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1.
Plant Biotechnol J ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600703

RESUMO

Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, we unveil a critical role played by a GmNF-YC9-mediated CCAAT-box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate-limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF-YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF-YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress-induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF-YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention.

2.
CNS Neurosci Ther ; 30(2): e14394, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37545321

RESUMO

AIMS: Adult hippocampal neurogenesis is an important player in brain homeostasis and its impairment participates in neurological diseases. Iron overload has emerged as an irreversible factor of brain aging, and is also closely related to degenerative disorders, including cognitive dysfunction. However, whether brain iron overload alters hippocampal neurogenesis has not been reported. We investigated the effect of elevated iron content on adult hippocampal neurogenesis and explored the underlying mechanism. METHODS: Mouse models with hippocampal iron overload were generated. Neurogenesis in hippocampus and expression levels of related molecules were assessed. RESULTS: Iron accumulation in hippocampus remarkably impaired the differentiation of neural stem cells, resulting in a significant decrease in newborn neurons. The damage was possibly attributed to iron-induced downregulation of proprotein convertase furin and subsequently decreased maturation of brain-derived neurotrophic factor (BDNF), thus contributing to memory decline and anxiety-like behavior of mice. Supportively, knockdown of furin indeed suppressed hippocampal neurogenesis, while furin overexpression restored the impairment. CONCLUSION: These findings demonstrated that iron overload damaged hippocampal neurogenesis likely via iron-furin-BDNF pathway. This study provides new insights into potential mechanisms on iron-induced neurotoxicity and the causes of neurogenesis injury and renders modulating iron homeostasis and furin expression as novel therapeutic strategies for treatment of neurological diseases.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Sobrecarga de Ferro , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Furina/metabolismo , Furina/farmacologia , Hipocampo/metabolismo , Neurogênese/fisiologia , Ferro/metabolismo
3.
Pflugers Arch ; 475(11): 1251-1263, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37747537

RESUMO

Studies have confirmed that hepatic iron overload is one of the important factors causing liver damage in the metabolic syndrome (MS). As a special form of autophagy, ferritinophagy is involved in the regulation of iron metabolism. Our previous studies have shown that chronic intermittent hypobaric hypoxia (CIHH) can improve the iron metabolism disorder. The aim of this study was to investigate how CIHH improves liver damage through ferritinophagy in MS rats. Male Sprague-Dawley rats aged 8-10 weeks were randomly divided into four groups: control (CON), CIHH (exposed to hypoxia at a simulated altitude of 5000 m for 28 days, 6 h daily), MS model (induced by a 16-week high-fat diet and 10% fructose water feeding), and MS + CIHH (exposed to CIHH after a 16-week MS inducement) groups. Liver index, liver function, iron content, tissue morphology, oxidative stress, ferritinophagy, ferroptosis, and iron metabolism-related protein expression were measured, and the ferritinophagy flux in the liver was further analyzed. Compared with CON rats, MS rats had an increased liver index, damaged liver tissue and function, increased iron content and iron deposition, disrupted iron metabolism, significantly increased oxidative stress indicators in the liver, significantly upregulated expression of ferroptosis-related proteins, and downregulated expression of nuclear receptor coactivator 4 (NCOA4) and ferritinophagy flux. After CIHH treatment, the degree of liver damage and various abnormal indicators in MS rats were significantly improved. CIHH may improve liver damage by promoting NCOA4-mediated ferritinophagy, reducing iron overload and oxidative stress, and thereby alleviating ferroptosis in MS rats.


Assuntos
Sobrecarga de Ferro , Síndrome Metabólica , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Hipóxia/metabolismo , Fígado/metabolismo , Ferro
4.
Sci China Life Sci ; 66(8): 1841-1857, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36929272

RESUMO

Iron is important for life, and iron deficiency impairs development, but whether the iron level regulates neural differentiation remains elusive. In this study, with iron-regulatory proteins (IRPs) knockout embryonic stem cells (ESCs) that showed severe iron deficiency, we found that the Pax6- and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1-/-IRP2-/- ESCs were significantly decreased after inducing neural differentiation. Consistently, in vivo study showed that the knockdown of IRP1 in IRP2-/- fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons. These findings suggest that low intracellular iron status significantly inhibits neurodifferentiation. When supplementing IRP1-/-IRP2-/- ESCs with iron, these ESCs could differentiate normally. Further investigations revealed that the underlying mechanism was associated with an increase in reactive oxygen species (ROS) production caused by the substantially low level of iron and the down-regulation of iron-sulfur cluster protein ISCU, which, in turn, affected the proliferation and differentiation of stem cells. Thus, the appropriate amount of iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation.


Assuntos
Deficiências de Ferro , Proteínas Ferro-Enxofre , Espécies Reativas de Oxigênio , Animais , Camundongos , Ferro/metabolismo , Proteína 1 Reguladora do Ferro/metabolismo , Proteína 2 Reguladora do Ferro/metabolismo , Proteínas Ferro-Enxofre/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
Antioxidants (Basel) ; 12(2)2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36829936

RESUMO

CHIR99021 is an aminopyrimidine derivative, which can efficiently inhibit the activity of glycogen synthesis kinase 3α (GSK-3α) and GSK-3ß. As an essential component of stem cell culture medium, it plays an important role in maintaining cell stemness. However, the mechanism of its role is not fully understood. In the present study, we first found that removal of CHIR99021 from embryonic stem cell culture medium reduced iron storage in mouse embryonic stem cells (mESCs). CHIR99021-treated Neuro-2a cells led to an upregulation of ferritin expression and an increase in intracellular iron levels, along with GSK3ß inhibition and Wnt/GSK-3ß/ß-catenin pathway activation. In addition, iron treatment activated the classical Wnt pathway by affecting the expression of ß-catenin in the Neuro-2a cells. Our data link the role of iron in the maintenance of cell stemness via the Wnt/GSK-3ß/ß-catenin signaling pathway, and identify intermediate molecules, including Steap1, Bola2, and Kdm6bos, which may mediate the upregulation of ferritin expression by CHIR99021. These findings reveal novel mechanisms of the maintenance of cell stemness and differentiation and provide a theoretical basis for the development of new strategies in stem cell treatment in disease.

6.
Cell Death Dis ; 14(2): 161, 2023 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-36841833

RESUMO

Ischemic stroke is associated with high mortality and morbidity rates worldwide. However, the molecular mechanisms underlying the neuronal damage incurred by stroke victims remain unclear. It has previously been reported that ischemic stroke can induce an increase in the levels of brain iron, which is an important factor of in the associated brain damage. Ferroportin 1 (FPN1), the only known cellular iron export protein, is found in brain microvascular endothelial cells (BMVECs) at the blood-brain barrier, and is considered the gateway for entry of plasma iron into the central nervous system. Despite the connection of brain iron to neuronal damage, the role of BMVECs FPN1 in ischemic stroke remains unexplored. Herein, we conditionally deleted Fpn1 in mouse endothelial cells (ECs), using VE-cadherin-Cre transgenic mice, and explored the impact on brain iron homeostasis after stroke. Our data demonstrated that Fpn1 knockout in ECs decreased the brain iron levels in mice, attenuated the oxidative stress and inflammatory responses after stroke, and inhibited both ferroptosis and apoptosis, ultimately alleviating neurological impairment and decreasing cerebral infarct volume during the acute phase of ischemic stroke. By contrast, we found that Fpn1 knockout in ECs delayed the recovery of neurological function in mice following ischemic stroke. We also found that ECs Fpn1 knockout decreased the brain iron levels after stroke, exacerbated glial cell proliferation, and inhibited neuronal development, indicating that the diminished brain iron levels hindered the repair of neural injury in mice. In conclusion, our findings reveal a dual consequence of FPN1 deficiency in ECs in the development of ischemic stroke. More specifically, iron deficiency initially exerts a neuroprotective effect during the acute phase of ischemic stroke but inhibits recovery during the later stages. Our findings are important to the development of iron- or FPN1-targeting therapeutics for the treatment of ischemic stroke.


Assuntos
Proteínas de Transporte de Cátions , AVC Isquêmico , Fármacos Neuroprotetores , Animais , Camundongos , Células Endoteliais/metabolismo , Ferro/metabolismo , AVC Isquêmico/metabolismo , Camundongos Transgênicos , Fármacos Neuroprotetores/metabolismo , Caderinas/metabolismo , Proteínas de Transporte de Cátions/genética
7.
Cell Death Dis ; 13(8): 667, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915080

RESUMO

Brain iron dysregulation associated with aging is closely related to motor and cognitive impairments in neurodegenerative diseases. The regulation of iron traffic at the blood-brain barrier (BBB) is crucial to maintain brain iron homeostasis. However, the specific mechanism has not been clarified in detail. Using various conditional gene knockout and overexpression mice, as well as cell co-culture of astrocyte and bEND.3 in the transwell, we found that astrocyte hepcidin knockdown increased the expression of ferroportin 1 (FPN1) of brain microvascular endothelial cells (BMVECs), and that it also induced brain iron overload and cognitive decline in mice. Moreover, BMVECs FPN1 knockout decreased iron contents in the cortex and hippocampus. Furthermore, hepcidin regulates the level of FPN1 of BMVECs with conditional gene overexpression in vivo and in vitro. Our results revealed that astrocytes responded to the intracellular high iron level and increased the secretion of hepcidin, which in turn diminished iron uptake at BBB from circulation through directly regulating FPN1 of BMVECs. Our results demonstrate that FPN1 of BMVECs is a gateway for iron transport into the brain from circulation, and the controller of this gateway is hepcidin secreted by astrocyte at its endfeet through physical contact with BMVECs. This regulation is indeed the major checkpoint for iron transport from the blood circulation to the brain. This study delineates the pathway and regulation of iron entry into the brain, providing potential therapeutic targets for iron dysregulation-related neurological diseases.


Assuntos
Hepcidinas , Ferro , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Proteínas de Transporte de Cátions , Células Endoteliais/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Ferro/metabolismo , Camundongos
8.
Cell Death Dis ; 12(5): 447, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953171

RESUMO

Ischaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.


Assuntos
Morte Celular/imunologia , Ferritinas/metabolismo , Ferroptose/imunologia , Mitocôndrias/imunologia , Traumatismo por Reperfusão/imunologia , Animais , Humanos , Camundongos , Camundongos Knockout
9.
Sci Rep ; 10(1): 4652, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157173

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

10.
Sci Bull (Beijing) ; 65(14): 1192-1202, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-36659149

RESUMO

Duplications of MECP2-containing genomic segments led to severe autistic symptoms in male. Transgenic mice overexpressing the human MECP2 gene exhibit autistic-like behaviors. Neural circuits underlying social defects in MECP2 transgenic (MECP2-TG) mice remain unknown. To observe neural activity of MECP2-TG mice in vivo, we performed calcium imaging by implantation of microendoscope in the hippocampal CA1 regions of MECP2-TG and wild type (WT) mice. We identified neurons whose activities were tightly associated with social interaction, which activity patterns were compromised in MECP2-TG mice. Strikingly, we rescued the social-related neural activity in CA1 and social defects in MECP2-TG mice by deleting the human MECP2 transgene using the CRISPR/Cas9 method during adulthood. Our data points to the neural circuitry responsible for social interactions and provides potential therapeutic targets for autism in adulthood.

11.
Gen Comp Endocrinol ; 284: 113268, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491376

RESUMO

CPFX is a highly effective antibiotic, but it has been reported to significantly impair both testicular function and structure in rats. In this study, we assessed reversal of CPFX-induced variation in mice testicular structure and testosterone synthesis by probiotic microbes in the infected model and normal model. We detected testicular weight, testicular structure and Leydig cell variables in numbers. We detected the levels of serum testosterone and steroidogenic enzymes, as well as DBC1, Sirt1, NF-κB, and related redox state and inflammatory response in the testes. The results showed that probiotic microbes had significantly elevated serum testosterone levels and steroidogenic enzymes, higher Sirt1, anti-oxidative enzymes and anti-inflammatory cytokine expression, and lower NF-κB, DBC1, oxidative damage, pro-inflammatory cytokine expression. The results suggest that the testis-protective, antiinflammatory and antioxidation effects of probiotics largely resulted from its ability to decrease oxidative stress and preserve antioxidant activity by stabilizing antioxidant defense systems, reducing oxidative damage and inflammatory response.


Assuntos
Ciprofloxacina/farmacologia , Probióticos/metabolismo , Testículo/metabolismo , Testículo/microbiologia , Testosterona/metabolismo , Animais , Antioxidantes/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocinas/metabolismo , Epitélio/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Peso Molecular , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Testículo/efeitos dos fármacos
12.
Sci Rep ; 9(1): 10556, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332209

RESUMO

In our study, we explored changes in the redox status and inflammatory response in the testes of the SAMP8 model of varying ages (2, 4, 8, 10 months old) compared with control mice SAMR1 by the methods of immunohistochemical staining, Western blotting, RT-PCR and Luminex multi-analyte cytokine profiling. We found that as ROS and inflammation levels increased during aging, steroidogenic enzymes (StAR and P450scc) reduced and led to the decline of testosterone production eventually. The pathways of P38 MAPK → COX2 and NF-κB → COX2 were detected by using specific inhibitors of SB203580 and Bay 11-7082 in isolated Leydig cells. These results indicated that activation of both p38 MAPK → COX2 and NF-κB → COX2 signaling pathways are functionally linked to the oxidative stress response and chronic inflammation during aging, and mediate their inhibitory effects on testosterone production.


Assuntos
Envelhecimento/metabolismo , Testículo/metabolismo , Testosterona/metabolismo , Envelhecimento/genética , Animais , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Oxirredução , Estresse Oxidativo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Testículo/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
J Cell Physiol ; 234(5): 7600-7607, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30370612

RESUMO

Iron plays an essential role in various cellular metabolic processes of the body. Maintenance of cellular iron homeostasis is particularly important for keeping the normal functions of the cells. Ferroportin 1 (FPN1) is the currently only known iron exporter on the cell membrane. It has been indicated that the regulation of FPN1 in response to the alteration of iron level mainly involves two processes, posttranscriptional repression by iron regulatory proteins (IRPs) and posttranslational degradation by hepcidin, the major iron-sensing hormone. However, whether there is any communication between the two types of regulations or which one plays dominant role has not been reported. In our study with IRP2-/- mice, we found that knockout of IRP2 increased FPN1 expression in the cerebral cortex of IRP2-/- mice, whereas the upregulation of FPN1 was more significant in IRP1/IRP2 dual knockdown fibroblasts. Interestingly, we found that the knockout of IRP2 severely affected the regulation effect of hepcidin on FPN1 in mouse brain. FPN1 level decreased dramatically in the brain of wild-type mice injected with hepcidin, but it did not decrease much in IRP2 knockout mice. Further investigation disclosed that the compromised hepcidin-FPN1 regulation in IRP2-/- cells was directly dependent on the existence of iron-responsive element (IRE) in FPN1 messenger RNA. These results indicate that IRPs and hepcidin coordinately regulate the FPN1 level in mice. This study will provide a more comprehensive understanding of the regulatory mechanisms of FPN1 expression.


Assuntos
Encéfalo/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Hepcidinas/metabolismo , Proteínas Reguladoras de Ferro/metabolismo , Ferro/metabolismo , Animais , Membrana Celular/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Homeostase/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Regulação para Cima/fisiologia
14.
Free Radic Biol Med ; 124: 1-11, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29807160

RESUMO

In order to discover new drug delivery approaches and to understand the mechanism of iron overload in cerebral ischemia/reperfusion (I/R), we aimed to investigate the effects of lycopene (LYC) in the form of nano-liposomes (L-LYC) on iron-regulating proteins and ischemic brain injury. We found that L-LYC significantly increased the LYC content in serum and the brain. Adult male Sprague-Dawley rats treated with L-LYC for 14 days were subjected to 60 min of ischemia and 7 days of reperfusion. The effects of L-LYC were evaluated by infarction volume, neurological score, neuronal apoptosis, and markers for oxidative stress. Levels of iron-regulating protein such as hepcidin and ferroportin (FPN1) were examined. L-LYC reduced cerebral infarction and improved neurobehavior of the rats more efficiently than "naked" LYC. L-LYC reduced protein levels of oxidases (e.g. nitric oxide synthase and NOX2), increased the level of Bcl-2, lowered caspase-3, and suppressed apoptosis through inhibiting MAPK-JNK. Furthermore, L-LYC suppressed hepcidin-mediated decrease in FPN1, a sole iron exporter, and normalized the levels of iron. We further demonstrated that the effect of L-LYC on hepcidin expression might result from its ability to attenuate the release of the inflammatory factor interleukin 6. The results demonstrated that nano-liposomal encapsulation significantly improved LYC efficacy in providing neuronal protection against I/R injury. The data also revealed a novel mechanism of L-LYC's neuroprotection by regulating iron metabolism in an ischemic brain.


Assuntos
Antioxidantes/administração & dosagem , Ferro/metabolismo , Lipossomos/química , Licopeno/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Animais , Lipossomos/administração & dosagem , Masculino , Nanoestruturas , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
15.
Cell Death Dis ; 8(3): e2676, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28300826

RESUMO

Inflammatory responses involving microglia and astrocytes contribute to the pathogenesis of neurodegenerative diseases (NDs). In addition, inflammation is tightly linked to iron metabolism dysregulation. However, it is not clear whether the brain inflammation-induced iron metabolism dysregulation contributes to the NDs pathogenesis. Herein, we demonstrate that the expression of the systemic iron regulatory hormone, hepcidin, is induced by lipopolysaccharide (LPS) through the IL-6/STAT3 pathway in the cortex and hippocampus. In this paradigm, activated glial cells are the source of IL-6, which was essential in the iron overload-activated apoptosis of neurons. Disrupting astrocyte hepcidin expression prevented the apoptosis of neurons, which were able to maintain levels of FPN1 adequate to avoid iron accumulation. Together, our data are consistent with a model whereby inflammation initiates an intercellular signaling cascade in which activated microglia, through IL-6 signaling, stimulate astrocytes to release hepcidin which, in turn, signals to neurons, via hepcidin, to prevent their iron release. Such a pathway is relevant to NDs in that it links inflammation, microglia and astrocytes to neuronal damage.


Assuntos
Apoptose/efeitos dos fármacos , Astrócitos/metabolismo , Hepcidinas/metabolismo , Lipopolissacarídeos/farmacologia , Neurônios/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Encefalite/metabolismo , Encefalite/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-6/metabolismo , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
J Cell Biochem ; 118(6): 1596-1605, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27925282

RESUMO

Disruption of iron homeostasis in brain has been found to be closely involved in several neurodegenerative diseases. Recent studies have reported that appropriate intermittent hypobaric hypoxia played a protective role in brain injury caused by acute hypoxia. However, the mechanisms of this protective effect have not been fully understood. In this study, Sprague-Dawley (SD) rat models were developed by hypobaric hypoxia treatment in an altitude chamber, and the iron level and iron related protein levels were determined in rat brain after 4 weeks of treatment. We found that the iron levels significantly decreased in the cortex and hippocampus of rat brain as compared to that of the control rats without hypobaric hypoxia treatment. The expression levels of iron storage protein L-ferritin and iron transport proteins, including transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin1 (FPN1), were also altered. Further studies found that the iron regulatory protein 2 (IRP2) played a dominant regulatory role in the changes of iron hemostasis, whereas iron regulatory protein 1 (IRP1) mainly acted as cis-aconitase. These results, for the first time, showed the alteration of iron metabolism during hypobaric hypoxia in rat models, which link the potential neuroprotective role of hypobaric hypoxia treatment to the decreased iron level in brain. This may provide insight into the treatment of iron-overloaded neurodegenerative diseases. J. Cell. Biochem. 118: 1596-1605, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Encéfalo/metabolismo , Hipóxia/metabolismo , Proteína 1 Reguladora do Ferro/metabolismo , Proteína 2 Reguladora do Ferro/metabolismo , Ferro/metabolismo , Animais , Apoferritinas/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Hipóxia Celular , Modelos Animais de Doenças , Homeostase , Masculino , Ratos , Ratos Sprague-Dawley , Receptores da Transferrina/metabolismo
17.
Cell Death Dis ; 7(11): e2475, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27853170

RESUMO

Mitochondrial ferritin (FtMt) is a mitochondrially localized protein possessing ferroxidase activity and the ability to store iron. FtMt overexpression in cultured cells protects against oxidative damage by sequestering redox-active, intracellular iron. Here, we found that acute exhaustive exercise significantly increases FtMt expression in the murine heart. FtMt gene disruption decreased the exhaustion exercise time and altered heart morphology with severe cardiac mitochondrial injury and fibril disorganization. The number of apoptotic cells as well as the levels of apoptosis-related proteins was increased in the FtMt-/- mice, though the ATP levels did not change significantly. Concomitant to the above was a high 'uncommitted' iron level found in the FtMt-/- group when exposed to acute exhaustion exercise. As a result of the increase in catalytic metal, reactive oxygen species were generated, leading to oxidative damage of cellular components. Taken together, our results show that the absence of FtMt, which is highly expressed in the heart, increases the sensitivity of mitochondria to cardiac injury via oxidative stress.


Assuntos
Cardiotônicos/metabolismo , Ferritinas/metabolismo , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Condicionamento Físico Animal , Doença Aguda , Animais , Apoptose , Cálcio/metabolismo , Deleção de Genes , Immunoblotting , Ferro/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/ultraestrutura , Miocárdio/patologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo
18.
Front Aging Neurosci ; 8: 308, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28066232

RESUMO

Ferroptosis, a newly identified form of regulated cell death, is characterized by overwhelming iron-dependent accumulation of lethal lipid reactive oxygen species (ROS). Preventing cellular iron overload by reducing iron uptake and increasing iron storage may contribute to inhibit ferroptosis. Mitochondrial ferritin (FtMt) is an iron-storage protein that is located in the mitochondria, which has a significant role in modulating cellular iron metabolism. Recent studies showed that FtMt played inhibitory effects on oxidative stress-dependent neuronal cell damage. However, the potential role of FtMt in the progress of ferroptosis in neuronal cells has not been studied. To explore this, we established ferroptosis models of cell and drosophila by erastin treatment. We found that overexpression of FtMt in neuroblastoma SH-SY5Y cells significantly inhibited erastin-induced ferroptosis, which very likely was achieved by regulation of iron homeostasis. Upon erastin treatment, significant increases of cellular labile iron pool (LIP) and cytosolic ROS were observed in wild-type SH-SY5Y cells, but not in the FtMt-overexpressed cells. Consistent with that, the alterations of iron-related proteins in FtMt-overexpressed cells were different from that of the control cells. We further investigated the role of FtMt in erastin-induced ferroptosis in transgenic drosophila. We found that the wild-type drosophilas fed an erastin-containing diet didn't survive more than 3 weeks. In contrast, the FtMt overexpressing drosophilas fed the same diet were survival very well. These results indicated that FtMt played a protective role in erastin-induced ferroptosis.

19.
Antioxid Redox Signal ; 18(2): 158-69, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22746342

RESUMO

AIMS: Mitochondrial ferritin (MtFt), which was recently discovered, plays an important role in preventing neuronal damage in 6-hydroxydopamine-induced Parkinsonism by maintaining mitochondrial iron homeostasis. Disruption of iron regulation also plays a key role in the etiology of Alzheimer's disease (AD). To explore the potential neuroprotective roles of MtFt, rats and cells were treated with Aß(25-35) to establish an AD model. RESULTS: We report that knockdown of MtFt expression significantly enhanced Aß(25-35)-induced neurotoxicity as shown by dysregulation of iron homeostasis, enhanced oxidative stress, and increased cell apoptosis. Opposite results were obtained when MtFt was overexpressed in SH-SY5Y cells prior to treatment with Aß(25-35). Further, MtFt inhibited Aß(25-35)-induced P38 mitogen-activated protein kinase and activated extracellular signal-regulated kinase (Erk) signaling. INNOVATION: MtFt attenuated Aß(25-35)-induced neurotoxicity and reduced oxidative damage through Erk/P38 kinase signaling. CONCLUSION: Our results show a protective role of MtFt in AD and suggest that regulation of MtFt expression in neuronal cells may provide a new neuroprotective strategy for AD.


Assuntos
Peptídeos beta-Amiloides/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ferritinas/fisiologia , Mitocôndrias/metabolismo , Estresse Oxidativo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Caspase 3/metabolismo , Citocromos c/metabolismo , Ativação Enzimática , Ferritinas/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Malondialdeído/metabolismo , RNA Interferente Pequeno , Ratos , Espécies Reativas de Oxigênio/metabolismo
20.
PLoS One ; 6(9): e25324, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21957487

RESUMO

Oxidative stress plays an important role in neuronal injuries caused by cerebral ischemia. It is well established that free iron increases significantly during ischemia and is responsible for oxidative damage in the brain. However, the mechanism of this ischemia-induced increase in iron is not completely understood. In this report, the middle cerebral artery occlusion (MCAO) rat model was performed and the mechanism of iron accumulation in cerebral ischemia-reperfusion was studied. The expression of L-ferritin was significantly increased in the cerebral cortex, hippocampus, and striatum on the ischemic side, whereas H-ferritin was reduced in the striatum and increased in the cerebral cortex and hippocampus. The expression level of the iron-export protein ferroportin1 (FPN1) significantly decreased, while the expression of transferrin receptor 1 (TfR1) was increased. In order to elucidate the mechanisms of FPN1 regulation, we studied the expression of the key regulator of FPN1, hepcidin. We observed that the hepcidin level was significantly elevated in the ischemic side of the brain. Knockdown hepcidin repressed the increasing of L-ferritin and decreasing of FPN1 invoked by ischemia-reperfusion. The results indicate that hepcidin is an important contributor to iron overload in cerebral ischemia. Furthermore, our results demonstrated that the levels of hypoxia-inducible factor-1α (HIF-1α) were significantly higher in the cerebral cortex, hippocampus and striatum on the ischemic side; therefore, the HIF-1α-mediated TfR1 expression may be another contributor to the iron overload in the ischemia-reperfusion brain.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Ferro/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/deficiência , Peptídeos Catiônicos Antimicrobianos/genética , Encéfalo/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Ferritinas/metabolismo , Técnicas de Silenciamento de Genes , Hepcidinas , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/genética , Interleucina-6/genética , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Camundongos , Ratos , Receptores da Transferrina/metabolismo , Traumatismo por Reperfusão/complicações , Regulação para Cima
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