FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Qiwen Feng,Yumeng Liu,Liping Zou,Mengying Lei,Changhong Zhu,Wei Xia
Fluorene-9-bisphenol (BHPF) is an emerging global endocrine-disrupting chemical found in numerous household products as a substitute of bisphenol A. Many studies have reported various toxicities associated with BHPF. However, the effect of BHPF on male reproduction, particularly on the structural integrity of the blood testis barrier (BTB) in mice, has not yet been extensively studied. Ferroptosis , a newly identified form of cell death, occurs in the testicular tissue following exposure to BPA, affecting male fertility. We investigated whether ferroptosis plays a role in BHPF-induced testicular damage. The findings indicated that BHPF exposure led decreases in serum testosterone (T) concentration and sperm concentration and motility in mice. Furthermore, BHPF disrupted the BTB by interfering with key BTB-related proteins, including Cx43, β-catenin, and ZO-1. Moreover, BHPF induced ferroptosis through the induction of lipid peroxidation, iron overload, oxidative stress , and mitochondrial dysfunction in the testicular tissue. Inhibition of ferroptosis using Fer-1 mitigated the BHPF-induced damage to the BTB and ferroptosis in TM4 cells. Overall, our findings indicated the detrimental effects of BHPF on male reproductive function in mice, suggesting ferroptosis as a mechanism underlying testicular damage.
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高影响因子
Advanced Healthcare Materials
·
2023
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IF 10
Ye Yuan,Chunyu Tian,Qi Wang,Xinyu Qiu,Yufang Wang,Hulin Jiang,Jifu Hao,Yujing He
As a distinctly different way from apoptosis, ferroptosis can cause cell death through excessive accumulation of lipid peroxide (LPO) and show great potential for cancer therapy. However, efficient strategies for ferroptosis therapy are still facing great challenges, mainly due to insufficient endogenous H 2 O 2 or relatively high pH value for Fenton reaction-dependent ferroptosis, and the high redox level of tumor cells attenuates the oxidation therapy. Herein, an efficient lipid-based delivery system to load oxidation catalyst and glutathione peroxidase 4 (Gpx4) inhibitor is orchestrated, intending to amplify Fenton reaction-independent ferroptosis by bidirectional regulation of LPO accumulation. Ferric ammonium citrate (FAC), Gpx4 inhibitor sorafenib (SF), and unsaturated lipids are constructed into mPEG 2K -DSPE-modified liposomes (Lip@SF&FAC). Influenced by the high level of intratumoral glutathione, FAC can be converted into Fe 2+ , and subsequently the formed iron redox pair (Fe 2+ /Fe 3+ ) catalyzes unsaturated phospholipids of liposomes into LPO via a Fenton reaction-independent manner. Meanwhile, SF can downregulate LPO reduction by inhibiting Gpx4 activation. In vitro and in vivo antitumor experiments show that Lip@SF&FAC induces massive LPO accumulation in tumor cells and ultimately exhibits strong tumor-killing ability with negligible side effect. Consequently, this two-pronged approach provides a new ferroptosis strategy for predominant LPO accumulation and enhanced cancer therapy.
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PHYTOTHERAPY RESEARCH
·
2023
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IF 7.2
Huihui Wang,Baoping Xie,Shuotao Shi,Rong Zhang,Qi Liang,Zhongqiu Liu,Yuanyuan Cheng
Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae . The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO-induced myocardial injury. Curdione and ferrostatin-1 significantly attenuated ISO-induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione-derived protection against ISO-induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO-induced MI via regulating Keap1/Trx1/GPX4 signaling pathway.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2023
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IF 5.4
Xinmei Wang,Shanshan Li,Jiayu Yu,Wenlin Wang,Zhuoqi Du,Shuchun Gao,Yin Ma,Ruixin Tang,Ting Liu,Shiping Ma,Qiang Fu,Xueyang Deng
s Ethnopharmacological relevance Saikosaponins B2 (SSB2) is one of the main active components isolated from Radix Bupleuri (Bupleurum chinense DC.), a herb widely used of traditional Chinese medicine. It has been used for the treatment of depression for more than two thousand years. However, the molecular mechanisms remain to be determined. Aim of the study In this study, we evaluated the anti-inflammatory effect and elucidated underlying molecular mechanisms of SSB2 in LPS-induced primary microglia and CUMS-induced mice model of depression. Method The effects of SSB2 treatment were investigated both in vitro and in vivo. The chronic unpredictable mild stimulation (CUMS) procedure was applied to establish the animal model of depression. Behavioural tests were used to evaluate the depressive-like behaviors in CUMS-exposed mice, including sucrose preference test, open field test, tail suspension test, and forced swimming test. The GPX4 gene of microglia was silenced using shRNA, and inflammatory cytokines were determined by Western Blot and immunofluorescence analysis. Endoplasmic reticulum stress and ferroptosis-related markers were detected by qPCR, flow cytometry and confocal microscopy. Result SSB2 reversed depressive-like behaviours in CUMS-exposed mice and relieved central neuroinflammation and ameliorated hippocampal neural damage. SSB2 alleviated LPS-induced activation of microglia through the TLR4/NF-κB pathway. LPS-induced ferroptosis, with increased levels of ROS, intracellular Fe 2+ , mitochondrial membrane potential, lipid peroxidation, GSH, SLC7A11, FTH, GPX4 and Nrf2, and decreased transcription levels of ACSL4 and TFR1, was attenuated with SSB2 treatment in primary microglia cells. GPX4 knockdown activated ferroptosis, induced endoplasmic reticulum (ER) stress, and abrogated the protective effects of SSB2. Further, SSB2 attenuated ER stress, balanced calcium homeostasis, reduced lipid peroxidation and intracellular Fe 2+ content by regulating the level of intracellular Ca 2+ . Conclusions Our study suggested that SSB2 treatment can inhibit ferroptosis, maintain calcium homeostasis, relieve endoplasmic reticulum stress and attenuate central neuroinflammation. SSB2 exhibited anti-ferroptosis and anti-neuroinflammatory effects through the TLR4/NF-κB pathway in a GPX4-dependent manner.
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CHEMICAL ENGINEERING JOURNAL
·
2023
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IF 15.1
Qiwen Pan,Fei Lin,Ruiqi Liu,Yilin Li,Xinyue Zhang,Rui Luo,Lingling Cai,Yang Liu,Wuguo Deng,Liru He
Nanocatalysts provide a platform for developing anti-tumor strategies by activating intratumoral chemical catalysis to produce highly toxic reactive oxygen species (ROS). However, the biological effect of nanocatalysts on tumor cells, which is pivotal for effective nanotherapy treatment, remains poorly understood. Herein, we present a general and facile method of synthesizing Fe/Ni-layered double hydroxides (LDHs) for enhanced apoptosis- and ferroptosis-induced cancer nano-therapy, as well as a potential mechanism underlying the anti-tumor effect based on transcriptome sequencing. An analysis of the chemical structure suggests that the Fe atoms interact strongly with the Ni atoms in Fe/Ni-LDH. Compared with Fe-OH and Ni-OH, Fe/Ni-LDH exhibited significantly better ROS-catalytic activity, with a V max of 5.015 × 10 −2 μM·s −1 , and generated massive amounts of •OH and O 2 •− radicals, enabling outstanding chemo-dynamic therapy. Both in vitro and in vivo experiments indicated a robust apoptosis-induced cell death pathway, increased intracellular oxidative stress, and accumulation of lipid peroxide (LPO), promoting ferroptosis-involved cancer-cell death, which was further confirmed by transcriptome sequencing. The Fe/Ni-LDH biocatalyst not only provides a robust nanoplatform for tumor suppression but also encourages further exploration and applications of nanobiocatalysts.
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高影响因子
Advanced Science
·
2023
·Vol. 10
·期 6
·2206009
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IF 15.1
Shanshan Zhang,Shujun Xia,Liang Chen,Yu Chen,Jianqiao Zhou
Covalent organic frameworks (COFs) have attracted increasing attention for biomedical applications. COFs-based nanosensitizers with uniform nanoscale morphology and tumor-specific curative effects are in high demand; however, their synthesis is yet challenging. In this study, distinct COF nanobowls are synthesized in a controlled manner and engineered as activatable nanosensitizers with tumor-specific sonodynamic activity. High crystallinity ensures an ordered porous structure of COF nanobowls for the efficient loading of the small-molecule sonosensitizer rose bengal (RB). To circumvent non-specific damage to normal tissues, the sonosensitization effect is specifically inhibited by the in situ growth of manganese oxide (MnO x ) on RB-loaded COFs. Upon reaction with tumor-overexpressed glutathione (GSH), the “gatekeeper” MnO x is rapidly decomposed to recover the reactive oxygen species (ROS) generation capability of the COF nanosensitizers under ultrasound irradiation. Increased intracellular ROS stress and GSH consumption concomitantly induce ferroptosis to improve sonodynamic efficacy. Additionally, the unconventional bowl-shaped morphology renders the nanosensitizers with enhanced tumor accumulation and retention. The combination of tumor-specific sonodynamic therapy and ferroptosis achieves high efficacy in killing cancer cells and inhibiting tumor growth. This study paves the way for the development of COF nanosensitizers with unconventional morphologies for biomedicine, offering a paradigm to realize activatable and ferroptosis-augmented sonodynamic tumor therapy.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2024
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IF 9.4
Mengmeng Sun,Qiushu Chen,Yingying Ren,Yong Zhuo,Shengyu Xu,Hanbing Rao,De Wu,Bin Feng,Yanying Wang
The effectiveness of chemokinetic therapy nanozymes is severely constrained because of the low H 2 O 2 levels in the tumor microenvironment. Unlike other self-produced H 2 O 2 nanozymes, the N -CNTs-encapsulated CoNi alloy (CoNiCoNC) with glucose oxidase and lactate oxidase activities has two ways to produce H 2 O 2 . It can facilitate the transformation of glucose and lactic acid into H 2 O 2 simultaneously. First, the H 2 O 2 generation pathway is favorable for aggravating energy metabolism. Second, some produced H 2 O 2 can be decomposed by CoNiCoNC to H 2 O and O 2 with the 4e − pathway to alleviate the TME hypoxia. Third, H 2 O 2 can be catalyzed to form OH to enhance reactive oxygen species (ROS) content. Through proteomic analysis, nanozymes substantially impact the metabolic pathways of cancer cells because of their aggravating energy metabolism. The high levels of ROS can cause mitochondrial lipid peroxidation and cellular ferroptosis. Consequently, the two-way H 2 O 2 -selective nanoenzymatic platform realizes the synergistic effect of starvation therapy and chemokinetics.
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Journal of Natural Medicines
·
2024
·
IF 2.5
Cao Yongyi,Wang Yu,Li Yueyang,Liu Sihan,Wang Lizhe,Zhou Li,Zhu Ting
Ferroptosis is a unique programmed cell death driven by iron-dependent phospholipid peroxidation. Tumor cells that escape from the conventional therapies appear more sensitive to ferroptosis. Therefore, it is extremely urgent to find safe and efficient active ingredients that induce ferroptosis in tumor cells. Herein, we identified that angelic acid, as a potent anti-tumor active ingredient in Angelica sinensis , profoundly sensitizes CRC cells to ferroptosis via a natural compound library screen. We revealed that angelic acid treatment is sufficient to predispose CRC cells to ferroptosis phenotype, evidenced by malondialdehyde (MDA) accumulation, lipid peroxidation, and upregulation of ferroptosis-associated markers CHAC1 and PTGS2, which is abolished by ferroptosis inhibitor Fer-1. Moreover, the results of network pharmacology showed that NRF2 is critical for angelic acid-mediated CRC cell ferroptosis. Mechanistically, angelic acid exerted its ferroptosis induction via directly binding and facilitating the degradation of NRF2. In addition, the syngeneic mouse models revealed that angelic acid boosts CRC cell sensitivity to ferroptosis inducer sulfasalazine with essentially no toxicity in vivo. Collectively, our findings highlighted a previously unrecognized anti-tumor mechanism of angelic acid and represented an appealing therapeutic strategy for CRC treatment. Graphical abstract
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高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Huan Wang,Xinchen Liu,Xiangyu Yan,Yong Du,Fang Pu,Jinsong Ren,Xiaogang Qu
Anticancer nanomedicines used for ferroptosis therapy generally rely on the direct delivery of Fenton catalysts to drive lipid peroxidation in cancer cells. However, the therapeutic efficacy is limited by the ferroptosis resistance caused by the intracellular anti-ferroptotic signals. Herein, we report the intrinsic ATPase-mimicking activity of a vanadium carbide MXene nanozyme (PVCMs) to pharmacologically modulate the nuclear factor erythroid 2-related factor 2 (Nrf2) program, which is the master anti-ferroptotic mediator in the ironclad defense system in triple-negative breast cancer (TNBC) cells. The PVCMs perform high ATPase-like activity that can effectively and selectively catalyze the dephosphorylation of ATP to generate ADP. Through a cascade mechanism initiated by falling energy status, PVCMs can powerfully hinder the Nrf2 program to selectively drive ferroptosis in TNBC cells in response to PVCMs-induced glutathione depletion. This study provides a paradigm for the use of pharmacologically active nanozymes to moderate specific cellular signals and elicit desirable pharmacological activities for therapeutic applications.
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Journal of Inflammation Research
·
2025
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IF 4.1
Yi-Xuan Zeng,Ni-Ren Li,Bing-Ying Deng,Yu-Feng Gu,Si-Fan Lu,Yi Liu
Background Ulcerative colitis is a chronic intestinal disease linked to intestinal barrier damage, ferroptosis and dysbiosis. Coix lacryma-jobi is a natural food with food-medicine homology, whose seed-derived oil (Coix seed oil, CSO) has been shown anti-inflammatory activity in vitro. Here, the effects and mechanisms of CSO on ulcerative colitis (UC) in vivo are systematically investigated.Methods Firstly, the UC mice was replicated by 3% DSS, and assessed the efficacy of CSO by observing the fecal occult blood, colon length, DAI score and pathological histomorphological changes of colon tissues. The anti-inflammatory and barrier-protective effects of CSO were observed by AB staining and qRT-PCR. Secondly, the biological targets of CSO were obtained from TCMSP database and Swiss Target Prediction database, ferroptosis targets were downloaded from FerrDb platform, and UC-related disease targets were obtained from GEO database, and the intersection of the above three was taken to obtain “CSO-UC-Ferroptosis” intersection targets, which were analysed by GO and KEGG enrichment, GSEA analysis, and immune cell infiltration and validation. Finally, the core genes of “CSO-UC-Ferroptosis” were molecular docking with the potential active components of CSO. In order to further verify the effect of CSO on ferroptosis, the GPX4 agonist RSL-3 was used to stimulate mice in vivo, and the levels of Iron, MDA and SOD were measured, and immunohistochemistry was used to detect the effects of tight junction proteins and the “CSO-UC-Ferroptosis” core protein in mice. Besides, the effect of CSO was further evaluated by observing the intercellular junctions of the colon tissues of each group under electron microscope. In addition, 16sRNA sequencing was performed on the intestinal contents of the mice to observe the effects of CSO on the intestinal flora of UC mice.Results CSO improved physiological parameters, reduced inflammation response and intestinal barrier damage, regulated ferroptosis, and restored gut microbiota balance in UC mice. Bioinformatics results showed that G6PD, ABCC1 were core targets at the intersection of CSO, UC and ferroptosis, which also demonstrated the similar expression of the core genes in DSS-induced UC mice models in vivo.Conclusion Our findings demonstrate for the first time that CSO ameliorated UC by regulating intestinal barrier damage, ferroptosis and the gut microbiota in DSS-induced mice, suggesting that CSO as a promising candidate for UC treatment and warranting further investigation.
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JOURNAL OF BIOLOGICAL CHEMISTRY
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2024
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IF 4
Qian Hu,Yanan Zhao,Wan-yang Sun,Zexian Ou,Wentao Duan,Zeyu Qiu,Yuanlong Ge,Daolin Tang,Tianfeng Chen,Xiang Cheng,Rong-rong He,Shu Wu,Zhenyu Ju
Ferroptosis is a type of regulated cell death driven by iron-dependent accumulation of lipid peroxidation, exhibiting unique morphological changes. While actin microfilaments are crucial for various cellular processes, including morphogenesis, motility, endocytosis, and cell death, their role in ferroptosis remains unclear. Here, our study reveals that actin microfilaments undergo remodeling and disassembly during ferroptosis. Interestingly, inhibitors that target actin microfilament remodeling do not affect cell sensitivity to ferroptosis, with the exception of CK-666 and its structural analogue CK-636. Mechanistically, CK-666 attenuates ferroptosis independently of its canonical function in inhibiting the Arp2/3 complex. Further investigation revealed that CK-666 modulates the ferroptotic transcriptome, prevents lipid degradation, and diminishes lipid peroxidation. In addition, CK-666 does not impact the labile iron pool within cells, nor does the inhibition of FSP1 impact its anti-ferroptosis activity. Notably, the results of DPPH assay and liposome leakage assay suggest that CK-666 mitigates ferroptosis by directly eliminating lipid peroxidation. Importantly, CK-666 significantly ameliorated renal ischemia-reperfusion injury and ferroptosis in renal tissue, underscoring its potential therapeutic impact.
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CANCER LETTERS
·
2016
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IF 5.992
Renyu Lin,Ziheng Zhang,Lingfeng Chen,Yunfang Zhou,Peng Zou,Chen Feng,Li Wang,Guang Liang
Head and neck cancer is the sixth most common cancer worldwide. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, exhibits a wide range of biological roles including a highly efficient and specific anti-tumor activity. Here, we aimed to examine the effect of DHA on head and neck carcinoma cells and elucidate the potential mechanisms. We used five head and neck carcinoma cell lines and two non-tumorigenic normal epithelial cell lines to achieve our goals. Cells were exposed to DHA and subjected to cellular activity assays including viability, cell cycle analysis, cell death, and angiogenic phenotype. Our results show that DHA causes cell cycle arrest which is mediated through Forkhead box protein M1 (FOXM1). We also demonstrate that DHA induces ferroptosis and apoptosis in head and neck carcinoma cells. Lastly, our results show that DHA alters the angiogenic phenotype of cancer cells by reducing the expression of angiogenic factors and the ability of cancer cells to support endothelial cell tubule formation. Our study suggests that DHA specifically causes head and neck cancer cell death through contribution from both ferroptosis and apoptosis. DHA may represent an effective strategy in head and neck cancer treatment.
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