RESUMEN
Tannic acid (TA)-derived carbon dots (TACDs) were synthesized for the first time via a solvothermal method using TA as one of the raw materials, which may effectively inhibit amyloid fibril aggregation and disaggregate mature fibril. The fluorescent property of TACDs were modulated by adjusting the ratio of TA to o-phenylenediamine (oPD), and TACDs fabricated with the precursor ratio as 1:1 showed the best fluorescent property. Circular dichroism spectra (CD) showed that the structure of ß-sheet decreased as the concentration of TACDs increased. The inhibition efficiency, as confirmed by thioflavin T (ThT) and transmission electron microscopy (TEM), is extraordinary at 98.16%, whereas disaggregation efficiency is noteworthy at 97.97%, and the disaggregated lysozyme fibrils did not reaggregate after 7 days. More critically, TACDs can also alleviate the cellular toxicity caused by Aß fibrils and improve cell viability. This work offers a new perspective on the design of scavengers for amyloid plaques.
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Carbono , Agregado de Proteínas , Taninos , Taninos/química , Taninos/farmacología , Carbono/química , Humanos , Agregado de Proteínas/efectos de los fármacos , Muramidasa/química , Muramidasa/metabolismo , Supervivencia Celular/efectos de los fármacos , Puntos Cuánticos/química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Amiloide/química , Amiloide/metabolismo , Fenilendiaminas/química , Fenilendiaminas/farmacología , Animales , PolifenolesRESUMEN
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.
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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 , FenilendiaminasRESUMEN
Cis-dichlorodiammineplatinum(II) (CDDP), while widely utilized in tumor therapy, results in toxic side effects that patients find intolerable. The specific mechanism by which CDDP inflicts ovarian damage remains unclear. This study aimed to explore the involvement of ferrostatin-1 (FER-1) and ferroptosis in CDDP-induced ovarian toxicity. This study established models of CDDP-induced injury in granulosa cells (GCs) and rat model of premature ovarian failure (POF). CCK-8 assessed the effects of CDDP and FER-1 on GC viability. FerroOrange and Mito-FerroGreen, DCFH-DA and MitoSox-Red, Rhodamine 123 and Transmission electron microscopy (TEM) measured Fe2+, reactive oxygen species (ROS), mitochondrial membrane potential and the mitochondrial morphology in GC cells, respectively. Serum hormone levels; organ indices; malondialdehyde, superoxide dismutase, and glutathione analyses; and western blotting were performed to examine ferroptosis's role in vitro. Molecular docking simulation was evaluated the interaction between FER-1 and GPX4 or FER-1 and NRF2. Molecular docking simulations were conducted to evaluate the interactions between FER-1 and GPX4, as well as FER-1 and NRF2. The findings revealed that CDDP-induced ovarian toxicity involved iron accumulation, increased ROS accumulation, and mitochondrial dysfunction, leading to endocrine disruption and tissue damage in rats. These changes correlated with NRF2, HO-1, and GPX4 levels. However, FER-1 decreased the extent of ferroptosis. Thus, ferroptosis appears to be a crucial mechanism of CDDP-induced ovarian injury, with GPX4 as potential protective targets.
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Cisplatino , Ciclohexilaminas , Ferroptosis , Simulación del Acoplamiento Molecular , Fenilendiaminas , Especies Reactivas de Oxígeno , Animales , Femenino , Ferroptosis/efectos de los fármacos , Ciclohexilaminas/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Cisplatino/efectos adversos , Fenilendiaminas/farmacología , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismo , Ovario/patología , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
Chemodynamic therapy is an appealing modality in cancer treatment. However, its therapeutic effectiveness is impeded by insufficient catalytic efficiency and overexpression of glutathione (GSH) at the tumor site. In this study, a poly(o-phenylenediamine) (PoPD)@copper sulfide (CuS) nanoplatform was developed as dual-level reactive oxygen species (ROS) amplifier for enhanced photothermal-chemodynamic therapy. The PoPD@CuS nanoplatform exhibited photothermal performance, chemodynamic performance, and GSH-depleting capability. Alongside its improved photothermal conversion efficiency with tumor pH-responsiveness, the photothermal behavior of PoPD@CuS could elevate chemodynamic activity by regulating the temperature spatiotemporally, leading to increased ROS production. Moreover, GSH depletion of PoPD@CuS could suppress ROS scavenging, further enhancing oxidative stress in the tumor region. Consequently, functioning as a dual-level ROS amplifier, PoPD@CuS showcased remarkable effectiveness in photothermal-chemodynamic combination therapy.
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Cobre , Especies Reactivas de Oxígeno , Especies Reactivas de Oxígeno/metabolismo , Cobre/química , Cobre/farmacología , Humanos , Animales , Fenilendiaminas/química , Fenilendiaminas/farmacología , Glutatión/metabolismo , Glutatión/química , Ratones , Terapia Fototérmica , Fototerapia/métodos , Línea Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
Spinal cord injury (SCI) results in irreversible neurological impairment. After SCI, Ferritinophagy-induced free iron released from ferritin can lead to extensive lipid peroxidation and aggravate neurological damage. NRF2/HO-1 pathway is to endow cells with a protective effect against oxidative stress, and it plays an important role in the transcriptional activation of a series of antioxidant and detoxification genes. UAMC-3203 is a ferrostatin-1(Fer-1) analogue with better solubility and stability, which can more effectively inhibit ferroptosis after SCI. A rat SCI model was constructed, and the recovery of motor function was observed after treatment with UAMC-3203. ELISA was employed to assess the impact of UAMC-3203 on inflammation-related factors, while immunofluorescence was utilized to investigate the influence of UAMC-3203 on neuronal count as well as the activation of astrocytes and microglia/macrophages. Malondialdehyde (MDA) were detected to reflect the level of oxidation products. Western blot analysis was used to measure the level of ferroptosis markers and the expression of NRF2/HO-1. Our findings demonstrate that UAMC-3203 inhibits the production of reactive oxygen species (ROS) and lipid peroxides, preventing ferroptosis and reducing neuronal degeneration. Additionally, UAMC-3203 suppresses astrocyte proliferation and microglia/macrophage activation, as well as the release of ferroptosis-related inflammatory factors. These combined effects contribute to the preservation of spinal cord tissue and the facilitation of motor function recovery. UAMC-3203 maybe inhibit ferroptosis after SCI to promote functional recovery.
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Ferroptosis , Factor 2 Relacionado con NF-E2 , Recuperación de la Función , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Ferroptosis/efectos de los fármacos , Ratas , Recuperación de la Función/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Modelos Animales de Enfermedad , Masculino , Ciclohexilaminas/farmacología , Estrés Oxidativo/efectos de los fármacos , Fenilendiaminas/farmacología , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Microglía/metabolismo , Microglía/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)RESUMEN
Osteoarthritis (OA) is a common joint disease associated with the aging of the population, and it reduces the quality of life of patients. It is characterized by the destruction of articular cartilage and the secretion of inflammatory cytokines. Owing to the unclear pathogenesis of OA, current treatment methods have significant limitations. Oxidative stress has been revealed to play an important role in the development of OA. Our experiments indicated that the levels of GSH decreased and the level of MDA increased in chondrocytes, which induced ferroptosis in chondrocytes in OA. We also revealed that ferroptosis was the main mechanism of cartilage destruction caused by the addition of the ferroptosis activator erastin and the ferroptosis inhibitor ferrostatin-1. NOX1 is the main modulator of oxidative stress by increasing the generation of reactive oxidative species (ROS). We suppressed the expression of NOX1 in chondrocytes through cell transfection. The expression of collagen II and MMP13, and the secretion of IL-1ß and TNF-α were reversed. An increase in the mitochondrial membrane potential and a decrease in the level of intracellular ROS indicate an improvement in oxidative damage. Additionally, we determined the effect of the Nrf2/HO-1 pathway on NOX1-mediated chondrocyte injury. We found that NOX1 inhibited the expression of Nrf2/HO-1, but the activation of Nrf2 improved the oxidative damage to chondrocytes in vivo and vitro. This study revealed that NOX1-mediated oxidative stress induces chondrocyte ferroptosis by inhibiting the Nrf2/HO-1 pathway. Our findings contribute to revealing the pathogenesis of OA, providing targets for drug design and optimizing the clinical treatment of OA.
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Condrocitos , Ferroptosis , Hemo-Oxigenasa 1 , NADPH Oxidasa 1 , Factor 2 Relacionado con NF-E2 , Osteoartritis , Estrés Oxidativo , Especies Reactivas de Oxígeno , Transducción de Señal , Condrocitos/metabolismo , Ferroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Animales , NADPH Oxidasa 1/metabolismo , NADPH Oxidasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Ratones , Osteoartritis/metabolismo , Osteoartritis/patología , Especies Reactivas de Oxígeno/metabolismo , Ciclohexilaminas/farmacología , Masculino , Cartílago Articular/metabolismo , Cartílago Articular/patología , Humanos , Proteínas de la Membrana , FenilendiaminasRESUMEN
Glyoxal (GL) is a reactive α-dicarbonyl compound generated from glycated proteins in the Maillard reaction. It has attracted particular attention over the past few years because of its possible clinical significance in chronic and age-related diseases. In this work, a reaction-based red emission fluorescent probe GL1 has been synthesized successfully by grafting an alkyl group onto an amino group to regulate its selectivity for GL. Under physiological conditions, the fluorescence intensity of GL1 at 640 nm obviously increased with the increase of GL concentration, and it exhibited high selectivity for GL over other reactive carbonyl compounds, as well as a lower detection limit (0.021 µM) and a larger Stokes shift (112 nm). At the same time, GL1 can selectively accumulate in mitochondria and can be used to detect exogenous and endogenous GL in living cells with low cytotoxicity.
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Colorantes Fluorescentes , Glioxal , Fenilendiaminas , Glioxal/química , Humanos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Fenilendiaminas/química , Fenilendiaminas/síntesis química , Carbocianinas/química , Células HeLa , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Imagen Óptica , Mitocondrias/metabolismoRESUMEN
Abnormal shifts in global climate, leading to extreme weather, significantly threaten the safety of individuals involved in outdoor activities. Hypothermia-induced coma or death frequently occurs in clinical and forensic settings. Despite this, the precise mechanism of central nervous system injury due to hypothermia remains unclear, hindering the development of targeted clinical treatments and specific forensic diagnostic indicators. The GEO database was searched to identify datasets related to hypothermia. Post-bioinformatics analyses, DEGs, and ferroptosis-related DEGs (FerrDEGs) were intersected. GSEA was then conducted to elucidate the functions of the Ferr-related genes. Animal experiments conducted in this study demonstrated that hypothermia, compared to the control treatment, can induce significant alterations in iron death-related genes such as PPARG, SCD, ADIPOQ, SAT1, EGR1, and HMOX1 in cerebral cortex nerve cells. These changes lead to iron ion accumulation, lipid peroxidation, and marked expression of iron death-related proteins. The application of the iron death inhibitor Ferrostatin-1 (Fer-1) effectively modulates the expression of these genes, reduces lipid peroxidation, and improves the expression of iron death-related proteins. Severe hypothermia disrupts the metabolism of cerebral cortex nerve cells, causing significant alterations in ferroptosis-related genes. These genetic changes promote ferroptosis through multiple pathways.
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Corteza Cerebral , Ferroptosis , Hipotermia , Neuronas , Ferroptosis/genética , Animales , Hipotermia/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Neuronas/metabolismo , Hierro/metabolismo , Peroxidación de Lípido , Masculino , Ratas , Fenilendiaminas/farmacología , CiclohexilaminasRESUMEN
Redox nanozymes have exhibited various applications in recognizing environmental pollutants but not aromatic amines (a type of typical pollutant). Herein, with Cu2+ as a node and tryptophan (Trp) as a linker, Cu-Trp as a specific ascorbic acid oxidase mimic was synthesized, which could catalyze ascorbic acid (AA) oxidation to dehydroascorbic acid (DHAA). Alternatively, with other natural amino acids as linkers to synthesize Cu-based nanozymes, such catalytic performances are also observed. The as-produced DHAA could react with o-phenylenediamine (OPD) and its derivatives (2,3-naphthalene diamine (NDA), 4-nitro-o-phenylenediamine (4-NO2-OPD), 4-fluoro-o-phenylenediamine (4-F-OPD), 4-chloro-o-phenylenediamine(4-Cl-OPD), and 4-bromo-o-phenylenediamine(4-Br-OPD)) to form a Schiff base and emit fluorescence. Based on the results, with Cu-Trp + AA and Cu-Arg (with arginine (Arg) as a linker) + AA as two sensing channels and extracted red, green, and blue (RGB) values from emitted fluorescence as read-out signals, a visual sensor array was constructed to efficiently distinguish OPD, NDA, 4-NO2-OPD, 4-F-OPD, 4-Cl-OPD, and 4-Br-OPD as low as 10 µM. Such detecting performance was further confirmed through discriminating binary, ternary, quinary, and senary mixtures with various concentration ratios, recognizing 18 unknown samples, and even quantitatively analyzing single aromatic amine. Finally, the discriminating ability was further validated in environmental waters, providing an efficient assay for large-scale scanning levels of multiple aromatic amines.
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Aminas , Ascorbato Oxidasa , Bases de Schiff , Bases de Schiff/química , Aminas/química , Aminas/análisis , Ascorbato Oxidasa/química , Ascorbato Oxidasa/metabolismo , Cobre/química , Cobre/análisis , Ácido Ascórbico/química , Ácido Ascórbico/análisis , Fenilendiaminas/química , Oxidación-ReducciónRESUMEN
The simple, effective and highly sensitive detection of hydrogen peroxide (H2O2), which belongs to the reactive oxygen species (ROS), at low concentrations plays an indispensable role in the field of environmental protection, biological research and safety. In this study, a dual-mode optical biosensor, UiO-66@OPD, was developed based on the inherent peroxidase mimicking activity of UiO-66 (Zr) and the optical reaction of ortho-phenylenediamine (OPD) by extending the π-system through oxidative coupling, prototropism and elimination to form OPDox, thereby exhibiting strong orangish absorbance and greenish fluorescence. The catalase-mimicking activity of UiO-66 (Zr) was demonstrated by the catalytic oxidation of methylene blue in the presence of H2O2. Moreover, the Michaelis-Menten kinetic model confirmed the intrinsic peroxidase-like activity of UiO-66@OPD as a modified MOFzyme. The synthesized UiO-66 (Zr) facilitated the oxidation of OPD to OPDox by degrading H2O2 to the hydroxyl radicals. During the oxidation process, the absorption peak at 415 nm and the fluorescence peak at 565 nm of the synthesized probe were significantly enhanced by increasing the H2O2 concentration. Moreover, a colorimetric and fluorometric ultrasensitive sensor shows a good linear relationship between the intensity enhancement and H2O2 concentration in the range of 0-600 nM for absorption and fluorescence spectra with R2 = 0.9772, and R2 = 0.9948, respectively. To demonstrate the biological performance and biocompatibility of UiO-66@OPD as a biosensor, MTT evaluation was performed for the three cell lines MCF-10 A, HEK293 and A549, indicating high biocompatibility and good cell viability for biological applications. Ultimately, this convenient, environmentally friendly, biocompatible and cost-effective catalase-mimicking-based sensor system will open a new perspective for the development of portable kite-based biosensors In vitro.
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Técnicas Biosensibles , Peróxido de Hidrógeno , Especies Reactivas de Oxígeno , Humanos , Técnicas Biosensibles/métodos , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/análisis , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/química , Fenilendiaminas/química , Estructuras Metalorgánicas/química , Límite de Detección , Circonio/química , Materiales Biocompatibles/químicaRESUMEN
BACKGROUND: Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease, whose primary hallmark is the occurrence of inflammatory lesions in white and grey matter structures. Increasing evidence in MS patients and respective murine models reported an impaired ionic homeostasis driven by inflammatory-demyelination, thereby profoundly affecting signal propagation. However, the impact of a focal inflammatory lesion on single-cell and network functionality has hitherto not been fully elucidated. OBJECTIVES: In this study, we sought to determine the consequences of a localized cortical inflammatory lesion on the excitability and firing pattern of thalamic neurons in the auditory system. Moreover, we tested the neuroprotective effect of Retigabine (RTG), a specific Kv7 channel opener, on disease outcome. METHODS: To resemble the human disease, we focally administered pro-inflammatory cytokines, TNF-α and IFN-γ, in the primary auditory cortex (A1) of MOG35-55 immunized mice. Thereafter, we investigated the impact of the induced inflammatory milieu on afferent thalamocortical (TC) neurons, by performing ex vivo recordings. Moreover, we explored the effect of Kv7 channel modulation with RTG on auditory information processing, using in vivo electrophysiological approaches. RESULTS: Our results revealed that a cortical inflammatory lesion profoundly affected the excitability and firing pattern of neighboring TC neurons. Noteworthy, RTG restored control-like values and TC tonotopic mapping. CONCLUSION: Our results suggest that RTG treatment might robustly mitigate inflammation-induced altered excitability and preserve ascending information processing.
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Carbamatos , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental , Neuronas , Fenilendiaminas , Tálamo , Animales , Ratones , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/metabolismo , Fenilendiaminas/farmacología , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Tálamo/metabolismo , Tálamo/efectos de los fármacos , Carbamatos/farmacología , Femenino , Corteza Auditiva/efectos de los fármacos , Corteza Auditiva/metabolismo , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Interferón gamma/metabolismoRESUMEN
N-(1,3-dimethylbutyl)-N '-phenyl-p-phenylenediamine (6PPD) and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) are ubiquitous in the environment and can cause toxicity to aquatic animals. However, research on the toxicological effects of 6PPD and 6PPD-Q on aquatic plants remains limited. The present study investigated the physiological, biochemical, and metabolic responses of the floating aquatic plant Eichhornia crassipes (E. crassipes) to environmentally relevant concentrations (0.1, 1, and 10 µg·L-1) of 6PPD and 6PPD-Q. We found that 6PPD and 6PPD-Q elicited minimal effects on plant growth, but 6PPD induced a concentration-dependent decrease in the content of photosynthetic pigments. Low doses (0.1 µg·L-1 and 1 µg·L-1) of 6PPD-Q significantly elevated Reactive Oxygen Species (ROS) content in E. crassipes roots, indicating oxidative damage. Furthermore, 6PPD-Q induced a more pronounced osmotic stress compared to 6PPD. Metabolic analyses revealed that carbohydrates were significantly altered under 6PPD and 6PPD-Q treatments. The findings of this study enhance the understanding of the environmental risks posed by 6PPD and 6PPD-Q to plants and reveal the potential mechanisms of phytotoxicity.
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Eichhornia , Estrés Oxidativo , Contaminantes Químicos del Agua , Eichhornia/metabolismo , Contaminantes Químicos del Agua/toxicidad , Fenilendiaminas/toxicidad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
A dual-template molecularly imprinted electrochemical sensor was developed for the simultaneous detection of serotonin (5-HT) and glutamate (Glu). First, amino-functionalized reduced graphene oxide (NRGO) was used as the modification material of a GCE to increase its electrical conductivity and specific surface area, using Glu and 5-HT as dual-template molecules and o-phenylenediamine (OPD) with self-polymerization ability as functional monomers. Through self-assembly and electropolymerization, dual-template molecularly imprinted polymers were formed on the electrode. After removing the templates, the specific recognition binding sites were exposed. The amount of NRGO, polymerization parameters, and elution parameters were further optimized to construct a dual-template molecularly imprinted electrochemical sensor, which can specifically recognize double-target molecules Glu and 5-HT. The differential pulse voltammetry (DPV) technique was used to achieve simultaneous detection of Glu and 5-HT based on their distinct electrochemical activities under specific conditions. The sensor showed a good linear relationship for Glu and 5-HT in the range 1 ~ 100 µM, and the detection limits were 0.067 µM and 0.047 µM (S/N = 3), respectively. The sensor has good reproducibility, repeatability, and selectivity. It was successfully utilized to simultaneously detect Glu and 5-HT in mouse serum, offering a more dependable foundation for objectively diagnosing and early warning of depression. Additionally, the double signal sensing strategy also provides a new approach for the simultaneous detection of both electroactive and non-electroactive substances.
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Técnicas Electroquímicas , Ácido Glutámico , Grafito , Límite de Detección , Impresión Molecular , Fenilendiaminas , Serotonina , Serotonina/sangre , Serotonina/análisis , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Animales , Ácido Glutámico/análisis , Ácido Glutámico/sangre , Ácido Glutámico/química , Grafito/química , Ratones , Fenilendiaminas/química , Depresión/diagnóstico , Depresión/sangre , Electrodos , Biomarcadores/sangre , Biomarcadores/análisis , Reproducibilidad de los ResultadosRESUMEN
Background: Myocardial infarction (MI) is characterized by irreversible cardiomyocyte death resulting from an inadequate supply of oxygenated blood to the myocardium. Recent studies have indicated that ferroptosis, a form of regulated cell death, exacerbates myocardial injury during MI. Concurrently, the upregulation of CD47 on the surface of damaged myocardium following MI impairs the clearance of dead cells by macrophages, thereby hindering efferocytosis. In this context, simultaneously inhibiting ferroptosis and enhancing efferocytosis may represent a promising strategy to mitigate myocardial damage post-MI. Methods: In this study, we engineered platelet membrane-coated hollow mesoporous silicon nanoparticles (HMSN) to serve as a drug delivery system, encapsulating ferroptosis inhibitor, Ferrostatin-1, along with an anti-CD47 antibody. We aimed to assess the potential of these nanoparticles (designated as Fer-aCD47@PHMSN) to specifically target the site of MI and evaluate their efficacy in reducing cardiomyocyte death and inflammation. Results: The platelet membrane coating on the nanoparticles significantly enhanced their ability to successfully target the site of myocardial infarction (MI). Our findings demonstrate that treatment with Fer-aCD47@PHMSN resulted in a 38.5% reduction in cardiomyocyte ferroptosis under hypoxia, indicated by decreased lipid peroxidation and increased in vitro. Additionally, Fer-aCD47@PHMSN improved cardiomyocyte efferocytosis by approximately 15% in vitro. In MI mice treated with Fer-aCD47@PHMSN, we observed a substantial reduction in cardiomyocyte death (nearly 30%), decreased inflammation, and significant improvement in cardiac function. Conclusion: Our results demonstrated that the cooperation between the two agents induced anti-ferroptosis effects and enhanced dead cardiomyocyte clearance by macrophage as well as anti-inflammation effects. Thus, our nanoparticle Fer-aCD47@PHMSN provides a new therapeutic strategy for targeted therapy of MI.
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Antígeno CD47 , Ferroptosis , Infarto del Miocardio , Miocitos Cardíacos , Nanopartículas , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Ferroptosis/efectos de los fármacos , Animales , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Nanopartículas/química , Ratones , Antígeno CD47/metabolismo , Fagocitosis/efectos de los fármacos , Ciclohexilaminas/farmacología , Ciclohexilaminas/química , Masculino , Fenilendiaminas/farmacología , Fenilendiaminas/química , Macrófagos/efectos de los fármacos , Plaquetas/efectos de los fármacos , Ratones Endogámicos C57BL , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Portadores de Fármacos/química , Humanos , EferocitosisRESUMEN
Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Crizotinib , Ferroptosis , Factor 2 Relacionado con NF-E2 , Factor de Transcripción STAT1 , Ferroptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Animales , Crizotinib/farmacología , Crizotinib/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Ratones , Transducción de Señal/efectos de los fármacos , Masculino , Fenilendiaminas/farmacología , Ratones Endogámicos C57BL , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Fosforilación/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the effects of Xiongcan Yishen Formula (XYF) on ferroptosis in mouse TM3 Leydig cells after oxidative stress injury (OSI) induced by H2O2.ãMethods: An oxidative stress injury model was established in mouse TM3 Leydig cells using H2O2 induction. The modeled TM3 cells were randomly divided into OSI group, XYF group, the ferroptosis inhibitor Ferrostatin-1 (F-1) group, and F-1+XYF group, which were respectively intervened with blank serum, 20% drug-containing serum, 2µmol/L F-1, and 2µmol/L F-1+ 20% drug-containing serum. A control group (normal TM3 cells + blank serum) was also set up. The morphology of cells in each group was observed, and the levels of testosterone, superoxide dismutase (SOD), reactive oxygen species (ROS), malondialdehyde (MDA), ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), glutathione peroxidase 4 (GPX4), fatty acid CoA ligase 4 (FACL4), total iron ions, and ferrous ions were detected. RESULTS: Compared with the model group, the control group showed significantly decreased expression of ROS, MDA, FACL4, total iron, and ferrous ions (P<0.05), and significantly increased levels of testosterone, SOD, GSH, FTH1, SLC7A11, and GPX4 (P<0.05). The male silkworm kidney-tonifying formula group significantly promoted testosterone secretion by TM3 cells and upregulated the expression of FTH1, SLC7A11, GPX4, GSH, and SOD in TM3 cells (P<0.05), while significantly downregulating ROS, MDA, FACL4, total iron ions, and ferrous ions (P<0.05). CONCLUSION: Following H2O2 exposure, oxidative stress can induce ferroptosis in mouse TM3 Leydig cells. XYF can antagonize OSI and ferroptosis in TM3 cells by activating the SLC7A11/GSH/GPX4 axis, which may underlie the mechanism of XYF in the treatment of male late-onset hypogonadism.
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Medicamentos Herbarios Chinos , Ferroptosis , Células Intersticiales del Testículo , Estrés Oxidativo , Animales , Ferroptosis/efectos de los fármacos , Masculino , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/efectos de los fármacos , Ratones , Estrés Oxidativo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno , Superóxido Dismutasa/metabolismo , Malondialdehído/metabolismo , Testosterona , Glutatión/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Ciclohexilaminas , FenilendiaminasRESUMEN
Atherosclerosis is a leading cause of cardiovascular diseases (CVDs), often resulting in major adverse cardiovascular events (MACEs), such as myocardial infarction and stroke due to the rupture or erosion of vulnerable plaques. Ferroptosis, an iron-dependent form of cell death, has been implicated in the development of atherosclerosis. Despite its involvement in CVDs, the specific role of ferroptosis in atherosclerotic plaque stability remains unclear. In this study, we confirmed the presence of ferroptosis in unstable atherosclerotic plaques and demonstrated that the ferroptosis inhibitor ferrostatin-1 (Fer-1) stabilizes atherosclerotic plaques in apolipoprotein E knockout (Apoe-/-) mice. Using bioinformatic analysis combining RNA sequencing (RNA-seq) with single-cell RNA sequencing (scRNA-seq), we identified Yes-associated protein 1 (YAP1) as a potential key regulator of ferroptosis in vascular smooth muscle cells (VSMCs) of unstable plaques. In vitro, we found that YAP1 protects against oxidized low-density lipoprotein (oxLDL)-induced ferroptosis in VSMCs. Mechanistically, YAP1 exerts its anti-ferroptosis effects by regulating the expression of glutaminase 1 (GLS1) to promote the synthesis of glutamate (Glu) and glutathione (GSH). These findings establish a novel mechanism where the inhibition of ferroptosis promotes the stabilization of atherosclerotic plaques through the YAP1/GLS1 axis, attenuating VSMC ferroptosis. Thus, targeting the YAP1/GLS1 axis to suppress VSMC ferroptosis may represent a novel strategy for preventing and treating unstable atherosclerotic plaques.
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Ferroptosis , Músculo Liso Vascular , Placa Aterosclerótica , Proteínas Señalizadoras YAP , Animales , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Proteínas Señalizadoras YAP/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Humanos , Masculino , Ratones Endogámicos C57BL , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Ratones Noqueados , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Fenilendiaminas/farmacología , Ciclohexilaminas/farmacología , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genéticaRESUMEN
The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviours that can be modelled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that Kv7/KCNQ channels may contribute to the transition from recreational to chronic drug use. However, to date, all such studies used noncontingent, experimenter-delivered drug model systems, and the extent to which this effect generalizes to rats trained to self-administer drugs is not known. Here, we tested the ability of retigabine (ezogabine), a Kv7 channel opener, to regulate instrumental behaviour in male Sprague Dawley rats. We first validated the ability of retigabine to target experimenter-delivered cocaine in a conditioned place preference (CPP) assay and found that retigabine reduced the acquisition of place preference. Next, we trained rats for cocaine-SA under a fixed-ratio or progressive-ratio reinforcement schedule and found that retigabine pretreatment attenuated the SA of low to moderate doses of cocaine. This was not observed in parallel experiments, with rats self-administering sucrose, a natural reward. Compared with sucrose-SA, cocaine-SA was associated with reductions in the expression of the Kv7.5 subunit in the nucleus accumbens, without alterations in Kv7.2 and Kv7.3. Therefore, these studies reveal a reward-specific reduction in SA behaviour and support the notion that Kv7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.
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Carbamatos , Cocaína , Fenilendiaminas , Ratas Sprague-Dawley , Autoadministración , Sacarosa , Animales , Fenilendiaminas/farmacología , Fenilendiaminas/administración & dosificación , Carbamatos/farmacología , Carbamatos/administración & dosificación , Cocaína/farmacología , Cocaína/administración & dosificación , Masculino , Ratas , Sacarosa/administración & dosificación , Sacarosa/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Canales de Potasio KCNQ/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Inhibidores de Captación de Dopamina/administración & dosificaciónRESUMEN
In recent years, great progress has been made on the study of nanozymes with enzyme-like properties. Here, bimetallic Fe and Ni nanoclusters were anchored on the nanosheets of nitrogen-rich layered graphitic carbon nitride by one-step pyrolysis at high temperature (Fe/Ni-CN). The loading content of Fe and Ni on Fe/Ni-CN is as high as 8.0%, and Fe/Ni-CN has a high specific surface area of 121.86 m2 g-1. The Fe/Ni-CN can effectively oxidize 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2, and exhibits efficient peroxidase-like activity, leading to a 17.2-fold increase compared to pure graphitic carbon nitride (CN). Similar to the natural horseradish peroxidase (HRP), the Fe/Ni-CN nanozyme follows catalytic kinetics. The Michaelis-Menten constant (Km) value of the Fe/Ni-CN nanozyme for TMB is about 8.3-fold lower than that for HRP, which means that the Fe/Ni-CN nanozyme has better affinity for TMB. In addition, the catalytic mechanism was investigated by combination of free radical quenching experiments and density-functional theory (DFT) calculations. The results show that the high peroxidase-like activity is due to the easy adsorption of H2O2 after bimetal loading, which is conducive to the production of hydroxyl radicals. Based on the extraordinary peroxidase-like activity, the colorimetric detection of p-phenylenediamine (PPD) was constructed with a wide linear range of 0.2-30 µM and a low detection limit of 0.02 µM. The sensor system has been successfully applied to the detection of residual PPD in real dyed hair samples. The results show that the colorimetric method is sensitive, highly selective and accurate. This study provides a new idea for the efficient enhancement of nanozyme activity and effective detection of PPD by a bimetallic synergistic strategy.
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Colorimetría , Grafito , Hierro , Níquel , Compuestos de Nitrógeno , Fenilendiaminas , Grafito/química , Fenilendiaminas/química , Colorimetría/métodos , Compuestos de Nitrógeno/química , Níquel/química , Hierro/química , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/química , Nitrilos/química , Límite de Detección , Catálisis , Bencidinas/químicaRESUMEN
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated. METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy. RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP. CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.