ANALYTICAL CHEMISTRY
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2023
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IF 7.4
Dan Sun,Guohua Qi,Xuan Yi,Hongyan Zhu,Yongdong Jin
Studying the oxidative stress, especially the reactive oxygen species (ROS) response of ferroptosis, is crucial for the diagnosis and treatment of cancer based on ferroptosis. However, reliable quantitative analysis of intracellular ROS in cancer treatment for drug screening is still a challenge. Herein, a superior ratiometric SERS nanoprobe was developed for in situ, real-time, and highly sensitive detection of content variation of H2O2 within living cells. The SERS nanoprobe was prepared by coassembly of the internal standard molecule p-mercaptobenzonitrile and the reporter molecule p-mercaptophenylboronic acid on the surface of gold nanoparticles, used for synergistic calibration and detection of H2O2, which enables reliable detection of the true content of intracellular H2O2 without the interference of other substances in cells. Based on the nanoprobe, we found that the level of intracellular H2O2 of cancer cells was increased after the nicotinamide adenine dinucleotide (NADH) treatment, with a dose-dependence to the concentration of NADH. High doses of NADH (above 20 mM) can induce cell death by means of ferroptosis associated with the level elevation of intracellular lipid hydroperoxides. This study highlights the potential of the SERS nanoprobe for tracking content variation of cellular H2O2 and understanding its roles in screening new anticancer drugs.
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JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 8.039
Haohao Wang,Di Wu,Chunyu Gao,Hongbo Teng,Yan Zhao,Zhongmei He,Weijia Chen,Ying Zong,Rui Du
In this study, 70 new seco-lupane triterpene derivatives were designed, synthesized, and characterized, and their in vitro anticancer activities were evaluated. Structure–activity relationship studies showed that most compounds inhibited the growth of a variety of tumor cells in vitro. With the extension of alkyl chains, the activity of azole compounds gradually increased while that of indole compounds first increased and then decreased. Moreover, all indole derivatives showed stronger anticancer activity than azole derivatives. In addition, compound 21 showed the strongest inhibitory effect on HepG2 cells with an IC50 value of 0.97 μM. Mechanistic studies showed that compound 21 coregulates the cell death process by inducing ferroptosis and regulating the cell cycle. In conclusion, compound 21 can be used as a ferroptosis inducer and cycle blocker to regulate the HepG2 death process, and it has the potential to become an effective new drug for the treatment of hepatocellular carcinoma.
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Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-20
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IF 11.3
Jiang Hao,Tian Hailong,Wang Zhihan,Li Bowen,Chen Rui,Luo Kangjia,Lu Shuaijun,Nice Edouard C.,Zhang Wei,Huang Canhua,Zhou Yuping,Zheng Shaojiang,Gao Feng
Background Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemo-resistance remaining a major obstacle in CRC treatment. Notably, the imbalance of redox homeostasis-mediated ferroptosis and the modulation of hypoxic tumor microenvironment are regarded as new entry points for overcoming the chemo-resistance of CRC.
Methods Inspired by this, we rationally designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform by co-assembling cisplatin (CDDP) and linoleic acid (LA)-tailored IR820 via enhanced ferroptosis against colorectal cancer chemo-resistance. In this nanoplatform, CDDP can produce hydrogen peroxide in CRC cells through a series of enzymatic reactions and subsequently release oxygen under laser-triggered photothermal to alleviate hypoxia. Additionally, the introduced LA can add exogenous unsaturated fatty acids into CRC cells, triggering ferroptosis via oxidative stress-related peroxidized lipid accumulation. Meanwhile, photothermal can efficiently boost the rate of enzymatic response and local blood flow, hence increasing the oxygen supply and oxidizing LA for enhanced ferroptosis.
Results This nanoplatform exhibited excellent anti-tumor efficacy in chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models.Conclusion sTaken together, this nanoplatform provides a promising paradigm via enhanced ferroptosis and alleviated hypoxia tumor microenvironment against CRC chemo-resistance.Graphical Abstract
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ADVANCED FUNCTIONAL MATERIALS
·
2023
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IF 19
Yanqiu Wang,Lu Tan,Wanqian Zhang,Yi Yang,Changqing Li,Hongli Li,Kaiyong Cai,Yan Hu,Zhong Luo,Minghan Liu
Intervertebral disc degeneration (IDD) remains an essential challenge in the clinics due to the ferroptosis of nucleus pulposus cells (NPCs) and the imbalance of extracellular matrix (ECM) metabolism. Here, a dynamic hydrogel (HPGO) based on oxidized hyaluronic acid (OHA) and polyvinyl alcohol (PVA) for the integration of oridonin (Ori)-loaded NPC membrane-based nanovesicles is proposed, which is further grafted with growth and differentiation factor 5 (GDF5) on the OHA chain via Schiff base ligation. The precursors can rapidly form mechanically resilience hydrogels after injection into nucleus pulposus (NP) through the formation of various dynamic bonds. Meanwhile, the acidic pH in the degenerated NP can trigger the responsive release of GDF5, which may cooperate with Ori to alleviate inflammation in the microenvironment for restoring the metabolic homeostasis of ECM. In addition, the Schiff base moieties in HPGO hydrogel can scavenge free ferrous ions in the microenvironment to strengthen the dynamic bonds for self-regulated reinforcement, thus providing mechanical support for the degenerated intervertebral discs (IVDs). Furthermore, HPGO hydrogel can enhance ferroptosis resistance of NPCs by activating the nuclear factor erythoid 2-related factor 2 signaling pathway. Overall, HPGO hydrogel can mechanically support the damaged IVDs as well as reversing their degenerative status through cooperative ferroptosis inhibition, which provides an approach for the clinical treatment of IDD.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2023
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IF 5.8
Yue Hu,Qing Nie,Xianling Cong,Wen Wu,Qiong Wu,Qihui Liu,Yuanyuan Li,Haiyan Liu,Jingyan Ge,Fangfang Chen
Cancer represents a significant global public health challenge, and conventional cancer therapies such as surgery and chemoradiotherapy are not enough due to the increased complexity of cancer. Nanotechnology has the potential to revolutionize tumor treatments by integrating gene therapy, tumor targeting, and drug delivery. In this study, we demonstrated that Snail2 plays a crucial role in the migration and invasion of lung and liver carcinoma. We proposed a novel approach to synergize the aminated crosslinking dextran coat of superparamagnetic iron oxide nano worms (CLIO-NH 2 , CN) with small interfering Snail2 RNA (siSnail2). The efficiency of siSnail2 delivery was significantly improved by coating CN with N-Isopropylacrylamide-modified polyethylenimine (CNP). In vitro, experiments revealed that CNP@siSnail2 effectively inhibited cancer cell EMT, migration, and invasion. Moreover, CNP@ siSnail2 promoted cancer cell death through various mechanisms, including apoptosis and ferroptosis . The combination of CNP@ siSnail2 and cisplatin significantly improved the anti-tumor effect of the treatment. Animal models demonstrated that the combined treatment of CNP@ siSnail2 and cisplatin resulted in excellent tumor inhibition effects. Our findings provide a potential combined treatment strategy for cancer therapy.
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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2025
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IF 3
Mengying Jin,Xiao Chen,Lanzhuoying Zheng,Yuanyuan Peng,Mingying Lin,Ke Liang,Xinran Liu,Zihan Xu,Yiming Yang,Baozhu Wei,Jing Wan
Background Astaxanthin (ASX), a fat-soluble carotenoid mainly sourced from Haematococcus pluvialis, shows promise for clinical applications in chronic inflammatory diseases. This study investigates whether ASX can mitigate atherosclerosis (AS) by modulating macrophage ferroptosis and provides astaxanthin-loaded polylactic acid-glycolic acid nanoparticles (ASX-PLGA NPs) as comparison. Method ApoE−/− mice were fed a high-fat diet with ASX or statin intervention. Plaque area, lipid aggregation, collagen content, and ferroptosis-related indicators were assessed. Moreover, ASX-PLGA NPs were synthesized and characterized and were used to pretreat macrophages induced with oxidized low-density lipoprotein (ox-LDL). Indicators linked to ferroptosis and oxidative stress were detected. Finally, the expression of nuclear factor erythroid -related factor 2 (NRF2) was evaluated. Results ASX intervention significantly delayed the progression of AS plaques, characterized by reductions in plaque area and increased collagen fibers. The observed improvements in AS were consistent with statins. ASX-PLGA NPs demonstrate good safety and stability and have better therapeutic effects than ASX alone. Indicators linked to ferroptosis and oxidative stress were significantly improved in groups containing ASX in vivo and vitro. Additionally, ASX facilitated the nuclear translocation of NRF2, which could be attenuated with ML385, a specific inhibitor of NRF 2. Conclusion ASX-PLGA NPs have better therapeutic effects than ASX alone. The regulation of NRF2/SLC7A11/GPX4 represents a novel mechanism by which ASX can counteract ferroptosis and impede AS progression.
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Discover Oncology
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2025
·Vol. 16
·期 1
·1-18
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IF 2.9
Guo Lin,Zhang Jia,Li Yuqiang,Gao Yuehong,Huang Jiali,Liu Mengru,Li Jing,Chai Wenshu,Li Yubin
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. In lung cancer, AHR activation stimulates cancer cell proliferation and promotes tissue invasion and metastasis, and targeting the AHR pathway is an effective way to prevent and treat lung cancer. In lung cancer, AHR binds to the NRF2 promoter region to promote carcinogenesis, but treatment research based on AHR/NRF2 pathway is insufficient. 3,3′-diindolylmethane (DIM), an active phytochemical derivative extracted from cruciferous vegetables, is a modulator of AHR. In this study, We investigated the medicinal value of DIM in NSCLC (non-small cell lung cancer) by in vivo and in vitro experiments and explored the underlying mechanisms. In vitro studies showed that DIM inhibited the viability of NSCLC and induced apoptosis and cycle arrest in cancer cells. DIM inhibited the migration and invasion of NSCLC cells by reversing the epithelial-mesenchymal transition. DIM induced ferroptosis in NSCLC cells; increased cellular Fe 2+ , ROS (reactive oxygen species), and MDA; decreased cellular GSH, AHR, NRF2, and GPX4; and disrupted the mitochondrial membrane potential. The effect of DIM-induced ferroptosis can be reversed by the AHR receptor antagonist CH-223191, ferroptosis inhibitor Fer-1, and ROS scavenger NAC. Overexpression of NRF2 reversed DIM-induced ferroptosis. Identical results were obtained in a nude mouse xenograft model. In summary, we have confirmed that DIM has significant potential in the treatment of non-small cell lung cancer. DIM induces cancer cell ferroptosis through the AHR/NRF2/GPX4 axis. These findings provide experimental basis for DIM treatment and future clinical research in non-small cell lung cancer.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Shuang Li,Bingjie Wang,Jiaojiao Tao,Yu Dong,Teng Wang,Xia Zhao,Tianze Jiang,Lianxiao Zhang,Hai Yang
Chemodynamic therapy (CDT) is a promising strategy for cancer treatment, however, its application is restricted by low hydrogen peroxide (H 2 O 2 ) concentration, insufficient reactive oxygen species (ROS) generation, and high glutathione (GSH) levels. Here, we developed an injectable thermosensitive hydrogel (DSUC-Gel) based on “sea urchin-like” copper sulfide nanoparticles (UCuS) loaded with dihydroartemisinin (DHA) and sulfasalazine (SAS) to overcome these limitations of CDT. DSUC was cleaved to release DHA, SAS and Cu 2+ under acidic tumor microenvironment to enhance CDT. DHA with peroxide bridge responded to intracellular Fe 2+ to alleviate H 2 O 2 deficiency. SAS prevented GSH synthesis by targeting SLC7A11 and inhibited glutathione peroxidase (GPX4) activity to induce endogenous ferroptosis. ROS produced by Fenton-like reaction of Cu 2+ promoted lipid peroxidation (LPO) accumulation to promote ferroptosis. Enhanced CDT and ferroptosis induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration. As a result, DSUC-Gel significantly inhibited tumor growth both in vitro and in vivo . Our study provides a novel approach for enhancing anti-tumor efficacy by combining CDT, endogenous ferroptosis and ICD.
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Journal of Materials Chemistry B
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2025
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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.
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EXPERIMENTAL ANIMALS
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2024
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IF 2.2
Jingzhi WANG,Zhongyu HUANG,Yiwen LI,Qian LI,Xi LI,Li CHEN
At present, there lacks a definitive pharmaceutical intervention or therapeutic approach for diabetes-associated cognitive impairment. Herein, we delved into the impact of electroacupuncture on cognitive function in high-fat diet/streptozocin (HFD/STZ)-induced T2DM mice and underlying mechanisms. Hippocampal insulin resistance was determined by western blot analysis. Cognitive function was evaluated by Morris water maze test. The morphology of the hippocampal neurons was observed through hematoxylin & eosin staining and Nissl staining. Synaptic plasticity was assessed by western blot analysis. Immunofluorescence, immunohistochemistry, western blot and real-time PCR were employed to detect the levels of ferroptosis markers, autophagy markers, and netrin-1. Electroacupuncture treatment exhibited ameliorative outcomes on spatial learning, memory function, hippocampal insulin resistance, neuronal damage, and synaptic plasticity in T2DM mice. Furthermore, it effectively suppressed neuronal ferroptosis within the hippocampus by upregulating GPX4 and SLC7A11 expression, and reducing 4-HNE expression. Meanwhile, electroacupuncture intervention increased the levels of Beclin1 and LC3II/LC3I, as well as decreased the levels of p62 and phosphorylated-mTOR in the hippocampus of T2DM mice, suggesting that electroacupuncture facilitated autophagy activation by inhibiting mTOR activity. 3-MA-mediated autophagy inhibition undermined the beneficial effects of electroacupuncture on neuronal ferroptosis and cognitive deficits in T2DM mice. Additionally, the beneficial effects of electroacupuncture on autophagy and ferroptosis was achieved by upregulation of netrin-1 in the hippocampus. Our study revealed that that electroacupuncture therapy inhibited neuronal ferroptosis via the activation of autophagy, thereby ameliorating cognitive deficits in T2DM mice.
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ADVANCED FUNCTIONAL MATERIALS
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2024
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IF 18.5
Jiahe Hu,Jiuxin Zhu,Kuan Wang,Xiuwei Yan,Lei Xu,Xiaoling Zhang,He Ding,Piaoping Yang,Shaoshan Hu,Rui Xie
Ferroptosis and cuproptosis are emerging modes of programmed cell death and have been increasingly used to eliminate tumor cells. However, converting ferroptosis/cuproptosis into effective treatments is challenging because of the inherent antioxidant and plasma membrane repair systems and inefficient copper ion delivery. Herein, an engineered doping method is developed to encapsulate ZnO 2 with Cu 2+ -doped ZIF-8 and modify the surface by transferrin (Tf). In the resulting ZnO 2 @Cu/ZIF-8-Tf nanosystem, Tf specifically binds to transferrin receptors for targeting and aggregation. In the tumor microenvironment, Cu 2+ /Fe 3+ is released from the nanosystem and reacted with glutathione (GSH) to produce Cu + /Fe 2+ . Excessive accumulation of Cu + interfered with the tricarboxylic acid cycle and induced coproptosis. Furthermore, the additional Fe 2+ caused iron overload and enhanced ferroptosis. ZnO 2 supplied hydrogen peroxide to mediate the overproduction of reactive oxygen species (ROS). Moreover, the depletion of GSH deactivated glutathione peroxidase 4 (GPX4) and inhibited the system X c − -GSH-GPX4 pathway, and the amplified ROS triggered lipid peroxidation and reprogrammed lipid metabolism, causing malfunctioning of both antioxidant and membrane repair systems. In summary, the ferroptosis/cuproptosis pathways are activated at multiple levels in the ZnO 2 @Cu/ZIF-8-Tf nanosystem, which ensures its outstanding antitumor effect.
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ACS Applied Materials & Interfaces
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2025
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IF 8.2
Meiru Zhang,Hui Xu,Xiaozan Wu,Botao Chen,Xiyu Gong,Yongju He
Cuproptosis is a new copper-dependent form of regulated cell death and shows enormous promise in cancer therapy. However, its therapeutic performance is compromised by the strictly regulated copper metabolism and highly expressed intracellular glutathione (GSH). Herein, an intelligent nanoplatform (NSeMON-P@CuT/LipD) is rationally developed as a copper metabolic disrupter, GSH consumer, and Fenton-like reaction trigger for cancer cuproptosis/ferroptosis/apoptosis therapy. NSeMON-P@CuT/LipD is constructed from the preparation of diselenide-bridged mesoporous organosilica nanoparticles, and then pemetrexed (Pem) is loaded followed by surface deposition with a Cu2+-3,3′-dithiobis(propionohydrazide) (TPH) coordinated network and coating with a diclofenac (DC)-encapsulated liposome. In response to the specific tumor microenvironment, the obtained NSeMON-P@CuT/LipD can release DC, Cu2+, and Pem and simultaneously amplify cellular oxidative stress by consuming GSH and catalyzing endogenous H2O2 into hydroxyl radicals (•OH). Both liberated DC and augmented oxidative stress can inhibit glycolysis, reduce ATP level, and then block copper transporter ATP7B, resulting in metabolic disorders and the high retention of copper in cells for •OH generation. Moreover, the overloaded copper can promote dihydrolipoamide S-acetyltransferase oligomerization and Fe–S cluster protein loss, thus evoking cuproptosis. Collectively, the augmented oxidative stress activates prominent ferroptosis, which cooperates with cuproptosis and Pem-mediated apoptosis to significantly inhibit the tumor growth of 4T1 tumor-bearing mice. This study demonstrates feasible strategies to enhance tumor cuproptosis using a single nanoplatform and may also inspire the design of advanced cuproptosis-related therapies.
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