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1.
Oxid Med Cell Longev ; 2022: 3112388, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35941905

RESUMO

Ferroptosis is a new programmed cell death characterized by the accumulation of lipid peroxidation mediated by iron and inflammation. Since the transcentury realization of ferroptosis as an iron-dependent modality of nonapoptotic cell death in 2012, there has been growing interest in the function of ferroptosis and its relationship to clinical diseases. Recent studies have shown that ferroptosis is associated with multiple diseases, including degenerative diseases, ischemia reperfusion injury, cardiovascular disease, and cancer. Cell death induced by ferroptosis has also been related to several skeletal diseases, such as inflammatory arthritis, osteoporosis, and osteoarthritis. Research on ferroptosis can clarify the pathogenesis of skeletal diseases and provide a novel therapeutic target for its treatment. In this review, we summarize current information about the molecular mechanism of ferroptosis and describe its emerging role and therapeutic potential in skeletal diseases.


Assuntos
Ferroptose , Traumatismo por Reperfusão , Apoptose , Humanos , Ferro/metabolismo , Peroxidação de Lipídeos
2.
Biomater Adv ; 138: 212936, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35913229

RESUMO

Traumatic optic neuropathy (TON) is the major contributor to optic nerve damage, where the retinal ganglion cells (RGCs) are substantially lost. However, the underlying pathological mechanisms for these conditions remain largely elusive. Present work conducted a study on TON rat model, where the iron-dependent cyclooxygenase-2 (COX-2) overexpression and lipid peroxidation were observed in RGCs, suggesting ferroptosis, an iron-dependent non-apoptotic cell death, is involved in TON-induced death of RGCs. Hence, the newly formulated hyaluronic acid (HA)-based deferoxamine (DFO) nanoparticles (DFO-NPs) were intravitreally administrated in the rat model. It was hypothesized that the effective delivery of DFO, iron chelator, to the RGCs might rescue RGC ferroptosis from TON-induced injury. Also, since DFO is poor in bioavailability and of very short half-life in vivo, its safe and efficient intravitreal delivery is critical. Therefore, DFO-NPs were prepared by chemical grafting DFO onto HA molecules, and then crosslinking them in microemulsion bubbles for nanoparticles formulation. The nanoparticles were highly accumulated around the ganglionic cells and DFO uptake was increased in RGCs, accompanied by the significantly inhibited the overexpression of COX-2 and inactivation of glutathione peroxidase 4 (GPX4). These results indicate that DFO-NPs acted as an effective ferroptosis inhibitor, for the prevention of TON-induced RGC death. The current study provides new insights into the underlying mechanism of TON-induced RGC death, which may help to explore a novel strategy for the treatment of TON.


Assuntos
Ferroptose , Nanopartículas , Traumatismos do Nervo Óptico , Animais , Ciclo-Oxigenase 2/metabolismo , Desferroxamina/farmacologia , Ferro/metabolismo , Nanopartículas/uso terapêutico , Traumatismos do Nervo Óptico/tratamento farmacológico , Ratos , Células Ganglionares da Retina
3.
Dis Markers ; 2022: 9716424, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909890

RESUMO

Background: The misdiagnosis of aortic dissection (AD) can lead to a catastrophic prognosis. There is currently a lack of stable serological indicators with excellent efficacy for the differential diagnosis of AD and coronary artery disease (CAD). A recent study has shown an association between AD and iron metabolism. Thus, we investigated whether iron metabolism could discriminate AD from CAD. Methods: This retrospective and multicenter cross-sectional study investigated the efficacy of biomarkers of iron metabolism for the differential diagnosis of AD. We collected biomarkers of iron metabolism, liver function, kidney function, and other biochemistry test, and further, logistic regression analysis was applied. Results: Between Oct. 8, 2020, and Mar. 1, 2021, we recruited 521 patients diagnosed with AD, CAD, and other cardiovascular diseases (OCDs) with the main symptoms of chest and back pain and assigned them to discovery set (n = 330) or validation set (n = 191). We found that six serum biomarkers, including serum iron, low-density lipoprotein, uric acid, transferrin, high-density lipoprotein, and estimated glomerular filtration rate, can serve as a novel comprehensive indicator (named FLUTHE) for the differential diagnosis of AD and CAD with a sensitivity of 0.954 and specificity of 0.905 to differentially diagnose AD and CAD more than 72 h past symptom onset. Conclusion: Our findings provide insight into the role of iron metabolism in diagnosing and distinguishing AD, which might in the future be a key component in AD diagnosis. Furthermore, we establish a novel model named "FLUTHE" with higher efficiency, safety, and economy, especially for patients with chest pain for more than 72 h.


Assuntos
Aneurisma Dissecante , Doença da Artéria Coronariana , Aneurisma Dissecante/diagnóstico , Biomarcadores , Doença da Artéria Coronariana/diagnóstico , Estudos Transversais , Humanos , Ferro/metabolismo , Estudos Retrospectivos
4.
Oxid Med Cell Longev ; 2022: 2405943, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910848

RESUMO

Background: Ferroptosis is a nonapoptotic form of programmed cell death, which may be related to the occurrence and development of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). Mucin 1 (MUC1) is a kind of macromolecule transmembrane glycoprotein. Previous studies have shown that MUC1 could relieve ALI in sepsis and predict whether sepsis patients would develop into ARDS. However, the role of MUC1 in the ferroptosis of sepsis-induced ALI/ARDS remains unclear. Materials and Methods: Sera samples from 50 patients with sepsis/septic shock were used to detect iron metabolism-related markers. Western blot and qRT-PCR were conducted to detect the expression levels of ferroptosis-related genes. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate inflammatory factors. Transmission electron microscopy (TEM) was used to assess morphological changes of cells. Results: The results showed that the iron metabolism-related indicators in sepsis-induced ARDS patients changed significantly, suggesting the iron metabolism disorder. The expression levels of ferroptosis-related genes in lung tissues of sepsis had marked changes, and the lipid peroxidation levels increased, while Ferrostatin-1 (Fer-1) could reverse the above results, which confirmed the occurrence of ferroptosis. In terms of mechanism studies, inhibition of MUC1 dimerization could increase the expression level of Keap1, reduce the phosphorylation level of GSK3ß, inhibit the entry of Nrf2 into the nucleus, further inhibit the expression level of GPX4, enhance the lipid peroxidation level of lung tissues, trigger ferroptosis, and aggravate lung injury. Besides, inhibiting MUC1 reversed the alleviating effect of vitamin E on ALI caused by sepsis, increased the aggregation of inflammatory cells in lung tissues, and aggravated alveolar injury and edema. Conclusions: Our study was the first to explore the changes of iron metabolism indicators in ALI/ARDS of sepsis, clarify the important role of ferroptosis in ALI/ARDS induced by sepsis, and reveal the effects and specific mechanisms of MUC1 in regulating ferroptosis, as well as the sensitization on vitamin E.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Síndrome do Desconforto Respiratório , Sepse , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Ferro/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Mucina-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Vitamina E
5.
PLoS One ; 17(8): e0270187, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35913911

RESUMO

While most productivity on the surface of the Earth today is fueled by oxygenic photosynthesis, for much of Earth history it is thought that anoxygenic photosynthesis-using compounds like ferrous iron or sulfide as electron donors-drove most global carbon fixation. Anoxygenic photosynthesis is still performed by diverse bacteria in niche environments today. Of these, the Chlorobi (formerly green sulfur bacteria) are often interpreted as being particularly ancient and are frequently proposed to have fueled the biosphere during late Archean and early Paleoproterozoic time before the rise of oxygenic photosynthesis. Here, we perform comparative genomic, phylogenetic, and molecular clock analyses to determine the antiquity of the Chlorobi and their characteristic phenotypes. We show that contrary to common assumptions, the Chlorobi clade is relatively young, with anoxygenic phototrophy, carbon fixation via the rTCA pathway, and iron oxidation all significantly postdating the rise of oxygen ~2.3 billion years ago. The Chlorobi therefore could not have fueled the Archean biosphere, but instead represent a relatively young radiation of organisms which likely acquired the capacity for anoxygenic photosynthesis and other traits via horizontal gene transfer sometime after the evolution of oxygenic Cyanobacteria.


Assuntos
Chlorobi , Ciclo do Carbono , Chlorobi/genética , Ferro/metabolismo , Oxigênio/metabolismo , Fotossíntese , Processos Fototróficos , Filogenia
6.
Nat Commun ; 13(1): 4445, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915109

RESUMO

Iron is critical for host-pathogen interactions. While pathogens seek to scavenge iron to spread, the host aims at decreasing iron availability to reduce pathogen virulence. Thus, iron sensing and homeostasis are of particular importance to prevent host infection and part of nutritional immunity. While the link between iron homeostasis and immunity pathways is well established in plants, how iron levels are sensed and integrated with immune response pathways remains unknown. Here we report a receptor kinase SRF3, with a role in coordinating root growth, iron homeostasis and immunity pathways via regulation of callose synthases. These processes are modulated by iron levels and rely on SRF3 extracellular and kinase domains which tune its accumulation and partitioning at the cell surface. Mimicking bacterial elicitation with the flagellin peptide flg22 phenocopies SRF3 regulation upon low iron levels and subsequent SRF3-dependent responses. We propose that SRF3 is part of nutritional immunity responses involved in sensing external iron levels.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Flagelina/metabolismo , Ferro/metabolismo , Proteínas Quinases/metabolismo
7.
Sci Rep ; 12(1): 13153, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915221

RESUMO

There is an urgent need in the medicinal fields to discover biocompatible nanoformulations with low cytotoxicity, which provide new strategies for promising therapies for several types of tumors. Bovine lactoperoxidase (LP) and lactoferrin (LF) have recently attracted attention in medicine for their antitumor activities with recognized safety pattern. Both LP and LF are suitable proteins to be coated or adsorbed to Cu and Fe nanometals for developing stable nanoformulations that boost immunity and strong anticancer effects. New nanometals of Cu and Fe NPs embedded in LP and LF forming novel nanocombinations of LP-CNPs and LF-FNPs had a spherical shape with an average nanosize of about 21 nm. The combination of LP-CNPs and LF-FNPs significantly exhibited the highest growth inhibitory efficacy, in terms of effectively lowering the half-maximal inhibitory concentration (IC50) values, against Caco-2, HepG2 and MCF7 cells comparing to nanometals, LP, LF and individual nanoproteins (LP-CNPs or LF-FNPs). The highest apoptotic effect of this nanocombination (LP-CNPs and LF-FNPs) was confirmed by the highest percentages of annexin-stained apoptotic cells and G0 population with the strongest alteration in the expression of two well-characterized apoptosis guards (p53 and Bcl-2) and the maximum suppression in the proliferation marker (Ki-67). Also, the in silico analysis predicted that LP-CNPs and LF-FNPs enhanced AMP-activated protein kinase (AMPK, p53 activator) activity and inhibited cancer migration-related proteases (cathepsin B and matrix metalloproteinase (MMP)-9). Our results offer for the first time that these novel nanocombinations of LP and LF were superior in their selectivity and apoptosis-mediating anticancer activity to Cu and Fe nanometals as well as the free form of these proteins or their individual nanoforms.


Assuntos
Lactoferrina , Lactoperoxidase , Animais , Apoptose , Células CACO-2 , Bovinos , Cobre/metabolismo , Humanos , Ferro/metabolismo , Lactoferrina/metabolismo , Lactoferrina/farmacologia , Lactoperoxidase/farmacologia , Proteína Supressora de Tumor p53/farmacologia
8.
Cell Metab ; 34(8): 1201-1213.e5, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35921818

RESUMO

Hepatocytes have important roles in liver iron homeostasis, abnormalities in which are tightly associated with liver steatosis and fibrosis. Here, we show that non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are characterized by iron-deficient hepatocytes and iron overload in hepatic stellate cells (HSCs). Iron deficiency enhances hepatocyte lipogenesis and insulin resistance through HIF2α-ATF4 signaling. Elevated secretion of iron-containing hepatocyte extracellular vesicles (EVs), which are normally cleared by Kupffer cells, accounts for hepatocyte iron deficiency and HSC iron overload in NAFLD/NASH livers. Iron accumulation results in overproduction of reactive oxygen species that promote HSC fibrogenic activation. Conversely, blocking hepatocyte EV secretion or depleting EV iron cargo restores liver iron homeostasis, concomitant with mitigation of NAFLD/NASH-associated liver steatosis and fibrosis. Taken together, these studies show that iron distribution disorders contribute to the development of liver metabolic diseases.


Assuntos
Sobrecarga de Ferro , Hepatopatia Gordurosa não Alcoólica , Animais , Modelos Animais de Doenças , Fibrose , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Ferro/metabolismo , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Células de Kupffer/metabolismo , Lipogênese , Fígado/metabolismo , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo
9.
Cell Death Dis ; 13(8): 667, 2022 Aug 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
10.
Oxid Med Cell Longev ; 2022: 5361241, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35915609

RESUMO

Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc- inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.


Assuntos
Ferroptose , Neoplasias Pancreáticas , Proteínas Quinases Ativadas por AMP , Ácido Ascórbico/farmacologia , Fator de Transcrição de Proteínas de Ligação GA , Glutationa/metabolismo , Heme Oxigenase-1 , Humanos , Ferro/metabolismo , Fator 2 Relacionado a NF-E2 , Fator 1 Nuclear Respiratório , Neoplasias Pancreáticas/tratamento farmacológico , Piperazinas
11.
Nat Commun ; 13(1): 4322, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918323

RESUMO

The profound impacts that maternal provisioning of finite energy resources has on offspring survival have been extensively studied across mammals. This study shows that in addition to calories, high hemoprotein concentrations in diving mammals necessitates exceptional female-to-pup iron transfer. Numerous indices of iron mobilization (ferritin, serum iron, total-iron-binding-capacity, transferrin saturation) were significantly elevated during lactation in adult female Weddell seals (Leptonychotes weddellii), but not in skip-breeders. Iron was mobilized from endogenous stores for incorporation into the Weddell seal's milk at concentrations up to 100× higher than terrestrial mammals. Such high rates of iron offload to offspring drew from the female's own heme stores and led to compromised physiologic dive capacities (hemoglobin, myoglobin, and total body oxygen stores) after weaning their pups, which was further reflected in shorter dive durations. We demonstrate that lactational iron transfer shapes physiologic dive thresholds, identifying a cost of reproduction to a marine mammal.


Assuntos
Caniformia , Mergulho , Focas Verdadeiras , Animais , Mergulho/fisiologia , Feminino , Ferro/metabolismo , Lactação , Oxigênio/metabolismo
12.
Epigenetics Chromatin ; 15(1): 28, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918756

RESUMO

BACKGROUND: Prenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the US Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies. RESULTS: In placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI -1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (-1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value < 0.01 (EARLI cord nCpGs = 4068, EARLI placenta nCpGs = 3647, MARBLES cord nCpGs = 4068, MARBLES placenta nCpGs = 9563) were consistently enriched in neuronal developmental pathways. CONCLUSIONS: Together, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.


Assuntos
Metilação de DNA , Placenta , Feminino , Sangue Fetal/metabolismo , Ácido Fólico/metabolismo , Humanos , Ferro/metabolismo , Placenta/metabolismo , Gravidez , Estudos Prospectivos , Vitaminas
13.
Artigo em Russo | MEDLINE | ID: mdl-35942838

RESUMO

BACKGROUND: Delta-He the difference between hemoglobin content in reticulocytes and erytrocytes is a relatively new laboratory indicator that is easily measured in everyday practice. This parameter is directly related to iron bioavailability for hemoglobin synthesis and can reflect various conditions accompanied by cytokine expression including systemic inflammation. OBJECTIVE: To analyze the prospects for practical application of hemoglobin delta in assessment of neurosurgical patients throughout in-hospital treatment. MATERIAL AND METHODS: We analyzed complete blood counts (Sysmex XN-1000 analyzer) with optical determination of reticulocyte hemoglobin and automatic calculation of Delta-He in 82 neurosurgical patients. Exclusion criteria were severe decompensated comorbidities, exacerbation of chronic infectious processes, cancer of other organs. Blood sampling for analysis of delta-hemoglobin was carried out before all diagnostic and therapeutic measures. Reference interval is indicated by the analyzer manufacturer as 1.7-4.4 pg. RESULTS: Delta-He values at admission ranged from -1.8 to 6.1 pg. There was a consistent decrease of these values throughout 3-4 postoperative days. Then, the values could increase or continued to decrease. Increment of the index was noted in 76 patients (92.7%). Such dynamics was observed in case of uncomplicated postoperative period. Further decrease of Delta-He was observed in 6 patients (7.3%). These ones were characterized by a longer recovery after surgery, and the events required additional medical or surgical correction were recorded. Negative dynamics of Delta-He values could precede clinical manifestations of certain complication. Clarification of diagnosis and correction of therapy were accompanied by gradual increase of Delta-He values. CONCLUSION: Estimation of Delta-He values over time can be used for monitoring of patients and effectiveness of therapy. From a practical point of view, it is important that examination can be performed at any time of the day.


Assuntos
Hemoglobinas , Reticulócitos , Biomarcadores/metabolismo , Hemoglobinas/análise , Hemoglobinas/metabolismo , Humanos , Ferro/metabolismo , Valores de Referência , Reticulócitos/química , Reticulócitos/metabolismo
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(6): 937-943, 2022 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-35790446

RESUMO

OBJECTIVE: To explore the mechanism by which berberine inhibits ferroptosis of mouse hippocampal neuronal cells (HT22). METHODS: Cultured HT22 cells were pretreated with 30 or 60 µmol/L berberine for 2 h before exposure to 0.5 µmol/L erastin for 8 h, and the cell proliferation, intracellular ferric iron level, changes in intracellular reactive oxygen species (ROS) and cell apoptosis were detected using CCK-8, Fe2+ fluorescent probe, fluorescent dye (DAPI) and fluorescent probe (H2DCFH-DA). RT-qPCR and Western blotting were used to detect the mRNA and protein expressions of Nrf2, HO-1 and GPX4 in the cells. We further tested the effects of treatments with 2 µmol/L ML385 (a Nrf2 inhibitor), 60 µmol/L berberine and erastin in the cells to explore the protective mechanism of berberine against erastin-induced ferroptosis in the neuronal cells. RESULTS: Treatment with 0.5 µmol/L erastin significantly lowered the viability of HT22 cells (P < 0.05) and increased the production of ROS, cell apoptosis rate and ferric iron level (P < 0.05). Pretreatment with 30 and 60 µmol/L berberine both significantly increased the vitality of erastin-exposed cells (P < 0.05) and lowered the levels of intracellular ROS and ferric iron content (P < 0.05). RT-qPCR and Western blotting showed that berberine obviously promoted the expressions of Nrf2, HO-1 and GPX4 in the cells (P < 0.05), and treatment with ML385 significantly inhibited the Nrf2-HO-1/GPX4 pathway, increased intracellular ROS and ferric iron contents and mitigated the protective effect of berberine against erastin-induced ferroptosis (P < 0.05). CONCLUSION: Berberine can inhibit erastin-induced ferroptosis in HT22 cells possibly by activating the Nrf2-HO-1/ GPX4 pathway.


Assuntos
Berberina , Ferroptose , Animais , Berberina/farmacologia , Corantes Fluorescentes , Hipocampo/metabolismo , Ferro/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Piperazinas , Espécies Reativas de Oxigênio/metabolismo
15.
Sci Rep ; 12(1): 11911, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831434

RESUMO

Despite interest in the clinical implications of soluble transferrin receptor (sTfR), previous studies on the association of sTfR with mortality in the general population are lacking. Therefore, we analysed the association between sTfR and all-cause mortality in the general United States adult population. We conducted a prospective cohort study using National Health and Nutrition Examination Survey data from 2003 to 2010. A total of 5403 premenopausal nonpregnant females were analysed in this study. The mean age was 34.2 years (range 20.0-49.9 years). Participants were divided into log(sTfR) tertiles. The primary outcome was all-cause mortality. The secondary outcome was chronic kidney disease (CKD) development (composite of estimated glomerular filtration rate < 60 ml/min/1.73 m2 and/or random urine albumin-to-creatinine ratio ≥ 30 mg/g). During a median 8.7 years of follow-up, 103 (1.9%) participants died. Compared with the reference group (log(sTfR) 0.45-0.57), the highest tertile of log(sTfR) was associated with all-cause mortality (log(sTfR) > 0.57, hazard ratio [HR] 1.77 [95% CI 1.05-2.98]) in a multivariable hazards model including covariates such as haemoglobin and ferritin. Patients in the highest tertile of log(sTfR) also had an increased risk of CKD relative to those in the reference tertile. High sTfR was associated with all-cause mortality and CKD regardless of anaemia and iron storage status.


Assuntos
Anemia Ferropriva , Anemia , Insuficiência Renal Crônica , Adulto , Anemia/diagnóstico , Anemia Ferropriva/diagnóstico , Feminino , Humanos , Ferro/metabolismo , Pessoa de Meia-Idade , Inquéritos Nutricionais , Estudos Prospectivos , Receptores da Transferrina , Transferrina , Adulto Jovem
16.
Cells ; 11(13)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35805124

RESUMO

Ferroptosis, which has been widely associated with many diseases, is an iron-dependent regulated cell death characterized by intracellular lipid peroxide accumulation. It exhibits morphological, biochemical, and genetic characteristics that are unique in comparison to other types of cell death. The course of ferroptosis can be accurately regulated by the metabolism of iron, lipids, amino acids, and various signal pathways. In this review, we summarize the basic characteristics of ferroptosis, its regulation, as well as the relationship between ferroptosis and chronic diseases such as cancer, nervous system diseases, metabolic diseases, and inflammatory bowel diseases. Finally, we describe the regulatory effects of food-borne active ingredients on ferroptosis.


Assuntos
Ferroptose , Neoplasias , Morte Celular , Doença Crônica , Humanos , Ferro/metabolismo , Neoplasias/genética , Neoplasias/metabolismo
17.
Cells ; 11(13)2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35805147

RESUMO

The tumor suppressor TP53 is the most commonly mutated gene in human cancers, and iron is necessary for cancer cell growth and proliferation, but there is a significant gap in knowledge for how the two cooperate to affect cellular physiology. Elucidating this role is complicated, however, because each TP53 mutation subtype exhibits unique phenotypic responses to changes in iron availability. The goal of this work was to determine how cells expressing distinct TP53 mutation subtypes respond to iron restriction. Utilizing a reverse genetics approach, we generated eight isogenic cell lines that either lacked TP53 expression, expressed wild-type TP53, or expressed one of the six most common TP53 "hotspot" mutations. We then employed isobaric peptide labeling and mass spectrometry to quantitively measure changes in global protein expression, both in response to induction of mutant TP53 expression, and in response to iron chelation. Our findings indicate that mutant TP53-dependent sensitivities to iron restriction are not driven by differences in responsiveness to iron chelation, but more so by mutant TP53-dependent differences in cellular antioxidant and lipid handling protein expression. These findings reinforce the importance of distinguishing between TP53 mutation subtypes when investigating approaches to target mutant TP53. We also identify unique TP53-dependent perturbances in protein expression patterns that could be exploited to improve iron-targeted chemotherapeutic strategies.


Assuntos
Antioxidantes , Proteína Supressora de Tumor p53 , Homeostase , Humanos , Ferro/metabolismo , Quelantes de Ferro , Lipídeos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Int J Mol Sci ; 23(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35806270

RESUMO

Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation.


Assuntos
Ferro , Doenças Neuroinflamatórias , Humanos , Inflamação/metabolismo , Ferro/metabolismo , Proteínas Reguladoras de Ferro/metabolismo , Microglia/metabolismo
19.
Int J Mol Sci ; 23(13)2022 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-35806422

RESUMO

Adipocyte iron overload is a maladaptation associated with obesity and insulin resistance. The objective of the current study was to determine whether and how adipose tissue macrophages (ATMs) regulate adipocyte iron concentrations and whether this is impacted by obesity. Using bone marrow-derived macrophages (BMDMs) polarized to M0, M1, M2, or metabolically activated (MMe) phenotypes, we showed that MMe BMDMs and ATMs from obese mice have reduced expression of several iron-related proteins. Furthermore, the bioenergetic response to iron in obese ATMs was hampered. ATMs from iron-injected lean mice increased their glycolytic and respiratory capacities, thus maintaining metabolic flexibility, while ATMs from obese mice did not. Using an isotope-based system, we found that iron exchange between BMDMs and adipocytes was regulated by macrophage phenotype. At the end of the co-culture, MMe macrophages transferred and received more iron from adipocytes than M0, M1, and M2 macrophages. This culminated in a decrease in total iron in MMe macrophages and an increase in total iron in adipocytes compared with M2 macrophages. Taken together, in the MMe condition, the redistribution of iron is biased toward macrophage iron deficiency and simultaneous adipocyte iron overload. These data suggest that obesity changes the communication of iron between adipocytes and macrophages and that rectifying this iron communication channel may be a novel therapeutic target to alleviate insulin resistance.


Assuntos
Resistência à Insulina , Sobrecarga de Ferro , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Inflamação/metabolismo , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Obesos , Obesidade/metabolismo , Fenótipo
20.
Molecules ; 27(13)2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35807217

RESUMO

The use of nanomaterials rationally engineered to treat cancer is a burgeoning field that has reported great medical achievements. Iron-based polymeric nano-formulations with precisely tuned physicochemical properties are an expanding and versatile therapeutic strategy for tumor treatment. Recently, a peculiar type of regulated necrosis named ferroptosis has gained increased attention as a target for cancer therapy. Here, we show for the first time that novel iron oxide nanoparticles coated with gallic acid and polyacrylic acid (IONP-GA/PAA) possess intrinsic cytotoxic activity on various cancer cell lines. Indeed, IONP-GA/PAA treatment efficiently induces ferroptosis in glioblastoma, neuroblastoma, and fibrosarcoma cells. IONP-GA/PAA-induced ferroptosis was blocked by the canonical ferroptosis inhibitors, including deferoxamine and ciclopirox olamine (iron chelators), and ferrostatin-1, the lipophilic radical trap. These ferroptosis inhibitors also prevented the lipid hydroperoxide generation promoted by the nanoparticles. Altogether, we report on novel ferroptosis-inducing iron encapsulated nanoparticles with potent anti-cancer properties, which has promising potential for further in vivo validation.


Assuntos
Ferroptose , Nanopartículas , Neoplasias , Apoptose , Linhagem Celular Tumoral , Ferro/metabolismo , Nanopartículas Magnéticas de Óxido de Ferro
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