Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 147
Filtrar
1.
Cardiovasc Res ; 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34849613

RESUMO

AIMS: De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this 'atherogenic transition'. METHODS AND RESULTS: Genome-wide sequencing studies, including ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) and RNA-seq, were performed on cells isolated from both murine SMC-lineage tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, ATF3 (Activating transcription factor 3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 were negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly downregulated in humans with advanced vascular disease. CONCLUSION: Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress. TRANSLATIONAL PERSPECTIVE: The recent CANTOS and COLCOT trials have shown that targeting inflammatory pathways lowers the risk of major adverse cardiovascular events. However, more specific targets are needed to avoid immunosuppressive side effects. Our data identify an upstream regulator of pro-inflammatory SMCs, ATF3, which is involved in the initial atherogenic transitioning of lesional SMCs. Restoring ATF3 activity may prevent the de-differentiation of SMCs and offer a novel translational approach for the suppression of complement-dependent inflammation in atherosclerotic lesions.

3.
Rev Sci Instrum ; 92(4): 043544, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34243392

RESUMO

The x-ray imaging crystal spectrometer (XICS) is proposed as the principal method of diagnostics for plasma ion temperature and rotation for the China Fusion Engineering Test Reactor (CFETR) for its simplicity in implementation and no reliance on neutral beams. For D-T experiments with the electron temperature as high as 35-40 keV at the core region, highly charged high-Z ions can serve as the diagnostic ions for the XICS. For the CFETR, Xe44+, Xe51+, and W64+ are selected as the impurity ions. Appropriate crystal parameters are selected, as well as the preliminary layout for the spectrometer. We estimated the general performance of the spectrometer, including the emissivity of the impurities, the spatial resolution of the x-ray detector, and the expected count rate of line emissions. For the application in the fusion reactor environment, the effect of neutron irradiation on the crystal is briefly discussed.

4.
J Cosmet Dermatol ; 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34240515

RESUMO

BACKGROUND: Patch test, as a helpful tool in clinic diagnosis and safety assessment of cosmetics, is affected by many factors. OBJECTIVES: To investigate the influencing factors of patch test reactions in a highly standardized large-scale dataset of Chinese. METHODS: Patch test data (n = 151,280) from safety assessments of cosmetic products were obtained following internationally standardized patch testing protocols during 2004-2017 in China. RESULTS: The frequency of patch test reactions was 1.45% (2,191/151,280), with majority of the reactions being "score 1" reactions (also known as doubtful reactions, n = 2,075) and a small number being "score 2" reactions (weak reactions, n = 116). Patch test reactions were 67% more frequent in winter (p < 0.001), associated with temperatures (p < 0.001), rather than relative humidity (P:0.29). The frequency of reactions was higher in men than in women (p:0.001), especially in winter. The risk to develop reactions clearly increased with age in women (p < 0.001), but not in men (p:0.14). In women, the frequency of reactions in the old group (≥50 years old) was 30% more than the young group (<30 years old). CONCLUSIONS: The frequency of patch test reactions to cosmetic products was 1.45% in our large-scale study. The influencing factors of patch test include season, sex, and age, which should be considered when conducting and interpreting patch testing.

5.
Cell Death Dis ; 12(7): 706, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267193

RESUMO

Ferroptosis, a newly defined mode of regulated cell death caused by unbalanced lipid redox metabolism, is implicated in various tissue injuries and tumorigenesis. However, the role of ferroptosis in stem cells has not yet been investigated. Glutathione peroxidase 4 (GPX4) is a critical suppressor of lipid peroxidation and ferroptosis. Here, we study the function of GPX4 and ferroptosis in hematopoietic stem and progenitor cells (HSPCs) in mice with Gpx4 deficiency in the hematopoietic system. We find that Gpx4 deletion solely in the hematopoietic system has no significant effect on the number and function of HSPCs in mice. Notably, hematopoietic stem cells (HSCs) and hematopoietic progenitor cells lacking Gpx4 accumulated lipid peroxidation and underwent ferroptosis in vitro. α-Tocopherol, the main component of vitamin E, was shown to rescue the Gpx4-deficient HSPCs from ferroptosis in vitro. When Gpx4 knockout mice were fed a vitamin E-depleted diet, a reduced number of HSPCs and impaired function of HSCs were found. Furthermore, increased levels of lipid peroxidation and cell death indicated that HSPCs undergo ferroptosis. Collectively, we demonstrate that GPX4 and vitamin E cooperatively maintain lipid redox balance and prevent ferroptosis in HSPCs.


Assuntos
Antioxidantes/farmacologia , Ferroptose/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Deficiência de Vitamina E/tratamento farmacológico , Vitamina E/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/enzimologia , Células-Tronco Hematopoéticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Deficiência de Vitamina E/enzimologia , Deficiência de Vitamina E/genética , Deficiência de Vitamina E/patologia
6.
Clin Chim Acta ; 520: 53-62, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34077755

RESUMO

The incidence of type 2 diabetes (T2D) is rising rapidly and has become an important public health problem. According to reports, people with T2D often have hyperlipidemia. Hence, in the current study, a plasma non-targeted lipidomics method was used to study the differences in lipid profile between 36 T2D-associated hyperlipidemia patients and 43 healthy controls by ultra-performance liquid chromatography coupled with quadrupole time-of-flight high-definition mass spectrometry (UPLC Q-TOF/MS). Furthermore, we studied the differences in lipid profile between 36 T2D-associated hyperlipidemia patients and 41 T2D patients. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), S-plot and heatmap were used to analyze the lipid changes between the groups. Compared with the healthy control group, 37 lipids were significantly altered in the T2D-associated hyperlipidemia group, and when compared with the T2D group, 22 lipids were significantly altered in the T2D-associated hyperlipidemia group. Of all the detected lipids categories which included sphingolipids, glycerolipids, glycerophospholipids, prenol lipids and saccharolipids, glycerophospholipids accounted for the largest proportion in the two groups. Also, this study found that glycerophospholipid metabolism pathway was the most relevant pathway for these lipid metabolisms. The identified lipids may enhance the disease prediction and provide a new tool to monitor the progression of T2D-associated hyperlipidemia.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperlipidemias , Cromatografia Líquida de Alta Pressão , Humanos , Lipidômica , Lipídeos , Metabolômica
7.
J Clin Endocrinol Metab ; 106(11): e4641-e4651, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34147035

RESUMO

CONTEXT: Iron overload is a known risk factor for type 2 diabetes (T2D); however, iron overload and iron deficiency have both been associated with metabolic disorders in observational studies. OBJECTIVE: Using mendelian randomization (MR), we assessed how genetically predicted systemic iron status affected T2D risk. METHODS: A 2-sample MR analysis was used to obtain a causal estimate. We selected genetic variants strongly associated (P < 5 × 10-8) with 4 biomarkers of systemic iron status from a study involving 48 972 individuals performed by the Genetics of Iron Status consortium and applied these biomarkers to the T2D case-control study (74 124 cases and 824 006 controls) performed by the Diabetes Genetics Replication and Meta-analysis consortium. The simple median, weighted median, MR-Egger, MR analysis using mixture-model, weighted allele scores, and MR based on a Bayesian model averaging approaches were used for the sensitivity analysis. RESULTS: Genetically instrumented serum iron (odds ratio [OR]: 1.07; 95% CI, 1.02-1.12), ferritin (OR: 1.19; 95% CI, 1.08-1.32), and transferrin saturation (OR: 1.06; 95% CI, 1.02-1.09) were positively associated with T2D. In contrast, genetically instrumented transferrin, a marker of reduced iron status, was inversely associated with T2D (OR: 0.91; 95% CI, 0.87-0.96). CONCLUSION: Genetic evidence supports a causal link between increased systemic iron status and increased T2D risk. Further studies involving various ethnic backgrounds based on individual-level data and studies regarding the underlying mechanism are warranted for reducing the risk of T2D.

8.
Signal Transduct Target Ther ; 6(1): 244, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145214
9.
Nucleic Acids Res ; 49(10): 5537-5552, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33999206

RESUMO

The intestinal invasion of pathogenic microorganisms can have serious health consequences. Recent evidence has shown that the N6-methyladenosine (m6A) mRNA modification is closely associated with innate immunity; however, the underlying mechanism is poorly understood. Here, we examined the function and mechanism of m6A mRNA modification and the YTH domain-containing protein YTHDF1 (YTH N6-methyladenosine RNA-binding protein 1) in the innate immune response against bacterial pathogens in the intestine. Ribo-seq and m6A-seq analyses revealed that YTHDF1 directs the translation of Traf6 mRNA, which encodes tumor necrosis factor receptor-associated factor 6, thereby regulating the immune response via the m6A modification near the transcript's stop codon. Furthermore, we identified a unique mechanism by which the P/Q/N-rich domain in YTHDF1 interacts with the DEAD domain in the host factor DDX60, thereby regulating the intestinal immune response to bacterial infection by recognizing the target Traf6 transcript. These results provide novel insights into the mechanism by which YTHDF1 recognizes its target and reveal YTHDF1 as an important driver of the intestinal immune response, opening new avenues for developing therapeutic strategies designed to modulate the intestinal immune response to bacterial infection.


Assuntos
Infecções por Escherichia coli/imunologia , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Ligação a RNA/imunologia , Animais , Células CACO-2 , Escherichia coli Enterotoxigênica/imunologia , Células Epiteliais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Suínos , Fator 6 Associado a Receptor de TNF/imunologia
10.
Blood ; 138(8): 689-705, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-33895792

RESUMO

Ferroportin (FPN), the body's sole iron exporter, is essential for maintaining systemic iron homeostasis. In response to either increased iron or inflammation, hepatocyte-secreted hepcidin binds to FPN, inducing its internalization and subsequent degradation. However, the E3 ubiquitin ligase that underlies FPN degradation has not been identified. Here, we report the identification and characterization of a novel mechanism involving the RNF217-mediated degradation of FPN. A combination of 2 different E3 screens revealed that the Rnf217 gene is a target of Tet1, mediating the ubiquitination and subsequent degradation of FPN. Interestingly, loss of Tet1 expression causes an accumulation of FPN and an impaired response to iron overload, manifested by increased iron accumulation in the liver together with decreased iron in the spleen and duodenum. Moreover, we found that the degradation and ubiquitination of FPN could be attenuated by mutating RNF217. Finally, using 2 conditional knockout mouse lines, we found that knocking out Rnf217 in macrophages increases splenic iron export by stabilizing FPN, whereas knocking out Rnf217 in intestinal cells appears to increase iron absorption. These findings suggest that the Tet1-RNF217-FPN axis regulates iron homeostasis, revealing new therapeutic targets for FPN-related diseases.

11.
Aging Cell ; 20(3): e13323, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33657282

RESUMO

There is growing interest in studying the genetic contributions to longevity, but limited relevant genes have been identified. In this study, we performed a genetic association study of longevity in a total of 15,651 Chinese individuals. Novel longevity loci, BMPER (rs17169634; p = 7.91 × 10-15 ) and TMEM43/XPC (rs1043943; p = 3.59 × 10-8 ), were identified in a case-control analysis of 11,045 individuals. BRAF (rs1267601; p = 8.33 × 10-15 ) and BMPER (rs17169634; p = 1.45 × 10-10 ) were significantly associated with life expectancy in 12,664 individuals who had survival status records. Additional sex-stratified analyses identified sex-specific longevity genes. Notably, sex-differential associations were identified in two linkage disequilibrium blocks in the TOMM40/APOE region, indicating potential differences during meiosis between males and females. Moreover, polygenic risk scores and Mendelian randomization analyses revealed that longevity was genetically causally correlated with reduced risks of multiple diseases, such as type 2 diabetes, cardiovascular diseases, and arthritis. Finally, we incorporated genetic markers, disease status, and lifestyles to classify longevity or not-longevity groups and predict life span. Our predictive models showed good performance (AUC = 0.86 for longevity classification and explained 19.8% variance of life span) and presented a greater predictive efficiency in females than in males. Taken together, our findings not only shed light on the genetic contributions to longevity but also elucidate correlations between diseases and longevity.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Loci Gênicos , Predisposição Genética para Doença , Longevidade/genética , Estudos de Coortes , Feminino , Genoma Humano , Humanos , Masculino , Metanálise como Assunto , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Fatores de Risco , Caracteres Sexuais , Análise de Sobrevida
12.
Semin Cell Dev Biol ; 115: 45-53, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33419608

RESUMO

Manganese serves as an indispensable catalytic center and the structural core of various enzymes that participate in a plethora of biological processes, including oxidative phosphorylation, glycosylation, and signal transduction. In pathogenic microorganisms, manganese is required for survival by maintaining basic biochemical activity and virulence; in contrast, the host utilizes a process known as nutritional immunity to sequester manganese from invading pathogens. Recent epidemiological and animal studies have shown that manganese increases the immune response in a wide range of vertebrates, including humans, rodents, birds, and fish. On the other hand, excess manganese can cause neurotoxicity and other detrimental effects. Here, we review recent data illustrating the essential role of manganese homeostasis at the host-pathogen interface and in the host immune system. We also discuss the accumulating body of evidence that manganese modulates various signaling pathways in immune processes. Finally, we discuss the key molecular players involved in manganese's immune regulatory function, as well as the clinical implications with respect to cancer immunotherapy.

13.
Biomed Chromatogr ; 35(6): e5073, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33453122

RESUMO

High-density lipoprotein cholesterol (HDL-C) is negatively correlated with atherosclerotic cardiovascular disease. The prevalence of hypo-HDL cholesterolemia is as high as 33.9%. The plasma metabolomic differences between hypo-HDL cholesterolemia populations and normal controls were investigated using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Participants with hypo-HDL cholesterolemia and normal controls were clearly discriminated from each other on the orthogonal partial least squares-discriminant analysis score plot and a total of 90 differential metabolites were identified, including down-regulated phosphatidylserine [18:0/20:3(8Z,11Z,14Z)], phosphatidylcholine [19:0/18:3(6Z,9Z,12Z)], phosphatidylserine, phosphatidylethanolamine [18:0/20:4(5Z,8Z,11Z,13E) (15Ke)], etc., and up-regulated triglyceride [15:0/18:1(9Z)/18:3(9Z,12Z,15Z)][iso6], 13-methyl-1-tritriacontene, tridodecylamine, etc. Most of the changed metabolites were lipids, notably, a significant part of which were odd chain fatty acid incorporated lipids. Carnitine shuttle was the most significant metabolic pathway, except for the disturbed glycerophospholipid metabolism, glycosphingolipid metabolism and sphingolipid metabolism in participants with hypo-HDL cholesterolemia. We identified the key metabolites and metabolic pathways that may be changed in hypo-HDL cholesterolemia participants, providing useful clues for studying the metabolic mechanisms and for early prevention of hypo-HDL cholesterolemia and dyslipidemia.


Assuntos
HDL-Colesterol/sangue , Cromatografia Líquida de Alta Pressão/métodos , Hipoalfalipoproteinemias/sangue , Espectrometria de Massas/métodos , Metabolômica/métodos , Humanos , Análise dos Mínimos Quadrados , Redes e Vias Metabólicas , Metaboloma/fisiologia
14.
Br J Nutr ; 126(9): 1420-1430, 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33431092

RESUMO

This meta-analysis aimed to study the relationship between abdominal obesity and the risk of CVD by waist circumference (WC), waist:hip ratio (WHR) and waist:height ratio (WHtR). We systematically searched PubMed, Embase and Web of Science. Prospective studies that estimated cardiovascular events by WC, WHR and WHtR were included in this study. Pooled relative risks with 95 % CI were calculated using random effects models. A total of thirty-one studies were included in the meta-analysis, including 669 560 participants and 25 214 cases. Compared the highest with the lowest category of WC, WHR and WHtR, the summary risk ratios were 1·43 (95 % CI, 1·30, 1·56, P < 0·001), 1·43 (95 % CI, 1·33, 1·54, P < 0·001) and 1·57 (95 % CI, 1·37, 1·79, P < 0·001), respectively. The linear dose-response analysis revealed that the risk of CVD increased by 3·4 % for each 10 cm increase of WC, and by 3·5 and 6·0 % for each 0·1 unit increase of WHR and WHtR in women, respectively. In men, the risk of CVD increased by 4·0 % for each 10 cm increase of WC, and by 4·0 and 8·6 % for each 0·1 unit increase of WHR and WHtR, respectively. Collectively, abdominal obesity is associated with an increased risk of CVD. WC, WHR and WHtR are good indicators for the prediction of CVD.

15.
Cell Death Differ ; 28(5): 1548-1562, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33398092

RESUMO

Iron homeostasis disturbance has been implicated in Alzheimer's disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer's mouse model and Alzheimer's patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aß aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

16.
Autophagy ; 17(8): 1962-1977, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32746697

RESUMO

Iron metabolism is involved in numerous physiological processes such as erythropoiesis, oxidative metabolism. However, the in vivo physiological functions of the iron metabolism-related gene Hfe in immune response during viral infection remain poorly understood. Here, we identified 5 iron metabolism-associated genes specifically affected during RNA virus infection by a high-throughput assay and further found that HFE was a key negative regulator of RIG-I-like receptors (RLR)-mediated type I interferons (IFNs) signaling. RNA virus infection inhibited the binding of HFE to MAVS (mitochondrial antiviral signaling protein) and blocked MAVS degradation via selective autophagy. HFE mediated MAVS autophagic degradation by binding to SQSTM1/p62. Depletion of Hfe abrogated the autophagic degradation of MAVS, leading to the stronger antiviral immune response. These findings established a novel regulatory role of selective autophagy in innate antiviral immune response by the iron metabolism-related gene Hfe. These data further provided insights into the crosstalk among iron metabolism, autophagy, and innate immune response.Abbreviations: ATG: autophagy-related; BAL: bronchoalveolar lavage fluid; BMDMs: bone marrow-derived macrophages; CGAS: cyclic GMP-AMP synthase; CQ: chloroquine; Dpi: days post-infection; ELISA: enzyme-linked immunosorbent assay; GFP: green fluorescent protein; HAMP: hepcidin antimicrobial peptide; Hpi: hours post-infection; HJV: hemojuvelin BMP co-receptor; IFNs: interferons; IL6: interleukin 6; IRF3: interferon regulatory factor 3; ISRE: interferon-stimulated response element; Lipo: clodronate liposomes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; MEFs: mouse embryonic fibroblasts; SLC40A1/FPN1: solute carrier family 40 (iron-regulated transporter), member 1; flatiron; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1/STING: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1; TFRC/TfR1: transferrin receptor; TNF/TNFα: tumor necrosis factor; WT: wild type.

17.
J Pineal Res ; 70(2): e12704, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33206394

RESUMO

Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time-course changes of ferroptosis-related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin-1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron-specific Fth conditional knockout (Fth-KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth-KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth-KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth-mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti-ferroptosis provides a potential therapeutic target for treating TBI.

18.
Cell Biosci ; 10(1): 137, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33292517

RESUMO

BACKGROUND: Macrophages that accumulate in atherosclerotic plaques contribute to progression of the lesions to more advanced and complex plaques. Although iron deposition was found in human atherosclerotic plaques, clinical and pre-clinical studies showed controversial results. Several epidemiological studies did not show the positive correlation between a systemic iron status and an incidence of cardiovascular diseases, suggesting that the iron involvement occurs locally, rather than systemically. RESULTS: To determine the direct in vivo effect of iron accumulation in macrophages on the progression of atherosclerosis, we generated Apoe-/- mice with a macrophage-specific ferroportin (Fpn1) deficiency (Apoe-/-Fpn1LysM/LysM). Fpn1 deficiency in macrophages dramatically accelerated the progression of atherosclerosis in mice. Pathophysiological evidence showed elevated levels of reactive oxygen species, aggravated systemic inflammation, and altered plaque-lipid composition. Moreover, Fpn1 deficiency in macrophages significantly inhibited the expression of ABC transporters (ABCA1 and ABCG1) by decreasing the expression of the transcription factor LXRα, which reduced cholesterol efflux and therefore promoted foam cell formation and enhanced plaque formation. Iron chelation relieved the symptoms moderately in vivo, but drastically ex vivo. CONCLUSIONS: Macrophage iron content in plaques is a critical factor in progression of atherosclerosis. The interaction of iron and lipid metabolism takes place in macrophage-rich atherosclerotic plaques. And we also suggest that altering intracellular iron levels in macrophages by systemic iron chelation or dietary iron restriction may be a potential supplementary strategy to limit or even regress the progression of atherosclerosis.

19.
ACS Nano ; 14(11): 15306-15316, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33185086

RESUMO

Two-dimensional (2D) membranes exhibit exceptional properties in molecular separation and transport, which reveals their potential use in various applications. However, ion sieving with 2D membranes is severely restrained due to intercalation-induced swelling. Here, we describe how to efficiently stabilize the lamellar architecture using Keggin Al13 polycations as pillars in a Ti3C2Tx membrane. More importantly, interlayer spacing can be easily adjusted with angstrom precision over a wide range (2.7-11.2 Å) to achieve selective and tunable ion sieving. A membrane with narrow d-spacing demonstrated enhanced selectivity for monovalent ions. When applied in a forward osmosis desalination process, this membrane exhibited high NaCl exclusion (99%) with a fast water flux (0.30 L m-2 h-1 bar-1). A membrane with wide d-spacing showed notable selectivity, which was dependent on the cation valence. When it was applied to acid recovery from iron-based industrial wastewater, the membrane showed good H+/Fe2+ selectivity, which makes it a promising substitute for traditional polymeric membranes. Thus, we introduce a possible route to construct 2D membranes with appropriate structures to satisfy different ion-sieving requirements in diverse environment-, resource-, and energy-related applications.

20.
Aging Cell ; 19(11): e13235, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33068460

RESUMO

Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post-ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno-associated virus (AAV) overexpressing cre recombinase into aged Fpn-floxed mice significantly worsened the symptoms post-ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR-124 was identified to regulate Fpn expression post-ICH. Higher serum miR-124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR-124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR-124/Fpn signaling manipulation. Our study demonstrated the critical role of miR-124/Fpn signaling in iron metabolism and neuronal death post-ICH in aged murine model. Thus, Fpn upregulation or miR-124 inhibition might be promising therapeutic approachs for this disease.


Assuntos
Hemorragia Cerebral/genética , Ferroptose/genética , Neurônios/metabolismo , Animais , Apoptose , Morte Celular , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...