RESUMEN

Numerous nanoparticles have been utilized to deliver Fe2+ for tumor ferroptosis therapy, which can be readily converted to Fe3+via Fenton reactions to generate hydroxyl radical (•OH). However, the ferroptosis therapeutic efficacy of large tumors is limited due to the slow conversion of Fe3+ to Fe2+via Fenton reactions. Herein, a strategy of intratumor Fe3+/2+ cyclic catalysis is proposed for ferroptosis therapy of large tumors, which was realized based on our newly developed hollow mesoporous iron sesquioxide nanoparticle (HMISN). Cisplatin (CDDP) and Gd-poly(acrylic acid) macrochelates (GP) were loaded into the hollow core of HMISN, whose surface was modified by laccase (LAC). Fe3+, CDDP, GP, and LAC can be gradually released from CDDP@GP@HMISN@LAC in the acidic tumor microenvironment. The intratumor O2 can be catalyzed into superoxide anion (O2•-) by LAC, and the intratumor NADPH oxidases can be activated by CDDP to generate O2•-. The O2•- can react with Fe3+ to generate Fe2+, and raise H2O2 level via the superoxide dismutase. The generated Fe2+ and H2O2 can be fast converted into Fe3+ and •OH via Fenton reactions. The cyclic catalysis of intratumor Fe3+/2+ initiated by CDDP@GP@HMISN@LAC can be used for ferroptosis therapy of large tumors.

Asunto(s)

Ferroptosis , Hierro , Ferroptosis/efectos de los fármacos , Animales , Catálisis , Humanos , Hierro/química , Línea Celular Tumoral , Nanopartículas/química , Porosidad , Ratones , Cisplatino/química , Cisplatino/uso terapéutico , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Ratones Endogámicos BALB C , Peróxido de Hidrógeno/química , Microambiente Tumoral/efectos de los fármacos , Ratones Desnudos , Femenino

RESUMEN

Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.

Asunto(s)

Ferroptosis , Radioisótopos de Yodo , Radiofármacos , Ferroptosis/efectos de los fármacos , Animales , Radiofármacos/química , Radiofármacos/uso terapéutico , Ratones , Radioisótopos de Yodo/uso terapéutico , Radioisótopos de Yodo/química , Línea Celular Tumoral , Humanos , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Hierro/química , Ratones Endogámicos BALB C , Inmunoterapia/métodos , Radioinmunoterapia/métodos , Femenino , Neoplasias/terapia

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. AIM OF THE STUDY: To elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. METHODS: The anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. RESULTS: In vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. CONCLUSION: Our results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.

Asunto(s)

Ferroptosis , Hippophae , Extractos Vegetales , Enfermedad Pulmonar Obstructiva Crónica , Especies Reactivas de Oxígeno , Proteína p53 Supresora de Tumor , Ferroptosis/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Humanos , Especies Reactivas de Oxígeno/metabolismo , Hippophae/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Ratones , Masculino , Ratones Endogámicos C57BL , Línea Celular , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Modelos Animales de Enfermedad , Simulación del Acoplamiento Molecular

RESUMEN

Ferroptosis, a recently identified form of cell death, holds promise for cancer therapy, but concerns persist regarding its uncontrolled actions and potential side effects. Here, we present a semiconducting polymer nanoprodrug (SPNpro) featuring an innovative ferroptosis prodrug (DHU-CBA7) to induce sono-activatable ferroptosis for tumor-specific therapy. DHU-CBA7 prodrug incorporate methylene blue, ferrocene and urea bond, which can selectively and specifically respond to singlet oxygen (1O2) to turn on ferroptosis action via rapidly cleaving the urea bonds. DHU-CBA7 prodrug and a semiconducting polymer are self-assembled with an amphiphilic polymer to construct SPNpro. Ultrasound irradiation of SPNpro leads to the production of 1O2 via sonodynamic therapy (SDT) of the semiconducting polymer, and the generated 1O2 activated DHU-CBA7 prodrug to achieve sono-activatable ferroptosis. Consequently, SPNpro combine SDT with the controlled ferroptosis to effectively cure 4T1 tumors covered by 2-cm tissue with a tumor inhibition efficacy as high as 100 %, and also completely restrain tumor metastases. This study introduces a novel sono-activatable prodrug strategy for regulating ferroptosis, allowing for precise cancer therapy.

Asunto(s)

Ferroptosis , Ratones Endogámicos BALB C , Polímeros , Profármacos , Semiconductores , Ferroptosis/efectos de los fármacos , Profármacos/farmacología , Profármacos/química , Profármacos/uso terapéutico , Animales , Polímeros/química , Femenino , Línea Celular Tumoral , Ratones , Terapia por Ultrasonido/métodos , Nanopartículas/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Oxígeno Singlete/metabolismo

RESUMEN

Bisphenol A (BPA) is an industrial pollutant that can cause immune impairment. Selenium acts as an antioxidant, as selenium deficiency often accompanies oxidative stress, resulting in organ damage. This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell (MDCC-MSB-1) via oxidative stress-induced endoplasmic reticulum (ER) stress. We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days. The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities (T-AOC, CAT, and GSH-Px), accumulation of peroxides (H2O2 and MDA), significant upregulation of ER stress-related markers (GRP78, IER 1, PERK, EIF-2α, ATF4, and CHOP), a significant increase in iron ion levels, significant upregulation of pyroptosis-related gene (NLRP3, ASC, Caspase1, GSDMD, IL-18 and IL-1ß), significantly increase ferroptosis-related genes (TFRC, COX2) and downregulate GPX4, HO-1, FTH, NADPH. In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results, demonstrating that the addition of antioxidant (NAC), ER stress inhibitor (TUDCA) and pyroptosis inhibitor (Vx765) alleviated oxidative stress, endoplasmic reticulum stress, pyroptosis, and ferroptosis. Overall, this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.

Asunto(s)

Compuestos de Bencidrilo , Pollos , Estrés del Retículo Endoplásmico , Ferroptosis , Fenoles , Piroptosis , Especies Reactivas de Oxígeno , Selenio , Animales , Compuestos de Bencidrilo/toxicidad , Ferroptosis/efectos de los fármacos , Piroptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Selenio/deficiencia , Fenoles/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Timo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.

Asunto(s)

Biología Computacional , Ferroptosis , Insuficiencia Cardíaca , Saponinas , Triterpenos , Animales , Ferroptosis/efectos de los fármacos , Triterpenos/farmacología , Saponinas/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Ratas , Biología Computacional/métodos , Masculino , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad Crónica , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Simulación de Dinámica Molecular , Miocardio/metabolismo , Miocardio/patología

RESUMEN

Recently we have shown that protein disulfide isomerase (PDI or PDIA1) is involved in mediating chemically-induced, glutathione (GSH) depletion-associated ferroptotic cell death through NOS activation (dimerization) and NO accumulation. The present study aims to determine the role of PDI in mediating chemically-induced hepatocyte injury in vitro and in vivo and whether PDI inhibitors can effectively protect against chemically-induced hepatocyte injury. We show that during the development of erastin-induced ferroptotic cell death, accumulation of cellular NO, ROS and lipid-ROS follows a sequential order, i.e., cellular NO accumulation first, followed by accumulation of cellular ROS, and lastly cellular lipid-ROS. Cellular NO, ROS and lipid-ROS each play a crucial role in mediating erastin-induced ferroptosis in cultured hepatocytes. In addition, it is shown that PDI is an important upstream mediator of erastin-induced ferroptosis through PDI-mediated conversion of NOS monomer to its dimer, which then leads to accumulation of cellular NO, ROS and lipid-ROS, and ultimately ferroptotic cell death. Genetic manipulation of PDI expression or pharmacological inhibition of PDI function each can effectively abrogate erastin-induced ferroptosis. Lastly, evidence is presented to show that PDI is also involved in mediating acetaminophen-induced liver injury in vivo using both wild-type C57BL/6J mice and hepatocyte-specific PDI conditional knockout (PDIfl/fl Alb-cre) mice. Together, our work demonstrates that PDI is an important upstream mediator of chemically-induced, GSH depletion-associated hepatocyte ferroptosis, and inhibition of PDI can effectively prevent this injury.

Asunto(s)

Glutatión , Hepatocitos , Proteína Disulfuro Isomerasas , Especies Reactivas de Oxígeno , Proteína Disulfuro Isomerasas/metabolismo , Proteína Disulfuro Isomerasas/genética , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Animales , Glutatión/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacología , Ferroptosis/efectos de los fármacos , Óxido Nítrico/metabolismo , Masculino , Humanos

RESUMEN

Purpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy. Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model. Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups. Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.

Asunto(s)

Antineoplásicos , Carcinoma Hepatocelular , Liberación de Fármacos , Ferroptosis , Estructuras Metalorgánicas , Piridinas , Estructuras Metalorgánicas/química , Animales , Humanos , Piridinas/química , Piridinas/administración & dosificación , Piridinas/farmacocinética , Piridinas/farmacología , Ratones , Células Hep G2 , Concentración de Iones de Hidrógeno , Ferroptosis/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Tamaño de la Partícula , Nanopartículas/química

RESUMEN

Glioblastoma (GBM) represents an aggressive brain tumor, characterized by intra- and inter-tumoral heterogeneity and therapy resistance, leading to unfavourable prognosis. An increasing number of studies pays attention on the regulation of ferroptosis, an iron-dependent cell death, as a strategy to reverse drug resistance in cancer. However, the debate on whether this strategy may have important implications for the treatment of GBM is still ongoing. In the present study, we used ferric ammonium citrate and erastin to evaluate ferroptosis induction effects on two human GBM cell lines, U-251 MG, with proneural characteristics, and T98-G, with a mesenchymal profile. The response to ferroptosis induction was markedly different between cell lines, indeed T98-G cells showed an enhanced antioxidant defence, with increased glutathione levels, as compared to U-251 MG cells. Moreover, using bioinformatic approaches and analysing publicly available datasets from patients' biopsies, we found that GBM with a mesenchymal phenotype showed an up-regulation of several genes involved in antioxidant mechanisms as compared to proneural subtype. Thus, our results suggest that GBM subtypes differently respond to ferroptosis induction, emphasizing the significance of further molecular studies on GBM to better discriminate between various tumor subtypes and progressively move towards personalized therapy.

Asunto(s)

Antioxidantes , Ferroptosis , Glioblastoma , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Línea Celular Tumoral , Antioxidantes/farmacología , Antioxidantes/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Compuestos Férricos/farmacología , Compuestos de Amonio Cuaternario/farmacología , Glutatión/metabolismo , Piperazinas

RESUMEN

Ferroptosis, triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DOX-induced cardiomyopathy (DIC), and thus limits the use of doxorubicin (DOX) in clinic. Here, we further showed that cardiac ferroptosis induced by DOX in mice was attributed to up-regulation of Hmox1, as knockdown of Hmox1 effectively inhibited cardiomyocyte ferroptosis. To targeted delivery of siRNA into cardiomyocytes, siRNA-encapsulated exosomes were injected followed by ultrasound microbubble targeted destruction (UTMD) in the heart region. UTMD greatly facilitated exosome delivery into heart. Consistently, UTMD assisted exosomal delivery of siHomox1 nearly blocked the ferroptosis and the subsequent cardiotoxicity induced by doxorubicin. In summary, our findings reveal that the upregulation of HMOX1 induces ferroptosis in cardiomyocytes and UTMD-assisted exosomal delivery of siHmox1 can be used as a potential therapeutic strategy for DIC.

Asunto(s)

Doxorrubicina , Exosomas , Ferroptosis , Hemo-Oxigenasa 1 , Microburbujas , Miocitos Cardíacos , ARN Interferente Pequeño , Ferroptosis/efectos de los fármacos , Animales , Doxorrubicina/farmacología , Exosomas/metabolismo , Ratones , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Hemo-Oxigenasa 1/metabolismo , ARN Interferente Pequeño/farmacología , Ratones Endogámicos C57BL , Masculino , Sistemas de Liberación de Medicamentos , Cardiomiopatías/metabolismo , Proteínas de la Membrana

RESUMEN

Recent evidence indicates that the damaged regions in osteoarthritis are accompanied by the accumulation of iron ions. Ferroptosis, as an iron-dependent form of cell death, holds significant implications in osteoarthritis. Melatonin, a natural product with strong scavenging abilities against reactive oxygen species and lipid peroxidation, plays a crucial role in the treatment of osteoarthritis. This study aims to demonstrate the existence of ferroptosis in osteoarthritis and explore the specific mechanism of melatonin in suppressing ferroptosis and alleviating osteoarthritis. Our findings reveal that melatonin reverses inflammation-induced oxidative stress and lipid peroxidation while promoting the expression of extracellular matrix components in chondrocytes, safeguarding the cells. Our research has revealed that NADPH oxidase 4 (NOX4) serves as a crucial molecule in the ferroptosis process of osteoarthritis. Specifically, NOX4 is located on mitochondria in chondrocytes, which can induce disorders in mitochondrial energy metabolism and dysfunction, thereby intensifying oxidative stress and lipid peroxidation. LC-MS analysis further uncovered that GRP78 is a downstream binding protein of NOX4. NOX4 induces ferroptosis by weakening GRP78's protective effect on GPX4 and reducing its expression. Melatonin can inhibit the upregulation of NOX4 on mitochondria and mitigate mitochondrial dysfunction, effectively suppressing ferroptosis and alleviating osteoarthritis. This suggests that melatonin therapy represents a promising new approach for the treatment of osteoarthritis.

Asunto(s)

Ferroptosis , Melatonina , Mitocondrias , NADPH Oxidasa 4 , Osteoartritis , Melatonina/farmacología , Ferroptosis/efectos de los fármacos , Osteoartritis/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , NADPH Oxidasa 4/metabolismo , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/patología , Estrés Oxidativo/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Humanos , Ratones

RESUMEN

LHPP, a novel, recognized tumor suppressor, exerts a critical influence on the regulation of tumor cell proliferation and survival by modulating various signaling pathways with its phosphatase activity. Here, we unveil a robust correlation between reduced LHPP expression and adverse prognosis in prostate cancer. We demonstrate that LHPP interacts with AKT, thereby dampening AKT phosphorylation and subsequently inhibiting ACSL4 phosphorylation at the T624 site. This interaction impedes phosphorylation-dependent ubiquitination, thwarting SKP2 from recognizing and binding to ACSL4 at the K621 site. As a result, ACSL4 is spared from lysosomal degradation, leading to its accumulation and the promotion of lipid peroxidation, and ferroptosis. Moreover, our findings reveal that Panobinostat, a potent histone-deacetylase inhibitor, intricately regulates LHPP expression at multiple levels through the inhibition of HDAC3. This complex modulation enhances the ferroptosis pathway, offering a novel mechanism for curtailing the growth of prostate tumors and highlighting its significant translational potential for clinical application.

Asunto(s)

Coenzima A Ligasas , Ferroptosis , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Masculino , Ferroptosis/efectos de los fármacos , Humanos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Coenzima A Ligasas/metabolismo , Línea Celular Tumoral , Animales , Fosforilación , Ratones , Histona Desacetilasas/metabolismo , Ratones Desnudos , Pirofosfatasa Inorgánica

RESUMEN

BACKGROUND: The clinical efficacy of cancer treatment protocols remains unsatisfactory; however, the emergence of ferroptosis-driven therapy strategies has renewed hope for tumor treatment, owing to their remarkable tumor suppression effects. Biologically based small-molecule inducers are used in conventional method to induce ferroptosis. Nevertheless, some molecular drugs have limited solubility, poor ability to target cells, and fast metabolism, which hinder their ability to induce ferroptosis over a prolonged period. Fortunately, further investigations of ferroptosis and the development of nanotechnology have demonstrated that nanoparticles (NPs) are more efficient in inducing ferroptosis than drugs alone, which opens up new perspectives for cancer therapy. OBJECTIVE: In order to organize a profile of recent advance in NPs for inducing ferroptosis in cancer therapy, and NPs were comprehensively classified in a new light.Materials and methods: We comprehensively searched the databases such as PubMed and Embase. The time limit for searching was from the establishment of the database to 2023.11. All literatures were related to "ferroptosis", "nanoparticles", "nanodelivery systems", "tumors", "cancer". RESULTS: We summarized and classified the available NPs from a new perspective. The NPs were classified into six categories based on their properties: (1) iron oxide NPs (2) iron - based conversion NPs (3) core-shell structure (4) organic framework (5) silica NPs (6) lipoprotein NPs. According to the therapeutic types of NPs, they can be divided into categories: (1) NPs induced ferroptosis-related immunotherapy (2) NPs loaded with drugs (3) targeted therapy of NPs (4) multidrug resistance therapy (5) gene therapy with NPs (6) energy conversion therapy. CONCLUSIONS: The insights gained from this review can provide ideas for the development of original NPs and nanodelivery systems, pave the way for related nanomaterials application in clinical cancer therapy, and advance the application and development of nanotechnology in the medical field.

Asunto(s)

Ferroptosis , Nanopartículas , Neoplasias , Ferroptosis/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Nanopartículas/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Animales

RESUMEN

Chemical probes interrogate disease mechanisms at the molecular level by linking genetic changes to observable traits. However, comprehensive chemical screens in diverse biological models are impractical. To address this challenge, we develop ChemProbe, a model that predicts cellular sensitivity to hundreds of molecular probes and drugs by learning to combine transcriptomes and chemical structures. Using ChemProbe, we infer the chemical sensitivity of cancer cell lines and tumor samples and analyze how the model makes predictions. We retrospectively evaluate drug response predictions for precision breast cancer treatment and prospectively validate chemical sensitivity predictions in new cellular models, including a genetically modified cell line. Our model interpretation analysis identifies transcriptome features reflecting compound targets and protein network modules, identifying genes that drive ferroptosis. ChemProbe is an interpretable in silico screening tool that allows researchers to measure cellular response to diverse compounds, facilitating research into molecular mechanisms of chemical sensitivity.

Asunto(s)

Transcriptoma , Humanos , Línea Celular Tumoral , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Femenino , Aprendizaje Automático , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Simulación por Computador

RESUMEN

Severe acute pancreatitis (SAP) is characterized by acute inflammation of the pancreas. The transcription factor BTB and CNC homology 1 (BACH1) has been implicated in various biological processes, including oxidative stress, apoptosis, and cell cycle regulation. However, its involvement in the pathogenesis of SAP remains relatively understudied. In the present work, our data demonstrated that BACH1 level was significantly increased in SAP patients, cellular, and animal models, while heat shock protein B1 (HSPB1) expression was weakened. Mechanistic assays validated that BACH1 acted as a transcriptional inhibitor of HSPB1. Moreover, HPDE6-C7 cells were stimulated with cerulein (Cer) and LPS to mimic the pathological stages of SAP in vitro. Depletion of BACH1 remarkably improved cell survival and alleviated the oxidative stress, ferroptosis, and inflammatory responses in SAP cell models. However, these changes were dramatically reversed upon co-inhibition of HSPB1. Animal findings confirmed that loss of BACH1 decreased pancreatic injury, inflammatory responses, and ferroptosis, but these effects were weakened by HSPB1 silence. Overall, these findings elucidate that the overexpression of BACH1 favors the ferroptosis and inflammation by transcriptionally inhibiting HSBP1, thereby exacerbating SAP progression.

Asunto(s)

Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Ferroptosis , Pancreatitis , Ferroptosis/efectos de los fármacos , Humanos , Animales , Pancreatitis/genética , Pancreatitis/metabolismo , Pancreatitis/inducido químicamente , Ratones , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Masculino , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Epigénesis Genética , Chaperonas Moleculares/genética , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Ratones Endogámicos C57BL , Línea Celular , Modelos Animales de Enfermedad

RESUMEN

BACKGROUND: Ischemic stroke leads a primary cause of mortality in human diseases, with a high disability rate worldwide. This study aims to investigate the function of ß-1,4-galactosyltransferase 1 (B4galt1) in mouse brain ischemia/reperfusion (I/R) injury. METHODS: Recombinant human B4galt1 (rh-B4galt1) was intranasally administered to the mice model of middle cerebral artery occlusion (MCAO)/reperfusion. In this study, the impact of rh-B4galt1 on cerebral injury assessed using multiple methods, including the neurological disability status scale, 2,3,5-triphenyltetrazolium chloride (TTC), Nissl and TUNEL staining. This study utilized laser speckle Doppler flowmeter to monitor the cerebral blood flow. Western blotting was performed to assess the protein expression levels, and fluorescence-labeled dihydroethidium method was performed to determine the superoxide anion generation. Assay kits were used for the measurement of iron, malondialdehyde (MDA) and glutathione (GSH) levels. RESULTS: We demonstrated that rh-B4galt1 markedly improved neurological function, reduced cerebral infarct volume and preserved the completeness of blood-brain barrier (BBB) for preventing damage. These findings further illustrated that rh-B4galt1 alleviated oxidative stress, lipid peroxidation, as well as iron deposition induced by I/R. The vital role of ferroptosis was proved in brain injury. Furthermore, the rh-B4galt1 could increase the levels of TAZ, Nrf2 and HO-1 after I/R. And TAZ-siRNA and ML385 reversed the neuroprotective effects of rh-B4galt1. CONCLUSIONS: The results indicated that rh-B4galt1 implements neuroprotective effects by modulating ferroptosis, primarily via upregulating TAZ/Nrf2/HO-1 pathway. Thus, B4galt1 could be seen as a promising novel objective for ischemic stroke therapy.

Asunto(s)

Isquemia Encefálica , Ferroptosis , Galactosiltransferasas , Hemo-Oxigenasa 1 , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Galactosiltransferasas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Infarto de la Arteria Cerebral Media , Proteínas de la Membrana , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo

RESUMEN

The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.

Asunto(s)

Antioxidantes , Caenorhabditis elegans , Ferroptosis , Neuronas , Vitamina A , Animales , Ferroptosis/efectos de los fármacos , Vitamina A/farmacología , Vitamina A/metabolismo , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Antioxidantes/farmacología , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/citología , Ciclohexilaminas/farmacología , Diferenciación Celular/efectos de los fármacos , Vitamina E/farmacología , Receptores de Ácido Retinoico/metabolismo , Receptores de Ácido Retinoico/genética , Tretinoina/farmacología , Organoides/efectos de los fármacos , Organoides/metabolismo , Neurogénesis/efectos de los fármacos , Ratones , Humanos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Transducción de Señal/efectos de los fármacos , Fenilendiaminas

RESUMEN

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be renoprotective in ischemia-reperfusion (I/R) injury, with several proposed mechanisms, though additional mechanisms likely exist. This study investigated the impact of luseogliflozin on kidney fibrosis at 48 h and 1 week post I/R injury in C57BL/6 mice. Luseogliflozin attenuated kidney dysfunction and the acute tubular necrosis score on day 2 post I/R injury, and subsequent fibrosis at 1 week, as determined by Sirius red staining. Metabolomics enrichment analysis of I/R-injured kidneys revealed suppression of the glycolytic system and activation of mitochondrial function under treatment with luseogliflozin. Western blotting showed increased nutrient deprivation signaling with elevated phosphorylated AMP-activated protein kinase and Sirtuin-3 in luseogliflozin-treated kidneys. Luseogliflozin-treated kidneys displayed increased protein levels of carnitine palmitoyl transferase 1α and decreased triglyceride deposition, as determined by oil red O staining, suggesting activated fatty acid oxidation. Luseogliflozin prevented the I/R injury-induced reduction in nuclear factor erythroid 2-related factor 2 activity. Western blotting revealed increased glutathione peroxidase 4 and decreased transferrin receptor protein 1 expression. Immunostaining showed reduced 4-hydroxynonenal and malondialdehyde levels, especially in renal tubules, indicating suppressed ferroptosis. Luseogliflozin may protect the kidney from I/R injury by inhibiting ferroptosis through oxidative stress reduction.

Asunto(s)

Lesión Renal Aguda , Ferroptosis , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Ferroptosis/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Masculino , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Sorbitol/análogos & derivados , Sorbitol/farmacología , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Estrés Oxidativo/efectos de los fármacos , Fibrosis , Modelos Animales de Enfermedad , Transportador 2 de Sodio-Glucosa

RESUMEN

BACKGROUND: Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. METHODS: A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. RESULTS: DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). CONCLUSIONS: Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.

Asunto(s)

Colitis Ulcerosa , Ferroptosis , Ginsenósidos , MicroARNs , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Ginsenósidos/farmacología , MicroARNs/genética , Ratones , Ferroptosis/efectos de los fármacos , Humanos , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Regulación hacia Arriba/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Sulfato de Dextran/toxicidad , Apoptosis/efectos de los fármacos

RESUMEN

The poor prognosis of hepatocellular carcinoma (HCC) is still an urgent challenge to be solved worldwide. Hence, assembling drugs and targeted short peptides together to construct a novel medicine delivery strategy is crucial for targeted and synergy therapy of HCC. Herein, a high-efficiency nanomedicine delivery strategy has been constructed by combining graphdiyne oxide (GDYO) as a drug-loaded platform, specific peptide (SP94-PEG) as a spear to target HCC cells, sorafenib, doxorubicin-Fe2+ (DOX-Fe2+), and siRNA (SLC7A11-i) as weapons to exert a three-path synergistic attack against HCC cells. In this work, SP94-PEG and GDYO form nanosheets with HCC-targeting properties, the chemotherapeutic drug DOX linked to ferrous ions increases the free iron pool in HCC cells and synergizes with sorafenib to induce cell ferroptosis. As a key gene of ferroptosis, interference with the expression of SLC7A11 makes the ferroptosis effect in HCC cells easier, stronger, and more durable. Through gene interference, drug synergy, and short peptide targeting, the toxic side effects of chemotherapy drugs are reduced. The multifunctional nanomedicine GDYO@SP94/DOX-Fe2+/sorafenib/SLC7A11-i (MNMG) possesses the advantages of strong targeting, good stability, the ability to continuously induce tumor cell ferroptosis and has potential clinical application value, which is different from traditional drugs.

Asunto(s)

Carcinoma Hepatocelular , Doxorrubicina , Ferroptosis , Neoplasias Hepáticas , Nanomedicina , Péptidos , Sorafenib , Ferroptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Doxorrubicina/farmacología , Doxorrubicina/química , Nanomedicina/métodos , Sorafenib/farmacología , Sorafenib/química , Línea Celular Tumoral , Animales , Péptidos/química , Péptidos/farmacología , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Sinergismo Farmacológico , Sistema de Transporte de Aminoácidos y+/metabolismo , Ratones Desnudos , ARN Interferente Pequeño , Ratones Endogámicos BALB C , Sistemas de Liberación de Medicamentos/métodos