IBRO Neuroscience Reports
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2024
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IF 2
Min Wei,Yi Liu,Dongsheng Li,Xingdong Wang,Xiaodong Wang,Yuping Li,Zhengcun Yan,Hengzhu Zhang
Background Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage. Methods We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH). Results Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites. Conclusions Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-23
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IF 10.6
Li Haiqiu,Dou Yichen,Yang Hang,Xing Hanlin,Zhu Cheng,Wang Tao,Xuan Zhaopeng,Yang Mingxi
Background Despite the higher sensitivity of melanoma towards ferroptosis and photodynamic therapy (PDT), the lack of efficient ferroptosis inducers and the poor solubility of photosensitizers restrict their synergistic strategies. With unique advantages, carbon dots (CDs) are expected to serve as innovative building blocks for combination therapy of cancers. Results Herein, an ferroptosis/PDT integrated nanoplatform for melanoma therapy is constructed based on chlorin e6-modified Fe ions-doped carbon dots (Fe-CDs@Ce6). As a novel type of iron-carbon hybrid nanoparticles, the as-prepared Fe-CDs can selectively activate ferroptosis, prevent angiogenesis and inhibit the migration of mouse skin melanoma cells (B16), but have no toxicity to normal cells. The nano-conjugated structures facilitate not only the aqueous dispersibility of Ce6, but also the self-accumulation ability of Fe-CDs@Ce6 within melanoma area without requiring extra targets. Moreover, the therapeutic effects of Fe-CDs@Ce6 are synergistically enhanced due to the increased GSH depletion by PDT and the elevated singlet oxygen ( 1 O 2 ) production efficiency by Fe-CDs. When combined with laser irradiation, the tumor growth can be significantly suppressed by Fe-CDs@Ce6 through cyclic administration. The T 2 -weighted magnetic resonance imaging (MRI) capability of Fe-CDs@Ce6 also reveals their potentials for cancer diagnosis and navigation therapy. Conclusions Our findings indicate the multifunctionality of Fe-CDs@Ce6 in effectively combining ferroptosis/PDT therapy, tumor targeting and MRI imaging, which enables Fe-CDs@Ce6 to become promising biocompatible nanoplatform for the treatment of melanoma. Graphic Abstract
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iScience
·
2024
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IF 4.6
Wenxiang Feng,Nan Zhu,Yubin Xia,Zehai Huang,Jianmin Hu,Zefeng Guo,Yuzhuz Li,Song Zhou,Yongguang Liu,Ding Liu
Kidney transplantation is essential for patients with end-stage renal disease; however, ischemia-reperfusion injury (IRI) during transplantation can lead to acute kidney damage and compromise survival. Recent studies have reported that antiferroptotic agents may be a potential therapeutic strategy, by reducing production of reactive oxygen species (ROS). Therefore, we constructed rutin-loaded polydopamine nanoparticles (PEG-PDA@rutin NPs, referred to as PPR NPs) to eliminate ROS resulting from IRI. Physicochemical characterization showed that the PPR NPs were ∼100 nm spherical particles with good ROS scavenging ability. Notably, PPR NPs could effectively enter lipopolysaccharide (LPS)-treated renal tubular cells, then polydopamine (PDA) released rutin to eliminate ROS, repair mitochondria, and suppress ferroptosis. Furthermore, in vivo imaging revealed that PPR NPs efficiently accumulated in the kidneys after IRI and effectively protected against IRI damage. In conclusion, PPR NPs demonstrated an excellent ability to eliminate ROS, suppress ferroptosis, and protect kidneys from IRI.
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-15
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IF 10.6
Sun Ying,Ma Yan-Yan,Shangguan Shijie,Ruan Yihang,Bai Tingjie,Xue Panpan,Zhuang Huilan,Cao Wenyu,Cai Huimei,Tang Enqi,Wu Zhou,Yang Mingzhen,Zeng Yixin,Sun Juan,Fan Yong,Zeng Xuemei,Yan Shuangqian
The activation of ferroptosis presents a versatile strategy for enhancing the antitumor immune responses in cancer therapy. However, developing ferroptosis inducers that combine high biocompatibility and therapeutic efficiency remains challenging. In this study, we propose a novel approach using biological nanoparticles derived from outer membrane vesicles (OMVs) of Escherichia coli for tumor treatment, aiming to activate ferroptosis and stimulate the immune responses. Specifically, we functionalize the OMVs by anchoring them with ferrous ions via electrostatic interactions and loading them with the STING agonist-4, followed by tumor-targeting DSPE-PEG-FA decoration, henceforth referred to as OMV/SaFeFA. The anchoring of ferrous ions endows the OMVs with peroxidase-like activity, capable of inducing cellular lipid peroxidation by catalyzing H 2 O 2 to • OH. Furthermore, OMV/SaFeFA exhibits pH-responsive release of ferrous ions and the agonist, along with tumor-targeting capabilities, enabling tumor-specific therapy while minimizing side effects. Notably, the concurrent activation of the STING pathway and ferroptosis elicits robust antitumor responses in colon tumor-bearing mouse models, leading to exceptional therapeutic efficacy and prolonged survival. Importantly, no acute toxicity was observed in mice receiving OMV/SaFeFA treatments, underscoring its potential for future tumor therapy and clinical translation.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2024
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IF 3.3
Li Tao,Yu-Feng Xue,Fei-Fei Sun,Xue He,Hong-Qian Wang,Cheng-Cheng Tong,Cheng Zhang,De-Xiang Xu,Xi Chen
Ferroptosis has been shown to be involved in carbon tetrachloride (CCl 4 )-induced acute liver injury (ALI). The mitochondrion-targeted antioxidant MitoQ can eliminate the production of mitochondrial reactive oxygen species (mtROS). This study investigated the role of MitoQ in CCl 4 -induced hepatocytic ferroptosis and ALI. MDA and 4HNE were elevated in CCl 4 -induced mice. In vitro, CCl 4 exposure elevated the levels of oxidized lipids in HepG2 cells. Alterations in the mitochondrial ultrastructure of hepatocytes were observed in the livers of CCl 4 -evoked mice. Ferrostatin-1 (Fer-1) attenuated CCl 4 -induced hepatic lipid peroxidation, mitochondrial ultrastructure alterations and ALI. Mechanistically, acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated in CCl 4 -exposed human hepatocytes and mouse livers. The ACSL4 inhibitor rosiglitazone alleviated CCl 4 -induced hepatic lipid peroxidation and ALI. ACSL4 knockdown inhibited oxidized lipids in CCl 4 -exposed human hepatocytes. Moreover, CCl 4 exposure decreased the mitochondrial membrane potential and OXPHOS subunit levels and increased the mtROS level in HepG2 cells. Correspondingly, MitoQ pretreatment inhibited the upregulation of ACSL4 in CCl 4 -evoked mouse livers and HepG2 cells. MitoQ attenuated lipid peroxidation in vivo and in vitro after CCl 4 exposure. Finally, MitoQ pretreatment alleviated CCl 4 -induced hepatocytic ferroptosis and ALI. These findings suggest that MitoQ protects against hepatocyte ferroptosis in CCl 4 -induced ALI via the mtROS-ACSL4 pathway.
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POULTRY SCIENCE
·
2024
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IF 3.8
Jiamei Zhu,Xueyan Dai,Yan Wang,Ting Cui,Bingyan Huang,Dianyun Wang,Wenjing Pu,Caiying Zhang
Cadmium ( Cd ) and high molybdenum ( Mo ) are injurious to the body. Previous research has substantiated that Cd and Mo exposure caused testicular injury of ducks, but concrete mechanism is not fully clarified. To further survey the toxicity of co-exposure to Cd and Mo in testis, 40 healthy 8-day-old Shaoxing ducks ( Anas platyrhyncha ) were stochasticly distributed to four groups and raised with basic diet embracing Cd (4 mg/kg Cd) or Mo (100 mg/kg Mo) or both. At the 16th week, testis tissues were gathered. The characteristic ultrastructural changes related to apoptosis and ferroptosis were observed in Mo or Cd or both groups. Besides, Mo or Cd or both repressed nuclear factor erythroid 2-related factor 2( Nrf2 ) pathway via decreasing Nrf2, Heme oxygenase-1 ( HO-1 ), NAD(P)H quinone oxidoreductase 1 ( NQO1 ), Glutamate-cysteine ligase catalytic subunit ( GCLC ) and Glutamate-cysteine ligase modifier subunit ( GCLM ) mRNA expression of and Nrf2 protein expression, then stimulated apoptosis by elevating Bcl-2 antagonist/killer-1 ( Bak-1 ), Bcl-2-associated X-protein ( Bax ), Cytochrome complex ( Cyt-C ), caspase-3 mRNA expression, cleaved-caspase-3 protein expression and apoptosis rate, as well as reducing B-cell lymphoma-2 ( Bcl-2 ) mRNA expression and ratio of Bcl-2 to Bax, and triggered ferroptosis by upregulating Acyl-CoA Synthetase Long Chain Family Member 4 ( ACSL4 ), transferrin receptor ( TFR1 ) and Prostaglandin-Endoperoxide Synthase 2 ( PTGS2 ) expression levels, and downregulating ferritin heavy chain 1 ( FTH1 ), ferritin light chain 1 ( FTL1 ), ferroportin 1 ( FPN1 ), solute carrier family 7 member 11 ( SCL7A11 ) and glutathione peroxidase 4 ( GPX4 ) expression levels. The most obvious changes of these indexes were observed in co-treated group. Altogether, the results announced that Mo or Cd or both evoked apoptosis and ferroptosis by inhibiting Nrf2 pathway in the testis of ducks, and co-exposure to Mo and Cd exacerbated these variations.
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Nature Communications
·
2024
·Vol. 15
·期 1
·1-13
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IF 14.7
Wen Ding,Feng Jing,Deng Ruiping,Li Kai,Zhang Hongjie
Sonodynamic therapy (SDT) as a non-invasive antitumor strategy has been widely concerned. However, the rapid electron (e - ) and hole (h + ) recombination of traditional inorganic semiconductor sonosensitizers under ultrasonic (US) stimulation greatly limits the production of reactive oxygen species (ROS). Herein, we report a unique Zn/Pt dual-site single-atom driven difunctional superimposition-augmented TiO 2 -based sonosensitizer (Zn/Pt SATs). Initially, we verify through theoretical calculation that the strongly coupled Zn and Pt atoms can assist electron excitation at the atomic level by increasing electron conductivity and excitation efficiency under US, respectively, thus effectively improving the yield of ROS. Additionally, Zn/Pt SATs can significantly enhance ferroptosis by producing more ROS and sonoexcited holes under US stimuli. Therefore, the establishment of dual-site single-atom system represents an innovative strategy to enhance SDT in cancer model of female mice and provides a typical example for the development of inorganic sonosensitizer in the field of antitumor therapy.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-23
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IF 12.6
Yang Yang,Lv Mingzhu,Liu Ruihong,Yu Peilu,Shen Ziyi,Bai Dazhang,Zhao Peilin,Yang Jin,Tang Xiaoping,Yang Hanfeng,Yong Yuan,Jiang Guohui
Background Intracerebral haemorrhage (ICH) is a devastating neurological disorder with high morbidity and mortality rates, largely owing to the lack of effective therapeutic strategies. Growing evidence has underscored the pivotal role of ferroptosis in intracerebral haemorrhage, and its contribution to neuronal death and exacerbation of brain injury, thus establishing it as a crucial target for therapeutic intervention. In recent years, polyoxometalate nanoclusters (NCs) have been applied in various neurodegenerative diseases, demonstrating neuroprotective effects. However, their impact on brain iron content and neurological function following ICH has yet to be reported. Here, we explored the potential of tungsten-based polyoxometalate (W-POM) NCs as ferroptosis inhibitors targeting the iron metabolic pathway mediated by S100A8/A9 for the treatment of ICH. Results We successfully synthesized ultra-small reduced W-POM NCs that can rapidly cross the blood-brain barrier and are cleared through the kidney. In vitro experiments demonstrated that W-POM NCs exhibit significant and stable ROS scavenging activity while effectively alleviating iron overload and associated neuronal damage. In vivo, W-POM NCs treatment restored iron metabolism homeostasis, suppressed neuroinflammation and oxidative stress, ultimately alleviating severe neurological damage and motor deficits in ICH mice. Proteomic combined with bioinformatic analyses identified two core genes, S100A8 and S100A9, most associated with W-POM NCs intervention in ICH. Further experiments confirmed that W-POM NCs act by modulating the toll-like receptor 4/hepcidin/ferroportin signaling pathway, thereby regulating iron metabolism and reducing secondary brain injury. Conclusions This study pioneers the application of polyoxometalates in intracerebral haemorrhage, offering a novel and promising therapeutic approach for the management of ferroptosis-related brain injuries.
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Biomedical Materials
·
2024
·Vol. 19
·期 2
·025018
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IF 3.9
Antong Jiang,Teng Wang,Xiaoling Lu,Yuxiang Tian,Zihan Jiang,Bin Xu,Hanyuan Zhang,Weijun Fang
The application of both chemotherapy and ferrotherapy together has shown great potential in increasing the effectiveness of cancer treatment. To achieve such a combination, we herein have synthesized Fe3O4 core/MIL-100(Fe) shell nanocomposites (FM) that can be used for tumor chemo-ferroptosis combination therapy. In these nanocomposites, the anticancer drug 10-hydroxycamptothecin (HCPT) and iron ions could be co-delivered into tumors. On one hand, the released HCPT molecules can enter the cell nucleus and bind with DNA, resulting in induction of tumor cell apoptosis. On the other hand, the iron ions could react with H2O2 leading to the production of ROS through the Fenton reaction, thereby triggering tumor cell ferroptosis. Consequently, a superior antitumor effect was achieved through the combination of the apoptosis and ferroptosis. Additionally, the Fe3O4 core endowed FM with high performance for magnetic resonance imaging, which further provided novel avenues for imaging guidance therapy. Therefore, we anticipate that application of these nanocomposites could have great potential in the field of tumor therapy.
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MEDIATORS OF INFLAMMATION
·
2024
·Vol. 2024
·期 1
·4777789
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IF 4.4
Zheng Liang,Dajin Pi,Jianwei Zhen,Haizhen Yan,Chuiyang Zheng,July Liang Chen,Wen Fan,Qingliang Song,Jinyue Pan,Dongdong Liu,Maoxing Pan,Qinhe Yang,Yupei Zhang
Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), which is distinguished by the accumulation of fat in the liver, damage to liver cells, and inflammation. Chaihu Shugan powder (CSP), a renowned traditional Chinese medicine (TCM) blend extensively utilized in China to address liver disease, has demonstrated its efficacy in reducing lipid buildup and effectively combating inflammation. Hence, the primary objective of this research is to examine the impacts and possible mechanisms of CSP on NASH through assessments of liver histopathology, lipidomic analysis, and gene expression. To induce a mouse model of NASH, we employed a diet which deficient in methionine and choline, known as methionine–choline deficient (MCD) diet. Initially, we examined the impact of administering CSP to NASH mice by assessing the levels of serum and liver indicators. We found that CSP was able to reduce lipid buildup and inflammation in mice. In addition, a total of 1009 genes exhibited enrichment in both the autophagy and ferroptosis pathways. The liver protein levels of Adenosine monophosphate-activated protein kinase–mammalian target of rapamycin (AMPK–mTOR)-mediated autophagy and ferroptosis markers, such as p-AMPK α /AMPK α , p-mTOR/mTOR, Beclin-1, microtubule associated protein 1 light chain 3 gamma (LC3), p62 (sequestosome 1 [SQSTM1/p62]), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor erythroid 2-related factor 2 (Nrf-2), ferritin heavy chain 1 (FTH1), and glutathione peroxidase 4 (GPX4), were restored by CSP. Furthermore, our findings indicated that the suppression of autophagy had a repressive impact on the occurrence of ferroptosis in the mouse model, indicating that autophagy activation likely plays a role in mediating ferroptosis in NASH.
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Kai Sun,Jiajia Ruan,Jiale Dai,Xinran Yang,Jiaying Yu,Hongshuai Wu,Jiaxing Xu
Ferroptosis, a distinct modality of necrotic cell death driven by excessive lipid peroxidation, has garnered significant attentions. However, the visualization of ferroptosis remains challenging due to the lack of specific probes, which severely restricts the study of ferroptosis execution mechanisms and the crosstalk between associated signaling pathways. Herein, a sulfonate-functionalized cyanine derivative (Cy7) was synthesized and firstly found based on On-Off-On switching cycle: Cy7 specifically chelated Fe 3+ to form Cy7-Fe 3+ complex by intramolecular charge transfer (ICT), with fluorescence restored via endogenous GSH. Leveraging this behavior, iron-free and iron-doped Cy7-nanomodels were then established to track the dynamic signaling of ferroptosis. Notably, high concentrations of iron-doped Cy7-nanomodels could be degraded within the acidic tumor microenvironment, releasing Fe 3+ and Cy7 fluorophore. Both in vitro and in vivo fluorescence imaging results showed that the iron-doped Cy7-nanomodels exhibited a characteristic On-Off-On fluorescence transition during cellular internalization and subsequent biological interactions: initial fluorescence quenching was through the chelation of locally high concentration of Fe 3+ with Cy7, followed by GSH-mediated reduction restoring fluorescence and generating the ferroptosis-promoting Fe 2+ . The fluorescence switching from On to Off reflected pre-ferroptotic cellular status, whereas the Off-to-On resurgence marked active ferroptotic signaling. This On-Off-On fluorescence signature provided direct evidence of tumor cells undergoing ferroptosis. Accordingly, our findings presented a novel fluorescent-based approach for visualizing the dynamic signaling of ferroptosis.
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Biomaterials Research
·
2025
·
IF 9.6
Liang Yan,Qi Feng,Yong Sun,Bo-ning Zeng,Chuan-chuan Sun,Qing-bing Zha,Xing-wang Zhang,Shi-ping Zhu
Ferroptosis, a form of lipid peroxidation-mediated cell death, plays a critical role in acute kidney injury (AKI) progression. Tripterine is an active component isolated from traditional medicinal herbs and exhibits diverse biological and pharmacological activities. However, poor bioavailability and cytotoxicity of tripterine has limited its further clinical application, and the underlying action mechanism of tripterine against AKI remains largely unknown. This study aimed to overcome these shortcomings by formulating tripterine into selenized phytosomes and to investigate the therapeutic effects of selenized tripterine phytosomes (Se@Tri-PTs) on ferroptosis-associated AKI. The data showed that Se@Tri-PTs improved the antioxidant capacity of tripterine while reducing its cytotoxicity. Upon erastin or RSL3 stimulation, Se@Tri-PTs maintained intracellular glutathione levels, decreased lipid ROS generation, and suppressed ferroptosis. Mechanistically, Se@Tri-PTs blocked autophagy-mediated degradation of glutathione peroxidase 4 (GPX4), thereby suppressing ferroptosis. Furthermore, Se@Tri-PTs maintained dual-specificity protein phosphatase 1 (DUSP1) protein levels in erastin-stimulated cells, and DUSP1 knockdown reversed Se@Tri-PTs-mediated inhibition of autophagy and ferroptosis. In line with in vitro results, Se@Tri-PTs administration obviously attenuated folic acid-induced AKI and autophagy-dependent ferroptosis in mice. Collectively, these results indicated that Se@Tri-PTs ameliorated ferroptosis and AKI by preserving DUSP1 levels to block autophagy-mediated degradation of GPX4, highlighting their potential in treating ferroptosis-related diseases.
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