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1.
Phytochemistry ; 191: 112911, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34418773

RESUMO

The pleiotropic effects of zinc deficiency on ion homeostasis have already been described in several plants. Tobacco (Nicotiana tabacum) heavy metal ATPases HMA4.1 and HMA4.2 are involved in zinc and cadmium root-to-shoot translocation. In previous research, we have shown that N. tabacum HMA4 RNAi plants and HMA4 double-nonsense mutants exhibit strongly reduced zinc and cadmium levels in leaves as well as stunted growth. In this study, the ionome and transcriptome of these lines were investigated to better characterize the effect of reduced zinc levels and to understand the impaired growth phenotype. We found that, under standard greenhouse fertilization rates, these lines accumulated up to 4- to 6-fold more phosphorus, iron, manganese, and copper than their respective controls. Under field conditions, HMA4 double-mutant plants also exhibited similar accumulation phenotypes, albeit to a lower extent. In both HMA4 RNAi plants and HMA4 mutants, transcription analysis showed a local zinc-deficiency response in leaves as well as an FIT1-mediated iron-deficiency response in roots, likely contributing to iron and manganese uptake at the root level. A phosphate-starvation response involving HHO2 was also observed in HMA4-impaired plant leaves. The high level of phosphorus observed in HMA4-impaired plants is correlated with leaf swelling and necrosis. The upregulation of aquaporin genes is in line with cellular water influx and the observed leaf swelling phenotype. These results highlight the involvement of HMA4 in zinc homeostasis and related regulatory processes that balance the micro- and macroelements in above-ground organs.


Assuntos
Cádmio , Tabaco , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Cádmio/metabolismo , Regulação da Expressão Gênica de Plantas , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo , Tabaco/metabolismo , Zinco/metabolismo
2.
Undersea Hyperb Med ; 48(3): 287-295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34390633

RESUMO

Objective: Decompression sickness (DCS) causes serious brain hypoxic-ischemic injury. This experiment was designed to observe whether hyperbaric oxygen (HBO2) pretreatment played a neuroprotective effect in decompression sickness rat models and to explore the mechanism of protective effects. Methods: Sprague-Dawley (SD) male rats were pretreated with HBO2 and then underwent decompression to establish the DCS rat model. Antioxidant capacities were evaluated by detecting peroxides (GPx), superoxide dismutase (SOD), catalase (CAT) activity and malondialdehyde (MDA) content in brains. The levels of metal elements manganese (Mn), zinc (Zn), iron (Fe) and magnesium (Mg) in brain tissues were assessed by flame atomic absorption spectrometry. Necrosis and apoptosis of neurons were assessed by H-E staining and immunohistochemical staining. Results: HBO2 pretreatment reduced the degree of necrosis and apoptosis in brain tissues of decompression sickness rat models. In addition, HBO2 pretreatment increased GPx, SOD and CAT activities and reduced MDA accumulation. It also increased the content of Mn, Zn, Fe and Mg in brain tissue, which are all related to free radical metabolism. Conclusion: These results suggested that HBO2 pretreatment has protective effects on brain injury of rats with decompression sickness. The mechanism of the protective effects may be related to reducing oxidative damage by affecting metal elements in vivo.


Assuntos
Encéfalo/metabolismo , Doença da Descompressão/complicações , Oxigenação Hiperbárica/métodos , Animais , Apoptose , Encéfalo/patologia , Química Encefálica , Caspase 3/análise , Catalase/análise , Catalase/metabolismo , Descompressão , Doença da Descompressão/metabolismo , Hipóxia-Isquemia Encefálica/etiologia , Ferro/análise , Ferro/metabolismo , Magnésio/análise , Magnésio/metabolismo , Masculino , Malondialdeído/análise , Malondialdeído/metabolismo , Manganês/análise , Manganês/metabolismo , Necrose , Neurônios/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/análise , Superóxido Dismutase/metabolismo , Zinco/análise , Zinco/metabolismo , Proteína X Associada a bcl-2/análise
3.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200394

RESUMO

Zinc is an effective anti-inflammatory and antioxidant trace element. The aim of this study was to analyse the protective effect of zinc and zinc-prolactin systems as additives of preservation solutions in the prevention of nephron damage caused during ischemia. The study used a model for storing isolated porcine kidneys in Biolasol®. The solution was modified with the addition of Zn at a dose of 1 µg/L and Zn: 1 µg/L with prolactin (PRL): 0.1 µg/L. After 2 h and 48 h of storage, the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, sodium, potassium, creatinine and total protein were determined. Zinc added to the Biolasol® composition at a dose of 1 µg/L showed minor effectiveness in the protection of nephrons. In turn, Zn2+ added to Biolasol + PRL (PRL: 0.1 µg/L) acted as a prolactin inhibitor. We do not recommend the addition of Zn(II) (1 µg/L) and Zn(II) (1 µg/L) + PRL (0.1 µg/L) to the Biolasol solution.


Assuntos
Isquemia/metabolismo , Rim/metabolismo , Prolactina/metabolismo , Zinco/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Creatinina/metabolismo , Criopreservação/métodos , L-Lactato Desidrogenase/metabolismo , Preservação de Órgãos/métodos , Perfusão/métodos , Potássio/metabolismo , Sódio/metabolismo , Suínos
4.
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
5.
Life Sci ; 281: 119770, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34197883

RESUMO

Metal ion homeostasis is an essential physiological mechanism necessary for achieving an adequate balance of these ions' concentrations in the different cellular compartments. This fact is of great importance because both an excess and a deficiency of cellular metal ion levels are usually equally harmful due to the exacerbated increase in oxidative stress that may occur in both cases. Metal ion homeostasis ensures an equilibrium among multiple functions associated with the body's antioxidative defense network controlled by metallic micronutrients such as zinc and copper, some of the central regulators of redox processes. These micronutrients significantly modulate the activity of some isoforms of superoxide dismutase (SOD) and other enzymes such as metallothioneins (MTs) and ceruloplasmin (CP), which are directly or indirectly involved in the regulation of redox homeostasis. Although it is well known that both melatonin (MEL) and vitamin D have important roles as natural antioxidants, often some of these effects are related to their actions on antioxidative processes dependent on metal ions. Thus, in addition to their classical antioxidative properties usually associated with mitochondrial effects, it is known that MEL and vitamin D modulate the expression and activity of Cu/Zn-dependent SOD isoforms, MTs and CP; function as copper chelators and regulate genomic and non-genomic mechanisms related to the zinc transport. This review summarizes the main findings related to the crucial participation of zinc and copper in physiological antioxidative status and their relationship with the non-classical antioxidant effects of MEL and vitamin D, suggesting a potential synergism among these four micronutrients.


Assuntos
Antioxidantes/farmacologia , Cobre/metabolismo , Homeostase , Melatonina/farmacologia , Vitamina D/farmacologia , Zinco/metabolismo , Ceruloplasmina/metabolismo , Humanos , Metalotioneína/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos
6.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298909

RESUMO

To ascertain the role of Zn(II) as an allosteric modulator on P2X4R, QM/MM molecular dynamic simulations were performed on the WT and two P2X4R mutants suggested by previous electrophysiological data to affect Zn(II) binding. The Gibbs free energy for the reduction of the putative P2X4R Zn(II) binding site by glutathione was estimated at -22 kcal/mol. Simulations of the WT P2X4R head domain revealed a flexible coordination sphere dominated by an octahedral geometry encompassing C126, N127, C132, C149, C159 and a water molecule. The C132A mutation disrupted the metal binding site, leading to a coordination sphere with a majority of water ligands, and a displacement of the metal ion towards the solvent. The C132A/C159A mutant exhibited a tendency towards WT-like stability by incorporating the R148 backbone to the coordination sphere. Thus, the computational findings agree with previous experimental data showing Zn(II) modulation for the WT and C132A/C159A variants, but not for the C132A mutant. The results provide molecular insights into the nature of the Zn(II) modulation in P2X4R, and the effect of the C132A and C132A/C159A mutations, accounting for an elusive modulation mechanism possibly occurring in other extracellular or membrane protein.


Assuntos
Cisteína/metabolismo , Domínios Proteicos/fisiologia , Proteína Ribossômica L10/metabolismo , Zinco/metabolismo , Ligantes , Proteínas de Membrana/metabolismo , Metais/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica/fisiologia , Receptores Purinérgicos P2X4 , Água/metabolismo
7.
Plant Mol Biol ; 106(6): 555-567, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275101

RESUMO

KEY MESSAGE: Root-specific expression of a cytokinin-degrading CKX gene in maize roots causes formation of a larger root system leading to higher element content in shoot organs. The size and architecture of the root system is functionally relevant for the access to water and soil nutrients. A great number of mostly unknown genes are involved in regulating root architecture complicating targeted breeding of plants with a larger root system. Here, we have explored whether root-specific degradation of the hormone cytokinin, which is a negative regulator of root growth, can be used to genetically engineer maize (Zea mays L.) plants with a larger root system. Root-specific expression of a CYTOKININ OXIDASE/DEHYDROGENASE (CKX) gene of Arabidopsis caused the formation of up to 46% more root dry weight while shoot growth of these transgenic lines was similar as in non-transgenic control plants. The concentration of several elements, in particular of those with low soil mobility (K, P, Mo, Zn), was increased in leaves of transgenic lines. In kernels, the changes in concentration of most elements were less pronounced, but the concentrations of Cu, Mn and Zn were significantly increased in at least one of the three independent lines. Our data illustrate the potential of an increased root system as part of efforts towards achieving biofortification. Taken together, this work has shown that root-specific expression of a CKX gene can be used to engineer the root system of maize and alter shoot element composition.


Assuntos
Proteínas de Arabidopsis/genética , Citocininas/metabolismo , Proteínas de Membrana/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Folhas de Planta/genética , Raízes de Plantas/genética , Zea mays/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Cobre/metabolismo , Regulação da Expressão Gênica de Plantas , Engenharia Genética/métodos , Manganês/metabolismo , Proteínas de Membrana/metabolismo , Minerais/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Folhas de Planta/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Brotos de Planta/genética , Brotos de Planta/metabolismo , Plantas Geneticamente Modificadas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transgenes/genética , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo , Zinco/metabolismo
8.
Chem Commun (Camb) ; 57(64): 7910-7913, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34278402

RESUMO

Structural data on the SARS-CoV-2 main protease in complex with a zinc-containing organic inhibitor are already present in the literature and gave hints on the presence of a zinc binding site involving the catalytically relevant cysteine and histidine residues. In this paper, the structural basis of ionic zinc binding to the SARS-CoV-2 main protease has been elucidated by X-ray crystallography. The zinc binding affinity and its ability to inhibit the SARS-CoV-2 main protease have been investigated. These findings provide solid ground for the design of potent and selective metal-conjugated inhibitors of the SARS-CoV-2 main protease.


Assuntos
Proteases 3C de Coronavírus/antagonistas & inibidores , SARS-CoV-2/enzimologia , Sítios de Ligação , COVID-19/virologia , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Cristalografia por Raios X , Humanos , Conformação Proteica , Zinco/metabolismo
9.
Gene ; 799: 145824, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34252531

RESUMO

The SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.


Assuntos
Proteínas de Transporte de Cátions/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso , Proteínas de Xenopus/fisiologia , Zinco/metabolismo , Animais , Transtorno Autístico/metabolismo , Bancos de Espécimes Biológicos , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Pulmão/fisiopatologia , Família Multigênica , Doenças Neurodegenerativas/etiologia , Estresse Oxidativo/fisiologia , Reino Unido , Vertebrados/genética
10.
Phys Chem Chem Phys ; 23(31): 16888-16896, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34328165

RESUMO

In this manuscript, three examples retrieved from the PDB are selected to demonstrate the existence and relevance of spodium bonding (SpB) in biological systems. SpB is defined as an attractive noncovalent interaction between elements of group 12 of the periodic table acting as a Lewis acid and any atom or group of atoms acting as an electron donor. The utilization of this term (SpB) is convenient to differentiate classical coordination bonds from noncovalent interactions. In the latter, the distance between the electron rich and the spodium atoms is longer than the sum of the covalent radii but shorter than the sum of the van der Waals radii. In most Zn-dependent metalloenzymes, the spodium atom is bonded to three imidazole moieties belonging to the side chains of histidine amino-acids. Herein, in addition to the investigation of the SpB in the active site of three exemplifying enzymes, theoretical models where the Zn(ii) atom is bonded either to three imidazole or triazole ligands are used in order to investigate the strength of the SpB and its competition with hydrogen bonding. A series of Lewis bases and anions have been used as SpB acceptors combined with six SpB donors (receptors) of general formula [ZnY3X]+ (Y = imidazole and triazole and X = Cl, N3 and SCH3). In addition to the investigation of the energetic and geometric features of the complexes, the SpB interactions have been further characterized using the natural bond orbital (NBO) method, quantum theory of "atoms-in-molecules" and the noncovalent interaction plot (NCI plot).


Assuntos
Modelos Biológicos , Proteínas/química , Teoria Quântica , Zinco/química , Sítios de Ligação , Proteínas/metabolismo , Zinco/metabolismo
11.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203496

RESUMO

The antimicrobial activity of surfactant-associated anionic peptides (SAAPs), which are isolated from the ovine pulmonary surfactant and are selective against the ovine pathogen Mannheimia haemolytica, is strongly enhanced in the presence of Zn(II) ions. Both calorimetry and ITC measurements show that the unique Asp-only peptide SAAP3 (DDDDDDD) and its analogs SAAP2 (GDDDDDD) and SAAP6 (GADDDDD) have a similar micromolar affinity for Zn(II), which binds to the N-terminal amine and Asp carboxylates in a net entropically-driven process. All three peptides also bind Cu(II) with a net entropically-driven process but with higher affinity than they bind Zn(II) and coordination that involves the N-terminal amine and deprotonated amides as the pH increases. The parent SAAP3 binds Cu(II) with the highest affinity; however, as shown with potentiometry and absorption, CD and EPR spectroscopy, Asp residues in the first and/or second positions distinguish Cu(II) binding to SAAP3 and SAAP2 from their binding to SAAP6, decreasing the Cu(II) Lewis acidity and suppressing its square planar amide coordination by two pH units. We also show that these metal ions do not stabilize a membrane disrupting ability nor do they induce the antimicrobial activity of these peptides against a panel of human pathogens.


Assuntos
Cobre/metabolismo , Peptídeos/química , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Zinco/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Mannheimia haemolytica/efeitos dos fármacos , Mannheimia haemolytica/patogenicidade , Peptídeos/metabolismo , Termodinâmica
12.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208404

RESUMO

Numerous studies indicate that zinc and the new zinc-related adipokine, zinc-α2-glycoprotein (ZAG), are involved in lipid metabolism. Excess body fat lowers blood concentrations of Zn and ZAG, leading not only to the development of obesity but also to other components of the metabolic syndrome. Zinc homeostasis disorders in the body negatively affect the lipid profile and cytokine secretion. Zinc appears to be a very important ZAG homeostasis regulator. The physiological effects of ZAG are related to lipid metabolism, but studies show that ZAG also affects glucose metabolism and is linked to insulin resistance. ZAG has a zinc binding site in its structure, which may indicate that ZAG mediates the effect of zinc on lipid metabolism. The review aimed to verify the available studies on the effects of zinc and ZAG on lipid metabolism. A literature review within the scope of this research area was conducted using articles available in PubMed (including MEDLINE), Web of Science and Cochrane Library databases. An analysis of available studies has shown that zinc improves hepatic lipid metabolism and has an impact on the lipid profile. Numerous studies have found that zinc supplementation in overweight individuals significantly reduced blood levels of total cholesterol, LDL (Low-density lipoprotein)cholesterol and triglycerides, potentially reducing cardiovascular morbidity and mortality. Some results also indicate that it increases HDL-C (High-density lipoprotein) cholesterol levels. ZAG has been shown to play a significant role in reducing obesity and improving insulin sensitivity, both in experimental animal model studies and in human studies. Furthermore, ZAG at physiologically relevant concentrations increases the release of adiponectin from human adipocytes. In addition, ZAG has been shown to inhibit in vitro leptin production. Further studies are needed to provide more data on the role of zinc and zinc-α2-glycoprotein.


Assuntos
Adipocinas/metabolismo , Metabolismo dos Lipídeos , Proteínas de Plasma Seminal/metabolismo , Zinco/metabolismo , Tecido Adiposo/metabolismo , Animais , Peso Corporal , Feminino , Humanos , Lipídeos/sangue , Fígado/metabolismo , Masculino , Sobrepeso/metabolismo , Zinco/administração & dosagem , Zinco/farmacologia
13.
Nat Commun ; 12(1): 3296, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075043

RESUMO

Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.


Assuntos
Endotélio Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Células Receptoras Sensoriais/metabolismo , Vasodilatação/fisiologia , Zinco/metabolismo , Idoso , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Canais de Cálcio Tipo N/metabolismo , Quelantes/farmacologia , Citoplasma/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/inervação , Etilenodiaminas/farmacologia , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Técnicas de Patch-Clamp , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/metabolismo , Ratos , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/metabolismo , Vasodilatação/efeitos dos fármacos
14.
Environ Pollut ; 284: 117377, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062438

RESUMO

The present research used zebrafish (5-28 days post-fertilization; dpf) as a model organism to investigate the effects of chronic exposure to environmentally relevant sub-lethal concentrations of waterborne (261 µg/L) and dietary zinc (Zn) (1500 mg Zn/kg dw), either independently or simultaneously, during development. The results showed that whole body contents of Zn were increased in all Zn treatment groups, with the highest accumulation of Zn observed in larvae simultaneously exposed to elevated waterborne and dietary Zn. In addition, exposure to elevated levels of Zn, either through the water or the diet, led to a decrease in whole body calcium (Ca) contents at 28 dpf. The findings also suggested that exposure to elevated levels of Zn resulted in a significant reduction in whole body manganese (Mn) contents. More importantly, the magnitude of decrease in Mn contents by Zn exposure was markedly higher than that in Ca and appeared to mirror the increases in whole body Zn accumulation. These results indicate that Mn regulation is more sensitive than Ca to disruption by Zn exposure in developing fish. Further examination of the Zrt-Irt-Like Protein (ZIP) family of transporters using droplet digital PCR technologies revealed that several zip transporters exhibited temporal and exposure route-specific changes following Zn exposure. In particular, the level of zip4 was influenced by Zn exposure regardless of the exposure routes, while changes in zip7 and zip8 levels were predominantly driven by waterborne exposure. Overall, our findings demonstrated that zebrafish during the developmental periods are sensitive to elevated levels of Zn seen in the environment, particularly following co-exposures to waterborne and dietary Zn. Future toxicological assessment of elevated Zn exposure should consider both the exposure routes and the life stages of fish.


Assuntos
Proteínas de Transporte de Cátions , Poluentes Químicos da Água , Animais , Retículo Endoplasmático/metabolismo , Larva/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Zinco/metabolismo , Zinco/toxicidade
15.
Nutrients ; 13(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063377

RESUMO

Deficiency of the micronutrient zinc is common in patients with chronic kidney disease (CKD). The aim of this review is to summarize evidence presented in literature for consolidation of current knowledge regarding zinc status in CKD patients, including those undergoing hemodialysis. Zinc deficiency is known to be associated with various risk factors for cardiovascular disease (CVD), such as increased blood pressure, dyslipidemia, type 2 diabetes mellitus, inflammation, and oxidative stress. Zinc may protect against phosphate-induced arterial calcification by suppressing activation of nuclear factor kappa light chain enhancer of activated B. Serum zinc levels have been shown to be positively correlated with T50 (shorter T50 indicates higher calcification propensity) in patients with type 2 diabetes mellitus as well as those with CKD. Additionally, higher intake of dietary zinc was associated with a lower risk of severe abdominal aortic calcification. In hemodialysis patients, the beneficial effects of zinc supplementation in relation to serum zinc and oxidative stress levels was demonstrated in a meta-analysis of 15 randomized controlled trials. Thus, evidence presented supports important roles of zinc regarding antioxidative stress and suppression of calcification and indicates that zinc intake/supplementation may help to ameliorate CVD risk factors in CKD patients.


Assuntos
Doenças Cardiovasculares/complicações , Insuficiência Renal Crônica/complicações , Zinco/sangue , Zinco/deficiência , Arteriosclerose , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/complicações , Humanos , Hipertensão/complicações , Inflamação , Minerais/sangue , Estresse Oxidativo , Fosfatos/sangue , Diálise Renal , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Fatores de Risco , Calcificação Vascular/sangue , Zinco/metabolismo
16.
Aquat Toxicol ; 237: 105875, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34098373

RESUMO

The aquatic environment receives a wide variety of contaminants that interact with each other, influencing their mutual toxicity. Therefore, studies of mixtures are needed to fully understand their deleterious effects on aquatic organisms. In the present experiment, we aimed to assess the effects of Cd and Zn mixtures in common carp during a one-week exposure. The used nominal waterborne metal levels were 0.02, 0.05 and 0.10 µM for Cd and 3, 7.5 and 15 µM for Zn. Our results showed on the one hand a fast Cd increase and on the other hand a delayed Zn accumulation. In the mixture scenario an inhibition of Cd accumulation due to Zn was marked in the liver but temporary in the gills. For Zn, the delayed accumulation gives an indication of the efficient homeostasis of this essential metal. Between the different mixtures, a stimulation of Zn accumulation by Cd rather than an inhibition was seen in the highest metal mixtures. However, when compared to an earlier single Zn exposure, a reduced Zn accumulation was observed. Metallothionein gene expression was quickly activated in the analysed tissues suggesting that the organism promptly responded to the stressful situation. Finally, the metal mixture did not alter tissue electrolyte levels.


Assuntos
Carpas , Poluentes Químicos da Água , Animais , Bioacumulação , Cádmio/metabolismo , Cádmio/toxicidade , Carpas/metabolismo , Brânquias/metabolismo , Homeostase , Metalotioneína/metabolismo , Poluentes Químicos da Água/toxicidade , Zinco/metabolismo , Zinco/toxicidade
17.
Nutrients ; 13(6)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070833

RESUMO

Studies have suggested an important role of the trace element zinc (Zn) in prostate biology and functions. Zn has been shown to exist in very high concentrations in the healthy prostate and is important for several prostatic functions. In prostate cancer (PCa), Zn levels are significantly decreased and inversely correlated with disease progression. Ideally, restoration of adequate Zn levels in premalignant/malignant prostate cells could abort prostate malignancy. However, studies have shown that Zn supplementation is not an efficient way to significantly increase Zn concentrations in PCa. Based on a limited number of investigations, the reason for the lower levels of Zn in PCa is believed to be the dysregulation of Zn transporters (especially ZIP and ZnT family of proteins), metallothioneins (for storing and releasing Zn), and their regulators (e.g., Zn finger transcription factor RREB1). Interestingly, the level of Zn in cells has been shown to be modulated by naturally occurring dietary phytochemicals. In this review, we discussed the effect of selected phytochemicals (quercetin, resveratrol, epigallocatechin-3-gallate and curcumin) on Zn functioning and proposes that Zn in combination with specific dietary phytochemicals may lead to enhanced Zn bioaccumulation in the prostate, and therefore, may inhibit PCa.


Assuntos
Homeostase/fisiologia , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Zinco/metabolismo , Humanos , Masculino , Neoplasias da Próstata/fisiopatologia
18.
Science ; 373(6551): 236-241, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34083449

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.


Assuntos
Coenzimas/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , RNA-Polimerase RNA-Dependente de Coronavírus/química , Óxidos N-Cíclicos/farmacologia , Ferro/metabolismo , SARS-CoV-2/efeitos dos fármacos , Enxofre/metabolismo , Motivos de Aminoácidos , Animais , Antivirais/farmacologia , Sítios de Ligação , Domínio Catalítico , Chlorocebus aethiops , Coenzimas/química , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Inibidores Enzimáticos/farmacologia , Ferro/química , Domínios Proteicos , RNA Helicases/metabolismo , SARS-CoV-2/enzimologia , SARS-CoV-2/fisiologia , Marcadores de Spin , Enxofre/química , Células Vero , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Zinco/metabolismo
19.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066955

RESUMO

Peptidoglycan recognition proteins (PGRPs) are ubiquitous among animals and play pivotal functions in insect immunity. Non-catalytic PGRPs are involved in the activation of immune pathways by binding to the peptidoglycan (PGN), whereas amidase PGRPs are capable of cleaving the PGN into non-immunogenic compounds. Drosophila PGRP-LB belongs to the amidase PGRPs and downregulates the immune deficiency (IMD) pathway by cleaving meso-2,6-diaminopimelic (meso-DAP or DAP)-type PGN. While the recognition process is well analyzed for the non-catalytic PGRPs, little is known about the enzymatic mechanism for the amidase PGRPs, despite their essential function in immune homeostasis. Here, we analyzed the specific activity of different isoforms of Drosophila PGRP-LB towards various PGN substrates to understand their specificity and role in Drosophila immunity. We show that these isoforms have similar activity towards the different compounds. To analyze the mechanism of the amidase activity, we performed site directed mutagenesis and solved the X-ray structures of wild-type Drosophila PGRP-LB and its mutants, with one of these structures presenting a protein complexed with the tracheal cytotoxin (TCT), a muropeptide derived from the PGN. Only the Y78F mutation abolished the PGN cleavage while other mutations reduced the activity solely. Together, our findings suggest the dynamic role of the residue Y78 in the amidase mechanism by nucleophilic attack through a water molecule to the carbonyl group of the amide function destabilized by Zn2+.


Assuntos
Amidoidrolases/metabolismo , Proteínas de Transporte/metabolismo , Drosophila melanogaster/metabolismo , Amidoidrolases/química , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Peptidoglicano , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estrutura Secundária de Proteína , Açúcares/metabolismo , Fatores de Virulência de Bordetella , Zinco/metabolismo
20.
Eur Rev Med Pharmacol Sci ; 25(10): 3772-3790, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34109586

RESUMO

Multiple epidemiological studies have suggested that industrialization and progressive urbanization should be considered one of the main factors responsible for the rising of atherosclerosis in the developing world. In this scenario, the role of trace metals in the insurgence and progression of atherosclerosis has not been clarified yet. In this paper, the specific role of selected trace elements (magnesium, zinc, selenium, iron, copper, phosphorus, and calcium) is described by focusing on the atherosclerotic prevention and pathogenesis plaque. For each element, the following data are reported: daily intake, serum levels, intra/extracellular distribution, major roles in physiology, main effects of high and low levels, specific roles in atherosclerosis, possible interactions with other trace elements, and possible influences on plaque development. For each trace element, the correlations between its levels and clinical severity and outcome of COVID-19 are discussed. Moreover, the role of matrix metalloproteinases, a family of zinc-dependent endopeptidases, as a new medical therapeutical approach to atherosclerosis is discussed. Data suggest that trace element status may influence both atherosclerosis insurgence and plaque evolution toward a stable or an unstable status. However, significant variability in the action of these traces is evident: some - including magnesium, zinc, and selenium - may have a protective role, whereas others, including iron and copper, probably have a multi-faceted and more complex role in the pathogenesis of the atherosclerotic plaque. Finally, calcium and phosphorus are implicated in the calcification of atherosclerotic plaques and in the progression of the plaque toward rupture and severe clinical complications. In particular, the role of calcium is debated. Focusing on the COVID-19 pandemia, optimized magnesium and zinc levels are indicated as important protective tools against a severe clinical course of the disease, often related to the ability of SARS-CoV-2 to cause a systemic inflammatory response, able to transform a stable plaque into an unstable one, with severe clinical complications.


Assuntos
Aterosclerose/patologia , Oligoelementos/metabolismo , Aterosclerose/metabolismo , COVID-19/patologia , COVID-19/virologia , Cálcio/sangue , Cálcio/metabolismo , Cobre/sangue , Cobre/metabolismo , Humanos , Ferro/sangue , Ferro/metabolismo , Magnésio/sangue , Magnésio/metabolismo , Metaloproteinases da Matriz/metabolismo , Fósforo/sangue , Fósforo/metabolismo , Risco , SARS-CoV-2/isolamento & purificação , Selênio/sangue , Selênio/metabolismo , Índice de Gravidade de Doença , Oligoelementos/sangue , Zinco/sangue , Zinco/metabolismo
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