FREE RADICAL BIOLOGY AND MEDICINE
·
2021
·
IF 7.376
Rong Fan,Jidong Sui,Xuepeng Dong,Biao Jing,Zhenming Gao
Acute pancreatitis (AP) is an inflammatory disorder associated with multiple organ failure . Pyroptosis and ferroptosis are two newly recognized cell death , and whether pyroptosis and ferroptosis are involved in AP remain largely elusive. The nature compound Wedelolactone (Wed) exhibits strong anti-inflammatory and antioxidant activities , the present study aims to investigate the effect of Wed on AP and unravel whether Wed could protect against AP and relevant lung injury against pyroptosis and ferroptosis. Our results showed that the pyroptosis inhibitor disulfiram or ferroptosis inhibitor ferrostatin-1 significantly alleviated AP and associated lung injury in the taurocholate or caerulein-induced murine AP model. Administration with Wed ameliorated AP and lung injury as evidenced by improved pathological injuries, reduced serum pancreatic digestive enzymes , and proinflammatory cytokines . The in vivo and in vitro data demonstrated that Wed broadly inhibited caspase1/caspase11 activation, reduced mature interleukin-1β (IL-1β) and N-terminal domain of gasdermin D (GSDMD-N) level. The oxidative stress and lipid peroxidation were also suppressed along with the up-regulation of the ferroptosis antagonism marker glutathione peroxidase-4 (GPX4) in Wed treatment group. Wed promoted the transcriptional activity and the selenium sensitivity of GPX4. Moreover, the protective effects of Wed in caerulein-stimulated pancreatic acinar cells were markedly abrogated by the down-regulation of GPX4. Collectively, our data suggest that pyroptosis and ferroptosis play crucial roles in AP. Wed mitigated AP and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis.
研究领域:
药理学
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炎症
·
细胞死亡机制
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氧化应激
·
胰腺病学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2024
·
IF 4.4
Lei Huang,Jiayi Wang,Jieqin Yu,Mengxuan Bian,Xingdong Xiang,Guanjie Han,Weisin Chen,Ning Wang,Jun Ge,Shunyi Lu,Jian Zhang
Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to abnormal oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation, making the OP-related bone healing a significant clinical challenge. As the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) is closely related to bone regeneration; currently, this study assessed the effects of Picein on BMSCs in vitro and bone regeneration in osteoporotic bone defect in vivo. Cell viability was determined by CCK-8 assay. The production of (ROS), malonaldehyde, superoxide dismutase activities, and glutathione was evaluated by using commercially available kits, and a flow cytometry analysis was adopted to detect macrophage polarization. Osteogenic capacity of BMSCs was evaluated by alkaline phosphatase (ALP) activity, ALP staining, and Alizarin red S staining. The expression of osteogenic-related proteins (OPN, Runx-2, OCN) and osteogenic-related genes (ALP, BMP-4, COL-1, and Osterix) were evaluated by Western blotting and real-time PCR (RT-PCR). In addition, proliferation, migration ability, and angiogenic capacity of human umbilical vein endothelial cells (HUVECs) were evaluated by EdU staining, scratch test, transwell assay, and tube formation assay, respectively. Angiogenic-related genes (VEGF, vWF, CD31) were also evaluated by RT-PCR. Results showed that Picein alleviated erastin-induced oxidative stress, enhanced osteogenic differentiation capacity of BMSCs, angiogenesis of HUVECs, and protects cells against ferroptosis through Nrf2/HO-1/GPX4 axis. Moreover, Picein regulate immune microenvironment by promoting the polarization of M2 macrophages in vitro. In addition, Picein also reduce the inflammation levels and promotes bone regeneration in osteoporotic bone defect in OP rat models in vivo. Altogether, these results suggested that Picein can promote bone regeneration and alleviate oxidative stress via Nrf2/HO-1/GPX4 pathway, offering Picein as a novel antioxidant agent for treating osteoporotic bone defect.
研究领域:
药理学
·
骨生物学
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氧化应激
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干细胞研究
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炎症
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再生医学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Baohong Li,Zichao Chen,Zhenyong Zhang,Hui Liu,Dongli Han,Haolin Yang,Zhen Zhang
Background: Breast cancer bone metastasis is closely associated with the bone microenvironment. Zuogui Pill (ZGP), a clinically approved formulation in China, effectively regulates the bone microenvironment for the prevention and treatment of osteoporosis. Purpose: Few reports have utilized the ZGP for bone metastasis models. This study investigated the intervention and bone-protective properties of ZGP against breast cancer bone metastasis, explored the potential mechanism, and screened for its active compositions by molecules fishing. Methods: To investigate the intervention efficacy of ZGP and its protein-level mechanism of action, the mouse bone metastasis model and in vitro cell co-culture model were constructed. Affinity ultrafiltration, molecular docking, cellular thermal shift assay and physical scale detection were used to investigate the affinity components of the RANKL protein in ZGP. Results: The administration of ZGP combined with zoledronic acid inhibited the development of tumors and secondary lung metastasis in mice. This translated to a prolonged survival period and enhanced quality of life. ZGP could disrupt the malignant cycle by modulating the Piezo1-Notch-1-GPX4 signaling pathway in the "bone-cancer" communication in the cell co-culture model. Furthermore, 25 chemical components of ZGP were identified, with 10 active compounds exhibiting significant affinity for the RANKL protein. Conclusion: The findings of this work highlighted ZGP's potential for intervening in the progression of breast cancer bone metastasis. Thus, this investigation served as an experimental foundation for expanding the application scope of ZGP and for advancing drug development efforts in bone metastasis treatment.
研究领域:
肿瘤学
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药理学
·
分子生物学
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细胞生物学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2025
·
IF 3.7
Mengxin Li,Wanqi Wu,Zhihao Ma,Shasha Zhang,Tianyue Guan,Jun Wang,Long Chen,Wanyi Xu,Hong Yu,Huizhen Chen,Jingquan Dong
Chronic intermittent hypoxia (CIH) caused by obstructive sleep apnea (OSA) exacerbates renal dysfunction, fibrosis, and chronic kidney disease (CKD) progression. This study investigates the renoprotective effects and mechanisms of atraric acid (AA), a natural compound from oakmoss with anti-inflammatory and antioxidant properties, against CIH-induced renal injury. A CIH mouse model was established, with groups including control, CIH, and CIH mice treated with AA (5, 10, 20 mg/kg). Mice underwent daily 8-h hypoxia exposure for 4 weeks. Renal pathology was assessed via HE and Masson staining, while fibrosis markers (α-SMA, collagen I, TGF-β1), oxidative stress (DHE staining, MDA levels), ferroptosis (iron content), and Nrf2/GPX4 pathway proteins were analyzed using biochemical assays and Western blotting. Results showed that AA treatment dose-dependently alleviated CIH-induced renal injury and fibrosis, reducing the expression of fibrotic proteins. AA suppressed ROS accumulation and lipid peroxidation while mitigating iron overload. Mechanistically, AA activated the Nrf2/Keap1 pathway, upregulating antioxidant proteins GPX4 and SLC7A11, thereby inhibiting oxidative stress and ferroptosis. These findings provide the first evidence that AA ameliorates CIH-related renal damage by targeting the Nrf2/GPX4 axis, offering a novel therapeutic strategy for CKD associated with OSA. The study highlights AA's potential in attenuating hypoxia-driven renal fibrosis through dual modulation of oxidative stress and ferroptosis pathways.
研究领域:
肾脏病学
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药理学
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分子生物学
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睡眠医学
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病理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
FOLIA BIOLOGICA
·
2022
·Vol. 68
·期 2
·59-71
·
IF 1.167
Shao ZC,Zhu BH,Huang AF,Su MQ,An LJ,Wu ZP,Jiang YJ,Guo H,Han XQ,Liu CM
Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase- 3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT /Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Menglong Gao,Lishun Dong,Yulong Yang,Jinjin Yan,Yuning Liang,Xiaolin Ma,Min Zhou,Hongfei Wu,Yarong Liu,Min Dai
Atherosclerosis (AS) is the underlying cause of many severe vascular diseases and is primarily characterized by abnormal lipid metabolism. Paeonol (Pae), a bioactive compound derived from Paeonia Suffruticosa Andr., is recognized for its significant role in reducing lipid accumulation. Our research objective is to explore the link between lipid buildup in foam cells originating from macrophages and the process of ferroptosis, and explore the effect and mechanism of Pae on inhibiting AS by regulating ferroptosis. In our animal model, ApoE-deficient mice, which were provided with a high-fat regimen to provoke atherosclerosis, were administered Pae. The treatment was benchmarked against simvastatin and ferrostatin-1. The results showed that Pae significantly reduced aortic ferroptosis and lipid accumulation in the mice. In vitro experiments further demonstrated that Pae could decrease lipid accumulation in foam cells induced by oxidized low-density lipoprotein (LDL) and challenged with the ferroptosis inducer erastin. Crucially, the protective effect of Pae against lipid accumulation was dependent on the SIRT1/NRF2/GPX4 pathway, as SIRT1 knockdown abolished this effect. Our findings suggest that Pae may offer a novel therapeutic approach for AS by inhibiting lipid accumulation through the suppression of ferroptosis, mediated by the SIRT1/NRF2/GPX4 pathway. Such knowledge has the potential to inform the creation of novel therapeutic strategies aimed at regulating ferroptosis within the context of atherosclerosis.
研究领域:
心血管疾病
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药理学
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分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Inflammation-London
·
2023
·Vol. 20
·期 1
·1-11
·
IF 5.1
Zhao Ziwen,Xu Zhao,Chang Jingwen,He Liwei,Zhang Zijin,Song Xiaoyu,Hou Xianbang,Fan Fangtian,Jiang Zhijun
Background Ferroptosis in alveolar and bronchial epithelial cells is one of the main mechanisms underlying the development of chronic obstructive pulmonary disease (COPD). Sodium pyruvate (NaPyr) is a natural antioxidant in the body, exhibiting anti-inflammatory and antioxidant activities. NaPyr has been used in a Phase II clinical trial as a novel therapy for COPD; however, the mechanism underlying NaPyr-mediated therapeutic benefits in COPD is not well understood. Objective We aimed to assess the protective effects of NaPyr and elucidate its potential mechanism in cigarette smoke extract (CSE)-induced ferroptosis.To minic the inflammatory response and ferroptosis triggered by cigarette smoke in COPD in an invitro cell based system, we expose a human bronchial epithelial cells to CSE. Methods To minic the inflammatory response and ferroptosis triggered by cigarette smoke in COPD in an invitro cell based system, the A549 (human lung carcinoma epithelial cells) and BEAS-2B (bronchial epithelial cells) cell lines were cultured, followed by treatment with CSE. To measure cellular viability and iron levels, we determined the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), mitochondrial superoxide (MitoSOX), membrane potential (MMP), and inflammatory factors (tumor necrosis factor [TNF] and interleukin [IL]-8), and examined CSE-induced pulmonary inflammation and ferroptosis. To clarify the molecular mechanisms of NaPyr in COPD therapy, we performed western blotting and real-time PCR (qPCR) to determine the expression of glutathione peroxidase 4 (GPX4), nuclear factor E2-related factor 2 (Nrf2), and cyclooxygenase 2 (COX2). Results We found that NaPyr effectively mitigated CSE-induced apoptosis and improved apoptosis induced by erastin, a ferroptosis inducer. NaPyr significantly decreased iron and MDA levels and increased GSH levels in CSE-induced cells. Furthermore, NaPyr suppressed ferroptosis characteristics, such as decreased levels of ROS, MitoSOX, and MMP. NaPyr significantly increases the expression levels of GPX4 and Nrf2, indicating that activation of the GPX4/Nrf2 axis could inhibit ferroptosis in alveolar and bronchial epithelial cells. More importantly, NaPyr inhibited the secretion of downstream inflammatory factors, including TNF and IL-8, by decreasing COX2 expression levels to suppress CSE-induced inflammation. Conclusion Accordingly, NaPyr could mitigate CSE-induced ferroptosis in alveolar and bronchial epithelial cells by activating the GPX4/Nrf2 axis and decreasing COX2 expression levels. In addition, NaPyr reduced the secretion of inflammatory factors (TNF and IL-8), affording a novel therapeutic candidate for COPD. Graphical Abstract
研究领域:
呼吸病学
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药理学
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细胞生物学
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分子生物学
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炎症
·
氧化应激
·
治疗学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Yuanlin Wang,Yaqian Han,Jingshi Li,Zhaotong Wang,Kai Li,Tiancheng Bai,Lei Wang,Ye Sun,Chunying Chen,Miao Yu
Ferroptosis serves as a pivotal mechanism in diverse clinical chemotherapeutics and physiological processes, profoundly impacting tumor metabolism and the tumor microenvironment. Recently, the immunosuppression induced by ferroptosis has raised major concerns regarding tumor recurrence upon ferroptosis-based antitumor therapies. However, due to the lack of cell specificity, the antitumor and immunosuppressive effects in ferroptosis are inherently intertwined. Herein, we address the conflicting challenges between immunosuppression and antitumor efficacy in ferroptosis-based therapy by enabling cell-specific ferroptosis, thereby targeting tumors while sparing immune cells. By employing a specially designed nanoagent, i.e. , ferrous selenide half-shell-covered gold, we induce notable upregulation of glutathione peroxidase 4 (GPX4) and downregulation of prostaglandin E2, leading to an increase in CD 4+ and CD 8+ T cell populations and intense antitumor immune responses. Despite the elevated level of GPX4, significant tumor cell ferroptosis is achieved, which is further promoted by the agent's photothermal and photocatalytic effects. Consequently, long-term immunological memory is established, yielding a long-lasting and recurrence-free antitumor efficacy spanning at least 200 days post-treatment. This work unlocks an avenue to balance immunosuppression reversal with tumor inhibition in ferroptosis-based therapies, providing promising prospects for antitumor therapies facing immunological hurdles in the tumor microenvironment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Ruping Quan,Yan Wang,Shoujing Liang,Dan Guo,Ying Sun,Jiayu Su,Weixi Xiang,Hualin Huang,Chao Lv,Hongmei Xiao
Mutations in glycoprotein, zona pellucida 3 ( ZP3 ), cause human ZP loss and empty follicle syndrome (EFS), yet the underlying mechanisms remain unknown. In this study, we generated Zp3 -knockout rats (r Zp3 -/- ) using CRISPR-Cas9, which recapitulated the EFS phenotype with follicular arrest and oocyte degeneration. Transmission electron microscopy revealed complete absence of the zona pellucida and transzonal projections, alongside shortened microvilli that correlated with radixin downregulation, indicating impaired oocyte-granulosa communication. Single-oocyte transcriptomics revealed dysregulated mitochondria-associated signaling pathways, such as glutathione metabolism and oxidative phosphorylation, consistent with energy deprivation and oxidative stress resulting from impaired cell dialogs between oocyte and granulosa cells. In oocytes of r Zp3 -/- , mitochondrial dynamics were severely disrupted, featuring reduced mitochondrial area, cristae hyperfusion. In addition, electron transport chain activity was impaired in oocytes of r Zp3 -/- , driving mitochondrial reactive oxygen species (ROS) overproduction. Consequently, r Zp3 -/- oocytes displayed ferroptosis hallmarks, including elevated lipid peroxidation, iron dysregulation, and glutathione peroxidase 4 (GPX4) inactivation. Pharmacological inhibition of ferroptosis in vitro using deferiprone partially rescued oocyte defects by restoring GPX4, attenuating mitochondrial ROS and lipid peroxidation, therefore inhibit apoptosis in r Zp3 -/- . This study establishes ZP3 as a guardian of mitochondrial homeostasis and implicates ferroptosis as a key pathway in EFS pathogenesis, offering novel therapeutic targets for EFS.
研究领域:
生殖生物学
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细胞生物学
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分子遗传学
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氧化应激与细胞死亡
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线粒体生理学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2026
·
IF 3.5
Yurou Li,Zhenzhen Yan,Wanrong Zhang,Xin Zheng,Zhengping Wu,Yinjie Jiang,Jie Zhou
Sodium aescinate (SA), a triterpenoid saponin derived from Aesculus hippocastanum seeds, is widely used clinically but has been linked to hepatotoxicity, nephrotoxicity, and phlebitis. We previously reported that SA triggers hepatocyte ferroptosis, and enhancing GSH synthesis via the CTH/cysteine axis activation only partially mitigates liver injury. In this study, we showed that SA disrupted redox homeostasis, promoted lipid peroxidation (LPO), and induced ferroptosis in hepatocytes, concomitant with suppressed Nrf2/PRDX6/GPX4 pathway activity. Mechanistically, SA downregulated the expression and transcriptional activity of Nrf2, reducing its binding to antioxidant response elements (AREs) in the promoters of PRDX6 and GPX4, thereby decreasing their expression. Nrf2 overexpression restored PRDX6 and GPX4 levels, enhanced antioxidant capacity, and attenuated SA-induced ferroptosis. Notably, PRDX6 regulated GPX4 expression and activity by modulating selenium utilization and selenoprotein biosynthesis during SA-induced hepatotoxicity. Both PRDX6 overexpression and selenium supplementation rescued GPX4 and protected against SA-induced ferroptotic damage. The protection conferred by Nrf2/PRDX6 overexpression or selenium supplementation was fully abrogated upon GPX4 knockdown or inhibition with RSL3. Collectively, SA induced ferroptotic liver injury by disrupting the Nrf2/PRDX6/GPX4 axis, culminating in GPX4 deficiency and redox collapse. This study suggests that this cascade represents a promising therapeutic target for SA-induced hepatotoxicity.
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DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-21
·
IF 8.9
He Qiongyao,He Wu,Ren Yanlin,Wu Wenbin,Dong Hui,Yuan Gang,Ren Huihui,Wang Xinwei,Lu Fuer,Wang Dingkun
Ferroptosis, an iron-dependent form of programmed cell death, is closely associated with tubular damage in diabetic nephropathy (DN). Glutathione peroxidase 4 (GPX4) is an important anti-oxidant enzyme, and plays a crucial role in protecting against ferroptosis. However, the regulatory mechanism of GPX4 expression levels in renal tubular epithelial cells (RTECs) remains elusive. This study reveals that ferroptosis occurs in the late-stage of DN, and the GPX4 level is significantly downregulated in DN patients, animal models and cell models. By applying database predictions, luciferase reporter assays and chromatin immunoprecipitation, we find that vitamin D receptor (VDR) transcription factor promotes GPX4 expression and plays a key role in inhibiting ferroptosis of RTECs. VDR knockout exacerbates ferroptosis in RTECs and worsens renal function, while intraperitoneal injection of VDR agonist paricalcitol significantly improves renal injury. Proteomics analysis suggests that E3 ligase PRPF19 mediates ubiquitination degradation of VDR and is an important therapeutic target for DN. Therefore, through molecular docking, targeted fishing technology using high-performance affinity beads, and surface plasmon resonance (SPR), we screen and identify berberine (BBR) as a novel inhibitor of PRPF19, which offers renal protection by inhibiting VDR degradation and tubular ferroptosis. These findings elucidate the role of ferroptosis in DN renal tubular injury, and suggest that PRPF19 is a promising therapeutic target.
研究领域:
医学
·
分子生物学
·
肾脏病学
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产品关联
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2026
·
IF 13.6
Luan Jing,He Jiyuan,Wu Dantong,Duan Yaning,Hou Guoyuan,Ma Shuang,Qin Jianhua,Sun Na,He Yuanzheng,Zhang Wei,Gao Minghui
Ferroptosis is a type of regulated necrosis driven by iron-dependent lethal accumulation of lipid peroxides. Selenoprotein thioredoxin reductase (TrxR) plays crucial roles in cellular redox homeostasis. However, its role in ferroptosis remains unclear. Here, we report TrxR1 positively regulates ferroptosis. The selenocysteine of TrxR1 is required for its regulation of ferroptosis. Mechanistically, the CRL4A CRBN E3 complex ubiquitinates KEAP1 at K84 and K312, driving KEAP1 degradation. Overexpression of TrxR1 increases KEAP1 stability by suppressing CRL4A CRBN E3 complex mediated KEAP1 ubiquitination and degradation, enhances the interaction between NRF2 and KEAP1, promotes NRF2 ubiquitination and drives NRF2 degradation, which results in downregulation of GPX4 expression, thereby sensitizing cells to ferroptosis. Furthermore, high level of TrxR1 sensitizes cancer cells to ferroptosis in vivo. CRBN inhibitor thalidomide and IKE combination treatment results in markedly retarded tumor progression. Our study reveals a crucial pro-ferroptotic role for TrxR1 and nominates it as a potential biomarker for guiding future ferroptosis-inducing therapies in select cancers.
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DOI
高影响因子
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