PeerJ
·
2022
·
IF 3.061
Tianyu Liu,Lei Yang,Hejun Gao,Yuzhen Zhuo,Zhengwei Tu,Yongqin Wang,Jing Xun,Qi Zhang,Lanqiu Zhang,Ximo Wang
APAP is one of the most commonly used antipyretic and pain medications, but excessive use can cause liver toxicity and damage. 3,4-dihydroxyphenylethyl alcohol glycoside (DAG) is a component isolated from Sargentodoxa cuneata known to have anti-apoptotic, anti-oxidation and anti-inflammatory effects. However, the effects of DAG on acute liver failure (ALF) are largely unknown. The purpose of this study is to study the protective effects and mechanism of DAG on APAP-induced ALF in mice. We established an ALF model in adult male pathogen-free C57BL/6 mice treated with APAP (300 mg/kg) by intraperitoneal injection and resolved by 24 h. Hematoxylin and eosin (HE) staining was used to evaluate the pathological changes in mouse liver tissue. The infiltration of neutrophils in liver tissue and reactive oxygen species (ROS) in AML12 cells were analyzed by flow cytometry. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were analyzed using relevant kits. Our results show that DAG reduced APAP-induced serum ALT and AST levels, histopathological changes, liver neutrophil infiltration and proinflammatory cytokines production, also attenuated the accumulation of MDA and the exhaustion of GSH, CAT and SOD. In vitro experiment indicated that DAG dose-dependently inhibited APAP-induced the levels of pro-inflammatory factors (IL-1β and IL18), and reactive oxygen species (ROS) and preventing GSH depletion in mouse AML12 hepatocytes. More interestingly, DAG inhibited the expression of ERK, HO-1, NLRP3, Caspase1 (p20) and Gasdermin-D and upregulated the expression of GPX4 in liver tissues and AML12hepatocytes. Therefore, our results indicate that DAG may act as a potential agent to treat ALF induced by APAP by inhibiting hepatocyte ferroptosis and pyroptosis.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Chiwei Peng,Xiang Fu,Kaixuan Wang,Ling Chen,Beijiao Luo,Ni Huang,Yunfeng Luo,Wei Chen
Intracerebral hemorrhage (ICH) is a severe stroke subtype with high disability and mortality, and no effective treatment is available. Previous research on intracerebral hemorrhage secondary brain injury drugs mainly targeted at cell apoptosis, inflammation and oxidative stress, but did not achieve good effects. In recent years, ferroptosis has become a focus concern in neurological diseases. Ferroptosis is a new type of programmed cell death caused by iron-dependent accumulation of lipid peroxides, in which glutathione peroxidase 4 (GPX4) is a key protein affecting ferroptosis. In this study, we used the STRING protein database to predict the proteins that may be co-expressed with GPX4, and studied the ability of Dauricine(Dau) to up-regulate the expression of GPX4 against ferroptosis and neuroprotection after intracerebral hemorrhage in normal cells in vitro, glutathione peroxidase 4 (GPX4) knockdown cells and collagenase injection in vivo in mouse models of intracerebral hemorrhage. The results showed that glutathione reductase (GSR) was a possible co-expression protein with GPX4. Dau could up-regulate the expression of glutathione peroxidase 4 (GPX4) in intracerebral hemorrhage(ICH) model, normal cells and GPX4 knockdown cells in vitro, and simultaneously up-regulate the expression of GSR in ICH mice. Dau could also reduce the levels of iron and lipid peroxidation, and have a neuroprotective effect on intracerebral hemorrhage(ICH) mice. It was tesified that Dauricine(Dau) could inhibit ferroptosis of nerve cells and alleviate brain injury after intracerebral hemorrhage by upregulating glutathione peroxidase 4 (GPX4) and glutathione reductase (GSR) co-expression. Therefore, Dau may be an effective drug for inhibiting ferroptosis and treating intracerebral hemorrhage.
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高影响因子
Exploration
·
2024
·
IF 0
Yuwei Li,Yuxi Duan,Yunyi Li,Yuan Gu,Lu Zhou,Zhongting Xiao,Xinying Yu,Yanjun Cai,Erzhuo Cheng,Qianqian Liu,Yong Jiang,Quan Yang,Feng Zhang,Qi Lei,Bin Yang
Cancer immunotherapy is the most promising method for tumor therapy, while ferroptosis could activate the immunogenicity of cancer and strengthen the cellular immune response. However, limited by the complex tumor microenvironment, the abundant glutathione (GSH) and low reactive oxygen species (ROS) seriously weaken ferroptosis and the immune response. Herein, the authors report photothermal metal-phenolic networks (MPNs) supplied with buthionine sulfoximine (BSO) by reducing levels of GSH and then trapping the tumor cells in the ferroptosis and immunotherapy cascade loop to eliminate colorectal cancer (CRC). The MPNs coated with the model antigen ovalbumin can accumulate at the tumor site, mediate immunogenic cell death (ICD) under NIR irradiation, and initiate tumoricidal immunity. Then the activated CD8 + T cells would release IFN-γ to inhibit GPX4 and promote the immunogenic ferroptosis induced by Fe 3+ and BSO. Finally, the tumor cells at intertumoral and intratumoral levels would be involved in the ferroptosis-dominated cancer-immunity circle for CRC eradication, resulting in outstanding therapeutic outcomes in both primary and distant tumor models. Overall, this strategy employs a photothermal nanoplatform to rapidly stimulate ICD and restrain the oxidation defense system, which provides a promising approach to significantly amplify the “cascade loop” of ferroptosis induction and immunotherapy for treatment of CRC.
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MOLECULAR MEDICINE
·
2024
·Vol. 30
·期 1
·1-14
·
IF 6
Yu Hao,Gan Daojing,Luo Zhen,Yang Qilin,An Dongqi,Zhang Hao,Hu Yingchun,Ma Zhuang,Zeng Qingchun,Xu Dingli,Ren Hao
Background In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD + levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes. Methods In vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD + levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis. Results AKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD + levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed. Conclusion Supplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD + , the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
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高影响因子
JOURNAL OF ENVIRONMENTAL MANAGEMENT
·
2025
·
IF 8.4
Xiaotian Huang,Zuhong Lin,Denglong Lu,Haipu Li
Tetrabromobisphenol A (TBBPA), a brominated flame retardant extensively used in consumer electronics, has been classified as a persistent environmental contaminant. While TBBPA-induced mitochondrial dysfunction is implicated in apoptosis, the precise oxidative stress-mediated mechanisms remain incompletely characterized. In this study, using human liver cancer cells (HepG 2 ) as an in vitro model, we systematically investigated TBBPA's mitochondrial toxicity and associated cell death pathways. In vitro assays demonstrated that 10 μM TBBPA induced approximately 50 % cell death and reduced cell viability. This treatment also markedly elevated intracellular reactive oxygen species (ROS) levels. A comprehensive analysis of mitochondrial function, including assessments of mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), ATP production, respiratory chain complex activities, and mitochondrial autophagy markers (LC3B, PINK1, Parkin), revealed that TBBPA entry into cells resulted in mitochondrial dysfunction. Furthermore, Ferroptosis biomarkers quantification further revealed TBBPA-driven Fe 2+ and malondialdehyde (MDA) accumulation, coupled with upregulated expression of ferroptosis-related proteins (GPX4, SLC7A11, COX-2, Beclin-1). These findings provide novel insights into the molecular pathways underlying TBBPA-induced cytotoxicity.
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高影响因子
Nanoscale
·
2024
·
IF 5.8
Jingjing Jiang,Qiong Zhang,Yue Zhang,Lintong Gao,Yan Feng,Xianshun Sun,Junjun Wang,Xiao-Jiao Zhu,Xingxing Chen,Hong-Ping Zhou
Currently, cuproptosis mainly focuses on the Cu2+ induced morphology of mitochondria (Mito), the observation of endoplasmic reticulum (ER)-related Cu2+ content in cuproptosis is relatively lacking. Herein, we develop a hydroxyflavone (HF) based NIR excited fluorescent probe, BHCO, for exhibiting specific recognition of Cu2+. BHCO can accurately locate in ER and detect Cu2+ content in cuproptosis process. The two-photon fluorescence nature of BHCO enables to track both ferroptosis and cuproptosis processes with high resolution. Furthermore, BHCO can upgrade reactive oxygen species (ROS) under 720 nm excitation, which facilitates ferroptosis occurrence. We firmly convince the nonlinear optical (NLO) small molecules could provide a valid tool for rapid tumors elimination through synergistic ferroptosis and cuproptosis.
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Weikang Guo,Wanyue Wang,Fei Lei,Ruxin Zheng,Xinyao Zhao,Yuze Gu,Mengdi Yang,Yunshun Tong,Yaoxian Wang
Cisplatin (DDP) resistance poses a significant challenge in the treatment of ovarian cancer. Studies have shown that the combination of certain polysaccharides derived from plants with DDP is an effective approach to overcoming drug resistance in some cancers. Angelica sinensis (Oliv.) Diels has been used for centuries in China to treat gynecological ailments. Numerous studies indicate that Angelica sinensis polysaccharide (ASP), an extract from Angelica sinensis , can inhibit various forms of cancer. However, the impact of ASP on ovarian cancer remains unexplored. Through both in vitro and in vivo experiments, our study revealed the capability of ASP to effectively reversing DDP resistance in cisplatin-resistant ovarian cancer cells, while exhibiting acceptable safety profiles in vivo. To elucidate the mechanism underlying drug resistance reversal, we employed RNA-seq analysis and identified GPX4 as a key gene. Considering the role of GPX4 in ferroptosis, we conducted additional research to explore the effects of combining ASP with DDP on SKOV3/DDP cells. In summary, our findings demonstrate that the combination of ASP and DDP effectively suppresses GPX4 expression in SKOV3/DDP cells, thereby reversing their resistance to DDP.
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高影响因子
NEW JOURNAL OF CHEMISTRY
·
2020
·Vol. 44
·期 8
·3478-3486
·
IF 3.288
Fan Gao,Fei Wang,Xuan Nie,Ze Zhang,Guang Chen,Lei Xia,Long-Hai Wang,Chang-Hui Wang,Zong-Yao Hao,Wen-Jian Zhang,Chun-Yan Hong,Ye-Zi You
Mitochondrial malfunction is considered to be a decisive signal of apoptosis. It would be a promising strategy to target mitochondria in cancer cells to generate reactive oxygen species (ROS), thus directly inducing mitochondrial damage. We herein reported a mitochondria-targeted, photo-responsive polymer (Mito-PNBE), which can self-assemble into nanoparticles (Fe–CO@Mito-PNBE) encapsulated with diphenylcyclopropenone (light-responsive CO prodrugs) and aminoferrocene-based prodrugs via hydrophobic interactions. Upon UV-irradiation, the rapid release of CO and aminoferrocene-based prodrugs caused by disassembly was observed. On one hand, the released carbon monoxide in mitochondria could enhance ROS generation and accelerate oxidative metabolism. On the other hand, the aminoferrocene-based prodrugs will release Fe3+/Fe2+ ions in the tumor microenvironment, thus triggering the Fenton reaction, which generates more ROS and damages the mitochondria. Thus, the synergistic effect of the two drugs produces enough amounts of ROS in the mitochondria, leading to mitochondrial collapse with an enhanced cancer therapeutic effect. This multifunctional platform has potential in precision cancer therapy.
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高影响因子
Drug Design Development and Therapy
·
2025
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IF 5.1
Yujun Chen,Yuhang Zhao,Qing Wang,Qiuchi Chen,Xiqun Chen,Kai Yang
Background Parkinson’s disease (PD) is a common neurodegenerative disorder. Emodin (EMD), which is derived from multiple Chinese medicinal herbs, has been reported to possess anti-inflammatory, anti-ferroptosis, and neuroprotective effects. However, the mechanisms underlying the regulation of PD-related ferroptosis remain unclear.Objective To investigate whether EMD protects dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced models of PD and to elucidate its underlying mechanisms.Methods Potential EMD targets were predicted using SEA and Swiss databases. The PD targets were identified using the OMIM and GeneCards databases. Overlapping genes were introduced to construct protein-protein interactions (PPI) and perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Molecular docking was used to ascertain the possibility of the binding of EMD to p53 and TfR1. The stability of EMD-p53 complex was validated by using molecular dynamics simulations using the YASARA. To validate these mechanisms, we used an MPTP-induced mouse model to investigate the beneficial effects of EMD. Motor function was assessed using the open field and rotarod tests. Malondialdehyde (MDA) and iron contents in the midbrain were determined. SH-SY5Y cells were subjected with 1-methyl-4-phenyl-pyridinium (MPP+) or ferroptosis inducer. Ferroptosis signaling, iron metabolism, and mitochondrial superoxide levels were investigated using Western blotting, qPCR, immunofluorescence, and flow cytometry.Results Enrichment analysis revealed that the shared targets of the PD and EMD gene sets were involved in iron metabolism, with TP53 being the most connected protein in the PPI network. Molecular docking analysis suggested that EMD formed a stable complex with p53 or TfR1. Molecular Dynamics Simulation further confirmed that the interactions between EMD and p53 remained stable over time. In vivo studies demonstrated the beneficial effects of EMD in an MPTP mouse model of PD. This action was achieved by inhibiting p53 expression and mitigating ferroptosis signaling in the substantia nigra (SN). EMD similarly attenuated cell injury and ferroptosis in SH-SY5Y cells by inhibiting p53-ferroptosis signaling. In contrast, pharmacological enhancement of p53 nullified these effects in the MPP+-treated SH-SY5Y cells.Conclusion These preliminary results indicate that EMD could exert neuroprotective effects against MPTP-induced toxicity, possibly via modulating p53-ferroptosis signaling.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Wang Kai,Wang Renji,Cai Jiarui,Hao Yiguang,Li Ruoyu,Wang Xiaodong,Zhao Yuanting,Yan Liang
Intervertebral disc degeneration (IDD) remains an essential challenge in the clinic. Previous studies have confirmed that persistent inflammation and extracellular matrix (ECM) degradation contribute to the progression of IDD. Inhibiting ferroptotic function is essential for preventing ferroptosis-mediated inflammation and breaking the vicious cycle of ECM degradation. In addition, optimizing the mechanical strength required for physiological maintenance of the ECM is equally important. Herein, this study identifies the potential role of ferroptosis in the pathogenesis of IDD via the bioinformatics analysis, and we thus proposed a novel concept of self-stiffening hydrogel, which enables first to suppress ferroptosis, next to improve inflammatory micro-environment, and finally to optimize mechanical properties to facilitate migration of nucleus pulposus cells. As such, we prepared a self-stiffening hydrogel composed of chitosan/oxidized hyaluronic acid hydrogel (CS/OHA) and curcumin (Cur)-loaded metal-organic frameworks coated by macrophage membrane (Cur-MNPs). The precursor has the potential to decoy inflammatory cytokines as broad-spectrum inflammatory factor inhibitors via coated macrophage membranes. Meanwhile, acidic IDD micro-environment can trigger the specific release of Cur to inhibit ferroptosis-related pathway for alleviating inflammation and restoring the metabolic homeostasis of ECM. Furthermore, the Schiff-base moieties within the hydrogel can scavenge free ferrous ions to mitigate iron overload, converting the unfavorable factors that cause ferroptosis into favorable ligands that optimize mechanical strength. In summary, the novel approach provides a promising paradigm for IDD treatment.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Meng Wang,Guoxiu Cao,Junjie Zhou,Jinyuan Cai,Xianjie Ma,Zhikun Liu,Xiaochao Huang,Hengshan Wang
Developing multitarget platinum(IV) prodrugs is an important strategy to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity. Herein, six novel ligustrazine-derived chalcones-modified platinum(IV) complexes were synthesized and evaluated for their anti-proliferative activities. Among them, 16a displayed higher cytotoxicity toward the tested cancer cell lines and lower cytotoxicity toward the human normal cells than CDDP or the combined group. Mechanistic studies revealed that 16a efficiently induced DNA damage and initiated a mitochondria-dependent apoptosis pathway. Besides, 16a significantly triggered ferroptosis by down-regulating expression levels of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11. Further, 16a obtained superior in vivo anti-tumor efficiency than CDDP in CDDP-resistant pancreatic cancer xenograft models but showed no significant side effects. In summary, our study suggested that 16a acts via a different anti-cancer mechanistic pathway than CDDP and may therefore encompass a novel practical strategy for cancer treatment.
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高影响因子
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