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1.
J Control Release ; 359: 12-25, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37244298

RESUMEN

Glioblastoma (GBM) is one of the most malignant tumors of the central nervous system and has a poor prognosis. GBM cells are highly sensitive to ferroptosis and heat, suggesting thermotherapy-ferroptosis as a new strategy for GBM treatment. With its biocompatibility and photothermal conversion efficiency, graphdiyne (GDY) has become a high-profile nanomaterial. Here, the ferroptosis inducer FIN56 was employed to construct GDY-FIN56-RAP (GFR) polymer self-assembled nanoplatforms against GBM. GDY could effectively load FIN56 and FIN56 released from GFR in a pH-dependent manner. The GFR nanoplatforms possessed the advantages of penetrating the BBB and acidic environment-induced in situ FIN56 release. Moreover, GFR nanoplatforms induced GBM cell ferroptosis by inhibiting GPX4 expression, and 808 nm irradiation reinforced GFR-mediated ferroptosis by elevating the temperature and promoting FIN56 release from GFR. In addition, the GFR nanoplatforms were inclined to locate in tumor tissue, inhibit GBM growth, and prolong lifespan by inducing GPX4-mediated ferroptosis in an orthotopic xenograft mouse model of GBM; meanwhile, 808 nm irradiation further improved these GFR-mediated effects. Hence, GFR may be a potential nanomedicine for cancer therapy, and GFR combined with photothermal therapy may be a promising strategy against GBM.


Asunto(s)
Ferroptosis , Glioblastoma , Grafito , Humanos , Animales , Ratones , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Terapia Fototérmica , Línea Celular Tumoral
2.
Neurochem Int ; 153: 105260, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34953963

RESUMEN

Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes ß-amyloid (Aß) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aß production via promoting the lysosomal degradation of ß-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3ß phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3ß activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.


Asunto(s)
Enfermedad de Alzheimer , Receptores de Calcitriol , Proteínas tau , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas , Humanos , Hierro , Ratones , Ratones Transgénicos , Fosforilación , Presenilina-1/genética , Receptores de Calcitriol/metabolismo , Proteínas tau/metabolismo
3.
EBioMedicine ; 45: 393-407, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31303501

RESUMEN

BACKGROUND: Recent studies have revealed that vitamin D deficiency may increase the risk of Alzheimer's disease, and vitamin D supplementation may be effective strategy to ameliorate the neurodegenerative process in Alzheimer's disease patients. Paricalcitol (PAL), a low-calcemic vitamin D receptor agonist, is clinically used to treat secondary hyperparathyroidism. However, the potential application of PAL for treating neurodegenerative disorders remains unexplored. METHODS: The APP/PS1 mice were intraperitoneally injected with PAL or vehicle every other day for 15 weeks. The ß-amyloid (Aß) production was confirmed using immunostaining and enzyme linked immunosorbent assay. The underlying mechanism was verified by western blot and immunostaining in vivo and in vitro. FINDINGS: Long-term PAL treatment clearly reduced ß-amyloid (Aß) generation and neuronal loss in APP/PS1 transgenic mouse brains. PAL stimulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) possibly through inhibiting sterol regulatory element binding protein-2 (SREBP2); PAL also promoted LRP1-mediated ß-site APP cleavage enzyme 1 (BACE1) transport to late endosomes, thus increasing the lysosomal degradation of BACE1. Furthermore, PAL diminished 8-hydroxyguanosine (8-OHdG) generation in neuronal mitochondria via enhancing base excision repair (BER), resulting in the attenuation of calpain-1-mediated neuronal loss. INTERPRETATION: The present data demonstrate that PAL can reduce Aß generation through accelerating BACE1 lysosomal degradation and can inhibit neuronal loss through suppressing mitochondrial 8-OHdG generation. Hence, PAL might be a promising agent for treating Alzheimer's disease. FUND: This study was financially supported by the Natural Science Foundation of China (U1608282).


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/genética , Ácido Aspártico Endopeptidasas/genética , Ergocalciferoles/farmacología , Neuronas/efectos de los fármacos , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Calpaína/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Lisosomas/efectos de los fármacos , Lisosomas/genética , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Neuronas/patología , Oligopéptidos/genética , Presenilina-1/genética , Proteolisis/efectos de los fármacos
4.
Redox Biol ; 14: 535-548, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29126071

RESUMEN

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurofibrillary tangles (NFTs) composed of Tau protein. α-Lipoic acid (LA) has been found to stabilize the cognitive function of AD patients, and animal study findings have confirmed its anti-amyloidogenic properties. However, the underlying mechanisms remain unclear, especially with respect to the ability of LA to control Tau pathology and neuronal damage. Here, we found that LA supplementation effectively inhibited the hyperphosphorylation of Tau at several AD-related sites, accompanied by reduced cognitive decline in P301S Tau transgenic mice. Furthermore, we found that LA not only inhibited the activity of calpain1, which has been associated with tauopathy development and neurodegeneration via modulating the activity of several kinases, but also significantly decreased the calcium content of brain tissue in LA-treated mice. Next, we screened for various modes of neural cell death in the brain tissue of LA-treated mice. We found that caspase-dependent apoptosis was potently inhibited, whereas autophagy did not show significant changes after LA supplementation. Interestingly, Tau-induced iron overload, lipid peroxidation, and inflammation, which are involved in ferroptosis, were significantly blocked by LA administration. These results provide compelling evidence that LA plays a role in inhibiting Tau hyperphosphorylation and neuronal loss, including ferroptosis, through several pathways, suggesting that LA may be a potential therapy for tauopathies.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Ácido Tióctico/uso terapéutico , Proteínas tau/genética , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Inflamación/complicaciones , Inflamación/genética , Inflamación/patología , Peroxidación de Lípido/efectos de los fármacos , Ratones Transgénicos , Mutación Puntual , Tauopatías/complicaciones , Tauopatías/tratamiento farmacológico , Tauopatías/genética , Tauopatías/patología , Proteínas tau/metabolismo
5.
Mol Med Rep ; 11(2): 940-6, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25355274

RESUMEN

Panax ginseng is traditionally used as a remedy for cancer, inflammation, stress and aging, and ginsenoside­Rg5 is a major bioactive constituent of steamed ginseng. The present study aimed to evaluate whether ginsenoside­Rg5 had any marked cytotoxic, apoptotic or DNA­damaging effects in human cervical cancer cells. Five human cervical cancer cell lines (HeLa, MS751, C33A, Me180 and HT­3) were used to investigate the cytotoxicity of ginsenoside­Rg5 using a 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay. Additionally, the effects of ginsenoside­Rg5 on the apoptosis of HeLa and MS751 cells were detected using DNA ladder assays and flow cytometry. DNA damage was assessed in the HeLa and MS751 cells using alkaline comet assays and by detection of γH2AX focus formation. The HeLa and MS751 cells were significantly more sensitive to ginsenoside­Rg5 treatment compared with the C­33A, HT­3 and Me180 cells. As expected, ginsenoside­Rg5 induced significant concentration­ and time­dependent increases in apoptosis. In addition, ginsenoside­Rg5 induced significant concentration­dependent increases in the level of DNA damage compared with the negative control. Consistent with the comet assay data, the percentage of γH2AX­positive HeLa and MS751 cells also revealed that ginsenoside­Rg5 caused DNA double­strands to break in a concentration­dependent manner. In conclusion, ginsenoside­Rg5 had marked genotoxic effects in the HeLa and MS751 cells and, thus, demonstrates potential as a genotoxic or cytotoxic drug for the treatment of cervical cancer.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Ginsenósidos/farmacología , Panax/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Fragmentación del ADN/efectos de los fármacos , Femenino , Células HeLa/efectos de los fármacos , Humanos , Neoplasias del Cuello Uterino/patología
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