Frontiers in Pharmacology
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2025
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IF 4.8
Yuming Zhai,Jiamei Fu,Jianfei Yang,Yabin Zhou
Background: Myocardial infarction (MI) is characterized by high morbidity. In this study, we aimed to elucidate potential targets of Shengxian Decoction (SXD) against MI.Methods: Pairing of SXD active ingredients and MI targets was conducted using the Chinese Medicine System Pharmacological Database, Gene Expression Omnibus (GEO), and STRING databases. The effects of SXD on MI were validated in vitro. Molecular docking was verified using cellular thermal shift assay (CETSA).Results: A total of 40 active ingredients and 28 MI-related targets were obtained. Cross-analysis on 28 targets and cell death-related genes identified two crucial ferroptosis-related targets, namely, dipeptidyl peptidase 4 (DPP4) and heme oxygenase 1 (HMOX1). In cobalt chloride (CoCl2)-induced hypoxic H9c2 cells, SXD could remarkably improve cell viability and inhibit cell death. Meanwhile, SXD treatment significantly affected the ferroptosis-related markers in hypoxic H9c2 cells. Molecular docking and CETSA results showed that quercetin had good binding activity with DPP4 and HMOX1.Conclusion: Important active ingredient quercetin in SXD could exert anti-ferroptosis protective roles on MI through targeting ferroptosis-related genes (DPP4/HMOX1), thereby contributing to the protective role of SXD on MI.
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ACS Applied Materials & Interfaces
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2025
·
IF 8.2
Jiangnan Xu,Xiu Luo,Weiwei Su,Guorong Jia,Huawei Cai,Danni Li,Rou Li,Xiangdong Wang,Yefa Yang,Tao Wang,Changjing Zuo
Transarterial radioembolization (TARE) is a primary palliative treatment for advanced liver cancer. Nonetheless, its therapeutic efficacy is frequently hindered by resistance to tumor cell apoptosis induced by inter-radiotherapy. Induction of multiple cell death modalities provides a potential solution to this challenge. Ferroptosis, a distinct form of cell death from apoptosis, is dependent on the intracellular Fe2+-mediated Fenton reaction for the production of hydroxyl radicals (·OH) and is gaining recognition as a promising approach for cancer treatment. In this study, we synthesized a therapeutic radionuclide iodine-131 (131I)-based TARE agent by combining 131I-labeled iron-based MIL-88B(Fe) nanoparticles (NPs) (abbreviated as 131I-MIL-88B(Fe)) with Lipiodol to achieve a combined apoptosis–ferroptosis tumor therapy. Specifically, a mixture of Lipiodol and 131I-MIL-88B(Fe) NPs was injected into the liver tumors through the hepatic artery. Lipiodol blocks the arterial blood supply of the tumor, causing tumor tissue necrosis, whereas 131I inter-radiotherapy damages deoxyribonucleic acid (DNA) through direct action or indirectly via the production of ·OH through H2O radiolysis, leading to tumor cell apoptosis. Importantly, hydrated electrons (eaq–), a byproduct of H2O radiolysis, promoted the conversion of Fe3+ to Fe2+ in MIL-88B(Fe) NPs, enhancing the efficacy of the Fenton reaction and triggering ferroptosis. In vitro experiments demonstrated that compared to 131I alone, 131I-MIL-88B(Fe) NPs significantly enhanced ferroptosis-mediated tumor cell death due to 131I-induced Fe2+ production, which increased catalytic activity in the Fenton reaction. In a rat model bearing orthotopic N1S1 liver tumors, TARE with Lipiodol and 131I-MIL-88B(Fe) NPs induced tumor cell necrosis, apoptosis, and ferroptosis, resulting in improved therapeutic outcomes. This study leverages eaq– to facilitate Fe3+/Fe2+ conversion for efficient ferroptosis, turning waste into a valuable resource. This demonstrated the innovative integration of multiple treatment strategies to augment the efficacy of TARE in liver cancer therapy.
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Oncology Letters
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2022
·Vol. 23
·期 6
·1-11
·
IF 3.111
Chi-Ming Liu,Lijie An,Zhengping Wu,Ai-Jun Ouyang,Mengqiao Su,Zichen Shao,Yi Lin,Xiaoyu Liu,Yinjie Jiang
6‑Gingerol is a bioactive compound isolated from Zingiber officinale. 6‑Gingerol has been shown to have anticancer effects in numerous types of cancer cell. The mechanisms underlying the anticancer effect of 6‑Gingerol in prostate cancer requires investigation. In the present study, the effect on cell viability of 6‑Gingerol on LNCaP, PC3 and DU145 prostate cancer cells were determined using the MTT and colony formation assays. 6‑Gingerol significantly inhibited cell migration, adhesion and invasion in LPS‑stimulated and LPS‑unstimulated prostate cancer cells. Furthermore, these changes were accompanied by alterations in the protein expression levels of epithelial‑mesenchymal transition biomarkers, including E‑cadherin, N‑cadherin, Vimentin and zonula occludens‑1. 6‑Gingerol also induced autophagy by significantly increasing LC3B‑Ⅱ and Beclin‑1 protein expression levels in prostate cancer cells. Combining 6‑Gingerol with LY294002, an autophagy inhibitor, significantly increased cell survival in DU145 cells. Furthermore, 6‑Gingerol significantly decreased the protein expression levels of glutathione (GSH) peroxidase 4 and nuclear factor erythroid 2‑related factor 2 in prostate cancer cells. Reactive oxygen species (ROS) levels were significantly increased but GSH levels were decreased following 6‑Gingerol treatment in prostate cancer cells. Co‑treatment with the ferroptosis inhibitor, ferrostatin‑1, significantly increased cell viability and significantly decreased ROS levels in 6‑Gingerol‑treated cells. These results suggested that 6‑Gingerol may have inhibited prostate cell cancer viability via the regulation of autophagy and ferroptosis. In addition, 6‑Gingerol inhibited cell migration, adhesion and invasion via the regulation of EMT‑related protein expression levels in LPS‑stimulated and LPS-unstimulated prostate cancer cells. In conclusion, 6‑Gingerol may induce protective autophagy, autophagic cell death and ferroptosis‑mediated cell death in prostate cancer cells. These findings may provide a strategy for the treatment and prevention of prostate cancer.
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EUROPEAN JOURNAL OF NEUROSCIENCE
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2025
·Vol. 62
·期 12
·e70358
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IF 2.4
Kai Zheng,Dongyan Zhang,Weidi Wang,Ying Chen,Chenlu Feng,Xiujuan Zhao
Perimenopausal depression is a subtype of depression whose pathogenesis remains unclear. Prefrontal cortex (PFC) is an advanced center for cognitive and emotional integration, which plays a critical role in the development of perimenopausal depression. This study aimed to explore the impact of quercetin on metabolic disorders in the PFC of perimenopausal depression rat models and its potential role in inhibiting ferroptosis using untargeted metabolomics technology. Female Wistar rats were randomly divided into four groups: sham group (C), model group (D), model + 17β-estradiol (E 2 ) group (E: 0.27 mg/kg.bw), and model + quercetin group (Q: 50 mg/kg.bw). The perimenopausal depression rat model was established by ovariectomy combined with chronic unpredictable mild stress. After the experiment, the PFC was collected for metabolomic analysis and related index detection. A total of 13 differential metabolites were identified in the model group. Spearman's rank correlation analysis revealed a significant correlation between differential metabolites and behavioral outcomes ( p < 0.01). Pathway enrichment analysis of differential metabolites indicated that the metabolic disorders in the PFC of the model group primarily involved lipid metabolism, amino acid metabolism, and carnitine synthesis, which were related to ferroptosis, characterized by the generation of lipid peroxides and the imbalance between oxidation and antioxidation systems. It is worth noting that quercetin can regulate metabolic disorders and inhibit ferroptosis in the PFC of rat models with perimenopausal depression by exerting anti-inflammatory, neuroprotective, and antioxidant effects, providing a new strategy for quercetin in the prevention and treatment of perimenopausal depression.
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JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-20
·
IF 9.429
Wu Longlong,Tian Xuan,Zuo Huaiwen,Zheng Weiping,Li Xiang,Yuan Mengshu,Tian Xiaorong,Song Hongli
Background Steatotic livers tolerate ischemia–reperfusion injury (IRI) poorly, increasing the risk of organ dysfunction. Ferroptosis is considered the initiating factor of organ IRI. Heme oxygenase oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) (HO-1/BMMSCs) can reduce hepatic IRI; however, the role of ferroptosis in IRI of steatotic grafts and the effect of HO-1/BMMSCs-derived exosomes (HM-exos) on ferroptosis remain unknown.Methods A model of rat liver transplantation (LT) with a severe steatotic donor liver and a model of hypoxia and reoxygenation (H/R) of steatotic hepatocytes were established. Exosomes were obtained by differential centrifugation, and the differentially expressed genes (DEGs) in liver after HM-exo treatment were detected using RNA sequencing. The expression of ferroptosis markers was analyzed. microRNA (miRNA) sequencing was used to analyze the miRNA profiles in HM-exos.Results We verified the effect of a candidate miRNA on ferroptosis of H/R treated hepatocytes, and observed the effect of exosomes knockout of the candidate miRNA on hepatocytes ferroptosis. In vitro, HM-exo treatment reduced the IRI in steatotic grafts, and enrichment analysis of DEGs suggested that HM-exos were involved in the regulation of the ferroptosis pathway. In vitro, inhibition of ferroptosis by HM-exos reduced hepatocyte injury. HM-exos contained more abundant miR-124-3p, which reduced ferroptosis of H/R-treated cells by inhibiting prostate six transmembrane epithelial antigen 3 (STEAP3), while overexpression of Steap3 reversed the effect of mir-124-3p. In addition, HM-exos from cell knocked out for miR-124-3p showed a weakened inhibitory effect on ferroptosis. Similarly, HM-exo treatment increased the content of miR-124-3p in grafts, while decreasing the level of STEAP3 and reducing the degree of hepatic ferroptosis.Conclusion Ferroptosis is involved in the IRI during LT with a severe steatotic donor liver. miR-124-3p in HM-exos downregulates Steap3 expression to inhibit ferroptosis, thereby attenuating graft IRI, which might be a promising strategy to treat IRI in steatotic grafts.Graphical Abstract
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PSYCHOPHARMACOLOGY
·
2023
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IF 3.4
Fei Yuxiang,Li Tao,Wu Ruoyu,Xu Xuejiao,Hu Sheng,Yang Ya,Jin Chenchen,Tang Wenlian,Zhang Xu,Du Qianming,Liu Chao
Background Ischemic stroke still ranks as the most fatal disease worldwide. Blood-brain barrier (BBB) is a promising therapeutic target for protection. Brain microvascular endothelial cell is a core component of BBB, the barrier function maintenance of which can ameliorate ischemic injury and improve neurological deficit. Se-methyl L-selenocysteine (SeMC) has been shown to exert cardiovascular protection. However, the protection of SeMC against ischemic stroke remains to be elucidated. This research was designed to explore the protection of SeMC from the perspective of BBB protection. Methods To simulate cerebral ischemic injury, C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), and bEnd.3 was exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). After the intervention of SeMC, the barrier function and the expression of tight junction and ferroptosis-associated proteins were determined. For mechanism exploration, LY294002 (Akt inhibitor) was introduced both in vivo and in vitro. Results SeMC lessened the brain infarct volume and attenuated the leakage of BBB in mice. In vitro, SeMC improved cell viability and maintained the barrier function of bEnd.3 cells. The protection of SeMC was accompanied with ferroptosis inhibition and tight junction protein upregulation. Mechanism studies revealed that the effect of SeMC was reversed by LY294002, indicating that the protection of SeMC against ischemic stroke was mediated by the Akt signal pathway. Conclusion These results suggested that SeMC exerted protection against ischemic stroke, which might be attributed to activating the Akt/GSK3β signaling pathway and increasing the nuclear translocation of Nrf2 and β-catenin, subsequently maintaining the integrity of BBB. Graphical abstract
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Advanced Science
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2023
·
IF 15.1
Yi Wang,Zelong Chen,Jiahui Li,Yafei Wen,Jiaxuan Li,Yinghua Lv,Zhichao Pei,Yuxin Pei
Mild magnetic hyperthermia therapy (MMHT) holds great potential in treating deep-seated tumors, but its efficacy is impaired by the upregulation of heat shock proteins (HSPs) during the treatment process. Herein, Lac-FcMOF, a lactose derivative (Lac-NH 2 ) modified paramagnetic metal-organic framework (FcMOF) with magnetic hyperthermia property and thermal stability, has been developed to enhance MMHT therapeutic efficacy. In vitro studies showed that Lac-FcMOF aggravates two-way regulated redox dyshomeostasis (RDH) via magnetothermal-accelerated ferricenium ions-mediated consumption of glutathione and ferrocene-catalyzed generation of ∙OH to induce oxidative damage and inhibit heat shock protein 70 (HSP70) synthesis, thus significantly enhancing the anti-cancer efficacy of MMHT. Aggravated RDH promotes glutathione peroxidase 4 inactivation and lipid peroxidation to promote ferroptosis, which further synergizes with MMHT. H22-tumor-bearing mice treated with Lac-FcMOF under alternating magnetic field (AMF) demonstrated a 90.4% inhibition of tumor growth. This work therefore provides a new strategy for the simple construction of a magnetic hyperthermia agent that enables efficient MMHT by downregulating HSPs and promoting ferroptosis through the aggravation of two-way regulated RDH.
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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2023
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IF 3.9
Qingqing Du,Xiaoyun Wu,Kai Ma,Weiwei Liu,Panwen Liu,Toshihiko Hayashi,Kazunori Mizuno,Shunji Hattori,Hitomi Fujisaki,Takashi Ikejima
Type 2 diabetes (T2DM) is induced by the abundance of glucose and lipids , which causes glucolipotoxicity to the pancreatic β-cells. Silibinin is a natural flavonoid possessing the regulatory activity on insulin production and therapeutic activity in diabetic mice; however, its effect on glucolipotoxicity is not fully explained. This in vitro study investigates the effects of silibinin on palmitic acid (PA) and high glucose (HG)-induced cell loss and ferroptosis of rat insulinoma INS-1 cells. In the cells treated with PA and HG, expressions of glucose transporter 4 (Glut4) and carnitine acyltransferase I (CPT1) for β-oxidation of fatty acids are reduced. Mitochondria are the metabolic organelles for glucose and fatty acids. The mitochondrial membrane potential (MMP) and ATP production were decreased, while the ROS level was elevated in the cells treated with PA and HG, indicating an induction of mitochondrial disorder . Cell loss was partially rescued by ferroptosis inhibition, suggesting an involvement of ferroptosis in the cells treated with PA and HG. More importantly, the increases in total iron, lipid ROS, MDA and COX-2, and the decrease in ferroptosis inhibitory molecules GSH, GPX4 and FSP1 appeared in the cells treated with PA and HG, confirming the occurrence of ferroptosis. Moreover, PINK1/parkin-mediated mitophagy , a vital process for selective elimination of damaged mitochondria, was blocked. Interestingly, silibinin rescued the mitochondria, restricted the ferroptosis and restored the mitophagy. By using the pharmacological stimulator and inhibitor of mitophagy, and si-RNA transfection to silence PINK1 expression, silibinin's protective effect against ferroptosis caused by PA and HG treatment was found to depend on mitophagy. Collectively, our current study reveals the new mechanisms for the protection of silibinin against the injury of INS-1 cells treated with PA and HG, elucidates the participation of ferroptosis in glucolipotoxicity, highlighting the involvement of mitophagy in defense against ferroptotic cell death.
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Frontiers in Bioengineering and Biotechnology
·
2023
·
IF 5.7
Wang Youwei,Chen Bing,Fan Jiang,Wang Zhong
Monitoring ferroptosis-related miRNAs is crucial for the treatment and prognosis of patients with intracerebral hemorrhage. In this work, a novel hydrophobic paper (h-paper)-based plasmonic substrate was produced by dropping DS Au nanorods with a narrow range of sizes and morphologies onto h-paper. Raman reporter molecules were adsorbed to the array surface, and surface-enhanced Raman scattering spectra at randomly selected points reveal uniform and significant SERS enhancement. Hairpin DNAs labelled with Raman reporters and hybridized with placeholder DNAs were decorated on SERS substrate to fabricate SERS biosensor. Target miRNAs initiated the “inverse Molecular Sentinel” process. During the process, PHs were removed and the conformation of HPs changed toward the hairpin structure, thus eliciting the proximity of Raman reporter to substrate and a stronger SERS signal. The proposed SERS biosensor performs well in terms of stability, reproducibility, and selectivity. The limits of detection of miR-122-5p and miR-140-5p in serum were 4.17 aM and 4.49 aM, respectively. Finally, the fabricated SERS biosensor was applied to detect miR-122-5p and miR-140-5p in ICH patients and healthy subjects, and the results obtained by SERS were consistent with the results from quantitative real-time polymerase chain reaction, revealing the accuracy of the method. This simple, rapid approach offers great potential for the simultaneous detection of miRNAs in practical clinical applications.
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Zhao Pan,Gong Liyang,Chang Le,Du Huiping,Geng Meijuan,Meng Siyu,Dai Liangliang
Chemodynamic therapy (CDT) is seriously limited by the inadequacy of exogenous catalytic ions and endogenous H 2 O 2 in tumors. Herein, a multifunction nano-bomb integrated with calcium peroxide (CaO 2 ) and β-lapachone as donors of H 2 O 2 and GSH-sensitive Fe-based coordination polymer as provider of catalytic ions was constructed for dual cascade-amplified tumor CDT. This hyaluronic acid (HA)-modified nano-bomb could be specially endocytosed by breast cancer cells through a targeting pathway, degraded and released cargoes in response to the GSH-rich cytoplasm. Furthermore, the released CaO 2 and β-lapachone could significantly self-generated sufficient H 2 O 2 , which could dual-cascade amplify CDT and induce severe oxidative to tumors via cooperating with the delivered iron ions from nano-bombs. Moreover, the unloaded iron and calcium ions could further accelerate tumor damage by overloading Ca 2+ and ferroptosis, as accompanied by good magnetic resonance imaging (MRI). In vitro and in vivo studies collectively reveal that this nano-bomb not only self-initiates double cascade-amplified CDT via self-generation of H 2 O 2 , but also efficiently activates ferroptosis and initiates Ca 2+ overloading, consequently significantly tumor growth suppression. This study offers a novel tumor-initiated nano-bomb for dual cascade-amplified CDT and bioimaging with activated ferroptosis and self-supplying H 2 O 2 .
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2025
·Vol. 55
·期 3
·1-15
·
IF 5.8
Congna Zi,Yulei Wei,Ying Zhu,Juan Fan
Regulator of G‑protein signaling 12 (RGS12) is a regulatory factor that is involved in various physiological processes. However, the role of RGS12 in myocardial ischemia/reperfusion injury (MIRI) currently remains unclear. The present study established a mouse model of MIRI by ligating the left main coronary artery followed by reperfusion. In addition, mouse HL‑1 cells were cultured in a hypoxic and serum‑free medium, followed by reoxygenation to establish an in vitro cell model of hypoxia/reoxygenation (H/R). Adenoviruses targeting RGS12 were subsequently used to either overexpress or silence RGS12 expression. RGS12 was highly expressed in both the myocardial tissues of mice with MIRI and HL‑1 cells subjected to H/R. The results from the in vitro experiments demonstrated that the knockdown of RGS12 reduced oxidative stress under a pathological environment, as indicated by decreased reactive oxygen species (ROS) levels and malondialdehyde activity and increased activities of superoxide dismutase and catalase. Furthermore, mice with MIRI and HL‑1 cells that underwent H/R stimulation exhibited increased ferroptosis, whereas RGS12 knockdown reversed these changes. These results showed that post‑RGS12 silencing the levels of Fe2+ and lipid ROS were decreased, the expression levels of glutathione peroxidase 4 and cystine transporter solute carrier family 7 member 11 were increased and mitochondrial structure was improved by preventing the loss of the mitochondrial crest. Mechanistically, the nuclear factor erythroid 2‑related factor 2 (Nrf2) pathway with anti‑ferroptosis and anti‑oxidative stress capacities was activated by RGS12 knockdown. Conversely, RGS12 overexpression exerted the opposite effects both in vivo and in vitro. Notably, it was demonstrated that penehyclidine hydrochloride (PHC), known to block the MIRI process, decreased RGS12 expression levels both in vivo and in vitro, and RGS12 overexpression inhibited the therapeutic effects of PHC on MIRI. In conclusion, the present study demonstrated that RGS12, a target of PHC, potentially enhanced the progression of MIRI by promoting oxidative stress and ferroptosis, and this effect may involve the regulation of the Nrf2 pathway.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
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IF 6.7
Changjun Zhang,Yi Lu,Jingqi Zhang,Anjie Zang,Jinhui Ren,Zhiyuan Zheng,Miaoliang Fan,Yuanyuan Xie
Recent advances in understanding the role of iron and ROS in cell death suggest new therapeutic avenues to treat organ damage including acute kidney injury (AKI). Inhibiting ferroptosis was expected to have great potential for the treatment of this disease. Ferroptosis is characterized by iron-dependent lipid peroxidation and currently, a majority of reported ferroptosis inhibitors belong to either radical-trapping antioxidants or iron chelators . However, clinically used iron chelators such as deferoxamine and deferiprone have limited efficacy against ferroptosis (generally with EC 50 > 100 μM), despite their proven safety. Herein, we present the rational design of novel ferroptosis inhibitors by incorporating the naturally occurring cinnamic acid scaffold and the 3-hydroxypyridin-4(1 H )-one iron-chelating pharmacophore . Through ABTS ˙ + radical-scavenging assay, oxygen radical absorbance capacity (ORAC) measurement, Fe 3+ affinity evaluation, and anti-erastin-induced HT22 cell ferroptosis assays, we identified compound 9c as the most prospective ferroptosis inhibitor (ABTS ˙ + , IC 50 = 4.35 ± 0.05 μM; ORCA = 23.79 ± 0.56 TE; pFe 3+ = 18.59; EC 50 = 14.89 ± 0.08 μM, respectively). Notably, 9c dose-dependently alleviated cell death in cisplatin-induced AKI model. Our results provide insight into the development of new ferroptosis inhibitors through rational incorporation of pharmacophores from existing ferroptosis inhibitors, and compound 9c could be a promising lead compound worth further investigation.
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