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1.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198528

RESUMO

Intracellular free zinc ([Zn2+]i) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn2+]i is a component of cellular signal transduction in biological systems. Although several transporters and ion channels that carry Zn2+ have been identified, proteins that are involved in Zn2+ supply into cells and their expression are poorly understood, particularly under inflammatory conditions. Here, we show that the expression of Zn2+ transporters ZIP8 and ZIP14 is increased via the activation of hypoxia-induced factor 1α (HIF-1α) in inflammation, leading to [Zn2+]i accumulation, which intrinsically activates transient receptor potential ankyrin 1 (TRPA1) channel and elevates basal [Zn2+]i. In human fibroblast-like synoviocytes (FLSs), treatment with inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α), evoked TRPA1-dependent intrinsic Ca2+ oscillations. Assays with fluorescent Zn2+ indicators revealed that the basal [Zn2+]i concentration was significantly higher in TRPA1-expressing HEK cells and inflammatory FLSs. Moreover, TRPA1 activation induced an elevation of [Zn2+]i level in the presence of 1 µM Zn2+ in inflammatory FLSs. Among the 17 out of 24 known Zn2+ transporters, FLSs that were treated with TNF-α and IL-1α exhibited a higher expression of ZIP8 and ZIP14. Their expression levels were augmented by transfection with an active component of nuclear factor-κB P65 and HIF-1α expression vectors, and they could be abolished by pretreatment with the HIF-1α inhibitor echinomycin (Echi). The functional expression of ZIP8 and ZIP14 in HEK cells significantly increased the basal [Zn2+]i level. Taken together, Zn2+ carrier proteins, TRPA1, ZIP8, and ZIP14, induced under HIF-1α mediated inflammation can synergistically change [Zn2+]i in inflammatory FLSs.


Assuntos
Proteínas de Transporte de Cátions/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/genética , Sinoviócitos/metabolismo , Canal de Cátion TRPA1/genética , Regulação para Cima/genética , Zinco/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Inflamação/patologia , Espaço Intracelular/metabolismo , Sinoviócitos/patologia , Canal de Cátion TRPA1/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203933

RESUMO

Natural resistance-associated macrophage proteins (Nramps) are specific metal transporters in plants with different functions among various species. The evolutionary and functional information of the Nramp gene family in Spirodela polyrhiza has not been previously reported in detail. To identify the Nramp genes in S. polyrhiza, we performed genome-wide identification, characterization, classification, and cis-elements analysis among 22 species with 138 amino acid sequences. We also conducted chromosomal localization and analyzed the synteny relationship, promoter, subcellular localization, and expression patterns in S. polyrhiza. ß-Glucuronidase staining indicated that SpNramp1 and SpNramp3 mainly accumulated in the root and joint between mother and daughter frond. Moreover, SpNramp1 was also widely displayed in the frond. SpNramp2 was intensively distributed in the root and frond. Quantitative real-time PCR results proved that the SpNramp gene expression level was influenced by Cd stress, especially in response to Fe or Mn deficiency. The study provides detailed information on the SpNramp gene family and their distribution and expression, laying a beneficial foundation for functional research.


Assuntos
Araceae/genética , Cádmio/toxicidade , Proteínas de Transporte de Cátions/genética , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Família Multigênica , Proteínas de Plantas/genética , Estresse Fisiológico/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Araceae/efeitos dos fármacos , Proteínas de Transporte de Cátions/química , Proteínas de Transporte de Cátions/metabolismo , Cromossomos de Plantas/genética , Sequência Conservada , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genes de Plantas , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas/genética , Estresse Fisiológico/efeitos dos fármacos , Sintenia/genética
3.
Nat Commun ; 12(1): 3683, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140503

RESUMO

Blood pressure has a daily pattern, with higher values in the active period. Its elevation at the onset of the active period substantially increases the risk of fatal cardiovascular events. Renin secretion stimulated by renal sympathetic neurons is considered essential to this process; however, its regulatory mechanism remains largely unknown. Here, we show the importance of transient receptor potential melastatin-related 6 (TRPM6), a Mg2+-permeable cation channel, in augmenting renin secretion in the active period. TRPM6 expression is significantly reduced in the distal convoluted tubule of hypotensive Cnnm2-deficient mice. We generate kidney-specific Trpm6-deficient mice and observe a decrease in blood pressure and a disappearance of its circadian variation. Consistently, renin secretion is not augmented in the active period. Furthermore, renin secretion after pharmacological activation of ß-adrenoreceptor, the target of neuronal stimulation, is abrogated, and the receptor expression is decreased in renin-secreting cells. These results indicate crucial roles of TRPM6 in the circadian regulation of blood pressure.


Assuntos
Pressão Sanguínea/fisiologia , Túbulos Renais Distais/metabolismo , Rim/metabolismo , Renina/metabolismo , Canais de Cátion TRPM/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Pressão Sanguínea/genética , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Regulação para Baixo , Feminino , Regulação da Expressão Gênica/genética , Homeostase , Isoproterenol/farmacologia , Rim/patologia , Magnésio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Interferência de RNA , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Regulação para Cima
4.
Nutrients ; 13(5)2021 May 10.
Artigo em Inglês | MEDLINE | ID: covidwho-1224082

RESUMO

BACKGROUND: Acute and chronic alcohol abuse has adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evaluating potential causal associations between alcohol consumption and COVID-19. METHODS: We conducted a Mendelian randomization study using data from UK Biobank to explore the association between alcohol consumption and risk of SARS-CoV-2 infection and serious clinical outcomes in patients with COVID-19. A total of 12,937 participants aged 50-83 who tested for SARS-CoV-2 between 16 March to 27 July 2020 (12.1% tested positive) were included in the analysis. The exposure factor was alcohol consumption. Main outcomes were SARS-CoV-2 positivity and death in COVID-19 patients. We generated allele scores using three genetic variants (rs1229984 (Alcohol Dehydrogenase 1B, ADH1B), rs1260326 (Glucokinase Regulator, GCKR), and rs13107325 (Solute Carrier Family 39 Member 8, SLC39A8)) and applied the allele scores as the instrumental variables to assess the effect of alcohol consumption on outcomes. Analyses were conducted separately for white participants with and without obesity. RESULTS: Of the 12,937 participants, 4496 were never or infrequent drinkers and 8441 were frequent drinkers. Both logistic regression and Mendelian randomization analyses found no evidence that alcohol consumption was associated with risk of SARS-CoV-2 infection in participants either with or without obesity (All q > 0.10). However, frequent drinking, especially heavy drinking (HR = 2.07, 95%CI 1.24-3.47; q = 0.054), was associated with higher risk of death in patients with obesity and COVID-19, but not in patients without obesity. Notably, the risk of death in frequent drinkers with obesity increased slightly with the average amount of alcohol consumed weekly (All q < 0.10). CONCLUSIONS: Our findings suggest that alcohol consumption has adverse effects on the progression of COVID-19 in white participants with obesity, but was not associated with susceptibility to SARS-CoV-2 infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas , Bancos de Espécimes Biológicos , COVID-19 , Proteínas de Transporte de Cátions/genética , Obesidade , Polimorfismo de Nucleotídeo Único , Vírus da SARS , Idoso , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/mortalidade , COVID-19/genética , COVID-19/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/mortalidade , Taxa de Sobrevida , Reino Unido/epidemiologia
5.
Nutrients ; 13(5)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068824

RESUMO

BACKGROUND: Acute and chronic alcohol abuse has adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evaluating potential causal associations between alcohol consumption and COVID-19. METHODS: We conducted a Mendelian randomization study using data from UK Biobank to explore the association between alcohol consumption and risk of SARS-CoV-2 infection and serious clinical outcomes in patients with COVID-19. A total of 12,937 participants aged 50-83 who tested for SARS-CoV-2 between 16 March to 27 July 2020 (12.1% tested positive) were included in the analysis. The exposure factor was alcohol consumption. Main outcomes were SARS-CoV-2 positivity and death in COVID-19 patients. We generated allele scores using three genetic variants (rs1229984 (Alcohol Dehydrogenase 1B, ADH1B), rs1260326 (Glucokinase Regulator, GCKR), and rs13107325 (Solute Carrier Family 39 Member 8, SLC39A8)) and applied the allele scores as the instrumental variables to assess the effect of alcohol consumption on outcomes. Analyses were conducted separately for white participants with and without obesity. RESULTS: Of the 12,937 participants, 4496 were never or infrequent drinkers and 8441 were frequent drinkers. Both logistic regression and Mendelian randomization analyses found no evidence that alcohol consumption was associated with risk of SARS-CoV-2 infection in participants either with or without obesity (All q > 0.10). However, frequent drinking, especially heavy drinking (HR = 2.07, 95%CI 1.24-3.47; q = 0.054), was associated with higher risk of death in patients with obesity and COVID-19, but not in patients without obesity. Notably, the risk of death in frequent drinkers with obesity increased slightly with the average amount of alcohol consumed weekly (All q < 0.10). CONCLUSIONS: Our findings suggest that alcohol consumption has adverse effects on the progression of COVID-19 in white participants with obesity, but was not associated with susceptibility to SARS-CoV-2 infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas , Bancos de Espécimes Biológicos , COVID-19 , Proteínas de Transporte de Cátions/genética , Obesidade , Polimorfismo de Nucleotídeo Único , Vírus da SARS , Idoso , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/mortalidade , COVID-19/genética , COVID-19/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/mortalidade , Taxa de Sobrevida , Reino Unido/epidemiologia
6.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069632

RESUMO

In tobacco, the efficiency of Zn translocation to shoots depends on Zn/Cd status. Previous studies pointed to the specific contribution of root parts in the regulation of this process, as well as the role of NtZIP4A/B (from the ZIP family; Zrt Irt-like Proteins). Here, to verify this hypothesis, NtZIP4A/B RNAi lines were generated. Then, in plants exposed to combinations of Zn and Cd concentrations in the medium, the consequences of NtZIP4A/B suppression for the translocation of both metals were determined. Furthermore, the apical, middle, and basal root parts were examined for accumulation of both metals, for Zn localization (using Zinpyr-1), and for modifications of the expression pattern of ZIP genes. Our results confirmed the role of NtZIP4A/B in the control of Zn/Cd-status-dependent transfer of both metals to shoots. Furthermore, they indicated that the middle and basal root parts contributed to the regulation of this process by acting as a reservoir for excess Zn and Cd. Expression studies identified several candidate ZIP genes that interact with NtZIP4A/B in the root in regulating Zn and Cd translocation to the shoot, primarily NtZIP1-like in the basal root part and NtZIP2 in the middle one.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Tabaco/metabolismo , Zinco/metabolismo , Adenosina Trifosfatases/metabolismo , Transporte Biológico/genética , Cádmio/metabolismo , Proteínas de Transporte de Cátions/genética , Regulação da Expressão Gênica de Plantas/genética , Homeostase , Proteínas de Plantas/genética , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Brotos de Planta/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Tabaco/genética
7.
BMC Genomics ; 22(1): 317, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932999

RESUMO

BACKGROUND: HAK/KUP/KT (High-affinity K+ transporters/K+ uptake permeases/K+ transporters) is the largest potassium transporter family in plants, and plays pivotal roles in K+ uptake and transport, as well as biotic and abiotic stress responses. However, our understanding of the gene family in barley (Hordeum vulgare L.) is quite limited. RESULTS: In the present study, we identified 27 barley HAK/KUP/KT genes (hereafter called HvHAKs) through a genome-wide analysis. These HvHAKs were unevenly distributed on seven chromosomes, and could be phylogenetically classified into four clusters. All HvHAK protein sequences possessed the conserved motifs and domains. However, the substantial difference existed among HAK members in cis-acting elements and tissue expression patterns. Wheat had the most orthologous genes to barley HAKs, followed by Brachypodium distachyon, rice and maize. In addition, six barley HAK genes were selected to investigate their expression profiling in response to three abiotic stresses by qRT-PCR, and their expression levels were all up-regulated under salt, hyperosmotic and potassium deficiency treatments. CONCLUSION: Twenty seven HAK genes (HvHAKs) were identified in barley, and they differ in tissue expression patterns and responses to salt stress, drought stress and potassium deficiency.


Assuntos
Proteínas de Transporte de Cátions , Hordeum , Proteínas de Transporte de Cátions/genética , Regulação da Expressão Gênica de Plantas , Hordeum/genética , Hordeum/metabolismo , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Potássio/metabolismo , Estresse Fisiológico/genética
8.
J Chem Inf Model ; 61(5): 2407-2417, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33886304

RESUMO

The CorA family of proteins plays a housekeeping role in the homeostasis of divalent metal ions in many bacteria and archaea as well as in mitochondria of eukaryotes, rendering it an important target to study the mechanisms of divalent transport and regulation across different life domains. Despite numerous studies, the mechanistic details of the channel gating and the transport of the metal ions are still not entirely understood. Here, we use all-atom and coarse-grained molecular dynamics simulations combined with in vitro experiments to investigate the influence of divalent cations on the function of CorA. Simulations reveal pronounced asymmetric movements of monomers that enable the rotation of the α7 helix and the cytoplasmic subdomain with the subsequent formation of new interactions and the opening of the channel. These computational results are functionally validated using site-directed mutagenesis of the intracellular cytoplasmic domain residues and biochemical assays. The obtained results infer a complex network of interactions altering the structure of CorA to allow gating. Furthermore, we attempt to reconcile the existing gating hypotheses for CorA to conclude the mechanism of transport of divalent cations via these proteins.


Assuntos
Proteínas de Transporte de Cátions , Simulação de Dinâmica Molecular , Proteínas de Bactérias/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Magnésio/metabolismo , Mutagênese Sítio-Dirigida
9.
Biochemistry (Mosc) ; 86(2): 168-178, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33832415

RESUMO

Monocytes and muscles demonstrate functionally contrasting behavior under conditions of zinc deficiency with relation to zinc storage system (muscle retain zinc in contrast to monocytes). We aimed to understand the effects of zinc status and HIV-1 Tat mediated inflammation on expression of zinc transporters in these types of cells. Expression of zinc transporters [ZnTs, ZIPs, and metallothionein (MT)] was quantified by qRT-PCR in RD, THP-1 cells separately and in co-cultured THP-1-RD cells. ZnT1 protein expression levels were confirmed by Western blot. Significant increase of MT and ZnT1 mRNA in response to zinc supplementation and decrease during zinc deficiency indicates significance of the genes encoding transporters in maintaining zinc homeostasis in these tissues. In the RD cells ZIP10 exhibited inverse relation to zinc status whereas no correlation was found in the THP-1 cells. Tat-induced inflammation resulted in the significant elevation of MT, IL6, ZIP7, ZIP8, ZIP9 transcripts in the co-cultured RD cells, whereas THP-1 cells demonstrated increased IL-1ß levels and reduced levels of ZIP7 and ZIP14. Zinc status and HIV-1Tat induced inflammation appear to influence differential expression of MT, ZnTs, and ZIPs in the muscle and monocyte cells.


Assuntos
Proteínas de Transporte de Cátions/genética , Inflamação , Monócitos/metabolismo , Músculos/metabolismo , Zinco/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica , HIV-1 , Humanos , Metalotioneína/genética , Monócitos/virologia , Músculos/virologia , RNA Mensageiro , Células THP-1 , Produtos do Gene tat do Vírus da Imunodeficiência Humana
10.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925597

RESUMO

Iron is a critical metal for several vital biological processes. Most of the body's iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.


Assuntos
Ferro/metabolismo , Ferro/fisiologia , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Enterócitos/metabolismo , Ferritinas/metabolismo , Hemoglobinas/metabolismo , Hepatócitos/metabolismo , Humanos , Ferro na Dieta/metabolismo , Fígado/metabolismo , Receptores da Transferrina/metabolismo , Baço/metabolismo , Transferrina/metabolismo
11.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925953

RESUMO

In the last years, research has shown that zinc ions play an essential role in the physiology of brain function. Zinc acts as a potent neuromodulatory agent and signaling ions, regulating healthy brain development and the function of both neurons and glial cells. Therefore, the concentration of zinc within the brain and its cells is tightly controlled. Zinc transporters are key regulators of (extra-) cellular zinc levels, and deregulation of zinc homeostasis and zinc transporters has been associated with neurodegenerative and neuropsychiatric disorders. However, to date, the presence of specific family members and their subcellular localization within brain cells have not been investigated in detail. Here, we analyzed the expression of all zinc transporters (ZnTs) and Irt-like proteins (ZIPs) in the rat brain. We further used primary rat neurons and rat astrocyte cell lines to differentiate between the expression found in neurons or astrocytes or both. We identified ZIP4 expressed in astrocytes but significantly more so in neurons, a finding that has not been reported previously. In neurons, ZIP4 is localized to synapses and found in a complex with major postsynaptic scaffold proteins of excitatory synapses. Synaptic ZIP4 reacts to short-term fluctuations in local zinc levels. We conclude that ZIP4 may have a so-far undescribed functional role at excitatory postsynapses.


Assuntos
Proteínas de Transporte/metabolismo , Neurônios/metabolismo , Zinco/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte/fisiologia , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Feminino , Expressão Gênica/genética , Homeostase/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Tecido Nervoso/metabolismo , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Transcriptoma/genética
12.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804198

RESUMO

Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions.


Assuntos
Proteínas de Transporte de Cátions/genética , Microambiente Celular/genética , Hepcidinas/genética , Ferro/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Hepcidinas/metabolismo , Homeostase/genética , Humanos , Fígado/metabolismo , Macrófagos/metabolismo , Ligação Proteica
13.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806756

RESUMO

The popularity of fasting and restricted food intake is increasing. While the body's adaptability to dietary insufficiency is crucial for health, molecular mechanisms of adaptive changes are not well understood. Here, we compared the effects of fasting and exercise on the expression of leukocyte genes and proteins involved in the storage, export, and acquisition of iron, an essential element with physiological roles. Healthy men participated in the study (age, 30-70 years; body weight, 60-100 kg; body mass index, 20-29.9 kg/m2). The participants performed an exercise test with a gradually increasing intensity until the individual maximum exercise capacity was reached, before and after 8-d fast. Blood samples were collected before, immediately after, and 3 h after exercise. Gene expression was analyzed by reverse-transcription quantitative polymerase chain reaction and protein levels were analyzed by immunobloting. Eight days of total starvation diet affected the body composition and decreased exercise capacity. Further, fasting decreased the expression of genes associated with iron storage and export, and increased the expression of genes involved in iron acquisition. Conversely, only PCBP2 protein increased after fasting; however, an upward trend was apparent for all proteins. In conclusion, the body adapts to starvation by adjusting iron economy.


Assuntos
Proteínas de Transporte de Cátions/genética , Jejum , Regulação da Expressão Gênica , Ferro/metabolismo , Leucócitos/metabolismo , Adulto , Proteínas de Transporte de Cátions/metabolismo , Jejum/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Fatores Sexuais , Fatores de Tempo
14.
Medicine (Baltimore) ; 100(13): e25258, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787609

RESUMO

RATIONALE: Hereditary hemochromatosis (HH) is a hereditary disorder of iron metabolism. It is classified into 4 main types depending on the underlying genetic mutation: human hemochromatosis protein (HFE) (type 1), hemojuvelin (HJV) (type 2A), HAMP (type 2B), transferrin receptor-2 (TFER2) (type 3), and ferroportin (type 4). Type 4 HH is divided into 2 subtypes according to different mutations: type 4A (classical ferroportin disease) and type 4B (non-classical ferroportin disease). Type 4B HH is a rare autosomal dominant disease that results from mutations in the Solute Carrier Family 40 member 1 (SLC40A1) gene, which encodes the iron transport protein ferroportin. PATIENT CONCERNS: Here we report 2 elderly Chinese Han men, who were brothers, presented with liver cirrhosis, diabetes mellitus, skin hyperpigmentation, hyperferritinaemia as well as high transferrin saturation. DIAGNOSIS: Subsequent genetic analyses identified a heterozygous mutation (p. Cys326Tyr) in the SLC40A1 gene in both patients. INTERVENTIONS: We treated the patient with iron chelator and followed up for 3 years. OUTCOMES: Iron chelator helped to reduce the serum ferritin and improve the condition of target organs, including skin, pancreas, liver as well as pituitary. LESSONS: Type 4B HH is rare but usually tends to cause multiple organ dysfunction and even death. For those patients who have difficulty tolerating phlebotomy, iron chelator might be a good alternative.


Assuntos
Proteínas de Transporte de Cátions/deficiência , Hemocromatose/genética , Hemocromatose/terapia , Quelantes de Ferro/uso terapêutico , Mutação/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Transporte de Cátions/genética , Humanos , Masculino , Pessoa de Meia-Idade
15.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33655331

RESUMO

The specific role and mechanism of ferroptosis in the development of pancreatic cancer (PC) remain to be elucidated. The present study aimed to investigate the effects of the overexpression of the KAI1 gene on the ferroptosis of the human PC cell line MIA PaCa­2. MIA PaCa­2 cells infected with pCMV­KAI1 and selected by G418 and KAI1 protein were analyzed by western blotting. The MIA PaCa­2 cells with a stable expression of the KAI1 gene were termed MIA PaCa­2­KAI1. The proliferative capacities of MIA PaCa­2 and MIA PaCa­2­KAI1 cells were detected using Cell Counting Kit­8. The reactive oxygen species (ROS) in the cells were compared by flow cytometry. The expressions of ferroportin (FPN) and glutathione peroxidase 4 (GPX4) protein were analyzed by western blotting. The KAI1 stable expression cell line was confirmed and relabeled as MIA PaCa­2­KAI1. No significant differences in the proliferation of MIA PaCa­2 and MIA PaCa­2­KAI1 were identified. Following treatment with a ferroptosis blocker, the increase in the proliferation of MIA PaCa­2­KAI1 (from 2.06±0.02 to 2.75±0.02) was more evident compared with MIA PaCa­2 (from 2.94±0.02 to 2.95±0.02; P<0.05). The ROS in MIA PaCa­2­KAI1 was significantly higher compared with MIA PaCa­2 (P<0.05). FPN and GPX4 protein demonstrated higher expression levels in MIA PaCa­2­KAI1 compared with MIA PaCa­2. Moreover, KAI1 exerted an obvious promotion effect on FPN expression. This study identified that the high expression of the KAI1 gene promoted the occurrence of ferroptosis in PC cells through its extensive effect on FPN and GPX4. KAI1­induced ferroptosis did not significantly inhibit the proliferation of PC cells.


Assuntos
Proteínas de Transporte de Cátions/genética , Ferroptose , Proteína Kangai-1/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Kangai-1/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
16.
Aging (Albany NY) ; 13(6): 8306-8319, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33686958

RESUMO

This study aimed to identify key genes related to coronary artery disease (CAD) and its association with immune cells infiltration. GSE20680 and GSE20681 were downloaded from GEO. We identified red and pink modules in WGCNA analysis and found 104 genes in these two modules. Next, least absolute shrinkage and selection operator (LASSO) logistic regression was used to screen and verify the diagnostic markers of CAD. We identified ASCC2, LRRC18, and SLC25A37 as the key genes in CAD diagnosis. We further studied the immune cells infiltration in CAD patients with CIBERSORT, and the correlation between key genes and infiltrating immune cells was analyzed. We also found immune cells, including macrophages M0, mast cells resting and T cells CD8, were associated with ASCC2, LRRC18 and SLC25A37. Gene enrichment analysis indicated that these genes mainly enriched in apoptotic signaling pathway for biological pathway analysis, riboflavin metabolism for KEGG analysis. The diagnostic efficiency of these key genes measured by AUC in the training set, testing set and validation cohort was 0.92, 0.96 and 0.83, respectively. In conclusion, ASCC2, LRRC18 and SLC25A37 can be used as diagnostic markers of CAD, and immune cell infiltration plays an important role in the onset and development of CAD.


Assuntos
Biomarcadores/análise , Proteínas de Transporte de Cátions/genética , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Proteínas Mitocondriais/genética , Proteínas Nucleares/genética , Doença da Artéria Coronariana/imunologia , Redes Reguladoras de Genes , Humanos , Transcriptoma
17.
Int J Nanomedicine ; 16: 1709-1724, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33688187

RESUMO

Background: Manganese Ferrite Nanoparticles (Mn-IONPs) are widely used in biomedical field and their cytotoxicity has been initially explored, but the mechanism remains obscure. The nano-bio interactions are believed to be crucial for cytotoxicity mechanism, while little data have been acquired. Methods: Mn-IONPs were synthesized by thermal decomposition of acetylacetonate precursor. After physicochemical characterization, we analyzed the metabolic conversion and removal of Mn-IONPs in RAW264.7 cells by Prussian blue staining, TEM, HRTEM and elemental quantitative analysis, followed by gene expression evaluation using quantitative RT-PCR. Results: Mn-IONPs were successfully synthesized. Both the uptake and cytotoxicity of Mn-IONPs on RAW264.7 cells were time- and dose-dependent. After internalized, Mn-IONPs were passed to daughter cells with passages on. Meanwhile, Mn-IONPs were exocytosed and digested to metal ions and further excreted out, resulted in the labeling rate and ions contents decreased gradually. As ion influx related genes, the expressions of ZIP14, IRP2, FtH and DMT1 were suppressed within 24 hours but overexpressed to a plateau at the 48th hour in a dose-dependent manner. At the 72nd hour, ZIP14 and DMT1 mRNA levels decreased toward normal, while IRP2 and FtH kept up-regulated. As efflux related genes, FPN, SLC30A10 and Hamp2 genes were up-regulated within 24-72 hours; SPCA1 was suppressed at the 24th and 72nd hour, while overexpressed at the 48th hour. All the efflux related genes' mRNA had a dose-dependent increasing manner at the corresponding time points. Conclusion: Mn-IONPs showed time- and dose-dependent cytotoxicity and cell labeling rate in RAW264.7 cells. Accompanying with the intracellular catabolic breakdown and exocytosis of Mn-IONPs, RAW264.7 cells also secreted and re-uptook manganese and iron ions to maintain intracellular homeostasis in the succeeding passages. And the metabolic conversion of Mn-IONPs in RAW264.7 cells can affect the expression of ZIP14, DMT1, FPN, SLC30A10, IRP2, FtH, Hamp2 and SPCA1 genes.


Assuntos
Proteínas de Transporte de Cátions/genética , Compostos Férricos/metabolismo , Regulação da Expressão Gênica , Compostos de Manganês/metabolismo , Nanopartículas/química , Animais , Proteínas de Transporte de Cátions/metabolismo , Morte Celular/genética , Proliferação de Células/genética , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Células RAW 264.7
18.
Nutrients ; 13(3)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673530

RESUMO

Anemia is a frequent finding in children with celiac disease but the detailed pathophysiological mechanisms in the intestine remain obscure. One possible explanation could be an abnormal expression of duodenal iron transport proteins. However, the results have so far been inconsistent. We investigated this issue by comparing immunohistochemical stainings of duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin, hephaestin and transferrin receptor 1 (TfR1) in duodenal biopsies between 27 children with celiac disease and duodenal atrophy, 10 celiac autoantibody-positive children with potential celiac disease and six autoantibody-negative control children. Twenty out of these 43 subjects had anemia. The expressions of the iron proteins were investigated with regard to saturation and the percentage of the stained area or stained membrane length of the enterocytes. The results showed the stained area of ferroportin to be increased and the saturation of hephaestin to be decreased in celiac disease patients compared with controls. There were no differences in the transporter protein expressions between anemic and non-anemic patients. The present results suggest an iron status-independent alteration of ferroportin and hephaestin proteins in children with histologically confirmed celiac disease.


Assuntos
Antígenos CD/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Doença Celíaca/metabolismo , Grupo dos Citocromos b/metabolismo , Proteínas de Membrana/metabolismo , Oxirredutases/metabolismo , Receptores da Transferrina/metabolismo , Fatores de Transcrição/metabolismo , Adolescente , Anemia Ferropriva/complicações , Anemia Ferropriva/metabolismo , Antígenos CD/genética , Proteínas de Transporte de Cátions/genética , Doença Celíaca/complicações , Criança , Pré-Escolar , Grupo dos Citocromos b/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Proteínas de Membrana/genética , Oxirredutases/genética , Receptores da Transferrina/genética , Fatores de Transcrição/genética
19.
BMC Gastroenterol ; 21(1): 111, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33673803

RESUMO

BACKGROUND: Hereditary hemochromatosis is a heterogenous group of inherited iron-overload conditions that is characterized by increased intestinal absorption and deposition in vital organs. Hepcidin is a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages through internalization of ferroportin-1, an iron exporter. Ferroportin disease is hereditary hemochromatosis which is affected by SLC40A1, a gene coding ferroportin-1, and phenotypically classified into two forms (classical and nonclassical). In nonclassical form, ferroportin mutations are responsible for a gain of function with full iron export capability but insensitivity to downregulation by hepcidin. Here, we report a case of nonclassical ferroportin disease. CASE PRESENTATION: A 46-year-old Japanese man showed elevated serum iron (284 µg/dl), ferritin (1722 ng/ml), transferrin saturation ratio (91.3%), and hepcidin-25 level (139.6 ng/ml). Magnetic resonance imaging (MRI) demonstrated a marked reduction in the signal intensity of the liver in T1- and T2-weighted images. The liver histology exhibited a large amount of iron that had accumulated predominantly in hepatocytes. We identified a heterozygous 1520A > G (p.H507R) mutation in the SLC40A1 gene. Phlebotomy (400 ml at a time) was monthly performed for 3 years in this patient. Importantly, the serum hepcidin level (1.0 ng/ml) was normal when the serum ferritin level was normal and hepatic iron accumulation was remarkably reduced after 3 years of phlebotomy. CONCLUSIONS: The present case demonstrated for the first time that there was a correlation between hepatic iron levels as measured by MRI and serum hepcidin levels through long-term phlebotomy in a patient with ferroportin disease with the p.H507R mutation of in SLC40A1.


Assuntos
Proteínas de Transporte de Cátions/genética , Hemocromatose , Hemocromatose/genética , Hemocromatose/terapia , Humanos , Ferro , Masculino , Pessoa de Meia-Idade , Mutação , Flebotomia
20.
Biochem Biophys Res Commun ; 550: 30-36, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33677133

RESUMO

The extracellular matrix (ECM) degradation of nucleus pulposus cells (NPCs) is mainly induced by metalloproteinases (MMPs). Zn2+ is an essential component of MMPs, but the effect of Zn2+ importers in controlling ECM metabolism remains unclear. The purpose of this research was to identify the involvement of Zn2+ importers in ECM degradation induced by inflammatory stimuli and excessive mechanical stressing. In this study, NPCs from Sprague-Dawley (SD) rats were separated and cultured. FluoZin-3 AM staining was applied to detect [Zn2+]i in NPCs treated with Interleukin-1ß (IL-1ß) or cyclic tensile strain (CTS) with a Flexcell Strain Unit. We found that intracellular Zn2+ concentration ([Zn2+]i) elevated dramatically, and ZIP8 is the predominant Zn2+ importer among all importers in senescent NPCs. The [Zn2+]i and MMP expression level both increased in IL-1ß and CTS treated NPCs. Furthermore, the expression of ZIP8 was also markedly increased. However, knockdown of ZIP8 with siRNA alleviated ECM degradation induced by inflammatory stimuli and CTS. Both stimuli activated NF-κB signaling pathway, and knockdown of ZIP8 effectively inhibited NF-κB signaling pathway activation. In conclusion, knockdown of ZIP8 can alleviate NPCs' ECM degradation caused by inflammatory stimuli and excessive mechanical stressing.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Matriz Extracelular/metabolismo , NF-kappa B/metabolismo , Núcleo Pulposo/metabolismo , Transdução de Sinais , Animais , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Colágeno Tipo II/metabolismo , Técnicas de Silenciamento de Genes , Inflamação/metabolismo , Masculino , Núcleo Pulposo/citologia , Ratos , Zinco/metabolismo
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