查找使用阿拉丁产品的科研文献

Hyaluronic acid-modified nanoparticles for chemo/sonodynamic therapy: Maximizing antitumor efficacy through the induction of ferroptosis and apoptosis

Siyu Tong,Shuang Zuo,Guodong Liu,Shiping Wang,Yu Chen,Ping He,Shan Liu

GSH-responsive HPCT enable CT/SDT synergistic therapy. • HPCT induces both ferroptosis and apoptosis. • HPCT actively target CD44-overexpressing tumor cells. • Dual death pathways overcome single-treatment limitations for enhanced efficacy. Cancer is one of the leading causes of death worldwide. Chemotherapy (CT) is one of the main clinical treatment modalities; however, it has limitations as a single treatment approach. To achieve a multi-modal synergistic therapy, this study designed and synthesized two amphiphilic molecules, PEG-SS-CPT and HA-SS-Ce6, and subsequently constructed intelligent nanoparticles HPCT through self-assembly, which possess both active targeting and glutathione (GSH) responsiveness for CT and sonodynamic therapy (SDT). This system employs hyaluronic acid (HA) to specifically target tumor cells that exhibit elevated CD44 expression. It responds to the high levels of GSH present in the tumor microenvironment, allowing for the release of CT drug camptothecin (CPT), while also producing singlet oxygen through Ce6 activation under ultrasound (US) stimulation, thereby simultaneously inducing apoptosis and ferroptosis in tumor cells. In the CT26 colon cancer-bearing mouse model, HPCT combined with US demonstrated a significant synergistic anti-tumor effect, with a tumor growth inhibition rate of 80.4 ± 3.1%, and did not cause significant systemic toxicity. This study indicates that through the rational design of intelligent nanoparticles integrating CT and SDT, it is possible to effectively overcome the limitations of single treatment modalities, providing a new strategy to enhance cancer treatment efficacy.

Mitochondrial calcium efflux drives ferroptosis via the CaMKII/HIF-1α/TFRC axis in cadmium-induced proximal tubular injury

Caiyu Lian,Mingcheng Sun,Yue Li,Lin Wang

Cadmium (Cd) exposure triggers ferroptosis in renal tubular cells. • TFRC upregulation drives Cd‑induced ferroptosis by promoting iron influx. • HIF‑1α directly binds the TFRC promoter to transactivate its expression. • mPTP‑mediated calcium efflux activates CaMKII/HIF‑1α/TFRC axis. Cadmium (Cd) is a ubiquitous environmental pollutant and well-established nephrotoxicant primarily targeting renal proximal tubular cells. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a key mechanism in Cd‑induced kidney injury. Despite the central role of mitochondria in ferroptosis, the precise organellar events linking Cd exposure to ferroptotic execution remain obscure. Using Sprague‑Dawley rats and renal proximal tubular cells, we found that Cd exposure instigated ferroptosis, evidenced by iron overload, altered ferroptosis markers, lipid peroxidation, and typical mitochondrial morphology under transmission electron microscopy. Pharmacological inhibition of ferroptosis significantly attenuated Cd‑induced cellular damage, identifying ferroptosis as a critical driver. Mechanistically, Cd triggered opening of the mitochondrial permeability transition pore (mPTP), leading to mitochondrial calcium efflux and activation of calcium/calmodulin‑dependent protein kinase II (CaMKII). Activated CaMKII in turn increased hypoxia-inducible factor-1α (HIF-1α) transcription and promoted its nuclear accumulation. Notably, upregulated HIF‑1α directly bound to the promoter of transferrin receptor (TFRC) to stimulate expression of this key iron transport mediator, as confirmed by chromatin immunoprecipitation assay. Moreover, genetic knockdown of TFRC markedly attenuated Cd‑triggered ferroptosis and consequent cytotoxicity, establishing TFRC as a critical executioner of Cd‑evoked renal injury. Taken together, these findings delineate a novel signaling axis from mPTP‑mediated calcium efflux to HIF‑1α‑dependent TFRC transactivation that drives ferroptosis in Cd‑induced nephrotoxicity, offering a mechanistic basis for understanding and mitigating the renal health risks posed by environmental Cd exposure. Download: Download high-res image (405KB) Download: Download full-size image

H₂S-Activatable dual-responsive fluorescent probe for bicolor visualization of Ferroptosis and drug-induced liver injury models

Xue Zhang,Peng Hou,Qi Zhang,Haijun Wang,Hongxia Cui,Likun Liu,Pengfei Qi,Haoqing Ren,Huiling Hou,Song Chen

Hydrogen sulfide (H 2 S) is a gas with dual roles in both environmental and biological systems. Although it is a natural atmospheric constituent and an enzymatically produced signaling molecule, elevated levels of H 2 S are associated with air pollution, cytotoxicity, and various diseases. Current methods for detecting H₂S are often limited by complex sample preparation, low sensitivity, and inadequate selectivity. To address these challenges, we report the development of a novel dual-channel and dual-responsive fluorescent probe HAR-H₂S , which enables rapid, sensitive, and selective detection of H₂S in both environmental and biological contexts. This probe employs coumarin and naphthalimide derivatives as fluorescent reporters and incorporates dual recognition sites for specific H₂S detection. Upon interaction with H₂S, the probe generates distinct blue and green fluorescent signals, facilitating bicolor imaging. The probe demonstrated excellent selectivity, low detection limits (26.4 nM and 35.1 nM), a relatively large spectral separation (126 nm) and rapid response times (within 3 min). HAR-H 2 S was successfully applied to quantify H 2 S in water samples (tap, river, and lake water) and to image H 2 S in various biological systems, including HeLa cells, HepG2 cells, zebrafish embryos, the ferroptosis model and mouse liver tissue sections. Our results highlight the potential of HAR-H 2 S as a versatile tool for H 2 S detection and imaging in both analytical and biological applications, thereby advancing the field of H 2 S research.

Metal–Phenolic Networks-Based Nanozyme Reprograms Tumor Metabolism and Immunosuppressive Microenvironment to Enhance Ferroptosis and Potentiate Cancer Immunotherapy

Rongying Ma,Qingchun Deng,Yumian Lin,Shuzhen Gu,Qianhong Su,Yougong Wang,Peiling Deng,Zhaoming Fu,Yong Yang,Yunlu Dai

The resistance of tumor cells to ferroptosis and their evasion from immune surveillance pose significant challenges in cancer treatment. Herein, a multifunctional nanozyme (PA-MPGD) is constructed via the assembly of metal–phenolic networks and concurrently loaded with glucose oxidase (GOx), piceatannol, and dioscin. The encapsulated GOx facilitates glucose consumption and hydrogen peroxide generation to hamper the pentose phosphate pathway of glucose and slash the biosynthesis of glutathione. Simultaneously, the nanozyme exhibiting catalase, peroxidase, and glutathione peroxidase-mimicking activities promotes oxygen formation, hydroxyl radical production, and glutathione depletion, thereby disintegrating the antioxidant capacity of tumor cells and inducing notable ferroptosis. Furthermore, in addition to the immunogenic cell death triggered by enhanced ferroptosis, repolarization of M2 tumor-associated macrophages into the M1 phenotype and inhibition of prostaglandin E2 synthesis were achieved by dioscin and piceatannol, respectively. They collectively contribute to reversing tumor microenvironment immunosuppression and eliciting a potent cellular immune response, which not only enables the elimination of primary tumors but also effectively resists lung metastasis of tumor cells. Overall, this study proposes a reliable strategy for enhancing ferroptosis and antitumor immunity to fulfill a more effective tumor therapy.

Synergistic Regulation of Ferroptosis via an Oral Solid Lipid Nanocomplex-Embedded Inulin Gel for Targeted Ulcerative Colitis Therapy

Luolan Ouyang,Jia Ke,Shanshan Xiang,Jing Ding,Shufen Zhang,Zixu Wang,Si Chen,Tingting Meng,Hong Yuan,Fangying Yu,Fuqiang Hu

Ulcerative colitis (UC), a chronic inflammatory disorder of the colon, remains challenging to treat due to limited efficacy with current therapies. Ferroptosis, a newly identified form of programmed cell death, contributes significantly to UC pathogenesis and might offer promising therapeutic potential. Herein, we developed an oral synergistic regulation of ferroptosis using a solid lipid nanocomplex-embedded inulin gel (SLN/Que&OA@Gel) for colon-targeted UC therapy; solid lipid was utilized to encapsulate oleic acid (OA) and quercetin (Que) for better intestinal bioavailability, which was further embedded in an inulin gel to realize colon targeting. The system combines OA─which modulates lipid composition to reduce ferroptosis susceptibility─with Que, an antioxidant that scavenges reactive oxygen species (ROS) and suppresses oxidative stress to limit ferroptosis progression. Simultaneously, the incorporation of the inulin gel matrix ensures gastrointestinal tract protection, mucoadhesion, prolonged retention time at the lesion site, and sustained drug release, which promise a better curative effect. In vivo studies demonstrate that SLN/Que&OA@Gel effectively remodels the UC-associated pathological microenvironment by alleviating intestinal damage, restoring intestinal barrier integrity, and reducing inflammation. This strategy of synergistic regulation of ferroptosis and microenvironment remodeling presents a promising therapeutic avenue for UC management.

Pollen of Brassica campestris L. ameliorates hyperuricemic and obstructive nephropathy by targeting the β-catenin/TCF4-ferroptosis pathway

Jiao Kong,Yujia Chen,Shuanghui Lu,Lvexiang Yuan,Tao He,Minlei Dong,Yingqiong Zhang,Xiaoyi Pan,Hui Zhou,Huidi Jiang

Ethnopharmacological relevance The pollen of Brassica campestris L. (BCP, syn. Brassica rapa L. subsp. oleifera (DC.) Metzg.), included in the Chinese Pharmacopoeia as a licensed patent medicine (Pule'an tablets), is used clinically for kidney-qi deficiency-related lower urinary tract symptoms in chronic prostatitis and benign prostatic hyperplasia. Prostatic obstruction is a common cause of obstructive uropathy that may progress to renal fibrosis. However, the renoprotective effects and the underlying mechanism remain to be fully elucidated. Aim of the study To study the renoprotective effects, the active fraction, the effective components of BCP and the underlying mechanisms. Materials and methods Mouse models of hyperuricemic nephropathy (HN) and unilateral ureteral obstruction (UUO) were established to evaluate the renoprotective effects of BCP. Transcriptomics and liquid chromatography-mass spectrometry were applied to explore potential mechanisms and intrarenal constituents. Erastin- and uric acid (UA)-induced HK-2 cells were employed to validate the cytoprotective effects of the potential active compounds, whose binding capability with direct target was confirmed by CETSA/SPR. Results BCP dose-dependently reduced UA levels and reversed the protein expression of UA-producing enzymes and renal transporters (for reabsorption and excretion) in HN mice. Additionally, BCP improved renal injury and fibrosis in HN mice and UUO mice by reducing UA and direct renoprotection, in which the flavonoids of BCP played a crucial role. Meanwhile, BCP alleviated renal fibrosis by inhibiting the β-catenin/TCF4-ferroptosis axis, which was achieved mainly by its bioactive components, kaempferol and kaempferol-3-glucuronide (K-3-G), in HK-2 cells. Furthermore, kaempferol and K-3-G were demonstrated to directly bind with β-catenin, block the transcriptional activation of β-catenin, and subsequently suppress ferroptosis. Conclusions BCP and its major bioactive compounds, kaempferol and K-3-G, exert nephroprotective effects by inhibiting the β-catenin/TCF4-ferroptosis axis.

Engineered ZFP36-overexpressing AC16 cell-derived extracellular vesicles attenuate ferroptosis-related endothelial injury and functionalize NiTi vascular interfaces

Demin Li,Yachen Hou,Yang Lu,Pengchong Du,Ge Zhang,Yan Lv,Ke Hu,Rilige Su,Bolin Jiao,Yangyang Wu,Yujia Wang,Jinying Zhang,Junnan Tang

ZFP36 was selected as an MI-associated candidate for donor-cell engineering. • ZFP36 OE -EV attenuated RSL3-induced ferroptosis-related endothelial injury. • ZFP36 OE -EV showed beneficial biological activity in a mouse MI model. • EV-functionalized NiTi interfaces improved vascular healing after implantation. Myocardial infarction (MI) is associated with persistent myocardial injury and vascular dysfunction despite advances in reperfusion therapy. Delayed endothelial recovery, inflammation, and vascular remodeling remain important challenges during post-MI repair and vascular intervention. Here, we investigated whether extracellular vesicles (EVs) derived from ZFP36-overexpressing AC16 cells could attenuate ferroptosis-related endothelial injury, improve cardiac function after MI, and be integrated into a bioactive NiTi surface for vascular repair. Bioinformatic screening identified ZFP36 as an MI-associated candidate linked to ferroptosis-related processes; increased expression was subsequently observed in the mouse MI model. ZFP36-overexpressing AC16 cells were generated, and the released EVs were designated ZFP36 OE -EV. In RSL3-treated HUVECs, ZFP36 OE -EV improved cell viability, reduced oxidative stress, preserved mitochondrial membrane potential, and partially restored ferroptosis-related molecular changes. In a mouse MI model, intramyocardial delivery of ZFP36 OE -EV improved cardiac function and reduced myocardial fibrosis. To explore the use of the same engineered EV preparation for vascular interface functionalization, ZFP36 OE -EV was immobilized onto a polydopamine/hyaluronic acid (PDA/HA)-modified NiTi surface to generate the NPH@Z-EV coating. The coating supported EV loading and gradual particle release in vitro. Under direct cell–material contact conditions, the NPH@Z-EV coating exhibited endothelial protective activity under ferroptosis-related stress. In a rat femoral artery injury model, the NPH@Z-EV coating supported vascular repair, with improved endothelial recovery, reduced local inflammatory activation, attenuated lipid peroxidation-associated vascular injury, and a VSMC marker pattern consistent with reduced phenotypic switching. These findings support further evaluation of engineered EVs as a strategy for functionalizing NiTi vascular interfaces to improve vascular healing after implantation.

Supramolecular Self-Assembled Nanomedicine Targeting Fatty Acid Metabolism to Potentiate Ferroptosis-Enhanced Photoimmunotherapy in Triple-Negative Breast Cancer

Fei Li,Junyong Wu,Xinyan Hao,Wenjie Xu,Jiemin Wang,Jiwen Zhang,Xingyu Wei,Niwen Feng,Fangyuan Liu,Dehua Liao

Triple-negative breast cancer (TNBC) presents a serious therapeutic challenge, largely owing to its metabolic adaptability and the immunosuppressive nature of its tumor microenvironment (TME). Photodynamic therapy (PDT) can cause oxidative injury and induce immunogenic cell death (ICD); however, its antitumor activity is often limited by inadequate reactive oxygen species (ROS) accumulation and weak immune activation. To address these barriers, a supramolecular self-assembled nanoplatform, termed OC@cRGD, was constructed through the co-assembly of the fatty acid synthase (FASN) inhibitor orlistat and the photosensitizer chlorin e6 (Ce6), followed by cyclic RGD (cRGD) modification to support integrin-mediated tumor targeting. This self-assembled design allows high drug loading and links metabolic interference with redox stress in a single nanoscale formulation. At the mechanistic level, orlistat disturbs lipid homeostasis and reduces the saturated fatty acid–based protection that helps TNBC cells resist membrane peroxidation. In parallel, light-activated PDT delivers a spatially restricted oxidative burst. After laser irradiation, these two processes act together to drive extensive iron-dependent lipid peroxidation, along with reduced GPX4 and FASN expression, thereby increasing cellular susceptibility to ferroptosis. This ferroptosis-reinforced PDT further induces pronounced ICD. In 4T1 tumor-bearing mice, OC@cRGD combined with laser irradiation inhibited tumor growth and reshaped the immune microenvironment, as reflected by dendritic cell maturation, M1-like macrophage polarization, and increased CD8 + T-cell infiltration. Overall, this work combines metabolic intervention with photoimmunotherapy and offers a metabolism-guided strategy for the development of self-assembled nanotherapeutics. Download: Download high-res image (231KB) Download: Download full-size image

Dapagliflozin Alleviates Non-Alcoholic Fatty Liver Disease in Mice by Inhibiting Ferroptosis through Activating the SIRT1/Nrf2 Pathway

Min Liu,BiYing Meng,Jing Dong,Lin Xiang

Ferroptosis inhibition by ferrostatin-1 attenuates nanoplastic-induced angiogenesis impairment in zebrafish larvae and human microvascular endothelial cells

Yuzhen Xia,Fang Wang,Lisha Zhao,Bingfeng Lin,Pingcui Xu,Lingmin Lu,Nani Wang

Nanoplastics (NPs) induce ferroptosis in endothelial cells and zebrafish. • NPs disrupt unsaturated fatty acid metabolism in zebrafish. • NPs downregulate GPX4 and induce lipid peroxidation in vitro and in vivo. • Targeting ferroptosis mitigates NPs-related cardiovascular injury. Nanoplastics (NPs) are widespread environmental pollutants, and their potential cardiovascular toxicity has raised growing concern. This study aimed to investigate whether NPs impair angiogenesis through ferroptosis induction. Zebrafish larvae were exposed to NPs (10-1000 μg/L) or erastin (5 μM) for 48 h. Rescue experiments were performed by co-treatment with ferrostatin-1 (Fer-1, 1 μM). Human microvascular endothelial cell line-1 were treated with NPs at 100 μg/mL for 24 h, with or without Fer-1 (1 μM). NPs exposure resulted in reduced body length, impaired intersegmental vessel formation, and downregulated expression of key angiogenesis-related genes in zebrafish larvae. Additionally, NPs inhibited tube formation, migration, and vascular endothelial growth factor A expression in HMEC-1 cells. Transcriptomic and metabolomic analyses revealed that NPs exposure disrupted unsaturated fatty acid metabolism. NPs induced lipid peroxidation, reactive oxygen species accumulation, elevated malondialdehyde levels, and downregulation of glutathione peroxidase 4 expression, all of which were reversed by treatment with the ferroptosis inhibitor Fer-1. Intervention with Fer-1 not only rescued NPs-induced intersegmental vessel defects but also upregulated the expression of angiogenesis-related genes, thereby effectively ameliorating NPs-induced vascular damage. These findings indicate that ferroptosis is a key mechanism underlying NPs-mediated vascular dysfunction.

Oxygen-augmented erythrocyte-liposome hybrids to overcome paclitaxel resistance in triple-negative breast cancer metastasis via enhanced ferroptosis

Xunyi You,Kehui Zhu,Wanjing Li,Hong Wang,Rui Zhong,Shen Li,Jiaxin Liu,Yee Shan Wong,Subbu S. Venkatraman,Ye Cao

A RBC-hitchhiking liposome with pH-responsive DOPE achieves active and passive lung metastasis targeting. • Hemoglobin alleviates tumor hypoxia, downregulates HIF-1α and P-gp, and triggers ferroptosis to reverse chemoresistance. • Co-encapsulated Hb-PTX liposome suppresses lung metastasis in 4T1 mice. Paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) is closely associated with ATP-binding cassette (ABC) transporters-medicated drug efflux and hypoxia-driven upregulation of hypoxia-inducible factor-1α (HIF-1α), which together promote tumor progression and metastasis. Although blood transfusion or hyperbaric oxygen therapy can partially alleviate systemic hypoxia, neither approach effectively relieves chemoresistance driven by intratumoral hypoxia. To address this challenge, we have developed a biomimetic hybrid delivery system (red blood cell hitchhiking-liposomes encapsulate hemoglobin and paclitaxel, RBC-LEHP) that utilizes red blood cell-hitchhiking technology along with pH-responsive liposomes, to co-deliver hemoglobin (Hb) and PTX to overcome hypoxia-associated chemoresistance. This system achieves dual-stage targeting: passive sequestration in pulmonary metastatic lesions through erythrocyte hitchhiking and active tumor internalization mediated by pH-sensitive DOPE phospholipids. Our study revealed that RBC-LEHP effectively alleviated the hypoxia microenvironment through Hb-mediated oxygenation upon tumor cellular internalization and downregulated HIF-1α and glutathione peroxidase 4 (GPX4), while simultaneously enhancing reactive oxygen species (ROS)-mediated lipid peroxidation to induce ferroptosis. This amplified oxidative stress further triggered mitochondrial dysfunction, suppressed P-glycoprotein (P-gp)-mediated PTX efflux, reversed PTX resistance, and promoted apoptotic cell death. In vivo results confirmed that RBC-LEHP-mediated therapeutic cascade of “lung targeted delivery → hypoxia alleviation → ferroptosis/chemotherapy → tumor suppression” significantly enhanced antitumor efficacy against TNBC. This biomimetic platform provides a promising strategy for overcoming physiological barriers and chemoresistance in metastatic TNBC therapy. Download: Download high-res image (511KB) Download: Download full-size image

L-Theanine Prevents Autophagy Impairment to Counteract Cadmium-Induced Hepatic Mitochondrial Dysfunction, Ferroptosis, and Glucolipid Dysmetabolism in Mice

Background: Cadmium (Cd) exposure impairs the autophagic response, a core mechanism for cell preservation and organismal homeostasis, eventually resulting in metabolic disturbances, mitochondrial dysfunction, and oxidative stress. L-theanine (LT) exhibits multiple health benefits with a high safety profile. However, the effects of LT on Cd exposure-induced impairments in autophagy and autophagy-related physiological functions remain unclear. Methods: This study investigated the effects of LT on the survival time of mice acutely exposed to Cd and the regulating effect of LT on autophagy and subsequent metabolic dysfunction in mice subjected to subchronic Cd exposure. Results: The results showed that acute Cd exposure resulted in 100% mortality within 8 h. However, LT treatment significantly prolonged the median survival time of mice from 4 h to 16 h and reduced the mortality to 60%. In the context of subchronic Cd exposure, autophagy was inhibited, as evidenced by the downregulation of the AMPK/mTOR signaling pathway mediated by DPP-4 and SIRT1. This exposure also promoted lipid peroxidation and ferroptosis, indicated by the inactivation of the AMPK/p-ACC axis and marked alterations in ferroptosis markers. Furthermore, mitochondrial dysfunction was suggested by the downregulation of the SIRT1/PGC-1α/Nrfs/TFAM signaling pathway and reductions in COX and SDH activities. Additionally, glucolipid metabolism was impaired, as indicated by the downregulation of the AMPK and PI3K/AKT signaling pathways and elevated lipid and glycogen accumulation in the liver of mice. LT significantly decreased the level of DPP-4 and upregulated SIRT1, leading to the activation of AMPK. This activation restored autophagy response by downregulating mTOR, promoted energy homeostasis by reducing lipid biosynthesis and enhancing fatty acid oxidation, blocked lipid peroxidation and ferroptosis through the phosphorylation of ACC at the serine 79 site and reducing the ubiquitination-mediated degradation of GPX4, and maintained mitochondrial function by upregulating the PGC-1α/Nrfs/TFAM signaling pathway. Conclusions: Collectively, LT effectively ameliorates mitochondrial dysfunction, ferroptosis and glucolipid dysmetabolism in Cd-exposed mice, and these effects are accompanied by findings consistent with modulation of autophagy-related signaling in the liver.