based chemotherapy for the treatment of LUAD patients.
研究领域:
肿瘤学
·
药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Qin Chen,Fen-Sheng Qiu,Wei Xie,Wen-Ying Yu,Zhao-An Su,Guang-Ming Qin,You-Kun Kang,Song-Lin Jiang,Chen-Huan Yu
Diabetic retinopathy (DR) is one of the chronic microvascular complications of type 2 diabetes mellitus (T2DM), which will cause retinal detachment and blindness without ideal therapies. Gypenoside A (GPA) are the main bioactive compound from Gynostemma pentaphyllum , and have various pharmacological effects. However, it suffered from poor bioavailability and potential cardiotoxicity in the clinical application. To overcome those limitations, in this study, nearly spherical nanoparticles (GPA-NP) with a mean particle size of 140.6 ± 22.4 nm were prepared by encapsulating GPA into mPEG-PLGA. This encapsulation efficiency was 84.4 ± 6.9 %, and the drug load was 4.02 %±0.35 %. The results showed that GPA-NP displayed more prolonged GPA release and higher bioavailability in vitro than GPA. GPA-NP obviously reduced the levels of oxidative stress markers and inflammatory cytokines in both retinal tissues of DR mice and high glucose-exposed HRMEC better than GPA alone. Mechanismly, GPA blocked the Nrf2-Keap1 interaction by binding with Kelch domain of Keap1 via alkyl and hydrogen bonds. Therefore, GPA-NP exerted more potent protectivity effects against high glucose-induced retinal microvascular endothelial ferroptosis in vitro and in vivo by activating Nrf2/HO-1/GPX4 pathway. It could be a promising therapeutic agent for preventing DR.
研究领域:
药理学
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纳米技术
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糖尿病
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眼科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Andrology
·
2024
·
IF 3.2
Yumeng Liu,Qiwen Feng,Liping Zou,Changhong Zhu,Wei Xia
Background Oligoasthenozoospermia is a common cause of male infertility, for which effective treatments are urgently needed. Humanin (HN) is a peptide associated with this condition. Objectives To investigate the ameliorative effect of [Gly14]-Humanin (HNG) on oligoasthenozoospermia and the mechanisms. Materials and methods Mice were treated with cyclophosphamide (CP) to construct a mice model of oligoasthenozoospermia. The resulting model mice were treated with saline or HNG. Subsequently, the testis weights, organ indices, testicular structure, sperm counts and motilities, litter sizes, and serum testosterone concentrations of the mice were determined. Differential gene expression in testicular tissues was determined by RNA sequencing. TM3, TM4, GC1, and GC2 cells were exposed to erastin to induce ferroptosis, followed by treatment with HNG or HNG + ML385 (a nuclear factor erythroid 2-related factor 2 inhibitor). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ions (Fe 2+ ) were determined and their expression of ferroptosis-related proteins was determined by immunofluorescence and western blot. Results The HNG treatment improved testis and sperm parameters and increased litter size and serum testosterone concentrations in model mice. Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis revealed significant differential expression of ferroptosis-related genes. The expression of ferroptosis-related proteins increased in testicular tissues after the HNG treatment. The concentrations of ROS, MDA, and Fe 2+ decreased and the concentrations of GSH increased in testicular tissues and in TM3 and TM4 cells after HNG treatment. In vitro experiments confirmed that HNG activated the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) pathway. However, these effects of HNG were blocked by ML385 treatment. Discussion and conclusion HNG demonstrated a therapeutic effect on oligoasthenozoospermia in a mouse model by reducing oxidative stress and ferroptosis. In TM3 and TM4 cells, HNG attenuated cellular oxidative stress and inhibited ferroptosis via the Nrf2/GPX4 pathway.
研究领域:
生殖生物学
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分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2025
·
IF 5.7
Xingyu Zhang,Chengyu Shi,Qiao Liu,Yuting Zhong,Lipeng Zhu,Yuetao Zhao
Combination of immunotherapy and photothermal therapy (PTT) provides a promising therapeutic performance for tumors. However, it still faces negative feedback from suppressive factors such as adenosine. Herein, we developed a new nanodrug that can combine adenosine blockade and ferroptosis to promote the photoimmunotherapy of triple negative breast cancer (TNBC). The nanodrug, named CuS-PEG@Apt, was constructed via the modification of copper sulfide (CuS) nanoparticles with adenosine aptamer and PEG. CuS-PEG@Apt could be effectively enriched in the tumor site and locally generate a strong photothermal effect, directly ablating tumors and inducing immunogenic death (ICD). On the other hand, the aptamers could block the adenosine pathway to inhibit the immune suppression by adenosine, which further promoted the anti-tumor immunity. Moreover, the CuS nanoparticles could consume GSH and inhibit GPX4 to cause the ferroptosis of tumor cells. Collectively, CuS-PEG@Apt achieved potent efficacy of tumor suppression via the combination of PTT, immune activation and ferroptosis, representing an appealing platform for TNBC treatment.
研究领域:
肿瘤学
·
免疫治疗
·
纳米医学
·
癌症生物学
✓ 已验证
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）