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1.
J Nat Prod ; 85(3): 479-484, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35196451

RESUMO

Bacteria use small molecules to impose strict regulation over the acquisition, uptake, and sequestration of transition metal ions. Low-abundance nutrient metals, such as Fe(III), need to be scavenged from the environment by high-affinity chelating molecules called siderophores. Conversely, metal ions that become toxic at high concentrations need to be sequestered and detoxified. Often, bacteria produce a suite of compounds that bind various metal ions at different affinities in order to maintain homeostasis. Turnerbactin, a triscatecholate siderophore isolated from the intracellular shipworm symbiont Teredinibacter turnerae T7901, is responsible for iron regulation and uptake. Herein, another series of compounds are described that complex with iron, copper, and molybdenum in solution. Teredinibactins belong to a class of metal-binding molecules that utilize a phenolate-thiazoline moiety in the coordination of metal ions. In contrast to other compounds in this class, such as yersiniabactin, the phenyl ring is decorated with a 2,4-dihydroxy-3-halo substitution pattern. UV-vis absorption spectroscopy based titration experiments with CuCl2 show the formation of an intermediate complex at substoichiometric concentrations and conversion to a copper-bound complex at 1:1 molar equiv.


Assuntos
Compostos Férricos , Sideróforos , Bactérias/metabolismo , Transporte Biológico , Ferro/metabolismo , Sideróforos/química
2.
J Clin Invest ; 132(9)2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499081

RESUMO

T follicular helper (Tfh) cells are a subset of CD4+ T cells that are essential in the pathogenesis of systemic lupus erythematosus (SLE). Notably, iron is required for activated CD4+ T lymphocytes to sustain high proliferation and metabolism. In this issue of the JCI, Gao et al. showed that CD4+ T cells from patients with SLE accumulated iron, augmenting their differentiation into Tfh cells and correlating with disease activity. Using human cells and murine models, the authors demonstrated that miR-21 was overexpressed in lupus T cells and inhibited 3-hydroxybutyrate dehydrogenase-2 (BDH2). The subsequent loss of BDH2 drove labile iron to accumulate in the cytoplasm and promoted TET enzyme activity, BCL6 gene demethylation, and Tfh cell differentiation. This work identifies a role for iron in CD4+ T cell biology and the development of pathogenic effectors in SLE. We await future investigations that could determine whether modulating iron levels could regulate Tfh cells in human health and disease.


Assuntos
Lúpus Eritematoso Sistêmico , Linfócitos T Auxiliares-Indutores , Animais , Humanos , Hidroxibutirato Desidrogenase/metabolismo , Ferro/metabolismo , Lúpus Eritematoso Sistêmico/genética , Ativação Linfocitária , Camundongos , Células T Auxiliares Foliculares
3.
Clin Transl Med ; 12(5): e854, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35538889

RESUMO

BACKGROUND: Iron is essential for all mammalian life, and either a deficiency or excess of iron can cause diseases. AMP-activated protein kinase (AMPK) is a critical regulator of metabolic homeostasis; however, it has not been established whether AMPK regulates iron metabolism. METHODS: Iron, hepcidin and ferroportin levels were examined in mice with global and hepatocyte-specific knockout of AMPKα1 and AMPKα2. Primary AMPKα1 or AMPKα2 deleted hepatocytes were isolated and cultured in hypoxia condition to explore PHD2, HIF and hydroxylated HIF1α levels. We performed immunoprecipitation, in vitro AMPK kinase assay and site-direct mutant assay to detect phosphorylation sites of PHD2. We also obtained liver tissues from patients with anaemia of chronic disease undergoing surgery, AMPKα1 and hydroxylated HIF1α levels were measured by immunohistochemical analysis. RESULTS: We found that mice with global deficiency of AMPKα1, but not AMPKα2, exhibited hypoferraemia as well as iron sequestration in the spleen and liver. Hepatocyte-specific, but not myeloid-specific, ablation of AMPKα1 also reduced serum iron levels in association with increased hepcidin and decreased ferroportin protein levels. Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling. Inhibition of PHD2 hydroxylation ameliorated abnormal iron metabolism in hepatic AMPKα1-deficient mice. Furthermore, we found hepatic AMPKα/PHD2/HIFα/ hepcidin axes were highly clinically relevant to anaemia of chronic disease. CONCLUSION: In conclusion, these observations suggest that hepatic AMPKα1 has an essential role in maintaining iron homeostasis by PHD2-dependent regulation of hepcidin, thus providing a potentially promising approach for the treatment of iron disturbances in chronic diseases.


Assuntos
Proteínas Quinases Ativadas por AMP , Hepcidinas , Prolina Dioxigenases do Fator Induzível por Hipóxia , Ferro , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Hepcidinas/metabolismo , Homeostase , Humanos , Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Ferro/metabolismo , Camundongos
4.
Front Cell Infect Microbiol ; 12: 847846, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35531339

RESUMO

The transition metals iron and copper are required by virtually all organisms but are toxic in excess. Acquisition of both metals and resistance to copper excess have previously been shown to be important for virulence of the most common airborne human mold pathogen, Aspergillus fumigatus. Here we demonstrate that the ambient availability of amino acids and proteins increases the copper resistance of A. fumigatus wild type and particularly of the ΔcrpA mutant that lacks export-mediated copper detoxification. The highest-protecting activity was found for L-histidine followed by L-asparagine, L-aspartate, L-serine, L-threonine, and L-tyrosine. Other amino acids and proteins also displayed significant but lower protection. The protecting activity of non-proteinogenic D-histidine, L-histidine-mediated growth inhibition in the absence of high-affinity copper uptake, determination of cellular metal contents, and expression analysis of copper-regulated genes suggested that histidine inhibits low-affinity but not high-affinity copper acquisition by extracellular copper complexation. An increase in the cellular copper content was found to be accompanied by an increase in the iron content, and, in agreement, iron starvation increased copper susceptibility, which underlines the importance of cellular metal balancing. Due to the role of iron and copper in nutritional immunity, these findings are likely to play an important role in the host niche.


Assuntos
Aspergillus fumigatus , Ferro , Aminoácidos/metabolismo , Cobre/metabolismo , Regulação Fúngica da Expressão Gênica , Histidina/genética , Histidina/metabolismo , Humanos , Ferro/metabolismo
5.
Bioengineered ; 13(4): 10026-10037, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35436415

RESUMO

Many dysregulated lncRNAs have been reported to perform an integral function in hepatocellular carcinoma (HCC). However, the role of long non-coding RNA (lncRNA) NRAV in HCC has not been elucidated. To address this issue, we investigated the function of NRAV in HCC in this research. Through bioinformatics prediction and real-time quantitative polymerase chain reaction validation, we found that NRAV plays an upmodulating role in HCC cells and tissues, and patients with high NRAV expression showed a poor prognosis. Cell viability was examined by conducting a Cell Counting Kit-8 analysis. Subsequently, the proliferation capacity of the cells was analyzed utilizing cell colony formation assay, and transwell invasion experiments were conducted to identify the cell invasion ability. To determine the association between NRAV and miR-199a-3p, and CDGSH iron-sulfur domain-containing protein 2 (CISD2), we conducted a dual luciferase assay. The protein and gene expressions were estimated utilizing Western blot. Findings illustrated that the overexpression of NRAV enhanced the HCC cell viability, proliferation and invasion, whereas they were inhibited significantly by down expression of NRAV. The dual-luciferase assay showed that miR-199a-3p is not only a target for NRAV but also interacts with the 3' UTR of CISD2 in HCC cells. MiR-199a-3p/CISD2 axis performs a function in NRAV-mediated cell behavior regulation. NRAV may trigger the Wnt/ß-catenin signaling via the modulation of the miR-199a-3p/CISD2 axis in HCC. The findings of this work can provide novel insights into clinical diagnosis and the treatment of HCC in the future.Abbreviations: HCC, hepatocellular carcinoma; LncRNA, long non-coding RNA; CISD2, CDGSH iron-sulfur domain-containing protein 2; CCK-8, Cell Counting Kit-8; cDNA, single-stranded complementary DNA; RT-qPCR, real-time quantitative polymerase chain reaction; BCA, bicinchoninic acid; ceRNA, competing endogenous RNAs.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Regiões 3' não Traduzidas , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Ferro/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Enxofre , Via de Sinalização Wnt/genética
6.
Int J Mol Sci ; 23(7)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35409372

RESUMO

Iron oxide nanoparticles have attracted a great deal of research interest in recent years for magnetic hyperthermia therapy owing to their biocompatibility and superior thermal conversion efficiency. Magnetoferritin is a type of biomimetic superparamagnetic iron oxide nanoparticle in a ferritin cage with good monodispersity, biocompatibility, and natural hydrophilicity. However, the magnetic hyperthermic efficiency of this kind of nanoparticle is limited by the small size of the mineral core as well as its low synthesis temperature. Here, we synthesized a novel magnetoferritin particle by using a recombinant ferritin from the hyperthermophilic archaeon Pyrococcus furiosus as a template with high iron atom loading of 9517 under a designated temperature of 90 °C. Compared with the magnetoferritins synthesized at 45 and 65 °C, the one synthesized at 90 °C displays a larger average magnetite and/or maghemite core size of 10.3 nm. This yields an increased saturation magnetization of up to 49.6 emu g-1 and an enhanced specific absorption rate (SAR) of 805.3 W g-1 in an alternating magnetic field of 485.7 kHz and 49 kA m-1. The maximum intrinsic loss power (ILP) value is 1.36 nHm2 kg-1. These results provide new insights into the biomimetic synthesis of magnetoferritins with enhanced hyperthermic efficiency and demonstrate the potential application of magnetoferritin in the magnetic hyperthermia of tumors.


Assuntos
Hipertermia Induzida , Nanopartículas de Magnetita , Apoferritinas , Ferritinas , Humanos , Hipertermia , Ferro/metabolismo , Campos Magnéticos , Óxidos , Temperatura
7.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35443532

RESUMO

Iron overload occurs as a result of multiple blood transfusions and increased iron absorption in thalassemia patients. Iron deposition in liver results in liver stiffness and fibrosis. Non invasive methods including imaging and serum biomarkers have been introduced for assessment of liver fibrosis. We aimed to study liver stiffness using transient elastography and serum hyaluronic acid levels and correlate them with serum ferritin levels in adult transfusion dependent beta thalassemia patients. MATERIAL: 70 transfusion dependent thalassemia patients of age ≥18 years, registered at Thalassemia Day Care Centre were subjected to investigations like CBC, Liver function tests, viral markers, serum ferritin, serum hyaluronic acid levels and transient elastography. Fibrosis indices like FIB-4, AAR and APRI were also calculated. 45 patients had T2*MRI reports with them; which were also included and analysed. Spearman coefficient r was used to test correlations between TE values and serum HA levels with other variables. OBSERVATION: 70 patients (41 male and 29 female) with mean age of 24.09±5.38 years and BMI 20.51 ±3.47 kg/m², were enrolled. Median values of hemoglobin, AST, ALT, TE, serum HA and serum ferritin were, 9.15 g/dl, 42 IU/L, 47.50 IU/L, 9.1 kPa, 284 ng/dl and 1841 ng/ml, respectively . TE values had significant positive correlation with serum ferritin (r=0.5, p < 0.001), ALT (r=0.59, p < 0.001), AST (r=0.58, p< 0.001), APRI (r=0.5, p<0.001) and FIB-4 (p=0.02), respectively and significant negative correlation with T2* MRI (ms) (r= -0.5, p<0.001). No significant correlation of HA was found with any variable. CONCLUSION: Transient elastography can be used as a non expensive, easily accessible and non invasive marker of liver iron overload. Further detailed studies are required to establish the role of serum Hyaluronic acid in thalassemia patients.


Assuntos
Técnicas de Imagem por Elasticidade , Sobrecarga de Ferro , Talassemia , Adolescente , Adulto , Biomarcadores , Técnicas de Imagem por Elasticidade/métodos , Feminino , Ferritinas , Fibrose , Humanos , Ácido Hialurônico , Ferro/metabolismo , Sobrecarga de Ferro/diagnóstico por imagem , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/patologia , Fígado/diagnóstico por imagem , Cirrose Hepática , Masculino , Talassemia/patologia , Talassemia/terapia , Adulto Jovem
8.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35443540

RESUMO

Anemia is common in patients with cancer and it's pathophysiology is complex and multifactorial . Conventional methods (Serum Iron, serum ferritin, TIBC, TSAT) to diagnosing iron deficiency anemia in cancer patients is affected by cancer type, duration, treatment, infection and inflammation related to cancer. RET-He measure the recent functional availability of iron and the correlation well with iron deficient / restricted erythropoiesis, and it is not affected by infection and inflammation related to cancer so it can be useful marker to rapidly rule out iron deficiency in cancer patients. Material: This is observation longitudinal study and study subjects including all type of diagnosed cancer patients with anemia (Hb <13 gm % in males and <12gm% in females) with or without treatment. Study duration was 18 month and 200 sample size was taken. Complete blood count (Hb, TLC, platelets, MCV, MCH, MCHC, reticulocyte hemoglobin) were analysed on SYSMEX XN 1000i. Serum Ferritin was estimated using AVANTOR CL-1000i and Serum iron, TIBC, TSAT was run on EBRA MANHEIN CHEM 5X machine. Bone marrow examination was done for diagnosis / staging . Iron stores were evaluated by Perl's Prussian blue stain and graded as per criteria laid down by Gale et al. Observation: At a cut off of 28.4 pg, RET-He achieved sensitivity of 96.77 % and specificity of 81.66% with NPV of 99.3% and PPV of 49.2% for iron deficient state in cancer patients. This cut off value rules out iron deficient erythropoiesis, reduces unnecessary iron studies and encourage early treatment of iron deficiency. There is also moderate agreement exist between iron stores of bone marrow and RET-He with Kappa 0.411 and p value <.0001. Conclusion: RET-He is better indicator of IDA in cancer patients as compared to other conventional methods of diagnosing IDA.This study also revealed a direct correlation between RET-He and bone marrow iron stores. In future it is advisable to use RET-He as a predictor of IDA, which is sensitive and specific at particular cut off points in routine evaluation in IDA in cancer patients.


Assuntos
Anemia Ferropriva , Anemia , Neoplasias , Anemia/diagnóstico , Anemia/etiologia , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/etiologia , Feminino , Ferritinas , Hemoglobinas/análise , Humanos , Inflamação , Ferro/metabolismo , Estudos Longitudinais , Masculino , Neoplasias/complicações , Curva ROC , Reticulócitos/química
9.
J Zhejiang Univ Sci B ; 23(4): 286-299, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35403384

RESUMO

Breast cancer is one of the most malignant tumors and is associated with high mortality rates among women. Lycium barbarum polysaccharide (LBP) is an extract from the fruits of the traditional Chinese herb, L. barbarum. LBP is a promising anticancer drug, due to its high activity and low toxicity. Although it has anticancer properties, its mechanisms of action have not been fully established. Ferroptosis, which is a novel anticancer strategy, is a cell death mechanism that relies on iron-dependent lipid reactive oxygen species (ROS) accumulation. In this study, human breast cancer cells (Michigan Cancer Foundation-7 (MCF-7) and MD Anderson-Metastatic Breast-231 (MDA-MB-231)) were treated with LBP. LBP inhibited their viability and proliferation in association with high levels of ferroptosis. Therefore, we aimed to ascertain whether LBP reduced cell viability through ferroptosis. We found that the structure and function of mitochondria, lipid peroxidation, and expression of solute carrier family 7 member 11 (SLC7A11, also known as xCT, the light-chain subunit of cystine/glutamate antiporter system Xc-) and glutathione peroxidase 4 (GPX4) were altered by LBP. Moreover, the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), rescued LBP-induced ferroptosis-associated events including reduced cell viability and glutathione (GSH) production, accumulation of intracellular free divalent iron ions and malondialdehyde (MDA), and down-regulation of the expression of xCT and GPX4. Erastin (xCT inhibitor) and RSL3 (GPX4 inhibitor) inhibited the expression of xCT and GPX4, respectively, which was lower after the co-treatment of LBP with Erastin and RSL3. These results suggest that LBP effectively prevents breast cancer cell proliferation and promotes ferroptosis via the xCT/GPX4 pathway. Therefore, LBP exhibits novel anticancer properties by triggering ferroptosis, and may be a potential therapeutic option for breast cancer.


Assuntos
Neoplasias da Mama , Medicamentos de Ervas Chinesas , Ferroptose , Neoplasias da Mama/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Glutationa/metabolismo , Humanos , Ferro/metabolismo
10.
Oxid Med Cell Longev ; 2022: 8979904, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35450412

RESUMO

α-Lipoic acid-plus (LAP), an amine derivative of α-lipoic acid, has been reported to protect cells from oxidative stress damage by reacting with lysosomal iron and is more powerful than desferrioxamine (DFO). However, the role of LAP in experimental carotid artery intimal injury (CAII) has not yet been well investigated. Therefore, we sought to uncover the role and potential endovascular protective mechanisms of LAP in endothelial injury. In vitro, oxyhemoglobin (OxyHb) stimulation of cultured human umbilical vein endothelial cells (HUVECs) simulated intimal injury. In vivo, balloon compression injury of the carotid artery was used to establish a rat CAII model. We found that the protein levels of cathepsin B/D, ferritin, transferrin receptor (TfR), cleaved caspase-3, and Bax increased in the injured endothelium and HUVECs but were rectified by DFO and LAP treatments, as revealed by western blotting and immunofluorescence staining. Additionally, DFO and LAP decreased oxidative stress levels and endothelial cell necrosis of the damaged endothelium. Moreover, DFO and LAP significantly ameliorated the increased oxidative stress, iron level, and lactic dehydrogenase activity of HUVECs and improved the reduced HUVEC viability induced by OxyHb. More importantly, DFO and LAP significantly reduced mitochondrial damage and were beneficial for maintaining lysosomal integrity, as indicated by acridine orange (AO), Lyso-Tracker Red, JC-1, and ATPB staining in HUVECs. Finally, LAP might offer more significant endovascular protective effects than DFO. Our data suggested that LAP exerted endovascular protective effects by inhibiting the apoptosis signaling pathway mediated by intralysosomal cathepsins by reacting with excessive iron in endothelial lysosomes after intimal injury.


Assuntos
Ácido Tióctico , Animais , Apoptose , Endotélio/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Ferro/metabolismo , Estresse Oxidativo , Ratos , Ácido Tióctico/metabolismo , Ácido Tióctico/farmacologia
11.
Methods Enzymol ; 666: 451-468, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35465927

RESUMO

Due to their biological importance and functional diversity, radical S-adenosylmethionine (rSAM) enzymes have become popular targets for electron paramagnetic resonance (EPR) spectroscopic studies. EPR spectroscopy is a powerful tool that allows for the observation of the iron-sulfur clusters as well as paramagnetic reaction intermediates, thus providing insight into their catalytic mechanisms. While the iron-sulfur clusters may be readily observable by EPR spectroscopy in the enzymes' resting states, radical intermediates are often elusive and must be trapped. Here, we describe a protocol for trapping and analyzing the Lys-Trp intermediate of the Lys-Trp-crosslinking rSAM enzyme SuiB, including modified expression and purification steps. This protocol is also intended to serve as a primer for trapping paramagnetic intermediates in other rSAM enzymes for studying by EPR spectroscopy.


Assuntos
Proteínas Ferro-Enxofre , S-Adenosilmetionina , Espectroscopia de Ressonância de Spin Eletrônica , Ferro/metabolismo , Proteínas Ferro-Enxofre/metabolismo , S-Adenosilmetionina/metabolismo , Enxofre/metabolismo
12.
Ecotoxicol Environ Saf ; 236: 113515, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35427877

RESUMO

Tetramethyl bisphenol A (TMBPA) is a commonly used bisphenol analog, used as a fire retardant. However, whether it inhibits the function of Leydig cells in late puberty remains unclear. In this study, 35-day-old male Sprague-Dawley rats were gavaged with 0, 10, 100, and 200 mg/kg body weight TMBPA for 21 days. TMBPA significantly reduced serum testosterone levels at 10 mg/kg and higher doses without altering serum luteinizing hormone and follicle-stimulating hormone levels. TMBPA significantly increased serum iron concentraion while reducing the ratio of serum glutathione (GSH) and GSH/GSSG (oxidized glutathione disulfide). In addition, TMBPA significantly increased testicular iron amount at 10 mg/kg and higher doses and malondialdehyde level at 200 mg/kg. TMBPA down-regulated the expression of Leydig cell genes, including Nr5a1, Star, Scarb1, Insl3, Cyp11a1, Cyp17a1, Hsd17b3, and Hsd11b1, and their proteins. In addition, TMBPA markedly down-regulated the expression of genes in the ferroptosis pathway (Tp53, Slc7a11, Sod1, Sod2, Cat, Sqstm1, Keap1, and Hmox1). TMBPA significantly reduced the levels of ferroptosis pathway proteins (TP53, SLC7A11, GPX4, SQSTM1, KEAP1, NRF2, and HMOX1) in Leydig cells in vivo. Immature and adult Leydig cell culture in vitro also showed that TMBPA significantly reduced testosterone concentrations in the medium, which can be reversed by a ferroptosis inhibitor. After 24 h of culture in primary Leydig cells at 10 and 50 µM, TMBPA significantly induced reactive oxygen species and lowered the mitochondrial membrane potential. TMBPA also altered protein levels in the ferroptosis pathway in Leydig cells in vitro. In conclusion, TMBPA directly inhibits the activity of rat Leydig cell steroidogenic enzymes and induces the ferroptosis of Leydig cells, thereby inhibiting the testosterone synthesis of Leydig cells in the late puberty.


Assuntos
Ferroptose , Células Intersticiais do Testículo , Animais , Compostos Benzidrílicos , Di-Hidrotaquisterol/metabolismo , Ferro/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Células Intersticiais do Testículo/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Fenóis , Ratos , Ratos Sprague-Dawley , Proteína Sequestossoma-1/metabolismo , Maturidade Sexual , Testosterona
13.
Adv Microb Physiol ; 80: 35-83, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35489793

RESUMO

Neisseria gonorrhoeae is an obligate human pathogen that is the cause of the sexually transmitted disease gonorrhoea. Recently, there has been a surge in gonorrhoea cases that has been exacerbated by the rapid rise in gonococcal multidrug resistance to all useful antimicrobials resulting in this organism becoming a significant public health burden. Therefore, there is a clear and present need to understand the organism's biology through its physiology and pathogenesis to help develop new intervention strategies. The gonococcus initially colonises and adheres to host mucosal surfaces utilising a type IV pilus that helps with microcolony formation. Other adhesion strategies include the porin, PorB, and the phase variable outer membrane protein Opa. The gonococcus is able to subvert complement mediated killing and opsonisation by sialylation of its lipooligosaccharide and deploys a series of anti-phagocytic mechanisms. N. gonorrhoeae is a fastidious organism that is able to grow on a limited number of primary carbon sources such as glucose and lactate. The utilization of lactate by the gonococcus has been implicated in a number of pathogenicity mechanisms. The bacterium lives mainly in microaerobic environments and can grow both aerobically and anaerobically with the aid of nitrite. The gonococcus does not produce siderophores for scavenging iron but can utilize some produced by other bacteria, and it is able to successful chelate iron from host haem, transferrin and lactoferrin. The gonococcus is an incredibly versatile human pathogen; in the following chapter, we detail the intricate mechanisms used by the bacterium to invade and survive within the host.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Gonorreia/microbiologia , Humanos , Ferro/metabolismo , Lactatos/metabolismo , Neisseria gonorrhoeae/metabolismo , Virulência
14.
Int J Mol Sci ; 23(8)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35457224

RESUMO

Divalent metal-iron transporter 1 (DMT1) is a mammalian iron transporter encoded by the SLC11A2 gene. DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis. Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with iron overload (AHMIO1), which has been described in eight patients so far. Here, we report two novel cases of this disease. The first proband is homozygous for a new SLC11A2 splicing variant (c.762 + 35A > G), becoming the first ever patient reported with a SLC11A2 splicing mutation in homozygosity. Splicing studies performed in this work confirm its pathogenicity. The second proband harbors the previously reported DMT1 G75R mutation in homozygosis. Functional studies with the G75R mutation in HuTu 80 cells demonstrate that this mutation results in improper DMT1 accumulation in lysosomes, which correlates with a significant decrease in DMT1 levels in patient-derived lymphoblast cell lines (LCLs). We also suggest that recombinant erythropoietin would be an adequate therapeutic approach for AHMIO1 patients as it improves their anemic state and may possibly contribute to mobilizing excessive hepatic iron.


Assuntos
Anemia Hipocrômica , Anemia , Sobrecarga de Ferro , Anemia/genética , Anemia Hipocrômica/genética , Animais , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Mamíferos/metabolismo , Mutação
15.
Artigo em Inglês | MEDLINE | ID: mdl-35457338

RESUMO

The conventional anaerobic digestion of sludge has the disadvantages of long digestion time and low methane production. Pretreatment is often used to mitigate these problems. In this study, three pretreatment methods, namely, the addition of iron powder, high-temperature thermal hydrolysis, and a combination of these methods, were compared for application with conventional continuous anaerobic digestion reactors. The results showed that pretreatment improved methane yield by 18.2-22.9%, compared to the control reactor (conventional anaerobic digestion). Moreover, it was recognized that the archaeal community in the sludge underwent significant changes after pretreatment. Specifically, the addition of iron powder reduced the diversity in the archaeal community, but increased the abundance of hydrogenotrophic methanogens without changing the community composition. Thermal hydrolysis at high temperatures had the reverse effect, as it increased the diversity of the archaeal community but inhibited the growth of acetoclastic methanogens. In the case of the combined pretreatment, the thermal hydrolysis had a dominant influence on the archaeal community. By comparing the changes in functional gene content, it was found that the functional abundance of the archaeal community in the transport and metabolism of carbohydrates, lipids, and amino acids was higher after pretreatment than in the control group.


Assuntos
Archaea , Esgotos , Anaerobiose , Archaea/genética , Archaea/metabolismo , Reatores Biológicos , Hidrólise , Ferro/metabolismo , Metano/metabolismo , Pós
16.
J Hazard Mater ; 433: 128835, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35398798

RESUMO

Mercury (Hg) is a pervasive environmental pollutant and poses serious health concerns as inorganic Hg(II) can be converted to the neurotoxin methylmercury (MeHg), which bioaccumulates and biomagnifies in food webs. Phytoplankton, representing the base of aquatic food webs, can take up Hg(II) and influence MeHg production, but currently little is known about how and to what extent phytoplankton may impact Hg(II) methylation by itself or by methylating bacteria it harbors. This study investigated whether some species of phytoplankton could produce MeHg and how the live or dead phytoplankton cells and excreted algal organic matter (AOM) impact Hg(II) methylation by several known methylators, including iron-reducing bacteria (FeRB), Geobacter anodireducens SD-1 and Geobacter sulfurreducens PCA, and the sulfate-reducing bacterium (SRB) Desulfovibrio desulfuricans ND132 (or Pseudodesulfovibrio mercurii). Our results indicate that, among the 4 phytoplankton species studied, none were capable of methylating Hg(II). However, the presence of phytoplankton cells (either live or dead) from Chlorella vulgaris (CV) generally inhibited Hg(II) methylation by FeRB but substantially enhanced methylation by SRB D. desulfuricans ND132. Enhanced methylation was attributed in part to CV-excreted AOM, which increased Hg(II) complexation and methylation by ND132 cells. In contrast, inhibition of methylation by FeRB was attributed to these bacteria incapable of competing with phytoplankton for Hg(II) binding and uptake. These observations suggest that phytoplankton could play different roles in affecting Hg(II) methylation by the two groups of anaerobic bacteria, FeRB and SRB, and thus shed additional light on how phytoplankton blooms may modulate MeHg production and bioaccumulation in the aquatic environment.


Assuntos
Chlorella vulgaris , Desulfovibrio desulfuricans , Desulfovibrio , Mercúrio , Compostos de Metilmercúrio , Bactérias/metabolismo , Chlorella vulgaris/metabolismo , Desulfovibrio/metabolismo , Desulfovibrio desulfuricans/metabolismo , Exsudatos e Transudatos/metabolismo , Ferro/metabolismo , Mercúrio/metabolismo , Mercúrio/toxicidade , Metilação , Compostos de Metilmercúrio/metabolismo , Compostos de Metilmercúrio/toxicidade , Fitoplâncton , Sulfatos/metabolismo
17.
J Biomed Nanotechnol ; 18(2): 327-342, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35484753

RESUMO

The most common type of kidney tumor, clear-cell renal cell carcinoma (ccRCC) with relatively insidious development and easily metastatic characteristics is generally insensitive to cytotoxic chemotherapy. The abundant polyunsaturated fatty acids (PUFAs) content in advanced ccRCC allows it to be intrinsically vulnerable to ferroptosis-based therapeutic strategies. Nevertheless, the strategy to cause the "iron overload" by administration with iron-based nanomaterials has limited therapeutic efficacy. And the classic ferroptosis agonist (RSL3) with low specificity for tumors, short half-life in the blood, poor water solubility and deficient accumulation at the tumor site prevents its reliable application in vivo. In this study, iron-based metal-organic framework nanoparticles (MIL-101(Fe) NPs) delivered RSL3 to ccRCC tumors, and then released the iron ions and RSL3 accompanied by the degradation of MIL-101(Fe) NPs in the acidic tumor microenvironment. The MIL-101(Fe)@RSL3 as a pH-responsive nanodrug causes cellular iron overload and promotes the hydroxyl radical (•OH) generation by Fenton reaction to attack PUFAs, leading to the aberrant accumulation of lipid peroxides (L-OOH). Additionally, RSL3 directly inhibits glutathione peroxidase 4 (GPX4) to detoxify L-OOH, and ferrous ions further catalyze the irreversible conversion of highly reactive lipid alkoxyl radicals (L-O•) from L-OOH to triggering waterfall-like cascade ferroptosis. In contrast to the limited antitumor efficiency of free RSL3, MIL-101(Fe)@RSL3 with high encapsulation efficiency (88.7%) shows a significant ccRCC-specific antitumor effect and negligible side effects. Taken together, MIL-101(Fe)@RSL3 could aggravate ferroptosis and be expected to be a promising nanodrug for ccRCC systemic therapy due to the targeted delivery and responsive release of RSL3 and iron ions.


Assuntos
Carcinoma de Células Renais , Ferroptose , Neoplasias Renais , Nanopartículas , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Ferro/metabolismo , Neoplasias Renais/tratamento farmacológico , Masculino , Nanopartículas/uso terapêutico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Microambiente Tumoral
18.
J Biomed Sci ; 29(1): 26, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477574

RESUMO

BACKGROUND: Stenotrophomonas maltophilia, a member of γ-proteobacteria, is a ubiquitous environmental bacterium that is recognized as an opportunistic nosocomial pathogen. FecABCD system contributes to ferric citrate acquisition in Escherichia coli. FeoABC system, consisting of an inner membrane transporter (FeoB) and two cytoplasmic proteins (FeoA and FeoC), is a well-known ferrous iron transporter system in γ-proteobacteria. As revealed by the sequenced genome, S. maltophilia appears to be equipped with several iron acquisition systems; however, the understanding of these systems is limited. In this study, we aimed to elucidate the ferric citrate acquisition system of S. maltophilia. METHODS: Candidate genes searching and function validation are the strategy for elucidating the genes involved in ferric citrate acquisition. The candidate genes responsible for ferric citrate acquisition were firstly selected using FecABCD of E. coli as a reference, and then revealed by transcriptome analysis of S. maltophilia KJ with and without 2,2'-dipyridyl (DIP) treatment. Function validation was carried out by deletion mutant construction and ferric citrate utilization assay. The bacterial adenylate cyclase two-hybrid system was used to verify intra-membrane protein-protein interaction. RESULTS: Smlt2858 and Smlt2356, the homologues of FecA and FecC/D of E. coli, were first considered; however, deletion mutant construction and functional validation ruled out their involvement in ferric citrate acquisition. FciA (Smlt1148), revealed by its upregulation in DIP-treated KJ cells, was the outer membrane receptor for ferric citrate uptake. The fciA gene is a member of the fciTABC operon, in which fciT, fciA, and fciC participated in ferric citrate acquisition. Uniquely, the Feo system of S. maltophilia is composed of a cytoplasmic protein FeoA, an inner membrane transporter FeoB, and a predicted inner membrane protein FeoI. The intra-membrane protein-protein interaction between FeoB and FeoI may extend the substrate profile of FeoB to ferric citrate. FeoABI system functioned as an inner membrane transporter of ferric citrate. CONCLUSIONS: The FciTABC and FeoABI systems contribute to ferric citrate acquisition in S. maltophilia.


Assuntos
Proteínas de Escherichia coli , Stenotrophomonas maltophilia , Proteínas de Bactérias/genética , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Compostos Férricos , Ferro/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Receptores de Superfície Celular/metabolismo , Stenotrophomonas maltophilia/genética , Stenotrophomonas maltophilia/metabolismo
19.
Curr Protoc ; 2(4): e413, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35384401

RESUMO

Ferroptosis is iron-dependent, lipid peroxidation-driven, regulated cell death that is triggered when cellular glutathione peroxidase 4 (GPX4)-mediated cellular defense is insufficient to prevent pathologic accumulation of toxic lipid peroxides. Ferroptosis is implicated in various human pathologies, including neurodegeneration, chemotherapy-resistant cancers, ischemia-reperfusion injury, and acute and chronic kidney diseases. Despite the fact that the ferroptotic process has been rigorously interrogated in multiple preclinical models, the lack of specific and readily available biomarkers to detect ferroptosis in vivo in mouse models makes it challenging to delineate its contribution to key pathologic events in vivo. Critical steps to practically evaluate ferroptosis include, but are not limited to, detecting increased cell death and pathologic accumulation of toxic lipid peroxides and testing augmentation of observed pathologic events by genetic inhibition of the glutathione-GPX4 axis or mitigation of the pathologic process by ferroptosis inhibitors. Here, we describe methods to evaluate these key features of the ferroptotic process in mice in vivo. Specifically, we describe methods to detect toxic lipid peroxides (4-hydroxynonenal) and cell death (based on terminal deoxynucleotidyl transferase dUTP nick end labeling staining) as well as a protocol to pharmacologically inhibit ferroptotic stress using liproxstatin-1. These protocols provide tools for understanding the ferroptotic process in mouse genetic or disease models. © 2022 Wiley Periodicals LLC. Basic Protocol 1: How to use liproxstatin-1 Basic Protocol 2: How to evaluate ferroptosis in mouse kidneys.


Assuntos
Ferroptose , Animais , Morte Celular , Ferro/metabolismo , Peroxidação de Lipídeos , Peróxidos Lipídicos , Camundongos
20.
Arkh Patol ; 84(2): 13-19, 2022.
Artigo em Russo | MEDLINE | ID: mdl-35417944

RESUMO

OBJECTIVE: To study, using a complex morphochemical approach, the localization of alpha-synuclein, iron compounds and iron-containing proteins in the structures of the substantia nigra of the brain in Parkinson's disease (PD). MATERIAL AND METHODS: Histochemistry and immunohistochemistry methods have been used to study the localization of pathological alpha-synuclein (α-Syn-p129), iron compounds and iron-containing proteins - transferrin receptor and ferritin in neurons and neuroglia in the substantia nigra of the brain of deceased PD patients and persons with no neurological symptoms detected during life (control). RESULTS: In the substantia nigra of PD patients, in comparison with the control, a stable accumulation of pathological alpha-synuclein (α-Syn-p129) in the bodies and processes of neurons was found, and in the neuroglia and neuropil - the accumulation of iron (II) and ferritin heavy chain, the reaction of microglia to protein CD68 was moderately elevated. The transmembrane protein CD71 was detected equally in the brains of PD patients and in controls. CONCLUSION: Synaptic protein alpha-synuclein in PD turns into a pathological metabolite that accumulates in the structures of substantia nigra, and probably disrupts the conduction of nervous excitation. Excessive accumulation of the ferritin heavy chain in neuroglia can increase the concentration of reactive forms of iron and increase neurotoxicity. The uniform distribution of the transmembrane glycoprotein CD71 in the of substantia nigra structures both in the control and in PD patients indicates the preservation of non-heme iron transport during the neurodegenerative process.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Apoferritinas/metabolismo , Encéfalo/patologia , Humanos , Ferro/metabolismo , Doença de Parkinson/metabolismo , Substância Negra/patologia , alfa-Sinucleína/metabolismo
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