Nutrients
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2022
·Vol. 14
·期 21
·4549
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IF 6.706
Tongtong Ba,Dai Zhao,Yiqin Chen,Cuiping Zeng,Cheng Zhang,Sai Niu,Hanchuan Dai
L-citrulline (L-cit) is a key intermediate in the urea cycle and is known to possess antioxidant and anti-inflammation characteristics. However, the role of L-cit in ameliorating oxidative damage and immune dysfunction against iron overload in the thymus remains unclear. This study explored the underlying mechanism of the antioxidant and anti-inflammation qualities of L-cit on iron overload induced in the thymus. We reported that L-cit administration could robustly alleviate thymus histological damage and reduce iron deposition, as evidenced by the elevation of the CD8+T lymphocyte number and antioxidative capacity. Moreover, the NF-κB pathway, NCOA4-mediated ferritinophagy, and ferroptosis were attenuated. We further demonstrated that L-cit supplementation significantly elevated the mTEC1 cells’ viability and reversed LDH activity, iron levels, and lipid peroxidation caused by FAC. Importantly, NCOA4 knockdown could reduce the intracellular cytoplasmic ROS, which probably relied on the Nfr2 activation. The results subsequently indicated that NCOA4-mediated ferritinophagy was required for ferroptosis by showing that NCOA4 knockdown reduced ferroptosis and lipid ROS, accompanied with mitochondrial membrane potential elevation. Intriguingly, L-cit treatment significantly inhibited the NF-κB pathway, which might depend on restraining ferritinophagy-mediated ferroptosis. Overall, this study indicated that L-cit might target ferritinophagy-mediated ferroptosis to exert antioxidant and anti-inflammation capacities, which could be a therapeutic strategy against iron overload-induced thymus oxidative damage and immune dysfunction.Keywords:L-citrulline;thymus;iron overload;ferritinophagy;ferroptosis
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Frontiers in Cell and Developmental Biology
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2022
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IF 6.081
Fan Zhang,Hualong Zhen,Hengshun Cheng,Fengying Hu,Yunfei Jia,Binbin Huang,Minmin Jiang
As one kind of endocrine disrupting chemical, di-(2-ethylhexyl) phthalate (DEHP) has been reported to cause liver dysfunction in epidemiological and experimental studies. Abnormal liver function in pregnancy is associated with adverse maternal and perinatal outcomes. Few studies have investigated the potential effect of gestational DEHP exposure on the liver in pregnant mice, and the underlying mechanisms remain unclear. In the present study, pregnant ICR mice were exposed to doses (0, 500, 1,000 mg/kg/day) of DEHP in the presence or absence of 5 mg/kg/day ferrostatin-1 (Fer-1, ferroptosis inhibitor) by oral gavage from gestation day 4 to day 18. HepG2 cells were exposed to different doses of monoethylhexyl phthalate (MEHP, a major metabolite of DEHP) in vitro . Hepatic function and pathologic changes were observed. Oxidative stress, iron metabolism, and ferroptosis-related indicators and genes were evaluated both in vivo and in vitro . The results showed that gestational DEHP exposure induced disordered liver function and hepatocyte morphology changes in pregnant mice, along with increased malondialdehyde (MDA) and Fe 2+ content and decreased glutathione (GSH) levels. The expression levels of the selected ferroptosis-related genes Slc7a11 , Gpx4 , and Nfr2 were significantly decreased, and Ptgs2 and Lpcat3 were significantly increased. Notably, Fer-1 attenuated DEHP-induced liver injury and ferroptosis. Furthermore, MEHP exhibited a synergistic effect with RSL3 (a GPX4 inhibitor) in promoting ferroptosis in vitro . Taken together, the results demonstrated that DEHP induced liver injury and ferroptosis in pregnant mice, probably by inhibiting the GPX4 pathway through lipid peroxidation and iron accumulation.
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CELL BIOLOGY INTERNATIONAL
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2022
·Vol. 47
·期 3
·598-611
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IF 4.473
Yangyang Wu,Shuo Zhou,An Zhao,Yuling Mi,Caiqiao Zhang
Oxidative stress is a major cause of ovarian aging and follicular atresia. There is growing evidence that showed potential roles of rutin in antidiabetic, anti-inflammatory, antitumor, antibacterial and antioxidant, although it is yet unclear what the underlying mechanism is. Here, we looked into the potential effects of rutin on oxidative stress in the prehierarchical small white follicles (SWFs) from 580-day-old (D580) laying chickens. According to the findings, aging D580 layer ferroptosis was much higher than it was for laying hens during the peak period (280-day-old, D280). In both naturally aged and d -gal-induced chicken SWFs, rutin treatment concurrently boosted cell proliferation and prevented apoptosis. In addition, rutin inhibited the increased ferroptosis in aging hens. Meanwhile, rutin markedly suppressed the elevated ferroptosis and descending antioxidant capacity of D280-culture-SWFs from chicken elicited by d -gal. Rutin's activation of the Nrf2/HO-1 pathway hastened the SWFs' verbal battle with oxidative damage and reduced ferroptosis. Furthermore, activation of the ferroptosis signal increased the oxidative damage in SWFs. In conclusion, rutin alleviated oxidative stress that was induced by ferroptosis in aging chicken SWFs through Nrf2/HO-1 pathway. These findings point to a novel mechanism by which rutin protects SWFs from oxidative stress by suppressing ferroptosis, which is presumably a fresh approach to slowing ovarian aging in laying hens.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Xuan Ma,Hui Chen,Lixing Cao,Shuang Zhao,Chong Zhao,Shutao Yin,Lihong Fan,Hongbo Hu
Ferroptosis is a new form of iron-dependent cell death . A growing body of evidence suggests that abnormal ferroptosis is involved in developing neurodegenerative diseases. 18β-glycyrrhetinic acid (GA) is a major bioactive component of licorice with multiple biological activities including neuroprotection. Give the role of ferroptosis in the neurodegenerative diseases, we hypothesized that the neuroprotective effect of GA might be associated with its ability to protect neuro-cells from ferroptosis. Results demonstrated that GA was able to prevent a well-known ferroptosis inducer ferroptosis inducer 56 (FIN56)-triggered ferroptosis in HT22 mouse neuronal cell. Further mechanistic investigation revealed that the protection of GA on ferroptosis is attributed its inhibiting effect on cellular labile iron accumulation and up-regulating coenzyme Q10 (CoQ10) levels. The findings of the present study uncovered a novel mechanism involved in the neuroprotective effect of GA, and imply that GA could be developed as a novel agent to manage ferroptosis-related diseases.
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Acta Pharmaceutica Sinica B
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2022
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IF 14.903
Lujing Geng,Tong Lu,Huaqing Jing,Yue Zhou,Xiaoyang Liang,Jiao Li,Nan Li
Ferroptosis (FPT), a novel form of programmed cell death, is characterized by overwhelming iron/reactive oxygen species (ROS)-dependent accumulation of lipid peroxidation (LPO). However, the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent. To overcome this obstacle, the bromodomain-containing protein 4 (BRD 4 )-inhibitor (+)-JQ1 (JQ1) and iron-supplement ferric ammonium citrate (FAC)-loaded gold nanorods (GNRs) are encapsulated into the zeolitic imidazolate framework-8 (ZIF-8) to form matchbox-like [email protected] /ZIF-8 for the amplified FPT therapy. The existence of matchbox (ZIF-8) is stable in physiologically neutral conditions but degradable in acidic environment, which could prevent the loaded agents from prematurely reacting. Moreover, GNRs as the drug-carriers induce the photothermal therapy (PTT) effect under the irradiation of near-infrared II (NIR-II) light owing to the absorption by localized surface plasmon resonance (LSPR), while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment (TME). On one hand, the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron (Fe 3+ /Fe 2+ ) and ROS to initiate the FPT treatment by LPO elevation. On the other hand, JQ1 as a small molecule inhibitor of BRD 4 protein can amplify FPT through downregulating the expression of glutathione peroxidase 4 (GPX4), thus inhibiting the ROS elimination and leading to the LPO accumulation. Both in vitro and in vivo studies reveal that this pH-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility. As a result, our study points out a PTT combined iron-based/BRD 4 -downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.
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Small
·
2023
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IF 13.3
Wen-Fang Song,Jin-Yue Zeng,Ping Ji,Zi-Yi Han,Yun-Xia Sun,Xian-Zheng Zhang
As an emerging cancer treatment strategy, ferroptosis is greatly restricted by excessive glutathione (GSH) in tumor microenvironment (TME) and low reactive oxygen species (ROS) generation efficiency. Here, this work designs self-assembled copper-alanine nanoparticles (CACG) loaded with glucose oxidase (GOx) and cinnamaldehyde (Cin) for in situ glutathione activated and enzymatic cascade-enhanced ferroptosis and immunotherapy. In response to GSH-rich and acidic TME, CACG allows to effectively co-deliver Cu 2+ , Cin, and GOx into tumors. Released Cin consumes GSH through Michael addition, accompanying with the reduction of Cu 2+ into Cu + for further GSH depletion. With the cascade of Cu + -catalyzed Fenton reactions and enzyme-catalyzed reactions by GOx, CACG could get rid of the restriction of insufficient hydrogen peroxide in TME, leading to a robust and constant generation of ROS. With the high efficiency of GSH depletion and ROS production, ferroptosis is significantly enhanced by CACG in vivo. Moreover, elevated oxidative stress triggers robust immune responses by promoting dendritic cells maturation and T cell infiltration. The in vivo results prove that CACG could efficiently inhibit tumor growth in 4T1 tumor-bearing mouse model without causing obvious systemic toxicity, suggesting the great potential of CACG in enhancing ferroptosis and immunotherapy for effective cancer treatment.
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ACS Applied Nano Materials
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2023
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IF 5.9
Yingli Luo,Xiaoming Yu,Yizhu Yao,Lin Zhu,Wenxiang Qin,Zhuohan Shan,Lanlan Song,Jilong Wang,Liangxing Wang,Hanhan Yan,Mayun Chen
Synergistic therapeutic nanomedicine with great biosafety was regarded as a promising strategy for cancer therapy in clinic. Due to the drug resistance and insufficient performance of chemotherapy, the response rate in non-small cell lung cancer is limited. As another effective strategy against tumor, ferroptosis may enhance the sensitivity of chemotherapy. Herein, we reported a biomimetic iron metal–organic framework (Fe-MOF) nanomedicine responding to the intracellular environment of non-small cell lung cancer therapy to accelerate tumor cell death by inducing the ferroptosis and apoptosis of tumor cells. We demonstrated that the doxorubicin (DOX)-loaded biomimetic Fe-MOF (mFe-MOFDOX) could dramatically promote degradation for Fe2+ generation and release of DOX in the intracellular acidic microenvironment. The mFe-MOFDOX nanoparticles enhanced the generation of reactive oxygen species (ROS) to induce comparable glutathione peroxidase 4 (GPX4)-mediated ferroptosis and assisted DOX-mediated apoptosis. Eventually, the combination of biomimetic nanoparticle-induced ferroptosis and chemotherapy-induced apoptosis inhibited tumor growth and lung metastasis, suggesting the promising potential of ferroptosis induction for promoting non-small cell lung cancer chemotherapy.
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Advanced Science
·
2023
·
IF 15.1
Jingshu Meng,Xiao Yang,Jing Huang,Zhan Tuo,Yan Hu,Zhiyun Liao,Yu Tian,Suke Deng,Yue Deng,Zhiyuan Zhou,Jonathan F. Lovell,Honglin Jin,Yang Liu,Kunyu Yang
Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH-OD) is designed to load sulfasalazine (SSZ), an FDA-approved drug with ferroptosis-inducing ability, for effective tumor-killing and activation of anti-tumor immunity. Compared to free SSZ, SSZ-loaded CH-OD (CH-OD-SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH-OD-SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH-OD-SSZ hydrogel induces the repolarization of macrophages to an M1-like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH-OD-SSZ hydrogel and anti-programmed cell death protein 1 (PD-1) immunotherapy achieves more than 50% ascites regression and generates long-term immune memory. Collectively, CH-OD-SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti-PD-1 immunotherapy.
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International Journal of Nanomedicine
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2023
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IF 8
Rui Liu,Dandan Shi,Lu Guo,Shan Xiao,Mengmeng Shang,Xiao Sun,Dong Meng,Yading Zhao,Xiaoxuan Wang,Jie Li
Introduction Triple-negative breast cancer (TNBC) is known to be the most aggressive form of breast cancer. Due to its high recurrence and mortality rates, the treatment of TNBC is a significant challenge for the medical community. Besides, ferroptosis is an emerging regulatory cell death that may provide new insights into the treatment of TNBC. As a central inhibitor of the ferroptosis process, the selenoenzyme glutathione peroxidase 4 (GPX4) is its classical therapeutic target. However, inhibition of GPX4 expression is quite detrimental to normal tissues. Ultrasound contrast agents, as an emerging visualization precision treatment, may provide a solution to the existing problem.Methods In this study, nanodroplets (NDs) carrying simvastatin (SIM) were constructed using the homogeneous/emulsification method. Then, the characterization of SIM-NDs was systematically evaluated. Meanwhile, in this study, the ability of SIM-NDs combined with ultrasound-targeted microbubble disruption (UTMD) to initiate ferroptosis and its respective mechanisms of ferroptosis induction were verified. Finally, the antitumor activity of SIM-NDs was investigated in vitro and in vivo using MDA-MB-231 cells and TNBC animal models.Results SIM-NDs exhibited excellent pH- and ultrasound-responsive drug release and noticeable ultrasonographic imaging ability, also showing good biocompatibility and biosafety. UTMD could promote increased intracellular reactive oxygen species and consume intracellular glutathione. However, SIM-NDs were efficiently internalized into cells under ultrasound irradiation, followed by the rapid release of SIM, which inhibited intracellular mevalonate production, and synergistically downregulated GPX4 expression, thereby promoting ferroptosis. Moreover, this combined treatment demonstrated strong antitumor ability in vitro and in vivo.Conclusion The combination of UTMD and SIM-NDs presents a promising avenue for harnessing ferroptosis in the treatment of malignant tumors.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Pang Wenyang,Cao Yin,Du Shuang,Liang Zuowen,Wang Hongliang,Liu Lingyun
Background Tire wear particles (TWPs) are a major source of micro- and nanoplastics. However, reports on nanoscale tire wear particles, especially regarding their potential hazards to the male reproductive system, remain scarce. Results Here, we examined whether nanoscale tire wear particles impair spermatogenesis and blood-testis barrier integrity through ROS-linked ferroptotic injury. Using a 70-day oral exposure model in pubertal male mice and complementary GC-2 and TM4 cell models, we found that high-dose particle exposure reduced epididymal sperm density, increased sperm abnormalities, disrupted seminiferous epithelial organization, and increased BTB permeability. TWPs shifted metabolomic profiles toward lipid and iron dysregulation, suppressed SLC7A11/GPX4, increased ACSL4 and labile Fe²⁺, and depleted junctional proteins. Ferrostatin-1 reduced lipid peroxidation, iron accumulation, cell death, and junctional protein loss, indicating a functional contribution of ferroptosis. Mechanistically, TWPs first induced total and mitochondrial reactive oxygen species and mitochondrial depolarization, which were restrained by N-acetylcysteine. Downstream, autophagic ferritin degradation amplified ferroptotic injury, as chloroquine or NCOA4 knockdown preserved ferritin, reduced malondialdehyde accumulation, restored GPX4/SLC7A11, and improved viability. NCOA4 depletion did not substantially blunt ROS induction, placing ferritinophagy after redox imbalance. Conclusions Together, these data define a ROS-initiated, NCOA4-dependent ferritinophagy-ferroptosis axis that connects nanoscale TWPs to BTB failure and impaired spermatogenic homeostasis. This work provides a mechanistic basis for future assessment of reproductive health risks associated with TWPs exposure. Graphical abstract
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Autophagy
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2026
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IF 18.6
Hui Han,Sheng Wang,Jiajia Lu,Jing Li,Jinlong Zheng,Yongchuan Li,Hongtao Lu,Aimin Chen
Sacral plexus transection (SPT), mostly caused by high‑energy trauma, induces secondary death of spinal motor neurons in the lumbosacral segments and contributes to poor clinical outcomes after nerve repair. This study aimed to investigate the protective effect of α‑ketoglutarate (AKG) against ferroptosis in spinal motor neurons following SPT and the underlying molecular mechanism. Our results showed that endogenous AKG levels were significantly decreased in the spinal cord of SPT rats and in oxidative stress‑injured motor neurons, accompanied by abnormal expression of core ferroptosis‑related proteins, including downregulated glutathione peroxidase 4 and solute carrier family 7 member 11, upregulated acyl-CoA synthetase long-chain family member 4, as well as Fe2+ overload, malondialdehyde accumulation, and glutathione depletion. Exogenous AKG supplementation markedly reversed these anomalies, suppressed ferroptosis, and improved neuronal survival. Mechanistically, AKG specifically enhanced O-GlcNAcylation at the Thr177 site of PTEN‑induced kinase 1 (PINK1) and suppressed its ubiquitin-mediated degradation, which in turn selectively activated PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and sustain mitochondrial homeostasis. Furthermore, downregulation of isocitrate dehydrogenase 1 (IDH1) after SPT was identified as a critical upstream event leading to endogenous AKG depletion. This study systematically elucidates the key role of the IDH1‑AKG‑PINK1 O‑GlcNAcylation ‑mitophagy axis in regulating SPT‑induced ferroptosis in spinal motor neurons, providing novel targets and experimental evidence for neuroprotective therapy of sacral plexus injury.
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Advanced Healthcare Materials
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2023
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IF 10
Yupeng Guan,Hanqi Lei,Chengyuan Xing,Binyuan Yan,Bingbiao Lin,Xiangwei Yang,Hai Huang,Yang Kang,Jun Pang
Chemotherapy remains the most essential treatment for prostate cancer, but multidrug resistance (MDR) contributes to chemotherapy failure and tumor-related deaths. The overexpression of P-glycoprotein (P-gp) is one of the main mechanisms behind MDR. Here, we report a multimodal nanoplatform with a reactive oxygen species (ROS) cascade for gas therapy/ferroptosis/chemotherapy in reversing MDR. The nanoplatform disassembles when responding to intracellular ROS and exerts three main functions: First, NO-targeted delivery could reverse MDR by downregulating P-gp expression and inhibiting mitochondrial function. Second, ferrocene-induced ferroptosis breaks the redox balance in the tumor intracellular microenvironment and synergistically acts against the tumor. Third, the release of paclitaxel is precisely controlled in situ in the tumor for chemotherapy that avoids damage to normal tissues. Excitingly, this multimodal nanoplatform is a promising weapon for reversing MDR and may provide a pioneering paradigm for synergetic cancer therapy. This article is protected by copyright. All rights reserved
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