查找使用阿拉丁产品的科研文献

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.

Curcumin alleviates BPAF-induced ferroptosis in caprine endometrial epithelial cells through inhibition of endoplasmic reticulum stress and autophagy

Ming Liu,Cheng-Fang Gao,Jing-Jing Wang,Sheng-Ji Yang,Yin-Qing Li,Lei Sang,Li-Jun Huo

Bisphenol AF (BPAF) is widely used as a substitute for bisphenol A (BPA) in the plastics industry. However, it is known to cause reproductive toxicity in both humans and animal models. Curcumin, a polyphenolic compound from turmeric, is known for its potent anti-inflammatory and antioxidant effects. We previously showed that curcumin alleviates BPAF-induced apoptosis in caprine endometrial epithelial cells (EECs). However, the underlying mechanisms of BPAF toxicity remain unclear. The aim of this study was to investigate whether ferroptosis contributes to BPAF-induced injury in EECs and to assess the protective role of curcumin. We demonstrate that BPAF triggers ferroptosis in EECs: ferroptosis-related factors (COX2, FACL4, and NCOA4 ) were upregulated, and GSH content was increased. These effects were significantly reversed by the ferroptosis inhibitor Fer-1, which restored cell viability and reduced MDA accumulation. Mechanistically, BPAF-induced ferroptosis was autophagy-dependent, as evidenced by upregulated ATG5, Beclin1, and LC3, and enhanced autophagic flux. Inhibition of autophagy by CQ significantly attenuated ferroptosis and improved cell viability. Furthermore, ER stress acted as an upstream regulator, as its inhibitor 4-PBA alleviated both autophagy and ferroptosis. BPAF also disrupted cellular iron homeostasis by promoting NCOA4-mediated ferritinophagy, resulting in intracellular iron accumulation. Curcumin pretreatment alleviated BPAF-induced ferroptosis by suppressing ferritinophagy and restoring iron homeostasis. Moreover, activation of the PI3K/AKT/mTOR and Nrf2/HO-1 pathways may exert protective effects by suppressing autophagy and lipid peroxidation. In conclusion, this study indicates that ferroptosis is a key mechanism underlying BPAF-induced cytotoxicity in EECs. Curcumin protects against this damage by inhibiting ER stress and autophagy, providing a potential therapeutic strategy for BPAF-related uterine diseases.

Genetically Engineered Membrane-Mimetic Liposome-Wrapped Violet Phosphorus Nanoplatform for Targeted Synergistic Ferroptosis/Photothermal/Immunotherapy of Hepatocellular Carcinoma

Shuo Li,Zhixiong Wang,Meiling Zhou,Weilu Jia,Zonghan Shi,XinYu Mao,Weijie Zhao,Boyu Xia,Zhe Wang,Xinhao Li,YeWei Zhang

Hepatocellular carcinoma (HCC), a highly prevalent malignancy, is mostly diagnosed at intermediate and advanced stages. Current monotherapies are limited by poor targeting, severe toxicity, drug resistance, and high metastatic risk, necessitating more effective precision therapeutic strategies. Photothermal therapy (PTT) and ferroptosis induction are promising for HCC treatment, but violet phosphorus nanoparticles (VPNs) alone confer limited PTT efficacy, while the ferroptosis inducers RSL3 and sulfasalazine (SSZ) are hampered by poor aqueous solubility, low biostability, and off-target toxicity, restricting their clinical translation. Herein, we constructed a glypican-3 (GPC3)-targeted multifunctional nanodelivery system for synergistic PTT-ferroptosis anti-HCC therapy. Liposomes coloading RSL3, SSZ and encapsulating VPNs (VRS@LP) were first synthesized. Macrophage membranes engineered to express the GPC3-specific single-chain antibody hGPC3 (M-hGPC3) were prepared via lentiviral transduction, then coated onto VRS@LP by mechanical extrusion to yield the targeted nanocarrier VRS@MLP-hGPC3.This nanocarrier achieves receptor-mediated endocytosis via specific hGPC3-GPC3 binding on HCC cells, with drug release triggered by the acidic lysosomal microenvironment. RSL3 inhibits glutathione peroxidase 4 (GPX4) activity, and SSZ blocks System xc–-mediated cystine uptake; their combination synergistically depletes intracellular glutathione (GSH) and potently induces ferroptosis in HCC cells. The nanoplatform-mediated PTT not only directly ablates tumor cells but also releases damage-associated molecular patterns (DAMPs), promoting dendritic cell maturation, T-cell activation, and tumor-associated macrophage polarization. Meanwhile, PTT-generated reactive oxygen species (ROS) synergize with ferroptosis to amplify oxidative injury and reduce HCC metastatic potential. The GPC3-targeted nanodelivery system enables precise synergistic PTT-ferroptosis therapy with high targeting efficiency, favorable biocompatibility and low systemic toxicity, significantly enhancing HCC therapeutic efficacy and suppressing metastasis. This work provides a potential strategy and experimental basis for precision HCC therapy, with promising clinical translational potential.

Shikonin suppresses diffuse large B-cell lymphoma progression by inducing ferritinophagy and ferroptosis via lncRNA ADPGK-AS1 downregulation

Can Chen,Xiaofei Chen,Xilian Huang,Yaping Xie,Pengfei Shi,Shenxian Qian,Zhenzhen Chen

Shikonin, a natural compound, exhibits antitumor effects in DLBCL, but its mechanism remains unclear. Shikonin’s cytotoxicity in DLBCL cells was assessed by MTT assays. Ferroptosis and lipid peroxidation markers were analysed via flow cytometry and biochemical kits. Mechanisms were explored using gene knockdown/overexpression, dual-luciferase assays, RNA pull-down, proteomics, RIP, FISH, and ChIP. Key proteins and genes involved in ferritinophagy and ferroptosis were examined by Western blot, RT-qPCR, and immunofluorescence, with findings validated in a nude mouse xenograft model. Shikonin triggers ferritinophagy and ferroptosis by increasing iron accumulation and lipid peroxidation. LncRNA ADPGK-AS1 protects against ferroptosis by regulating MT2A via eIF4G1 interaction. Shikonin triggers ferritinophagy and ferroptosis by disrupting iron metabolism and redox balance. The eIF4G1–ADPGK-AS1/MT2A axis mitigates these effects, revealing shikonin’s antitumor mechanism and therapeutic potential.

Shogaol triggers apoptosis and ferroptosis in Ewing sarcoma by targeting the polo-like kinase 1/nucleophosmin 1 axis

Zhengyu Wu,Huimou Chen,Yu Zhou,Sidong Zhang,Zhihua Li,Yadong Song,Jing Hu

Ewing sarcoma is an aggressive pediatric bone cancer with poor prognosis, highlighting the urgent need for novel therapeutics. This study demonstrates the potent anti-tumor activity of shogaol, a bioactive compound from ginger, against Ewing sarcoma, using both in vitro and in vivo model systems. In vitro, shogaol significantly inhibited cell proliferation and induced both apoptosis and ferroptosis in Ewing sarcoma cells, as evidenced by increased lipid reactive oxygen species, Malondialdehyde, and Fe 2+ levels, as well as altered expression of BAX, BCL2, GPX4, and SLC3A2. In vivo , shogaol significantly inhibited tumor cell growth in a subcutaneous xenograft mouse model using SKNMC cells. Using transcriptome sequencing and proteomics, we found that shogaol targeted the PLK1/NPM1 axis: it downregulated polo-like kinase 1 (PLK1), leading to reduced phosphorylation of NPM1 at Thr199. This facilitated the increased interaction between the E3 ligase TRIM28 and NPM1, leading to its ubiquitination and subsequent degradation, which in turn inhibited the MAPK signaling pathway. Key findings were validated by CETSA, isothermal dose-response fingerprinting, co-immunoprecipitation, and ubiquitination assays. These results demonstrate that shogaol exerts dual cytotoxic effects through the PLK1/NPM1 axis, presenting a potential natural therapeutic approach for Ewing sarcoma.

PTPRE promotes gastric cancer cell resistance to 5-fluorouracil by inhibiting ferroptosis via the Src/FAK/TRIB3 axis

Ming Liu,Xiaomei Liao,Fangchao Wang,Pengqing Jiao,Zhongkai Wang

Acquired drug resistance is a major cause of failure in gastric cancer treatment. The protein tyrosine phosphatase receptor type E (PTPRE) plays an oncogenic role in certain tumours; however, its function in chemotherapy-resistant gastric cancer remains unclear. Therefore, we analysed PTPRE expression in gastric cancer using The Cancer Genome Atlas. In vitro experiments were then conducted to investigate the effects of PTPRE on the resistance of cancer cells to 5-fluorouracil (5-FU) and its potential mechanisms. The results were further validated in vitro using xenograft studies. We found that PTPRE is upregulated in gastric cancer tissues and participates in the induction of 5-FU resistance. Mechanistic studies revealed that PTPRE suppressed ferroptosis in gastric cancer cells and promoted 5-FU resistance by activating the Src/FAK pathway to upregulate TRIB3 expression. In summary, PTPRE suppresses ferroptosis in gastric cancer cells via the Src/FAK/TRIB3 signalling pathway, thereby inducing 5-FU resistance. Intervention with PTPRE and its downstream targets may represent a potential approach for the clinical treatment of 5-FU-resistant gastric cancer.

Salvianolic Acid B Protects Against Contrast-Induced Acute Kidney Injury by Attenuating Ferroptosis via the SIRT1/Nrf2 Pathway

Hongtao Yuan,Xiang Shi,Jiaming Qin,Yue Wang,Yinuo Yuan,Yutong Zhang,Yiran Wang,Chen Zhang,Jinxia Zhu,Lihua Chen,Shuangshuang Xie,Wen Shen

Contrast-induced acute kidney injury (CI-AKI) poses a significant clinical challenge and contributes to a considerable healthcare burden. Ferroptosis has been increasingly recognized as an important mechanism of renal tubular epithelial cell injury in CI-AKI. Salvianolic acid B (SalB), a natural compound with anti-inflammatory and antioxidant properties, has shown protective effects in various kidney diseases. However, its role in CI-AKI-associated ferroptosis has not been fully clarified. In this study, we established a rat model of CI-AKI by subcutaneous injection of carbon tetrachloride for 6 weeks followed by iopamidol administration, and an in vitro model using iopamidol-treated HK-2 cells. Effects of tubular injury and ferroptosis were examined both in vivo and in vitro. Cycloheximide chase assay, cellular thermal shift assay, and molecular docking were used to assess the binding capacity of SalB to SIRT1. Our results showed that SalB significantly alleviated renal injury, reduced iron accumulation, oxidative stress levels, and lipid peroxidation, upregulated the expression of SLC7A11 and GPX4, and downregulated ACSL4 expression in both iopamidol-treated rat kidneys and HK-2 cells. Mechanistically, SalB targeted and bound to SIRT1, enhancing its stability, thereby promoting Nrf2 upregulation and nuclear translocation, which in turn enhanced the expression of SLC7A11 and GPX4 and attenuated ferroptosis. Silencing either SIRT1 or Nrf2 in HK-2 cells partially abrogated the protective effect of SalB. Collectively, our results support SalB as a viable treatment strategy for CI-AKI. Graphical Salvianolic acid B (SalB) protects against contrast-induced acute kidney injury (CI-AKI) by inhibiting ferroptosis in renal tubular epithelial cells. Mechanistically, SalB enhances SIRT1 protein stability, activates Nrf2 signaling, and promotes its nuclear translocation, thereby upregulating downstream anti-ferroptotic molecules such as SLC7A11 and GPX4, reducing lipid peroxidation and renal injury.

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.

Machine learning-optimized charge transfer nanocrystals for synergistic NIR photothermal therapy, ferroptosis, and electrochemical detection of breast cancer

Arsalan Ahmed,Mehar Muhammad Hamza Maqbool,Weiping Zhou,Nosherwan Adil,Anam Zulfiqar,Yanjie Zhu,Di He,Yongjian Zhuang,Oleg G. Sinyashin,Asiya R. Mustafina,Rustem R. Zairov,Naeem Akhtar,Cong Yu

Machine learning optimized nanocrystals with narrow band in the NIR-I region were synthesized. • DBT-F 4 TCNQ derive nanocrystals offer excellent photothermal and sensing performance. • Designed theranostic platform integrates cancer therapy with precise electrochemical sensing. • DBT-F 4 TCNQ derive nanocrystals demonstrated effective glutathione depletion. Despite significant advances in near-infrared (NIR) photothermal agents, most current systems face challenges including large band gaps and poorly defined crystalline morphology, compromised responsiveness in the tumor microenvironment due to inefficient and time-consuming optimization, and dependence on separate, cancer type-specific diagnostic platforms for effective treatment. To overcome these challenges, we rationally synthesized a novel class of charge transfer complex-derived nanocrystals (CTNs) with well-defined morphology and a significantly reduced band gap in the NIR-I region, achieved for the first time through the unique combination of DBT as the electron donor with F 4 TCNQ, TCNB, and DTTCNQ as acceptors. Additionally, we employed machine learning (ML) to systematically optimize donor-to-acceptor ratios in CTNs, ultimately identifying DBT-F 4 TCNQ as the most effective formulation, with strong NIR absorption, excellent photothermal conversion, and superior electrocatalytic efficiency. Interestingly, ML-optimized DBT-F 4 TCNQ derived from CTNs demonstrated effective cysteine-triggered intracellular depletion of glutathione (GSH), thereby promoting reactive oxygen species (ROS) accumulation and inducing ferroptosis. Additionally, the in vivo antitumor efficacy was validated through NIR-triggered photothermal therapy combined with ROS-mediated ferroptosis, while the diagnostic potential of the designed CTNs was demonstrated via in-direct electrochemical monitoring of choline released from 4T1 cancer cells. Thus, the designed ML-optimized CTNs derived from the novel DBT-F 4 TCNQ combination hold great promise as a next-generation theranostic platform by integrating therapeutic efficacy with diagnostic precision.

A self-sufficient nanoreactor orchestrating calcium overload and sonodynamic/chemodynamic-amplified ferroptosis for oral squamous cell carcinoma therapy

Wu Lei,Wang Chuiyin,Chen Qian,Wang Aiqi,Peng Meiying,Zhang Gengming,Cao Mingxin,Guo Zhaoyang,Yang Xiaoying,Wang Yinsong

Bacteria-derived components hold great promise for cancer therapy owing to their versatile biological properties. We previously reported that Porphyromonas gingivalis cell walls (PgCW), rich in intrinsic µ-oxo bisheme ([Fe(III)PPIX] 2 O), can effectively mediate both sonodynamic therapy (SDT) and chemodynamic therapy (CDT). More recently, we identified PgCW’s inherent potential to trigger ferroptosis. However, its therapeutic efficacy is limited by the hypoxic tumor microenvironment (TME) and insufficient endogenous hydrogen peroxide (H 2 O 2 ) required for catalytic reactions. Herein, a self-sufficient nanoreactor (DCP) was developed by depositing calcium peroxide (CaO 2 ) within dendritic large-pore mesoporous silica nanoparticles (DLMSNs), followed by the electrostatic adsorption of PgCW. Under ultrasound irradiation, DCP combines SDT and CDT with continuous glutathione (GSH) depletion to trigger ferroptosis. In the acidic TME, the decomposition of CaO 2 generates O 2 to enhance PgCW-mediated SDT, supplies H 2 O 2 for Fenton-like CDT, and releases Ca 2+ to induce calcium overload. The abundant reactive oxygen species (ROS) from CaO 2 -supplemented SDT and CDT, together with GSH exhaustion, amplify ferroptosis, driving severe lipid peroxidation (LPO) and cell membrane rupture to release damage-associated molecular patterns (DAMPs) for primary tumor regression. Furthermore, intracellular calcium overload synergistically promotes this ferroptosis-mediated immunogenic cell death (ICD), which, combined with the innate adjuvanticity of PgCW, drives robust systemic immune activation to suppress distant tumors. In summary, this nanoreactor overcomes TME limitations through self-sufficient substrate supply and efficiently combines calcium overload with amplified ferroptosis to suppress the growth and metastasis of oral squamous cell carcinoma (OSCC). These findings suggest a potential strategy for precision cancer immunotherapy. Graphical

Ultrasound-Activatable Sonodynamic Amplifiers Reprogram Tryptophan Catabolism for Potentiating Remotely-Controlled Ferroptosis-Immunotherapy of Triple Negative Breast Cancer

Tianxing Zhou,Junnian Chen,Xingya Rao,Haifeng Zhang,Huocheng Yang,Menghuan Li,Zhong Luo

Triple-negative breast cancer (TNBC) is a highly invasive malignancy that responds poorly to current standard therapies. Sonodynamic therapy (SDT) can deliver both reactive oxygen species (ROS)-dependent tumor cytotoxicity and immunostimulatory benefits that holds significant promise for TNBC treatment, but its efficacy is blunted by the elevated Indoleamine 2,3-dioxygenase 1 (IDO1)-driven tryptophan (Trp) catabolism in TNBC, which strengthens antioxidant defenses while exacerbating the immunosuppressive tumor microenvironment. Here we develop an ultrasound-activatable sonodynamic amplifier (PMFN) that reprograms TNBC-intrinsic IDO1-dependent Trp catabolism to potentiate remotely controllable sonodynamic ferroptosis-immunotherapy. We first developed Fe(III)-coordinated tetraphenylporphyrin (FeTPP) as a ferrocatalytic sonosensitizer via molecular-dynamics-assisted virtual screening, which was co-formulated with the IDO1 inhibitor Navoximod (NLG919) into cRGD-modified liposomes for TNBC-targeted delivery. Upon ultrasonication, NLG919 blocks Trp-to-kynurenine (Kyn) conversion to suppress the Nrf2-GPX4 antioxidant axis and mitigate regulatory T cells (Tregs)-associated immunosuppression, while FeTPP amplifies ROS stress through a sonodynamic reaction to drive lipid peroxidation. These effects synergistically promoted immunogenic ferroptosis of TNBC cells and relieved immune suppression, thereby enhancing ferroptosis-immunotherapeutic efficacy. In mouse models, PMFN markedly inhibited primary TNBC growth and abrogated metastasis, providing an approach for advancing TNBC treatment in the clinic.

Iron-Tannic Acid Hydrogel Mediated Mild Photothermal Therapy Combined With Ferroptosis Enhances Anti-Tumor Immunity in Colorectal Cancer

Yuan Zhu,Xi Yu,Tao Wang,Wanyi Liu,Chang Lu,Jiani Zhong,Yujie He,Wei Li,Kunxi Zhang,Peihao Yin,Zeting Yuan

Postoperative recurrence and metastasis are the primary causes of mortality in colorectal cancer (CRC). And its immunosuppressive tumor microenvironment (TME) often results in the poor response to immune checkpoint blockade (ICB). This study designed an injectable and adhesive tannic acid-iron hydrogel for locally mild photothermal therapy (PTT, ≤ 45°C) and ferroptosis to prevent the postoperative recurrence and metastasis in combination with programmed death ligand 1 (PD-L1) checkpoint blockade immunotherapy. First, this system was assembled from tannic acid (TA) and gelatin microspheres to form an injectable and adhesive hydrogel (Gel/TA). Subsequently, the metal-polyphenol network (MPNs) was introduced via Fe 3+ -TA interactions, providing photothermal conversion and Fe 3+ release capabilities (Gel/TA/Fe 3+ ). Gel/TA/Fe 3+ hydrogels not only ablated tumor cells and induced immunogenic cell death (ICD) under near-infrared (NIR) irradiation, but also elicited ferroptosis of both tumor cells and tumor-associated macrophage (TAMs), resulting in dendritic cells (DCs) maturation, T-cell infiltration and down-regulation of ferroptosis-sensitive M2-type TAMs levels. Therefore, in cooperation with αPD-L1, Gel/TA/Fe 3+ could not only evoke an immune response against the primary tumor, but also promote an abscopal effect against distant metastatic tumor. This work presented a novel material for CRC postoperative therapy via the synergistic effect of immediate tumor-cell killing and enhanced immunotherapy.