INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Lei Shu,Peili Luo,Qingxin Chen,Jingyang Liu,Ying Huang,Chuanbin Wu,Xin Pan,Zhengwei Huang
Chemotherapy agents for lung cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung cancer as it induces non-apoptotic cell death, namely ferroptosis. However, a bottleneck exists in FIN56-induced ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the ferroptosis treatment effect by increasing oxidative stress and connecting with the autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung cancer tumors. Notably, ferroptosis and autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of ferroptosis treatment for lung cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.
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Small
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2024
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IF 13
Tianliang Li,Bin Cao,Tianhao Su,Lixing Lin,Dong Wang,Xinting Liu,Haoyu Wan,Haiwei Ji,Zixuan He,Yingying Chen,Lingyan Feng,Tong-Yi Zhang
Nanozymes with multienzyme-like activity have sparked significant interest in anti-tumor therapy via responding to the tumor microenvironment (TME). However, the consequent induction of protective autophagy substantially compromises the therapeutic efficacy. Here, a targeted nanozyme system (Fe-Arg-CDs@ZIF-8/HAD, FZH) is shown, which enhances synergistic anti-tumor ferroptosis/apoptosis therapy by leveraging machine learning (ML). A novel ML model, termed the sequential backward Tree-Classifier for Gaussian Process Regression (TCGPR), is proposed to improve data pattern recognition following the divide-and-conquer principle. Based on this, a Bayesian optimization algorithm is employed to select candidates from the extensive search space. Leveraging this fresh material discovery framework, a novel strategy for enhancing nanozyme-based tumor therapy, has been developed. The results reveal that FZH effectively exerts anti-tumor effects by sequentially responding to the TME, having a cascade reaction to induce ferroptosis. Moreover, the endogenous elevation of high concentration nitric oxide (NO) serves as a direct mechanism for killing tumor cells while concurrently suppressing the protective autophagy induced by oxidative stress (OS), enhancing synergistic ferroptosis/apoptosis therapy. Overall, a novel strategy for improving nanozyme-based tumor therapy has been proposed, underlying the integration of ML, experiments, and biological applications.
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International Journal of Nanomedicine
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2024
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IF 6.6
Yiran Zhang,Qingcheng Song,Yueyao Zhang,Jiheng Xiao,Xiangtian Deng,Xin Xing,Hongzhi Hu,Yingze Zhang
Background Although systemic chemotherapy is a standard approach for osteosarcoma (OS) treatment, its efficacy is limited by the inherent or acquired resistance to apoptosis of tumor cells. Ferroptosis is considered as an effective strategy capable of stimulating alternative pathways of cancer cell demise. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy.Methods and Results A novel nanovehicle composed of arginine-glycine-aspartate (RGD) modified mesoporous silica-coated iron oxide loading Fin56 was rationally prepared (FSR-Fin56). With the RGD-mediated targeting affinity, FSR-Fin56 could achieve selective accumulation and accurate delivery of cargos into cancer cells. Upon exposure to NIR light, the nanovehicle could generate localized hyperthermia and disintegrate to liberate the therapeutic payload. The released Fin56 triggered the degradation of GPX4, while Fe3+ depleted the intracellular GSH pool, producing Fe2+ as a Fenton agent. The local rise in temperature, in conjunction with Fe2+-mediated Fenton reaction, led to a rapid and significant accumulation of ROS, culminating in LPOs and ferroptotic death. The outstanding therapeutic efficacy and safety of the nanovehicle were validated both in vitro and in vivo.Conclusion The Fin56-loaded FSR nanovehicle could effectively disturb the redox balance in cancer cells. Coupled with NIR laser irradiation, the cooperative CDT and PTT achieved a boosted ferroptosis-inducing therapy. Taken together, this study offers a compelling strategy for cancer treatment, particularly for ferroptosis-sensitive tumors like osteosarcoma.
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BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Xinrui Meng,Jingjing Liu,Jia Kang,Menghan Wang,Zhanghui Guan,Dong Tian,Xinping Chen
Gastric ulcer is a highly prevalent digestive tract disease across the world, which is recurrent and hard to cure, sometimes transforming into gastric cancer if left untreated, posing great threat to human health. To develop new medicines for gastric ulcer, we ran a series of screens with ethanol stress model in GES-1 cells, and we uncovered that lamivudine rescued cells from ethanol toxicity. Then, we confirmed this discovery using the well-established ethanol-induced gastric ulcer model in mice and our findings suggest that lamivudine can directly activate phosphoglycerate kinase 1 (PGK1, EC 2.7.2.3), which binds and stimulates superoxide dismutase 1 (SOD1, EC 1.15.1.1) to inhibit ferroptosis and ultimately improve gastric ulcer. Moreover, AAV-PGK1 exhibited comparable gastroprotective effects to lamivudine. The findings are expected to offer novel therapeutic strategies for gastric ulcer, encompassing both lamivudine and AAV-PGK1.
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Materials Research Express
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2024
·Vol. 11
·期 6
·065403
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IF 1.8
Hongfeng Lin,Jianhong Chen,Zhongyan Zhang,Yuxu Wang
In the current study, Fe3O4/Ag nanohybrids demonstrating high efficiency in liver cancer ferroptosis therapy and MR imaging were synthesized using a facile one-pot approach. Subsequently, their morphology, chemical composition, structure, Fenton reaction activity, and magnetic resonance (MR) contrast effect were systemically assessed. Importantly, the in vitro studies demonstrated that the Fe3O4/Ag nanohybrids had a high therapeutic efficiency in treating liver cancer cells and performed exceptionally well during T2-weight MR imaging. Correspondingly, these Fe3O4/Ag nanohybrids demonstrate significant potential for use in the field of biomedicine.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Changyong Wang,Hongyan Zhao,Yaoyang Liu,Minghai Qu,Shanyu Lv,Guoguo He,Hongshuo Liang,Kemiao Chen,Lin Yang,Yonghua He,Chaoyan Ou
Manganese (Mn) is an essential trace element for maintaining bodily functions. Excessive exposure to Mn can pose serious health risks to humans and animals, particularly to the nervous system. While Mn has been implicated as a neurotoxin, the exact mechanism of its toxicity remains unclear. Ferroptosis is a form of programmed cell death that results from iron-dependent lipid peroxidation. It plays a role in various physiological and pathological cellular processes and may be closely related to Mn-induced neurotoxicity. However, the mechanism of ferroptosis in Mn-induced neurotoxicity has not been thoroughly investigated. Therefore, this study aims to investigate the role and mechanism of ferroptosis in Mn-induced neurotoxicity. Using bioinformatics, we identified significant changes in genes associated with ferroptosis in Mn-exposed animal and cellular models. We then evaluated the role of ferroptosis in Mn-induced neurotoxicity at both the animal and cellular levels. Our findings suggest that Mn exposure causes weight loss and nervous system damage in mice. In vitro and in vivo experiments have shown that exposure to Mn increases malondialdehyde, reactive oxygen species, and ferrous iron, while decreasing glutathione and adenosine triphosphate. These findings suggest that Mn exposure leads to a significant increase in lipid peroxidation and disrupts iron metabolism, resulting in oxidative stress injury and ferroptosis. Furthermore, we assessed the expression levels of proteins and mRNAs related to ferroptosis, confirming its significant involvement in Mn-induced neurotoxicity.
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Scientific Reports
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2018
·Vol. 8
·期 1
·1-11
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IF 4.122
Wu Chuanhong,Zhao Wenwen,Yu Jie,Li Shaojing,Lin Ligen,Chen Xiuping
Neurodegenerative diseases (NDD) are typically associated with neuron loss in nervous system areas. Interventions with related death mechanisms may ameliorate NDD progression. Oxidative stress plays an important role in NDD cell death routines. However, tert-butylhydroperoxide (t-BHP), a widely used oxidative stress stimulus, induces neural cell death through a mechanism that remains elusive. In our study, the ferroptosis marker events occurred after co-treatment with 100 μM t-BHP for 1 h, all of which were reversed in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine, implying the occurrence of ferroptosis. Moreover, mitochondrial dysfunction accompanied by a decreased in membrane potential and ATP production, increased mitochondrial ROS generation. Furthermore, this mitochondrial dysfunction could be reversed by Fer-1. In addition, JNK1/2 and ERK1/2 were activated upstream of the ferroptosis and mitochondrial dysfunction. In summary, these data suggest that ferroptosis, coupled with mitochondrial dysfunction, was involved in t-BHP-induced PC12 death. JNK1/2 and ERK1/2 played important roles in t-BHP-induced cell death. Overall, this study might provide clues to the oxidative stress-based strategies for cell protection in NDD.
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ACS Nano
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2024
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IF 15.8
Ying Huang,Huisi Zhao,Yu Zhang,Chuanqi Zhao,Jinsong Ren,Xiaogang Qu
The nanozyme with NADPH oxidase (NOX)-like activity can promote the consumption of NADPH and the generation of free radicals. In consideration of that the upregulation of glucose-6-phosphate dehydrogenase (G6PD) would accelerate the compensation production of NADPH, for inhibition of G6PD activity, our designed bioorthogonal nanozyme can in situ catalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone (DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined platform can disrupt NADPH homeostasis, leading to the collapse of the antioxidant defense system in the tumor cells. The enzyme-like activity of PdCuFe is further enhanced when irradiated by NIR-II light. The destruction of NADPH homeostasis can promote ferroptosis and, in turn, facilitate mild photothermal therapy. Our design can realize NADPH depletion and greatly improve the therapeutic effect through metabolic regulation, which may provide inspiration for the design of bioorthogonal catalysis
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Arabian Journal of Chemistry
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2024
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IF 5.3
Chenwei Xiong,JingJing Shang,Zhentang Yu,Junjie Zhang,Kaisong Miao,Changlin Yu,Yong Huang,Yiping Weng,Xindie Zhou
Background Osteoarthritis (OA) is a chronic joint disease characterized by degeneration of the articular cartilage or inflamed joints. Britanin is a guaiacyl-type sesquiterpene lactone possessing anti-inflammatory and antioxidant activities. Methods In this study, western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescent staining method were used to clarifying the molecular mechanisms of britanin in alleviating chondrocyte ferroptosis. The effect of britanin on reactive oxygen species (ROS) and lipid peroxidation levels in chondrocytes was examined by Dihydroethidium (DHE) stain and fluorescent dye BODIPY581 / 591 C11. The destabilized medial meniscus (DMM) model was used to mimic OA, then britanin was injected into the knee articular cavity. The morphological analysis was performed by hematoxylin and eosin (H&E) staining, Safranin O-Fast green staining and Micro-computed tomography (Micro-CT) analysis. Immunohistochemical analysis and Immunofluorescence assay was conducted to verify the effect of britanin in vivo . Results The results revealed that britanin treatment regulates the expression of chondrocyte extracellular matrix–related factors, such as ADAMTS5, MMP13, SOX9, aggrecan, and COL2A1. Britanin also significantly reversed the influence of interleukin (IL)-1β on the levels of reactive oxygen species and lipid peroxidation and upregulated glutathione peroxidase 4 (GPX4) expression in IL-1β-induced chondrocytes. Erastin could alleviate the effects of britanin on chondrocytes. Moreover, britanin could prevent IL-1β-induced oxidative stress and ferroptosis in chondrocytes. Britanin also upregulated the expression of nuclear factor E2–related factor 2 (Nrf2) in IL-1β-induced chondrocytes, and Nrf2 activator played a similar role as that of britanin in IL-1β-induced chondrocytes. Furthermore, injecting britanin into the knee joints of OA rats alleviated cartilage destruction caused by surgical resection. Conclusions These findings confirmed that britanin can inhibit ferroptosis in OA chondrocytes through the Nrf2-GPX4 pathway. Thus, britanin has the potential to be developed as a drug for OA therapy.
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PHYTOMEDICINE
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2024
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IF 6.7
Shanshan Guo,Lang Zhou,Xueqi Liu,Li Gao,Yuanyuan Li,Yonggui Wu
Background In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. Purpose In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. Methods We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. Results Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. Conclusion This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.
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FREE RADICAL BIOLOGY AND MEDICINE
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2024
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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.
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SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Mengzhu Lv,Xiaoyu Mao,Zheng Lu,Yanzhu Yang,Jiangtao Huang,Yuqin Cheng,Chuan Ye,Zhixu He,Liping Shu,Dashuang Mo
N -(1,3-dimethylbutyl)- N′ -phenyl- p -phenylenediamine (6PPD), which is widely used as an antiozonant in rubber tires, has recently got much attention for its acute aquatic toxicity. However, the developmental toxicity of 6PPD in cerebrovascular network remains unknown. Here, we investigated the effects of 6PPD exposure in cerebral vascular using zebrafish. 6PPD would not affect the body length and shape of zebrafish larvae at the concentrations ranging from 20 μg/L to 1000 μg/L. 6PPD induced developmental defects in the brain in a concentration-dependent manner. The trunk vascular development would not be affected while the cerebrovascular network was disrupted upon 6PPD exposure. 6PPD would trigger excessive Reactive Oxygen Species (ROS) in the brain, indicating abnormal oxidative stress. Mechanistically, brain-specific transcriptome analysis showed that 6PPD could potentially cause the blockage of arachidonic acid (AA) metabolism-related genes and the upregulation of ferroptosis-related genes. Besides, treatment with ferroptosis inhibitor N -Acetyl-L-cysteine (NAC) attenuated oxidative damage and improved the construction of cerebrovascular network upon 6PPD exposure. Moreover, using a human vascular endothelial cell line, we further confirmed that 6PPD could trigger abnormal oxidative stress and defective expansion capacity, implying the conserved toxicity cross species. These findings are useful for the elucidation of toxicity underlying 6PPD in cerebrovascular systems of both zebrafish and humans.
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危险品化学品经营许可证（带存储）