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1.
J Biol Chem ; 299(3): 102941, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36702251

RESUMO

Glutamine synthetase (GS), which catalyzes the ATP-dependent synthesis of L-glutamine from L-glutamate and ammonia, is a ubiquitous and conserved enzyme that plays a pivotal role in nitrogen metabolism across all life domains. In vertebrates, GS is highly expressed in astrocytes, where its activity sustains the glutamate-glutamine cycle at glutamatergic synapses and is thus essential for maintaining brain homeostasis. In fact, decreased GS levels or activity have been associated with neurodegenerative diseases, with these alterations attributed to oxidative post-translational modifications of the protein, in particular tyrosine nitration. In this study, we expressed and purified human GS (HsGS) and performed an in-depth analysis of its oxidative inactivation by peroxynitrite (ONOO-) in vitro. We found that ONOO- exposure led to a dose-dependent loss of HsGS activity, the oxidation of cysteine, methionine, and tyrosine residues and also the nitration of tryptophan and tyrosine residues. Peptide mapping by LC-MS/MS through combined H216O/H218O trypsin digestion identified up to 10 tyrosine nitration sites and five types of dityrosine cross-links; these modifications were further scrutinized by structural analysis. Tyrosine residues 171, 185, 269, 283, and 336 were the main nitration targets; however, tyrosine-to-phenylalanine HsGS mutants revealed that their sole nitration was not responsible for enzyme inactivation. In addition, we observed that ONOO- induced HsGS aggregation and activity loss. Thiol oxidation was a key modification to elicit aggregation, as it was also induced by hydrogen peroxide treatment. Taken together, our results indicate that multiple oxidative events at various sites are responsible for the inactivation and aggregation of human GS.


Assuntos
Glutamato-Amônia Ligase , Ácido Peroxinitroso , Processamento de Proteína Pós-Traducional , Humanos , Cromatografia Líquida , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Ácido Peroxinitroso/química , Ácido Peroxinitroso/farmacologia , Espectrometria de Massas em Tandem , Tirosina/metabolismo , Ativação Enzimática/efeitos dos fármacos , Oxirredução , Mutação , Agregação Patológica de Proteínas/induzido quimicamente
2.
PLoS One ; 16(11): e0260519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34847196

RESUMO

Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory drugs, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic that induces ER stress and is a commonly used model of AKI. 4-phenylbutyrate (4-PBA) is a chemical chaperone and histone deacetylase (HDAC) inhibitor and has been shown to protect the kidney from ER stress, apoptosis, and structural damage in a tunicamycin model of AKI. The renal protection provided by 4-PBA is attributed to its ability to prevent misfolded protein aggregation and inhibit ER stress; however, the HDAC inhibitor effects of 4-PBA have not been examined in the TM-induced model of AKI. As such, the main objective of this study was to determine if histone hyperacetylation provides any protective effects against TM-mediated AKI. The FDA-approved HDAC inhibitor vorinostat was used, as it has no ER stress inhibitory effects and therefore the histone hyperacetylation properties alone could be investigated. In vitro work demonstrated that vorinostat inhibited histone deacetylation in cultured proximal tubular cells but did not prevent ER stress or protein aggregation induced by TM. Vorinostat induced a significant increase in cell death, and exacerbated TM-mediated total cell death and apoptotic cell death. Wild type male mice were treated with TM (0.5 mg/kg, intraperitoneal injection), with or without vorinostat (50 mg/kg/day) or 4-PBA (1 g/kg/day). Mice treated with 4-PBA or vorinostat exhibited similar levels of histone hyperacetylation. Expression of the pro-apoptotic protein CHOP was induced with TM, and not inhibited by vorinostat. Further, vorinostat did not prevent any renal damage or decline in renal function caused by tunicamycin. These data suggest that the protective mechanisms found by 4-PBA are primarily due to its molecular chaperone properties, and the HDAC inhibitors used did not provide any protection against renal injury caused by ER stress.


Assuntos
Injúria Renal Aguda , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Tunicamicina/efeitos adversos , Vorinostat/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Animais , Linhagem Celular , Modelos Animais de Doenças , Masculino , Camundongos , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/prevenção & controle , Tunicamicina/farmacologia
3.
J Ethnopharmacol ; 268: 113640, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33307058

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia chebula Retz. (T.chebula) is an important medicinal plant in Tibetan medicine and Ayurveda. T.chebula is known as the "King of Tibetan Medicine", due to its widespread clinical pharmacological activity such as anti-inflammatory, antioxidative, antidiabetic as well as anticancer in lots of in vivo and in vitro models. In this study, we use transgenic and/or RNAi Caenorhabditis elegans (C.elegans) model to simulation the AD pathological features induced by Aß, to detect the effect of TWE on improving Aß-induced toxicity and the corresponding molecular mechanism. AIM OF STUDY: The study aimed to tested the activities and its possible mechanism of T.chebula to against Aß1-42 induced toxicity and Aß1-42 aggregation. MATERIALS AND METHODS: Using transgenic C.elegans strain CL2006 and CL4176 as models respond to paralytic induced by Aß toxicity. The transcription factors DAF-16 and SKN-1 were analyzed used a fluorescence microscope in transgenic strains (DAF-16:GFP, SKN-1:GFP). The function of DAF-16 and SKN-1 was further investigated using loss-of-function strains by feeding RNA interference (RNAi) bacteria. To evaluate the aggregation level of Aß in the transgenic C.elegans, Thioflavin S (ThS) staining and WB visualized the levels of Aß monomers and oligomers. RESULTS: TWE treatment can significantly improve the paralysis of transgenic C.elegans caused by Aß aggregation (up to 14%). The Aß aggregates in transgenic C.elegans are significantly inhibited under TWE exposure (up to 70%). TWE increases the nuclear localization of the key transcription factor DAF-16 and HSF-1, which in turn leads to the expression of downstream Hsp-16.2 protein and exerts its inhibitory effect on Aß aggregation. Meanwhile, paralysis improved has not observed in SKN-1 mutation and/or RNAi C.elegans. CONCLUSION: Our results indicate that TWE can protect C.elegans against the Aß1-42-induced toxicity, inhibition Aß1-42 aggregation and delaying Aß-induced paralysis. The neuroprotective effect of TWE involves the activation of DAF-16/HSF-1/Hsp-16.2 pathway.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Fragmentos de Peptídeos/toxicidade , Extratos Vegetais/uso terapêutico , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/prevenção & controle , Terminalia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Relação Dose-Resposta a Droga , Humanos , Fragmentos de Peptídeos/antagonistas & inibidores , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Agregação Patológica de Proteínas/patologia
4.
Int J Biol Macromol ; 163: 128-134, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32615214

RESUMO

The protein misfolded structure called amyloids is related with extensive range of pathologies like local amyloidosis and neurodegenerative diseases. Several studies have reported the potential of insulin to generate local amyloidosis under certain state. Reports also showed that fibrils of insulin generated local amyloid mass due to continuous subcutaneous injection in mouse as well as rat. The present study was designed to examine the consequence of insulin fibril injections in rats, as well as the ability of enzymes, Lumbrokinase (LK) and Serratiopeptidase (SP) in diminishing this amyloid mass progression. The results showed that insulin fibrils generated amyloid masses in rats after subcutaneous injection for two weeks which was significantly condensed in size for the groups injected with insulin fibrils combined with LK or SP. At higher doses of LK and SP, the absence of amyloid structure was observed in histopathological studies. Light microscopy, polarized microscopy as well as Lumia live in vivo imaging system was used to analyze the results. In conclusion, the overall outcome of this study showed the anti-amyloid potential of enzyme LK and SP in the attenuation of local amyloidosis.


Assuntos
Endopeptidases/farmacologia , Insulina/efeitos adversos , Peptídeo Hidrolases/farmacologia , Placa Amiloide/metabolismo , Placa Amiloide/prevenção & controle , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/prevenção & controle , Animais , Benzotiazóis/química , Vermelho Congo/química , Modelos Animais de Doenças , Reação no Local da Injeção/patologia , Reação no Local da Injeção/prevenção & controle , Injeções Subcutâneas , Insulina/administração & dosagem , Masculino , Microscopia de Fluorescência , Microscopia de Polarização , Placa Amiloide/induzido quimicamente , Placa Amiloide/patologia , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/patologia , Ratos , Ratos Wistar , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/patologia
5.
Neurobiol Dis ; 141: 104947, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422283

RESUMO

Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to α-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3-4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal α-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn aggregation (pSyn) in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific exacerbation of synucleinopathy-induced behavioral and biochemical deficits. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD.


Assuntos
Dieldrin/toxicidade , Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Praguicidas/toxicidade , Agregação Patológica de Proteínas , alfa-Sinucleína/toxicidade , Animais , Dopamina/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/metabolismo , Fatores Sexuais , Substância Negra/metabolismo , Substância Negra/patologia , alfa-Sinucleína/administração & dosagem
6.
Anal Bioanal Chem ; 412(24): 6485-6497, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32322953

RESUMO

Extracellular accumulation of amyloid beta peptide (Aß) is believed to be one of the main factors responsible for neurodegeneration in Alzheimer's disease (AD). Metals could induce Aß aggregation, by their redox activity or binding properties to amyloid ß fibrils, leading to their accumulation and deposition outside neurons. For this reason, metal chelation may have an acknowledged part to play in AD prevention and treatment. In the current work, the role of different selenium species, including selenium nanoparticles, in Aß aggregation, was studied by evaluating their metal-chelating properties and their ability both to inhibit metal-induced Aß1-42 aggregation fibrils and to disaggregate them once formed. Transition biometals such as Fe(II), Cu(II), and Zn(II) at 50 µM were selected to establish the in vitro models. The DPPH assay was used to determine the antioxidant capacity of the evaluated selenium species. Selenium nanoparticles stabilized with chitosan (Ch-SeNPs) and with both chitosan and chlorogenic acid polyphenol (CGA@ChSeNPs) showed the highest antioxidant properties with EC50 of 0.9 and 0.07 mM, respectively. UV-Vis and d1(UV-Vis) spectra also revealed that selenium species, in particular selenomethionine (SeMet), were able to interact with metals. Regarding Aß1-42 incubation experiments, Fe(II), Cu(II), and Zn(II) induced Aß aggregation, in a similar way to most of the evaluated selenium species. However, Ch-SeNPs produced a high inhibition of metal-induced Aß aggregation, as well as a high disaggregation capacity of Aß fibrils in both the presence and absence of biometals, in addition to reducing the length and width (20% of reduction in the presence of Zn(II)) of the generated Aß fibrils. Graphical abstract.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Metais/efeitos adversos , Agregados Proteicos/efeitos dos fármacos , Selênio/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Antioxidantes/química , Cobre/efeitos adversos , Humanos , Ferro/efeitos adversos , Nanopartículas/química , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Selênio/química , Zinco/efeitos adversos
7.
Biometals ; 33(2-3): 97-106, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32170541

RESUMO

Alterations in metal ion homeostasis appear coupled to neurodegenerative disorders but mechanisms are unknown. Amyloid formation of the protein α-synuclein in brain cells is a hallmark of Parkinson's disease. α-Synuclein can bind several metal ions in vitro and such interactions may affect the assembly process. Here we used biophysical methods to study the effects of micromolar concentrations of Cu2+ and Fe3+ ions on amyloid formation of selected α-synuclein variants (wild-type and A53T α-synuclein, in normal and N-terminally acetylated forms). As shown previously, Cu2+ speeds up aggregation of normal wild-type α-synuclein, but not the acetylated form. However, Cu2+ has a minimal effect on (the faster) aggregation of normal A53T α-synuclein, despite that Cu2+ binds to this variant. Like Cu2+, Fe3+ speeds up aggregation of non-acetylated wild-type α-synuclein, but with acetylation, Fe3+ instead slows down aggregation. In contrast, for A53T α-synuclein, regardless of acetylation, Fe3+ slows down aggregation with the effect being most dramatic for acetylated A53T α-synuclein. The results presented here suggest a correlation between metal-ion modulation effect and intrinsic aggregation speed of the various α-synuclein variants.


Assuntos
Amiloide/metabolismo , Cobre/farmacologia , Compostos Férricos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Amiloide/biossíntese , Cobre/química , Relação Dose-Resposta a Droga , Compostos Férricos/química , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Conformação Proteica , alfa-Sinucleína/genética
8.
Cells ; 9(2)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085572

RESUMO

Research on repurposing the old alcohol-aversion drug disulfiram (DSF) for cancer treatment has identified inhibition of NPL4, an adaptor of the p97/VCP segregase essential for turnover of proteins involved in multiple pathways, as an unsuspected cancer cell vulnerability. While we reported that NPL4 is targeted by the anticancer metabolite of DSF, the bis-diethyldithiocarbamate-copper complex (CuET), the exact, apparently multifaceted mechanism(s) through which the CuET-induced aggregation of NPL4 kills cancer cells remains to be fully elucidated. Given the pronounced sensitivity to CuET in tumor cell lines lacking the genome integrity caretaker proteins BRCA1 and BRCA2, here we investigated the impact of NPL4 targeting by CuET on DNA replication dynamics and DNA damage response pathways in human cancer cell models. Our results show that CuET treatment interferes with DNA replication, slows down replication fork progression and causes accumulation of single-stranded DNA (ssDNA). Such a replication stress (RS) scenario is associated with DNA damage, preferentially in the S phase, and activates the homologous recombination (HR) DNA repair pathway. At the same time, we find that cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.


Assuntos
Dissuasores de Álcool/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Dano ao DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Dissulfiram/farmacologia , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Proteína com Valosina/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-30870786

RESUMO

Phenothiazine molecules are effective and commonly used antipsychotic drugs, especially in the treatment of schizophrenia. However, they produce strong extrapyramidal side-effects manifested by drug-induced parkinsonism. Because Parkinson's disease as a neurodegenerative illness is associated with the formation of amyloid fibrils in neuronal cells, it is postulated that the development of phenothiazine-induced parkinsonism may be related to the phenothiazine-induced formation of fibrillar aggregates. The effect of phenothiazine compounds (fluphenazine (FPh), chlorpromazine (ChP) and propionylpromazine (PP)) on the fibrillogenesis of poly-l-lysine (PLL) was studied using Fourier-transform infrared (FTIR) spectroscopy supported by principal component analysis (PCA), vibrational circular dichroism (VCD), transmission electron microscopy (TEM) and Congo red binding assay. The fibrillogenesis of PLL is accompanied by fibril formation with charged or uncharged polypeptides with PPII (polyproline-like extended helix), α-helix or ß-sheet conformations. All of the phenothiazine molecules investigated effectively reduced the temperature required to induce the formation of ß-sheet-rich fibrils from α-helix-rich fibrils of PLL.


Assuntos
Amiloide/metabolismo , Antipsicóticos/efeitos adversos , Doença de Parkinson Secundária/etiologia , Fenotiazinas/efeitos adversos , Polilisina/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Estrutura Secundária de Proteína/efeitos dos fármacos , Amiloide/química , Amiloide/ultraestrutura , Antipsicóticos/química , Dicroísmo Circular , Humanos , Modelos Moleculares , Doença de Parkinson Secundária/metabolismo , Fenotiazinas/química , Polilisina/química , Agregação Patológica de Proteínas/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
10.
Sci Signal ; 12(572)2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862700

RESUMO

The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson's disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn2+-elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn2+ exposure. Welders exposed to Mn2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn2+-treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.


Assuntos
Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Exossomos/metabolismo , Manganês/toxicidade , Doença de Parkinson Secundária/metabolismo , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Exossomos/patologia , Manganês/farmacologia , Camundongos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Príons/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/patologia
11.
Neurochem Res ; 43(12): 2333-2342, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30302613

RESUMO

Trans-cinnamaldehyde (CNM) has recently drawn attention due to its potent anti-inflammatory and antioxidant properties. The current study explored the memory enhancing effects of CNM against lipopolysaccharide (LPS)-induced neuroinflammation in mice. CNM and curcumin (a reference antioxidant) were administered at a dose of 50 mg/kg i.p. 3 h after a single LPS injection (0.8 mg/kg, i.p.) and continued daily for 7 days. Our results displayed that CNM and curcumin significantly ameliorated the LPS-induced impairment of learning and memory, neuroinflammation, oxidative stress and neuronal apoptosis. Memory functions and locomotor activity were assessed by Morris water maze, object recognition test and open field test. Both CNM and curcumin activated the nuclear factor erythroid 2 related factor 2 (Nrf2) and restored levels of downstream antioxidant enzymes superoxide dismutase and glutathione-S-transferase (GST) in the hippocampus. They also attenuated LPS-induced increase in hippocampal contents of interleukin-1ß (IL-1ß), malondialdehyde and caspase-3. Immunohistochemistry results showed that both CNM and curcumin reduced Aß1-42 protein accumulation in brain of mice. Remarkably CNM's effect on IL-1ß was less pronounced than curcumin; however it showed higher GST activity and more potent anti-apoptotic and anti-amylodogenic effect. We conclude that, CNM produces its memory enhancing effects through modulation of Nrf2 antioxidant defense in hippocampus, inhibition of neuroinflammation, apoptosis and amyloid protein burden.


Assuntos
Acroleína/análogos & derivados , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Lipopolissacarídeos/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Agregação Patológica de Proteínas/tratamento farmacológico , Acroleína/farmacologia , Acroleína/uso terapêutico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/metabolismo , Distribuição Aleatória
12.
Biochim Biophys Acta Mol Basis Dis ; 1864(11): 3595-3604, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30251679

RESUMO

Cysteine (Cys) residues are major causes of crystallin disulfide formation and aggregation in aging and cataractous human lenses. We recently found that disulfide linkages are highly and partly conserved in ß- and γ-crystallins, respectively, in human age-related nuclear cataract and glutathione depleted LEGSKO mouse lenses, and could be mimicked by in vitro oxidation. Here we determined which Cys residues are involved in disulfide-mediated crosslinking of recombinant human γD-crystallin (hγD). In vitro diamide oxidation revealed dimer formation by SDS-PAGE and LC-MS analysis with Cys 111-111 and C111-C19 as intermolecular disulfides and Cys 111-109 as intramolecular sites. Mutation of Cys111 to alanine completely abolished dimerization. Addition of αB-crystallin was unable to protect Cys 111 from dimerization. However, Cu2+-induced hγD-crystallin aggregation was suppressed up to 50% and 80% by mutants C109A and C111A, respectively, as well as by total glutathionylation. In contrast to our recently published results using ICAT-labeling method, manual mining of the same database confirmed the specific involvement of Cys111 in disulfides with no free Cys111 detectable in γD-crystallin from old and cataractous human lenses. Surface accessibility studies show that Cys111 in hγD is the most exposed Cys residue (29%), explaining thereby its high propensity toward oxidation and polymerization in the aging lens.


Assuntos
Catarata/patologia , Cisteína/metabolismo , Agregação Patológica de Proteínas/patologia , Multimerização Proteica/genética , gama-Cristalinas/metabolismo , Adolescente , Fatores Etários , Idoso , Catarata/genética , Cátions Bivalentes/toxicidade , Criança , Pré-Escolar , Cobre/toxicidade , Dissulfetos/metabolismo , Glutationa/farmacologia , Humanos , Cristalino/efeitos dos fármacos , Cristalino/metabolismo , Cristalino/patologia , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Mutação , Estresse Oxidativo/efeitos dos fármacos , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , gama-Cristalinas/química , gama-Cristalinas/genética
13.
Artigo em Inglês | MEDLINE | ID: mdl-29698685

RESUMO

Cadmium is a highly toxic environmental pollutant that can cause many adverse effects including cancer, neurological disease and kidney damage. Aquatic amphibians are particularly susceptible to this toxicant as it was shown to cause developmental abnormalities and genotoxic effects. In mammalian cells, the accumulation of heme oxygenase-1 (HO-1), which catalyzes the breakdown of heme into CO, free iron and biliverdin, was reported to protect cells against potentially lethal concentrations of CdCl2. In the present study, CdCl2 treatment of A6 kidney epithelial cells, derived from the frog, Xenopus laevis, induced the accumulation of HO-1, heat shock protein 70 (HSP70) and HSP30 as well as an increase in the production of aggregated protein and aggresome-like structures. Treatment of cells with inhibitors of HO-1 enzyme activity, tin protoporphyrin (SnPP) and zinc protoporphyrin (ZnPP), enhanced CdCl2-induced actin cytoskeletal disorganization and the accumulation of HO-1, HSP70, aggregated protein and aggresome-like structures. Treatment of cells with hemin and baicalein, which were previously shown to provide cytoprotection against various stresses, induced HO-1 accumulation in a concentration-dependent manner. Also, treatment of cells with hemin and baicalein suppressed CdCl2-induced actin dysregulation and the accumulation of aggregated protein and aggresome-like structures. This cytoprotective effect was inhibited by SnPP. These results suggest that HO-1-mediated protection against CdCl2 toxicity includes the maintenance of actin cytoskeletal and microtubular structure and the suppression of aggregated protein and aggresome-like structures.


Assuntos
Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Proteínas de Choque Térmico HSP30/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase-1/metabolismo , Rim/efeitos dos fármacos , Agregação Patológica de Proteínas/induzido quimicamente , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Linhagem Celular , Suplementos Nutricionais , Inibidores Enzimáticos/farmacologia , Flavanonas/antagonistas & inibidores , Flavanonas/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/química , Hemina/antagonistas & inibidores , Hemina/metabolismo , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Rim/citologia , Rim/metabolismo , Rim/patologia , Metaloporfirinas/farmacologia , Microscopia Confocal , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/prevenção & controle , Protoporfirinas/farmacologia , Proteínas de Xenopus/agonistas , Proteínas de Xenopus/antagonistas & inibidores , Proteínas de Xenopus/química , Proteínas de Xenopus/metabolismo , Xenopus laevis
14.
Sci Rep ; 8(1): 5275, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29588456

RESUMO

Anesthetic agents have been implicated in the causation of neurological and cognitive deficits after surgery, the exacerbation of chronic neurodegenerative disease, and were recently reported to promote the onset of the neurologic respiratory disease Congenital Central Hypoventilation Syndrome (CCHS), related to misfolding of the transcription factor Phox2B. To study how anesthetic agents could affect neuronal function through alterations to protein folding, we created neuronal cell models emulating the graded disease severity of CCHS. We found that the gas anesthetic isoflurane and the opiate morphine potentiated aggregation and mislocalization of Phox2B variants, similar to that seen in CCHS, and observed transcript and protein level changes consistent with activation of the endoplasmic reticulum (ER) unfolded protein response. Attenuation of ER stress pathways did not result in a correction of Phox2B misfolding, indicating a primary effect of isoflurane on protein structure. We also observed that isoflurane hindered the folding and activity of proteins that rely heavily on ER function, like the CFTR channel. Our results show how anesthetic drugs can alter protein folding and induce ER stress, indicating a mechanism by which these agents may affect neuronal function after surgery.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Proteínas de Homeodomínio/metabolismo , Hipoventilação/congênito , Isoflurano/efeitos adversos , Morfina/efeitos adversos , Agregação Patológica de Proteínas/induzido quimicamente , Apneia do Sono Tipo Central/induzido quimicamente , Fatores de Transcrição/metabolismo , Linhagem Celular , Regulador de Condutância Transmembrana em Fibrose Cística/análise , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Homeodomínio/análise , Humanos , Hipoventilação/induzido quimicamente , Hipoventilação/metabolismo , Hipoventilação/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Dobramento de Proteína/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Apneia do Sono Tipo Central/metabolismo , Apneia do Sono Tipo Central/patologia , Fatores de Transcrição/análise , Resposta a Proteínas não Dobradas/efeitos dos fármacos
15.
J Mol Recognit ; 31(6): e2697, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29318655

RESUMO

Dysfunctional accumulation of amyloid ß-protein (Aß) mediated by Cu2+ exhibits higher neurotoxicity and accelerates the progress of Alzheimer's disease, so inhibition of Cu2+ -mediated Aß aggregation and cytotoxicity has been considered as a therapeutic strategy for the disease. Herein, a nonapeptide was designed by linking HH to the C-terminus of a peptide inhibitor of Aß aggregation, LVFFARK (LK7). We found that the nonapeptide, LK7-HH, possessed dual functionality, including enhanced inhibition capability on Aß aggregation as compared to LK7, and chelating Cu2+ with a dissociation constant of 5.50 µM. This enabled LK7-HH to arrest the generation of reactive oxygen species catalyzed by Cu2+ or Cu2+ -Aß complex, and to inhibit Cu2+ -induced Aß aggregation. Moreover, in contrast with the cytotoxicity of LK7 aggregates, LK7-HH was biocompatible because HH conjugation made its aggregation behavior different from LK7. Thus, LK7-HH efficiently suppressed Cu2+ -mediated Aß aggregation and cytotoxicity. An equimolar concentration of LK7-HH increased cell viability from 50% to 90% when treating Aß40 -Cu2+ complexes. The results provided insights into the roles of HH in enhancing the inhibition of Aß and Cu2+ -induced Aß aggregations, in eliminating Cu2+ -induced cytotoxicities by arresting generation of reactive oxygen species, and in making the peptide biocompatible. Therefore, this work would contribute to the design of potent peptide-based inhibitors of Cu2+ -mediated Aß aggregation and cytotoxicity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Quelantes/farmacologia , Peptídeos/química , Agregação Patológica de Proteínas/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Cobre/toxicidade , Humanos , Peptídeos/genética , Peptídeos/farmacologia , Agregados Proteicos/genética , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/patologia , Espécies Reativas de Oxigênio/química
16.
Mol Neurobiol ; 55(1): 138-144, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28822080

RESUMO

Soluble epoxide hydrolase (sEH) is widely expressed in the mammalian brain and possesses dual enzymatic activities, including C-terminal epoxide hydrolase (C-EH) which degrades epoxyeicosatrienoic acid (EET), a beneficial arachidonic acid metabolite. In the present study, the neuroprotective effect of sEH inhibition on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using genetic and pharmacological approaches. MPTP (15 mg/kg) was intraperitoneally injected in sEH knockout (KO) mice and C57BL/6J mice as wild-type (WT) mice. Compared with the MPTP-treated WT mice, MPTP-induced reductions in striatal dopamine content and nigral tyrosine hydroxylase level (TH, a biomarker of dopaminergic neurons) were less significant in the treated sEH mice. Furthermore, MPTP-induced HO-1 elevation (a redox-regulated protein), α-synuclein aggregation, and caspase 12 activation (a hallmark of ER stress) were less prominent in sEH KO mice than in WT mice. These data indicate that sEH KO mice are more resistant to MPTP-induced neurotoxicity. The pharmacological effect of N-[1-(1-oxopropyl)-4-piperidinyl]-N0-[4-(trifluoromethoxy)phenyl)-urea (TPPU, an sEH inhibitor) on MPTP-induced neurotoxicity was investigated in WT mice. TPPU (1 mg/kg, i.p.) attenuated MPTP-induced reduction in striatal dopamine content, TH-positive cell numbers, TH, and pro-caspase 9 protein levels (an initiator caspase of apoptosis) in mouse SN. Moreover, TPPU reduced MPTP-induced HO-1 elevation, α-synuclein aggregation and caspase 12 activation, indicating that TPPU is effective in attenuating MPTP-induced oxidative stress, apoptosis, protein aggregation, and ER stress. In conclusion, our study suggests that sEH is a potential target for developing therapies for parkinsonism. Furthermore, sEH inhibitors may be of clinical significance for treating CNS neurodegenerative diseases.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Epóxido Hidrolases/antagonistas & inibidores , Intoxicação por MPTP/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piperidinas/uso terapêutico , Agregação Patológica de Proteínas/tratamento farmacológico , alfa-Sinucleína/antagonistas & inibidores , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Epóxido Hidrolases/metabolismo , Intoxicação por MPTP/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , alfa-Sinucleína/metabolismo
17.
Nutr Neurosci ; 21(2): 92-96, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27697018

RESUMO

Multiple sclerosis (MS) is a disease which manifests demyelination of neuronal cells in the brain. Despite extensive research on the mechanisms of disease development and progression, the exact mechanism is not elucidated yet, which has hampered drug development and subsequent treatment of the disease. We have recently shown that the serum levels of arsenic and malondialdehyde, a lipid peroxidation marker, are high in MS patients. In this article, we would like to formulate the hypothesis that arsenic may cause MS by induction of inflammation, degeneration, and apoptosis in neuronal cells. The induction of ROS generation in cells upon exposure to arsenic as a heavy metal may be involved in the pathogenesis of MS. Tau protein, a member of the family of microtubule-associated proteins, is mainly expressed in neurons and contribute to the assembly of neuronal microtubules network. Arsenic may affect the hyperphosphorylation and aggregation of tau proteins and may be involved in the cascade leading to deregulation of tau function associated with neurodegeneration. For validation of this hypothesis, studies might be conducted to evaluate the association of arsenic levels and tau protein levels in MS patients. Further studies might also focus on the trafficking along microtubules in neurons of MS patient with regard to hyperphosphorylation of tau protein. This hypothesis may add a new dimension to the understanding of MS etiology and help to design novel therapeutic agents against potential targets that might be discovered. If this hypothesis proves to be true, tau phosphorylation inhibitors can be potential candidates for MS drug development.


Assuntos
Arsênio/toxicidade , Inflamação/diagnóstico , Esclerose Múltipla/diagnóstico , Agregação Patológica de Proteínas/diagnóstico , Proteínas tau/metabolismo , Animais , Apoptose , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Progressão da Doença , Humanos , Inflamação/induzido quimicamente , Peroxidação de Lipídeos , Malondialdeído/sangue , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Esclerose Múltipla/induzido quimicamente , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação , Agregação Patológica de Proteínas/induzido quimicamente , Proteínas tau/genética
18.
Toxicology ; 394: 11-18, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196190

RESUMO

Cigarette smoking is a significant risk factor for cataract. However, the mechanism by which cigarette smoke (CS) causes cataract remains poorly understood. We had earlier shown that in CS-exposed guinea pig, p-benzoquinone (p-BQ) derived from CS in the lungs is carried by the circulatory system to distant organs and induces various smoke-related pathogeneses. Here, we observed that CS exposure caused accumulation of the p-BQ-protein adduct in the eye lens of guinea pigs. We also observed accumulation of the p-BQ-protein adduct in resected lens from human smokers with cataract. No such accumulation was observed in the lens of never smokers. p-BQ is a strong arylating agent that forms Michael adducts with serum albumin and haemoglobin resulting in alterations of structure and function. A major protein in the mammalian eye lens is αA-crystallin, which is a potent molecular chaperone. αA-crystallin plays a key role in maintaining the integrity and transparency of the lens. SDS-PAGE indicated that p-BQ induced aggregation of αA-crystallin. Various biophysical techniques including UV-vis spectroscopy, fluorescence spectroscopy, FT-IR, bis-ANS titration suggested a perturbation of structure and chaperone function of αA-crystallin upon p-BQ modification. Our results indicate that p-BQ is a causative agent involved in the modification of αA-crystallin and pathogenesis of CS-induced cataract. Our findings would educate public about the impacts of smoking on eye health and help to discourage them from smoking. The study might also help scientists to develop new drugs for the intervention of CS-induced cataract at an early stage.


Assuntos
Benzoquinonas/toxicidade , Catarata/etiologia , Catarata/metabolismo , Fumar Cigarros/efeitos adversos , alfa-Cristalinas/metabolismo , Idoso , Animais , Benzoquinonas/química , Benzoquinonas/farmacocinética , Benzoquinonas/intoxicação , Catarata/induzido quimicamente , Catarata/patologia , Fumar Cigarros/metabolismo , Fumar Cigarros/patologia , Escherichia coli/genética , Escherichia coli/metabolismo , Cobaias , Humanos , Cápsula do Cristalino/efeitos dos fármacos , Cápsula do Cristalino/metabolismo , Cápsula do Cristalino/patologia , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , alfa-Cristalinas/biossíntese , alfa-Cristalinas/química , alfa-Cristalinas/genética
19.
Neuroscience ; 367: 47-59, 2017 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-29080716

RESUMO

Ubiquitin-proteasome system (UPS) has emerged as major molecular mechanism which modulates synaptic plasticity. However, very little is known about what happens if this system fails during postnatal brain development. In the present study, MG132 was administered intracerebroventricularly in BALB/c mice pups at postnatal day one (P1), a very crucial period for synaptogenesis. Both 20S proteasome and calpain activities were found to be reduced in the mid brain of MG132-administered pups after 24 h. Mice (P40) which received MG132 on P1 were subjected to Morris water maze (MWM) training. Analysis showed spatial learning and memory of MG132 mice was significantly impaired when compared to age-matched controls. Hematoxylin and eosin as well as Cresyl Violet staining revealed substantial loss of cellular connections, distorted architecture and increased pyknosis in hippocampal CA1 and CA3 regions of MG132 mice. Immunohistochemical analysis of MG132 mice showed increased accumulation of intracellular amyloid-ß in hippocampal cells when compared to control. Moreover, double immunostaining revealed increased expression of amyloid precursor protein C-terminal fragments (APP-CTFß) without affecting ß-secretase expression in MG132 mice. Real-Time PCR analyses showed significant increase in hippocampal expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit glutamate A1 (GluA1), but no change in the brain-derived neurotrophic factor (Bdnf) expression in MG132 mice. Western blot analyses showed decreased levels of pThr286-CaMKIIα:CaMKIIα and pSer133-CREB:CREB ratio but increased pro:mature BDNF ratio in the hippocampus of MG132 mice. Taken together, postnatal proteasome inhibition could lead to accumulation of intracellular amyloid-ß protein aggregates, which mediate hippocampus-dependent spatial memory impairments in adult mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Deficiências da Aprendizagem/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Aprendizagem Espacial/fisiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Animais Recém-Nascidos , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Deficiências da Aprendizagem/induzido quimicamente , Leupeptinas/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteassoma/toxicidade , Agregação Patológica de Proteínas/induzido quimicamente , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Aprendizagem Espacial/efeitos dos fármacos
20.
BMC Neurosci ; 18(1): 51, 2017 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-28651647

RESUMO

BACKGROUND: In the recent decade, iron oxide nanoparticles (IONPs) have been proposed for several applications in the central nervous system (CNS), including targeting amyloid beta (Aß) in the arteries, inhibiting the microglial cells, delivering drugs, and increasing contrast in magnetic resonance imaging. Conversely, a notable number of studies have reported the role of iron in neurodegenerative diseases. Therefore, this study has reviewed the recent studies to determine whether IONPs iron can threaten the cellular viability same as iron. RESULTS: Iron contributes in Fenton's reaction and produces reactive oxygen species (ROS). ROS cause to damage the macromolecules and organelles of the cell via oxidative stress. Iron accumulation and oxidative stress are able to aggregate some proteins, including Aß and α-synuclein, which play a critical role in Alzheimer's and Parkinson's diseases, respectively. Iron accumulation, oxidative stress, and protein aggregation make a positive feedback loop, which can be toxic for the cell. The release of iron ions from IONPs may result in iron accumulation in the targeted tissue, and thus, activate the positive feedback loop. However, the levels of IONPs induced toxicity depend on the size, concentration, surface charge, and the type of coating and functional groups of IONPs. CONCLUSION: IONPs depending on their properties can lead to iron accumulation, oxidative stress and protein aggregation in the neural cells. Therefore, in order to apply IONPs in the CNS, the consideration of IONPs properties is crucial.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Citotoxinas/farmacologia , Compostos Férricos/toxicidade , Nanopartículas Metálicas/toxicidade , Animais , Humanos , Ferro/metabolismo , Estresse Oxidativo , Agregação Patológica de Proteínas/induzido quimicamente , Agregação Patológica de Proteínas/metabolismo
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