BMC Complementary Medicine and Therapies
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2025
·Vol. 25
·期 1
·451
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IF 3.4
Pan Sunfeng,Xiong Lie,Li Jiakun,Wang Zhenjun,Su Yujuan,Fang Gaofeng,Zhu Minda,Shi Hanqiang,Li Jiayan,Liu Zhaoyan,Han Chunmao,Shi Yanbo
Background Venous leg ulcer (VLU) is among the most severe clinical manifestations of chronic venous disease (CVD) and imposes substantial burdens on both patients and society. VLU pathogenesis is closely associated with the impairment of vascular endothelial cells. In this study, tissue samples from the patients’ s skins around wound at different stages of CVD were collected during operation and used to elucidate the involvement of ferroptosis in the pathogenesis of VLU. Also the potential mechanism through which Huoxue Shengji (HXSJ) decoction alleviates ferroptosis in human umbilical vein endothelial cells (HUVECs) was investigated. Methods During surgical procedure such as great saphenous vein high ligation and stripping surgery, matched skin tissues from the normal, hyperpigmentation (HPT), lipodermatosclerosis (LDS), and VLU regions were collected from 10 patients with VLU, and the levels of iron and glutathione peroxidase 4 (GPX4) were quantified to evaluate ferroptosis. In vitro, HUVECs were used to iron overload induction using exogenous 100 µM ferric ammonium citrate (FAC) or 100 µM hemin, or ferroptosis induction with 10 µM erastin, and treated with 10 µg/ml HXSJ decoction for 24 h. Subsequently, lipid peroxidation (LPO) damage, mitochondrial function, and key genes involved in ferroptosis were assessed. Results Iron deposition in the affected skin of patients with CVD gradually increased before progression to VLU and significantly decreased during the VLU stage. Moreover, GPX4 expression increased significantly in the HPT stage but was gradually suppressed with further deterioration of CVD. The in vitro results indicated that in both the iron overload and ferroptosis models, HXSJ decoction effectively upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11, xCT), and GPX4, which was accompanied by the inhibition of malondialdehyde and protein carbonylation production, the alleviation of ferrous ion accumulation, and the restoration of mitochondrial function. Conclusions This study demonstrated that iron accumulation-mediated inactivation of GPX4 serves as a crucial mechanism in VLU formation through ferroptosis induction. Notably, the therapeutic mechanism through which HXSJ decoction alleviates ferroptosis involves Nrf2/xCT/GPX4 pathway activation and a reduction in ferrous ion accumulation. These findings may provide novel insights into VLU pathogenesis and give possible reason for developing traditional Chinese medicine therapies targeting ferroptosis and VLUs. Graphical
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AQUATIC TOXICOLOGY
·
2025
·
IF 4.3
Hao Wu,Jinwei Gao,Dong Liu,Xiangrong Liu,Feiming Chen,Jiayuan Qin,Yunfei Ye,Zhenzhen Xiong,Jiayu Wu,Can Yang,Min Xie,Rui Song,Dongsheng Ou
In recent years, deltamethrin (DEL) pollution poses a significant threat to aquaculture; however, the protective role of vitamin C (VC) against acute toxicity in crucian carp has not been well understood. This study provides compelling evidence that exposure to 2.0 mg/L waterborne VC significantly mitigates DEL-induced 96-hour mortality in crucian carp ( p < 0.001). Importantly, this research represents the first documentation of the protective effects of waterborne VC in fish, which is mediated through the modulation of the aryl hydrocarbon receptor (AhR)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway—a mechanism not previously reported in crucian carp. The observed protective effect is attributed to the enhancement of antioxidant and anti-inflammatory responses via this signaling pathway. Exposure to DEL at 6.2 μg/L resulted in severe oxidative stress, characterized by significantly increased malondialdehyde (MDA) levels and depletion of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) in the liver and intestine ( p < 0.01). Histopathological damage, including hepatic vacuolation, shortened villi, and inflammation, as well as elevated reactive oxygen species (ROS), was observed. Co-exposure to VC normalized antioxidant markers, reduced MDA and ROS levels, and alleviated tissue damage ( p < 0.05). Mechanistically, VC counteracted the suppression of AhR/Nrf2 by DEL, leading to the statistically significant upregulation of antioxidant genes ( gst, sod, cat ) and suppression of pro-inflammatory cytokines ( il1β, il6, tnfα ) ( p < 0.05). VC exhibited tissue-specific regulation by enhancing hepatic Nrf2 defenses and co-activating intestinal AhR/Nrf2, as confirmed by Western blot analysis. Our study shows that waterborne VC effectively protects against acute DEL toxicity under current experimental conditions, suggesting its potential as an eco-friendly emergency intervention in aquaculture during sudden pesticide exposure. Further research is needed to confirm its effectiveness in complex pond systems and various fish species.
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NEUROSCIENCE
·
2025
·
IF 2.8
Siqi Quan,Mengyuan Li,Zhouli Yue,Hui Liu,Shuaijun Peng,Roujia Guo,Xiaoyan Fang,Yucheng Li
Neuroinflammation and oxidative stress are major pathogenic drivers of depression, with the Keap1/Nrf2/HO-1 pathway serving as a key regulator of both processes. Formononetin (FMN) is a naturally occurring isoflavone with anti-inflammatory and antioxidant activities; however, its potential to exert antidepressant effects through activation of this pathway has not been investigated. In this study, lipopolysaccharide (LPS, 1 mg/kg, i.p.) was used to induce neuroinflammation and depressive-like behaviors in mice, and FMN (20 or 40 mg/kg) was administered for seven days prior to LPS challenge. FMN dose-dependently alleviated LPS-induced behavioral deficits, including reduced sucrose preference, decreased locomotor activity, and prolonged immobility in the tail suspension test. Hematoxylin-eosin (HE) and Nissl staining revealed that FMN markedly attenuated LPS-induced hippocampal neuronal damage. FMN also inhibited microglial activation, as evidenced by reduced Iba-1 expression, decreased NF-κB phosphorylation, and downregulation of both mRNA and protein levels of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6. Furthermore, LPS-induced lipid peroxidation was significantly attenuated, as indicated by lower levels of 4-hydroxynonenal (4-HNE). Molecular docking suggested a potential direct interaction between FMN and Keap1, while Western blot analysis confirmed that FMN downregulated Keap1 and upregulated Nrf2 and HO-1 protein expression. Collectively, these findings demonstrate that FMN alleviates LPS-induced neuroinflammation and depressive-like behaviors, likely through activating the Keap1/Nrf2/HO-1 pathway, supporting its potential as a preventive candidate for inflammation-associated depression.
研究领域:
神经药理学
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分子生物学
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精神病学
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炎症研究
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氧化应激
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PHYTOMEDICINE
·
2025
·
IF 8.3
Shaowei Zheng,Ya Gao,Houkang Cao,Kai Guo,Wenxiu Wang,Guiying Lu,Shasha Wang,Mingli Zhong,Bo Li,Kefeng Zhang,Riming Wei,Jianzhao Wu
Background Acute liver failure (ALF) is associated with ferroptosis and currently lacks specific drugs and therapies. Previous studies have shown the hepatoprotective activity of Sophoricoside (SOP) in diverse models of hepatic injury. However, the role of SOP in ALF caused by lipopolysaccharide (LPS)/D-galactosamine (D-GalN) is still unknown. Purpose To investigate the therapeutic effects of SOP on ALF and its underlying mechanisms of action. Methods In vivo , an ALF mouse model was established using LPS and D-GalN. RNA sequencing was used to identify differentially expressed genes, which were subsequently confirmed by Western blot and qRT-PCR. In vitro , erastin was used to induce ferroptosis in HepG2 cells. Subsequently, the cells were treated with SOP, the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385, and the glutathione peroxidase 4 (GPX4) inhibitor RSL3. Additionally, siRNA was utilized for Nrf2 knockdown. Measurements of biochemical markers, reactive oxygen species (ROS) levels, alterations in mitochondrial membrane potential, qRT-PCR, and Western blot analysis were used to confirm the effectiveness and mechanism of SOP. Finally, the interaction between SOP and Nrf2 was verified through molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA). Results In vivo , experimental analysis revealed that SOP ameliorated liver injury, hepatocyte Fe 2+ accumulation, and oxidative stress. RNA sequencing analysis indicated that SOP reversed the abnormal expression of genes related to Nrf2 and the ferroptosis pathway. In vitro , SOP ameliorated erastin-induced oxidative stress, ROS accumulation, and mitochondrial membrane potential loss. After the application of pharmacological inhibitors and siRNA knockdown, the SOP’s inhibitory effect on ferroptosis was antagonized. Conclusion SOP alleviated ALF by activating the Nrf2/GPX4 signaling pathway, thereby mitigating oxidative stress and ferroptosis.
研究领域:
药理学
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分子生物学
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肝病学
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细胞生物学
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生物化学
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Frontiers in Pharmacology
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2026
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IF 5.4
Shan Luo,Yake Lan,Ruoqi Zhang,Zhongqiu Luan
Introduction Diabetic nephropathy (DN), as a complication of diabetes, is one of the major causes of end-stage renal disease. Licochalcone B (LCB), a flavonoid active component derived from licorice, is well known for its anti-inflammatory and antioxidant properties. However, the influence of LCB on DN remains unclear. This research investigated the effect of LCB on DN and elucidated the regulatory mechanism. Methods We employed male C57BL/6 mice to construct a DN mouse model induced by a high-fat diet (HFD)/streptozotocin (STZ). In vitro , a high glucose (HG)-induced injury model in HK-2 (human renal tubular epithelial) cells was used to further confirm the protective effects of LCB. Results LCB treatment (20 mg/kg and 40 mg/kg) decreased blood glucose levels, kidney injury, glycogen deposition, and collagen accumulation in the DN mice. Moreover, LCB at a dosage of 40 mg/kg reduced albumin, creatinine, and blood urea nitrogen levels by about 70.7%, 33.4%, and 45.6%, respectively, indicating an improvement in kidney function. In renal tissues, LCB suppressed oxidative stress and apoptosis in HFD/STZ-induced mice. Consistent with in vivo findings, LCB alleviated HG-induced oxidative stress and apoptosis in HK-2 cells. Transcriptome analysis revealed that LCB affects oxidative stress and renal function-related pathways to alleviate DN. Further mechanistic studies demonstrated that LCB treatment upregulates the expressions of heme oxygenase-1 (HO-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2), suggesting activation of the Nrf2/HO-1 signaling pathway. Conclusion Taken together, this research demonstrates that LCB suppresses oxidative stress and apoptosis accompanied by modulating the Nrf2/HO-1 pathway to ameliorate DN, which provides a promising strategy for DN treatment.
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Pharmaceuticals
·
2026
·Vol. 19
·期 6
·965
·
IF 5.7
Mei Mei,Huawei Sun,Kai Zhang,Feng Zhang,Shiqing Sun,Enbin Yu,Yu Zhang
Background:To investigate the protective effects ofPhellodendron amurenseRupr. polysaccharides (PAP), alkaloids, and flavonoids in alleviating diabetic kidney disease (DKD) and to elucidate the role of the PI3K/AKT/GSK-3β/Nrf2 signaling pathway.Methods:Active components were extracted and quantified. In vitro, high-glucose (HG)-induced human kidney-2 (HK-2) cells were used to screen the optimal fraction via CCK-8, reactive oxygen species (ROS), TdT-mediated dUTP Nick-End Labeling (TUNEL), and Western Blot (WB) assays. In vivo, a DKD rat model was established using 2% Streptozotocin (STZ) and a high-fat with high-sugar diet. Rats were treated with PAP and LY294002. Renal damage and signaling pathway proteins were evaluated using histological staining and WB.Results:Among the tested components, PAP conferred the most pronounced cytoprotection against HG-induced injury in HK-2 cells. PAP significantly reduced glomerular damage, collagen deposition, and glycogen accumulation in the kidneys of DKD rats. Mechanistically, PAP activated the PI3K/AKT/GSK-3β/Nrf2 pathway, upregulating HO-1 and NQO1, while inhibiting the TGF-β1/Smad2 pathway and Bcl-2/Bax-mediated apoptosis. These protective effects were significantly attenuated by LY294002.Conclusions:Among the tested fractions under the present experimental conditions, PAP exhibited the most pronounced protective activity. These protective effects were partially mediated through the PI3K/AKT/GSK-3β/Nrf2 pathway, which enhanced antioxidant capacity while reducing fibrosis and apoptosis.
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ENVIRONMENTAL POLLUTION
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2026
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IF 7.2
Zixu Li,Muge Xu,Yahan Zhang,Yao Chen,Weiwei Feng,Ting Zhao,Liuqing Yang,Guanghua Mao,Xiangyang Wu
The widespread presence of plastic pollutants, particularly phthalate esters such as dibutyl phthalate (DBP), poses a significant threat to both ecosystems and human health. Despite the accumulating evidence of DBP toxicity, the mechanisms driving DBP-induced hepatotoxicity remain poorly understood. In this study, an integrated approach combining network toxicology, molecular docking, and multidimensional experimental validation was applied to elucidate the molecular pathways through which DBP causes liver damage. Ferroptosis was identified as a central player in DBP-induced hepatotoxicity. The results showed that DBP activates the aryl hydrocarbon receptor (AhR), regulating the NRF2/HO-1 signaling axis, which in turn induces iron overload and lipid peroxidation. Furthermore, ferroptotic hepatocytes release high-mobility group box 1 (HMGB1), activating the TLR4/NF-κB pathway in macrophages and amplifying inflammatory responses that exacerbate liver injury. Crucially, inhibition of either AhR expression or ferroptosis significantly attenuated these changes, highlighting the potential of AhR and ferroptosis as therapeutic targets. Together, these findings establish a novel mechanistic framework for DBP-induced hepatotoxicity: the AhR–NRF2/HO-1–ferroptosis–HMGB1/TLR4 axis. This study advances our understanding of plasticizer toxicity and offers insights for risk assessment and intervention strategies for combating environmental hepatotoxins.
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Food Bioscience
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2026
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IF 6.2
Qidong Xue,Kangning Li,Jie Mi,Dekun Cheng,Ruijie Liu,Ming Chang
Doxorubicin (Dox)-induced cardiotoxicity is a major dose-limiting adverse effect of chemotherapy and is closely linked to oxidative stress and impaired endogenous antioxidant defenses. Food-derived polyphenols that reinforce cellular redox resilience may therefore offer a safe adjuvant strategy. Pinus koraiensis nut skin (PNS), an underutilized nut-processing residue, is rich in polyphenols, yet its bioactive profile and cardioprotective mechanism remain insufficiently defined. Here, we optimized the extraction of PNS polyphenols (PNSP), profiled its phytochemical composition, and investigated its protective effects against Dox-induced cardiomyopathy (DIC). Under optimized conditions, PNSP exhibited strong in vitro antioxidant capacity. UPLC-Q-TOF-MS tentatively identified 26 phytochemicals dominated by procyanidins and flavonoids. In a zebrafish DIC model, post-treatment with PNSP (10 – 40 μg/mL) dose-dependently rescued cardiac dysfunction. Notably, 40 μg/mL PNSP restored heart rate from 112.00 ± 24.28 to 157.00 ± 13.98 beats/min and reduced ROS accumulation. Mechanistically, PNSP reactivated endogenous antioxidant enzymes (SOD, GSH-Px) by activating the Nrf2/Keap1 signaling pathway. Procyanidin C1 and the Pinus -specific flavonoid pinobanksin 3-acetate were identified as key ligands that competitively occupy the Keap1 Kelch pocket, thereby facilitating Nrf2 nuclear translocation. This non-covalent, competitive activation mechanism was robustly validated by molecular docking, stable Keap1 protein expression, and enhanced ARE-luciferase reporter activity. Collectively, these findings identify PNSP as a food-relevant Nrf2 activator with potential to mitigate chemotherapy-associated cardiotoxicity, highlighting its potential as a high-value functional food ingredient.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
·
IF 8
Zhe Li,Bingbing Liu,Lianghong Zhou,Na Chen,Yi Wang,Su Yang,Xinyi Fan,Yuan Wang,Xiaodong Chen
Sarcopenic obesity (SO), characterized by concurrent muscle loss and excessive adiposity, lacks effective interventions. This study investigated the enhanced effects of the selenomethionine (Se-Met) and magnolol (Mag) combination against SO using an integrated computational-experimental approach. Network pharmacology and molecular docking predicted peroxisome proliferator-activated receptor γ (PPARγ) and the nuclear factor erythroid 2-related factor 2 - glutathione peroxidase 4 (Nrf2 - GPX4) axis as core targets, which was corroborated by single-cell transcriptomic data analysis showing their co-expression in muscle progenitor cells. In high-fat diet (HFD)-fed mice, the combined Se-Met and Mag treatment ameliorated metabolic dysregulation, reduced intramuscular lipid deposition, and improved muscle function more effectively than monotherapies. In C2C12 myotubes, the combination co-activated PPARγ to enhance lipid clearance and potentiated the Nrf2-GPX4 antioxidant axis. Notably, it modulated ferroptosis-related signaling by downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4) and upregulating ferritin heavy chain 1 (FTH1) and heme oxygenase-1 (HO-1), an effect abolished by Nrf2 inhibition. Pharmacological inhibition of either PPARγ or Nrf2 reversed the protective benefits. Our findings reveal that Se-Met and Mag in combination target PPARγ and Nrf2-GPX4 pathways while regulating ferroptosis-related signaling to alleviate ferroptosis-associated markers, with phenotypic characteristics consistent with ferroptosis inhibition, thereby offering a novel nutraceutical strategy for SO.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Weiwei Yang,Shulan Pang,Yi Li,Jiahong Chen,Qiuhong Jiao,Ailin Liu,Tiansen Liu,Tao Huang,Hongjie Wang,Xiufeng Xu,Yuqing Zhang,Peikang Dong,Tao Wang
Integrative computational analyses identify PPARG as a key target of polydatin in aortic dissection. • Docking and MD support stable binding of polydatin to PPARγ and Keap1. • Transcriptomic and WGCNA analyses link polydatin to oxidative-stress regulation. • Polydatin attenuates BAPN-induced aortic dissection in mice. • Polydatin may protect the aortic wall via the PPARγ/Nrf2 antioxidant axis. Aortic dissection (AD) is a life-threatening vascular disease characterized by medial degeneration, extracellular matrix (ECM) destruction, inflammation, and oxidative stress. Polydatin (PD), a natural stilbene glucoside, has cardiovascular protective potential, but its mechanism against AD remains unclear. This study investigated the therapeutic mechanism of PD in AD by integrating network pharmacology, transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), molecular modeling, and in vivo validation. IGF1, PPARG, and KDR were identified as core targets in the PD–AD network, with PPARG prioritized for its association with vascular redox homeostasis, inflammation, and antioxidant defense. Molecular docking and molecular dynamics simulations indicated stable interactions between PD and PPARγ and Keap1, a key regulator of Nrf2 stability. In a β-aminopropionitrile (BAPN)-induced AD mouse model, PD significantly reduced aortic dilation and medial injury, preserved elastic fiber architecture, and attenuated ECM degradation. PD also decreased ROS and MDA levels, restored SOD, GSH-Px, and CAT activities, and upregulated PPARγ, Nrf2, HO-1, and NQO1 expression. These findings suggest that PD alleviates AD by restoring vascular redox homeostasis, potentially involving PPARγ-associated signaling and Nrf2-related antioxidant responses, supporting PD as a potential therapeutic candidate for AD-related vascular degeneration. Download: Download high-res image (327KB) Download: Download full-size image
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Pharmacology Research & Perspectives
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2021
·Vol. 9
·期 3
·e00791
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IF 2.794
Suoli Cheng,Xueqin Liu,Fan Gong,Xiaoling Ding,Xuebing Zhou,Cuiyun Liu,Fei Zhao,Xiaoliang Li,Jiandang Shi
The pathogenesis of steroid-induced avascular necrosis of femoral head (SANFH) is complex, and there is a lack of effective early prevention method. The aim of the present study was to evaluate the effect of dexamethasone (DEX) on the biological behavior of bone marrow mesenchymal stem cells (BMSCs) and to explore the possibility of DEX in the clinical treatment of SANFH. The effect of DEX on the proliferation of BMSCs was evaluated by Counting Kit-8 assay, western blot assay, and enzyme-linked immunosorbent assay. Flow cytometry and western blot assay were performed to detect the effect of DEX on the apoptosis of BMSCs. Quantitative real-time PCR and western blot assay were performed to detect the effect of DEX on the expression of endoplasmic reticulum stress (ERS)-related genes. Immunoblotting analysis was conducted for detecting the nuclear-cytoplasmic distribution of Nrf2. DEX could significantly inhibit the proliferation of BMSCs and promote apoptosis of BMSCs. DEX could increase the expression of PERK, ATF6, and IRE1a, and induce nuclear translocation of Nrf2. The addition of ML385 could reverse the effect of DEX on BMSCs. DEX could activate the PERK-Nrf2 pathway to promote ERS and finally affect the cell proliferation and apoptosis of BMSCs.
研究领域:
药理学
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细胞生物学
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干细胞研究
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骨科
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2026
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IF 3.6
Peng Wan,Fuyuan Cao,Gai Li,Xiaohui Hao,Yu Mu,Jian Sun,Ling Xue,Nan Liu
Indium lung disease is characterized by interstitial pneumonia, pulmonary alveolar proteinosis (PAP), pulmonary fibrosis, and lung cancer. However, this is insofar irreversible. The disease is believed to be caused by inhalation of indium and its compounds. We constructed a rat model of indium lung disease to explore the possible role of the NF-κB/Nrf2 pathway in indium‑tin oxide nanoparticle (Nano-ITO)-induced pulmonary injury and to reveal the regulatory mechanism. To integrate computational network toxicology and molecular docking with a rat model to identify core molecular targets and pathways underpinning ITO toxicity, and evaluate whether modulation of the NF-κB/Nrf2 axis by sulforaphane or all-trans retinoic acid mitigates Nano-ITO-induced lung injury. Toxicity prediction, target mining and integration with oxidative stress and vascular remodeling gene sets identified intersection targets that were analyzed by PPI, GO/KEGG/Reactome enrichment and topological analysis to select core nodes. Molecular docking probed interactions between ITO components and proteins in NF-κB/Nrf2 pathways. Next, we evaluated the NF-κB/Nrf2 signaling pathway to elucidate the molecular mechanism of sulforaphane in regulating inflammation, oxidative stress, vascular remodeling, vascular hyperplasia, PAP, cholesterol accumulation, and interstitial fibrosis in indium lung disease induced by Nano-ITO. Findings show that the NF-κB/Nrf2 signaling pathway is involved in Nano-ITO-induced vascular remodeling, cholesterol crystal formation, alveolar protein deposition, collagen hyperplasia, and interstitial fibrosis in rats. Sulforaphane can effectively attenuate Nano-ITO-induced inflammation, oxidative stress and vascular remodeling, as manifested by decreased expression of CD31, α-SMA, Collagen I, SP-A, SP-D, and inflammatory cytokine, via activating Nrf2 and inhibiting the NF-κB signaling pathway.
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