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1.
Adv Sci (Weinh) ; : e2404753, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39303219

RESUMEN

Several studies have observed renal cell ferroptosis during cisplatin-induced acute kidney injury (AKI). However, the mechanism is not completely clear. In this study, oxidized arachidonic acid (AA) metabolites are increased in cisplatin-treated HK-2 cells. Targeted metabolomics showed that the end product of pyrimidine biosynthesis is decreased and the initiating substrate of pyrimidine biosynthesis is increased in cisplatin-treated mouse kidneys. Mitochondrial DHODH, a key enzyme for pyrimidine synthesis, and its downstream product CoQH2, are downregulated. DHODH overexpression attenuated but DHODH silence exacerbated cisplatin-induced CoQH2 depletion and lipid peroxidation. Mechanistically, renal DHODH acetylation is elevated in cisplatin-exposed mice. Mitochondrial SIRT3 is reduced in cisplatin-treated mouse kidneys and HK-2 cells. Both in vitro SIRT3 overexpression and in vivo NMN supplementation attenuated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis. By contrast, Sirt3 knockout aggravated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis, which can not be attenuated by NMN. Additional experiments showed that cisplatin caused mitochondrial dysfunction and SIRT3 SUMOylation. Pretreatment with mitochondria-target antioxidant MitoQ alleviated cisplatin-caused mitochondrial dysfunction, SIRT3 SUMOylation, and DHODH acetylation. MitoQ pretreatment protected against cisplatin-caused AKI and renal cell ferroptosis. Taken together, these results suggest that mitochondrial dysfunction-evoked DHODH acetylation partially contributes to renal cell ferroptosis during cisplatin-induced AKI.

2.
Redox Biol ; 73: 103179, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38733909

RESUMEN

Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3-/- mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.


Asunto(s)
Cadmio , Ferroptosis , Mitocondrias , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Sirtuina 3 , Animales , Ferroptosis/efectos de los fármacos , Ratones , Cadmio/toxicidad , Cadmio/efectos adversos , Sirtuina 3/metabolismo , Sirtuina 3/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Acetilación , Humanos , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Línea Celular , Masculino , Ratones Noqueados , Coenzima A Ligasas
3.
Environ Pollut ; 351: 124060, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38685555

RESUMEN

Arsenic (As) is a notorious environmental toxicant widely present in various natural environments. As exposure has been correlated with the decline in sperm motility. Yet, the mechanism has not been fully elucidated. Adult male C57 mice were given 0, 1, or 15 mg/L NaAsO2 for 10 weeks. The mature seminiferous tubules and sperm count were decreased in As-exposed mice. Sperm motility and several sperm motility parameters, including average path velocity (VAP), straight-line velocity (VSL), curvilinear velocity (VCL), beat-cross frequency (BCF), linearity (LIN), straightness (STR), and amplitude of lateral head displacement (ALH), were declined in As-exposed mice. RNA sequencing and transcriptomics analyses revealed that differentially expressed genes (DEGs) were mainly enriched in metabolic pathways. Untargeted metabolomics analyses indicated that energy metabolism was disrupted in As-exposed mouse testes. Gene set enrichment analysis showed that glycolysis and oxidative phosphorylation were disturbed in As-exposed mouse testes. As-induced disruption of testicular glucose metabolism and oxidative phosphorylation was further validated by RT-PCR and Western blotting. In conclusion, As exposure causes decline in sperm motility accompanied by energy metabolism disorders in mouse testes.


Asunto(s)
Arsénico , Metabolismo Energético , Ratones Endogámicos C57BL , Motilidad Espermática , Testículo , Animales , Masculino , Ratones , Motilidad Espermática/efectos de los fármacos , Arsénico/toxicidad , Testículo/efectos de los fármacos , Testículo/metabolismo , Metabolismo Energético/efectos de los fármacos , Espermatozoides/efectos de los fármacos
4.
Int Immunopharmacol ; 113(Pt A): 109359, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36288647

RESUMEN

Numerous studies demonstrated that bleomycin (BLM) caused acute lung injury (ALI). This study explored the role of mitochondrial reactive oxygen species (ROS) on BLM-induced ALI and pulmonary epithelial ferroptosis. Male C57BL/6J mice were intratracheally injected with BLM (3.0 mg/kg). BEAS-2B cells, human bronchial epithelial cells, were cultured with BLM (10 µg/ml). Pulmonary MDA and 4-HNE, two markers of lipid peroxidation, were elevated in BLM-exposed mice. Oxidized lipids were upregulated in BLM-exposed BEAS-2B cells. Ferroptosis-characteristic ultrastructure, mainly disappearance of mitochondrial bilayer membrane structure and cristae, was observed in BLM-exposed pulmonary epithelium. Ferrostatin-1, a specific inhibitor of ferroptosis, attenuated BLM-evoked pulmonary lipid peroxidation, ferroptosis-characteristic mitochondrial ultrastructure and pulmonary epithelial death. The in vitro experiments showed that mitochondrial membrane potentials (MMPs) were decreased and mitochondrial ROS were increased in BLM-exposed BEAS-2B cells. Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, prevented BLM-induced MMP reduction and mitochondrial ROS elevation in BEAS-2B cells. The in vivo experiment found that MitoQ attenuated BLM-evoked GSH depletion and lipid peroxidation in mouse lungs. Moreover, MitoQ prevented BLM-induced ferroptosis-characteristic mitochondrial changes, pulmonary epithelial death and ALI. In conclusion, mitochondrial ROS are an initiator of BLM-induced pulmonary epithelial ferroptosis. Mitochondria-targeted antioxidants may be used as potential therapeutic agents for BLM-induced ALI.


Asunto(s)
Lesión Pulmonar Aguda , Ferroptosis , Masculino , Ratones , Humanos , Animales , Bleomicina/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Pulmón , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Mitocondrias
5.
Int Immunopharmacol ; 107: 108687, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35279512

RESUMEN

Our earlier studies indicated that reactive oxygen species (ROS) were involved in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). The present study aimed to explore the role of mitochondria-derived ROS on renal cell ferroptosis during LPS-induced AKI. Male CD-1 mice were intraperitoneally injected with LPS (2.0 mg/kg). Renal MDA and 4HNE residue, two markers of lipid peroxidation, were increased in LPS-exposed mice. Oxidized lipids were detected in LPS-treated human HK-2 cells. In vivo, ferroptosis-characteristic ultrastructure changes, including cell volume reduction, nuclear pyknosis and smaller mitochondria, were shown in renal cortex. In vitro, abnormal alteration of mitochondrial membrane potential was observed in LPS-treated human HK-2 cells. Ferrostatin-1, a specific inhibitor of ferroptosis, attenuated LPS-evoked renal lipid peroxidation, ferroptosis-characteristic mitochondrial damage and renal cell death. Mechanistically, mitochondria-derived ROS were elevated in LPS-stimulated HK-2 cells. MitoQ, a mitochondria-targeted antioxidant, almost completely scavenged LPS-stimulated mitochondrial ROS in human HK-2 cells. Moreover, pretreatment with MitoQ attenuated LPS-induced GSH depletion and lipid peroxidation in mouse kidney. Finally, pretreatment with MitoQ alleviated LPS-induced renal cell death and AKI. Taken together, these results suggest that mitochondria-derived ROS contribute, at least partially, to renal cell ferroptosis during LPS-induced AKI. Mitochondria-targeted antioxidants may be potential therapeutic agents for sepsis-induced AKI.


Asunto(s)
Lesión Renal Aguda , Ferroptosis , Lesión Renal Aguda/tratamiento farmacológico , Animales , Antioxidantes/uso terapéutico , Femenino , Humanos , Riñón/metabolismo , Lipopolisacáridos/metabolismo , Masculino , Ratones , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo
6.
Int J Dermatol ; 61(3): 337-345, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34435665

RESUMEN

BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disease, featured by epidermal hyperproliferation. Psoriasis exhibits metabolic abnormalities, which can further aggravate the condition of psoriasis. The present study aimed to investigate the role of psoriatic keratinocytes (KCs) in the metabolic reprogramming of dermal mesenchymal stem cells (DMSCs). METHODS: Dermal mesenchymal stem cells were cocultured with primary KCs either from psoriatic lesions or from normal subjects using Transwell plate. Glycolysis and mitochondrial metabolism of DMSCs were detected by Seahorse Metabolic Analyzer. Expression levels of proteins were analyzed by Western blotting. DMSCs proliferation was assessed using 5-ethynyl-2'-deoxyuridine assay and Cell Counting Kit-8. RESULTS: In comparison with normal KCs, coculture of psoriatic KCs with DMSCs dramatically increased glycolytic and mitochondrial metabolism, and expression levels of stem cell factor, epidermal growth factor, glucose transporter 1, and c-Myc. Moreover, psoriatic KCs were more potent than normal KCs in the stimulation of DMSC proliferation. CONCLUSIONS: In conclusion, psoriatic KCs display a higher potency in metabolic reprogramming and stimulation of DMSC proliferation, possibly contributing to the pathogenesis of psoriasis. However, whether the intervention of metabolic reprogramming of DMSCs can alleviate psoriasis remains to be determined.


Asunto(s)
Células Madre Mesenquimatosas , Psoriasis , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Humanos , Queratinocitos
7.
J Nanosci Nanotechnol ; 21(3): 1784-1788, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33404448

RESUMEN

We have studied the oxidation behaviors of aluminum (Al) nanopowders with different particle sizes using a real-time synchrotron X-ray scattering during annealing in air. The Al nanopowders with small particle size of 78 nm at room temperature (RT) were a single crystal. The surface of the nanopowders was first oxidized to amorphous Al oxide near 450 °C, and then crystallized to γ-Al2O3 phase at 550 °C. The inside of the nanopowders existed as crystal Al phase at 680 °C, high compared to the melting temperature of Al bulk, 660 °C. In contrast, the Al nanopowders with large particle size of 816 nm at RT have multi grains inside a particle. The surface and grain boundary of the powders were first oxidized to amorphous Al oxide near 470 °C, and then crystallized to γ-Al2O3 phase at 550 °C. The inside of the powders existed as amorphous Al phase at 620 °C, melted at 656 °C, and then oxidized gradually above 656 °C.

8.
J Nanosci Nanotechnol ; 21(3): 2046-2050, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33404491

RESUMEN

We have studied the annealing behaviors of pure Al (Al-1050) and Al-Mg-Si alloy (Al-6061) with plate-type using a real-time synchrotron X-ray scattering in vacuum. At room temperature (RT), the crystal domain size of Al phase in the Al-Mg-Si alloy was small as 70 nm, compared to that in the pure Al, 142 nm. The crystal Al phase in the Al-Mg-Si alloy has more thermal stability than that in the pure Al. The crystal Al phase in the Al-Mg-Si alloy was thermally stable in amount and size up to 250 °C. These are due to the existence of intermetallic crystal Mg2Si phase, which is thermally stable in amount and size up to 250 °C.

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