NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2025
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IF 3.1
Li Yue,Li Hailan,Sun Minhui,Chen Hong,Xiao Yao,Wang Jieman,Zhang Yuanyuan,Fang Shuhua,Kou Junping
Silibinin (Sil) is a major bioactive component of silymarin, extracted from the fruit and seeds of Silybum marianum . Silibinin meglumine (SM) is a water-soluble derivative of silibinin that has shown significant potential in liver fibrosis. However, the potential effects and underlying mechanisms of SM on acute liver failure (ALF) are still not fully understood. This study aims to find the likely mechanism. An ALF mouse model and a cell model were established with GalN/LPS. SM was administered to mice via the tail vein or to a hepatocyte line (alpha mouse liver 12, AML12). The results showed that SM particularly lowered the mortality and improved liver pathological lesions in ALF mice. Meanwhile, SM improved the levels of GSH, SOD, TNF-α, IL-6, IL-1β, and IL-10 in the liver tissues and serum. Additionally, SM enhanced cell viability and reduced oxidative stress in vitro. In the AKT/GSK3β/Nrf2/GPX4 pathway, the subpathway of AKT/GSK3β was inhibited, and the subpathway of Nrf2/GPX4 was activated by SM both in vivo and in vitro. In addition, ferrostatin-1, a ferroptosis inhibitor, and the silencing of AKT using siRNA weakened the protective effect of SM, indicating that this process is mediated in an AKT-dependent manner. All the results suggested that SM inhibits inflammation and oxidative stress by modulating the AKT/GSK3β/Nrf2/GPX4 pathway.
研究领域:
药理学
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肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
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2024
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IF 4.8
Mengmeng Zhang,Jingbo Liu,Yiding Yu,Wenshuo Ren,Rui Yuan,Xuanting Liu,Xiaomin Shang,Zhiyang Du,Meng-Lei Xu,Ting Zhang
Genistein (GEN) is the most abundant aglycone in soy isoflavones and is a key factor distinguishing soybeans from other food sources. It holds significant nutritional value and exhibits notable biological activity. However, the low water solubility of genistein limits its widespread application. To improve its water solubility, this study prepared γ-cyclodextrin (γ-CD)/GEN inclusion complexes and investigated their mechanism of action in alleviating hydrogen peroxide-induced oxidative stress damage in PC12 cells. The results showed that γ-CD/GEN could be uniformly and stably dispersed in the system. Cell experiments indicated that γ-CD/GEN significantly increased cell survival after treatment with organic hydrogen peroxide, and promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of glutathione peroxidase 4 (GPx4). It also improved mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels, thereby alleviating cell damage caused by oxidative stress. Further Nrf2 knockdown experiments revealed that γ-CD/GEN failed to provide protection, and no protective effect was observed under RSL3 intervention. In conclusion, γ-CD/GEN exerts antioxidant effects by activating the Nrf2/GPx4 pathway, thereby reducing oxidative stress damage induced by organic hydrogen peroxide, providing a theoretical basis for the development of novel antioxidants.
研究领域:
药理学
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分子生物学
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神经科学
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产品关联
DOI
高影响因子
Bioengineering & Translational Medicine
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2025
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IF 5.7
Lulu Chen,Bicheng Chen,Xiang Su
An abdominal aortic aneurysm (AAA) is a life-threatening vascular condition characterized by the dilation of the abdominal aorta, with ferroptosis playing a significant role in its pathogenesis. This study investigates the therapeutic potential of engineering biomimetic nanovesicles to deliver phosphatidylethanolamine-binding protein 1 (PEBP1) mRNA for inhibiting ferroptosis in vascular smooth muscle cells (VSMCs) and preventing AAA progression. Differential gene expression analysis of the AAA transcriptomic dataset GSE57691 identified 243 differentially expressed genes (DEGs), intersecting with 12 ferroptosis-related genes. Single-cell analysis of dataset GSE237230 highlighted PEBP1 as a key gene in VSMCs. Overexpression of PEBP1 in VSMCs enhanced proliferation, reduced reactive oxygen species (ROS) and iron levels, and inhibited apoptosis and ferroptosis via the NRF2/GPX4 axis. The engineered biomimetic nanovesicles demonstrated significant uptake by VSMCs and effective delivery of PEBP1 mRNA. In vivo studies confirmed that these nanovesicles substantially inhibited AAA progression in mice. This study presents a novel bioengineering approach for AAA treatment by targeting ferroptosis through PEBP1 mRNA delivery, offering a promising molecular strategy for the prevention and management of AAA.
研究领域:
生物医学工程
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纳米技术
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分子生物学
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心血管疾病研究
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基因治疗
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2025
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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
Biomaterials Advances
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2025
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IF 6
Zhidong Lin,Luoqi Mai,Huitong Luo,Zetao Wang,Yongpeng Lin,HongShen Wang,Shaohua Chen,Guoyi Su,Xulin Hu,Bolai Chen,Xiaodong Cao
Intervertebral disc degeneration (IVDD) is a leading cause of lower back pain, characterized by the ferroptosis of nucleus pulposus cells (NPCs) and imbalance in reactive oxygen species (ROS) metabolism. Icariin (ICA), an active compound from traditional Chinese medicine, scavenges ROS and inhibits ferroptosis, but its poor water solubility and low bioavailability limit clinical use. A dual-crosslinked hydrogel (HP@ICA) is developed to address these challenges. Cyclodextrin is integrated into polyvinyl alcohol to enhance ICA loading via hydrophobic interactions. Methacrylic acid and phenylboronic acid are incorporated into hyaluronic acid, enabling dynamic bonding with polyvinyl alcohol. Ultraviolet crosslinking creates a secondary crosslinked hydrogel with pH and ROS responsiveness, self-healing properties, and improved ICA solubility, increasing its water solubility tenfold. Enhanced solubility boosts ICA's free radical scavenging capacity by 103 %, suppressing ferroptosis and promoting NP cell regeneration, as demonstrated by reduced iron ion concentrations, lower malondialdehyde levels, and restored glutathione peroxidase 4 activity. Ferroptosis inhibition facilitates type II collagen production in NP cells. Mechanistic studies reveal activation of the Nrf2-GPX4 pathway as key to regeneration. These findings suggest a promising regenerative therapeutic approach for IVDD.
研究领域:
生物医学工程
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再生医学
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药剂纳米技术
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骨科
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2022
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IF 8.101
Pingcui Xu,Bingfeng Lin,Xuehui Deng,Kai Huang,Yan Zhang,Nani Wang
Ferroptosis plays an essential role in the pathology of osteoporosis . This study investigated whether vitamin D receptor (VDR) activation could protect against age-related osteoporosis through an anti-ferroptosis mechanism. d -galactose (D-gal)-induced mice and VDR-knockout mice were used in the in-vivo study. The VDR activator (1,25(OH) 2 D 3 ) attenuated senescence and ferroptosis in the D-gal-induced bone, as illustrated by downregulated senescence-associated secretory phenotype genes, improved mitochondrial morphology, elevated glutathione , and decreased lipid peroxidation markers (malondialdehyde and 4-hydroxynonenal). The pre-osteoblast MC3T3-E1 cells and primary rat osteoblasts were applied in the in-vitro studies. 1,25(OH) 2 D 3 or ferroptosis inhibitor (ferrostatin-1) treatment downregulated the cellular senescence markers in D-gal-induced osteoblasts. Mechanistically, 1,25(OH) 2 D 3 activated the VDR and its downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway , resulting in the downregulation of lipid peroxidation. Nrf2 knockdown or addition of GPX4 inhibitor (RSL-3) blocked the protective effect of 1,25(OH) 2 D 3 against D-gal-induced ferroptosis and senescence. VDR knockdown impeded the 1,25(OH) 2 D 3 -induced activation of Nrf2/GPX4 pathway in osteoblasts. Proteomics and immunofluorescence analysis confirmed that ferroptosis and suppression of the Nrf2/GPX4 pathway occurred in VDR-knockout mice. Our data demonstrated that ferroptosis played an essential role in age-related osteoporosis. The VDR activation attenuated osteoblast ferroptosis via stimulating the Nrf2/GPX4 signaling pathway.
研究领域:
药理学
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老年学
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骨骼生物学
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细胞信号传导
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产品关联
DOI
PubMed
高影响因子
Andrology
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2024
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IF 3.2
Yumeng Liu,Qiwen Feng,Liping Zou,Changhong Zhu,Wei Xia
Background Oligoasthenozoospermia is a common cause of male infertility, for which effective treatments are urgently needed. Humanin (HN) is a peptide associated with this condition. Objectives To investigate the ameliorative effect of [Gly14]-Humanin (HNG) on oligoasthenozoospermia and the mechanisms. Materials and methods Mice were treated with cyclophosphamide (CP) to construct a mice model of oligoasthenozoospermia. The resulting model mice were treated with saline or HNG. Subsequently, the testis weights, organ indices, testicular structure, sperm counts and motilities, litter sizes, and serum testosterone concentrations of the mice were determined. Differential gene expression in testicular tissues was determined by RNA sequencing. TM3, TM4, GC1, and GC2 cells were exposed to erastin to induce ferroptosis, followed by treatment with HNG or HNG + ML385 (a nuclear factor erythroid 2-related factor 2 inhibitor). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ions (Fe 2+ ) were determined and their expression of ferroptosis-related proteins was determined by immunofluorescence and western blot. Results The HNG treatment improved testis and sperm parameters and increased litter size and serum testosterone concentrations in model mice. Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis revealed significant differential expression of ferroptosis-related genes. The expression of ferroptosis-related proteins increased in testicular tissues after the HNG treatment. The concentrations of ROS, MDA, and Fe 2+ decreased and the concentrations of GSH increased in testicular tissues and in TM3 and TM4 cells after HNG treatment. In vitro experiments confirmed that HNG activated the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) pathway. However, these effects of HNG were blocked by ML385 treatment. Discussion and conclusion HNG demonstrated a therapeutic effect on oligoasthenozoospermia in a mouse model by reducing oxidative stress and ferroptosis. In TM3 and TM4 cells, HNG attenuated cellular oxidative stress and inhibited ferroptosis via the Nrf2/GPX4 pathway.
研究领域:
生殖生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Yizhi Wang,Jiawen Han,Shifang Zhan,Chenyu Guo,Shuangneng Yin,Lin Zhan,Qianyi Zhou,Ruiying Liu,Hua Yan,Xiaoyan Wang,Dan Yan
Doxorubicin (Dox), a chemotherapeutic agent frequently used to treat cancer, elicits cardiotoxicity, a condition referred to as Dox-induced cardiotoxicity (DIC), and ferroptosis plays a contributory role in its pathophysiology. Fucoidan, a polysaccharide with various biological activities and safety profile, has potential therapeutic and pharmaceutical applications. This study aimed to investigate the protective effects and underlying mechanisms of fucoidan in DIC. Echocardiography, biomarkers of cardiomyocyte injury, serum creatine kinase, creatine kinase isoenzyme and lactate dehydrogenase, as well as histological staining results, revealed that fucoidan significantly reduced myocardial damage and improved cardiac function in DIC mice. Transmission electron microscopy; levels of lipid reactive oxygen species, glutathione, and malondialdehyde; ferroptosis-related markers; and regulatory factors such as glutathione peroxidase 4 (GPX4), transferrin receptor protein-1, ferritin heavy chain-1, heme oxygenase-1 in the heart tissue were measured to explore the effect of fucoidan on Dox-induced ferroptosis. These results suggested that fucoidan could inhibit cardiomyocyte ferroptosis caused by Dox. In vitro experiments revealed that silencing nuclear factor-erythroid 2-related factor 2 (Nrf2) in cardiomyocytes reduced the inhibitory effect of fucoidan on ferroptosis. Hence, fucoidan has the potential to ameliorate DIC by inhibiting ferroptosis via the Nrf2/GPX4 pathway.
研究领域:
药理学
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毒理学
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心脏病学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2024
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IF 9.4
Lei Huang,Shihao Zhang,Mengxuan Bian,Xingdong Xiang,Lan Xiao,Jiayi Wang,Shunyi Lu,Weisin Chen,Cheng Zhang,Guokang Mo,Libo Jiang,Yulin Li,Jian Zhang
The treatment of osteoporotic bone defect remains a big clinical challenge because osteoporosis (OP) is associated with oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation. Anti-oxidative nanomaterials such as selenium nanoparticles (SeNPs) have positive effect on osteogenesis owing to their pleiotropic pharmacological activity which can exert anti-oxidative stress functions to prevent bone loss and facilitate bone regeneration in OP. In the current study a strategy of one-pot method by introducing Poly (lactic acid-carbonate) (PDT) and β-Tricalcium Phosphate (β-TCP) with SeNPs, is developed to prepare an injectable, anti-collapse, shape-adaptive and adhesive bone graft substitute material (PDT-TCP-SE). The PDT-TCP-SE bone graft substitute exhibits sufficient adhesion in biological microenvironments and osteoinductive activity, angiogenic effect and anti-inflammatory as well as anti-oxidative effect in vitro and in vivo . Moreover, the PDT-TCP-SE can protect BMSCs from erastin-induced ferroptosis through the Sirt1/Nrf2/GPX4 antioxidant pathway, which, in together, demonstrated the bone graft substitute material as an emerging biomaterial with potential clinical application for the future treatment of osteoporotic bone defect. Statement of significance Injectable, anti-collapse, adhesive, plastic and bioactive bone graft substitute was successfully synthesized. Incorporation of SeNPs with PDT into β-TCP regenerated new bone in-situ by moderating oxidative stress in osteoporotic bone defects area. The PDT-TCP-SE bone graft substitute reduced high ROS levels in osteoporotic bone defect microenvironment. The bone graft substitute could also moderate oxidative stress and inhibit ferroptosis via Sirt1/Nrf2/GPX4 pathway in vitro . Moreover, the PDT-TCP-SE bone graft substitute could alleviate the inflammatory environment and promote bone regeneration in osteoporotic bone defect in vivo. This biomaterial has the advantages of simple synthesis, biocompatibility, anti-collapse, injectable, and regulation of oxidative stress level, which has potential application value in bone tissue engineering.
研究领域:
生物医学工程
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材料科学
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组织工程
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骨科
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生物材料
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）