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1.
EMBO J ; 43(13): 2789-2812, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38811853

RESUMO

It has remained unknown how cells reduce cystine taken up from the extracellular space, which is a required step for further utilization of cysteine in key processes such as protein or glutathione synthesis. Here, we show that the thioredoxin-related protein of 14 kDa (TRP14, encoded by TXNDC17) is the rate-limiting enzyme for intracellular cystine reduction. When TRP14 is genetically knocked out, cysteine synthesis through the transsulfuration pathway becomes the major source of cysteine in human cells, and knockout of both pathways becomes lethal in C. elegans subjected to proteotoxic stress. TRP14 can also reduce cysteinyl moieties on proteins, rescuing their activities as here shown with cysteinylated peroxiredoxin 2. Txndc17 knockout mice were, surprisingly, protected in an acute pancreatitis model, concomitant with activation of Nrf2-driven antioxidant pathways and upregulation of transsulfuration. We conclude that TRP14 is the evolutionarily conserved enzyme principally responsible for intracellular cystine reduction in C. elegans, mice, and humans.


Assuntos
Caenorhabditis elegans , Cisteína , Cistina , Camundongos Knockout , Oxirredução , Proteoma , Tiorredoxinas , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Humanos , Cistina/metabolismo , Camundongos , Tiorredoxinas/metabolismo , Tiorredoxinas/genética , Cisteína/metabolismo , Proteoma/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Peroxirredoxinas/metabolismo , Peroxirredoxinas/genética
2.
Mol Ther ; 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38796706

RESUMO

Neuroglobin, a member of the globin superfamily, is abundant in the brain, retina, and cerebellum of mammals and localizes to mitochondria. The protein exhibits neuroprotective capacities by participating in electron transfer, oxygen supply, and protecting against oxidative stress. Our objective was to determine whether neuroglobin overexpression can be used to treat neurological disorders. We chose Harlequin mice, which harbor a retroviral insertion in the first intron of the apoptosis-inducing factor gene resulting in the depletion of the corresponding protein essential for mitochondrial biogenesis. Consequently, Harlequin mice display degeneration of the cerebellum and suffer from progressive blindness and ataxia. Cerebellar ataxia begins in Harlequin mice at the age of 4 months and is characterized by neuronal cell disappearance, bioenergetics failure, and motor and cognitive impairments, which aggravated with aging. Mice aged 2 months received adeno-associated viral vectors harboring the coding sequence of neuroglobin or apoptosis-inducing factor in both cerebellar hemispheres. Six months later, Harlequin mice exhibited substantial improvements in motor and cognitive skills; probably linked to the preservation of respiratory chain function, Purkinje cell numbers and connectivity. Thus, without sharing functional properties with apoptosis-inducing factor, neuroglobin was efficient in reducing ataxia in Harlequin mice.

3.
Biology (Basel) ; 12(2)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36829435

RESUMO

Boosting trophic support to striatal neurons by increasing levels of brain-derived neurotrophic factor (BDNF) has been considered as a target for therapeutic intervention for several neurodegenerative diseases, including Huntington's disease (HD). To aid in the implementation of such a strategy, a thorough understanding of BDNF cortical-striatal transport is critical to help guide its strategic delivery. In this manuscript, we investigate the dynamic behavior of BDNF transport along the cortical-striatal axis in Q140 primary neurons, a mouse model for HD. We examine this by using single-molecule labeling of BDNF conjugated with quantum dots (QD-BDNF) to follow the transport along the cortical-striatal axis in a microfluidic chamber system specifically designed for the co-culture of cortical and striatal primary neurons. Using this approach, we observe a defect of QD-BDNF transport in Q140 neurons. Our study demonstrates that QD-BDNF transport along the cortical-striatal axis involves the impairment of anterograde transport within axons of cortical neurons, and of retrograde transport within dendrites of striatal neurons. One prominent feature we observe is the extended pause time of QD-BDNF retrograde transport within Q140 striatal dendrites. Taken together, these finding support the hypothesis that delinquent spatiotemporal trophic support of BDNF to striatal neurons, driven by impaired transport, may contribute to the pathogenesis of HD, providing us with insight into how a BDNF supplementation therapeutic strategy may best be applied for HD.

4.
World J Diabetes ; 12(9): 1442-1462, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34630899

RESUMO

Despite the existence of treatment for diabetes, inadequate metabolic control triggers the appearance of chronic complications such as diabetic retinopathy. Diabetic retinopathy is considered a multifactorial disease of complex etiology in which oxidative stress and low chronic inflammation play essential roles. Chronic exposure to hyperglycemia triggers a loss of redox balance that is critical for the appearance of neuronal and vascular damage during the development and progression of the disease. Current therapies for the treatment of diabetic retinopathy are used in advanced stages of the disease and are unable to reverse the retinal damage induced by hyperglycemia. The lack of effective therapies without side effects means there is an urgent need to identify an early action capable of preventing the development of the disease and its pathophysiological consequences in order to avoid loss of vision associated with diabetic retinopathy. Therefore, in this review we propose different therapeutic targets related to the modulation of the redox and inflammatory status that, potentially, can prevent the development and progression of the disease.

5.
Antioxidants (Basel) ; 10(2)2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498744

RESUMO

The loss of redox homeostasis induced by hyperglycemia is an early sign and key factor in the development of diabetic retinopathy. Due to the high level of long-chain polyunsaturated fatty acids, diabetic retina is highly susceptible to lipid peroxidation, source of pathophysiological alterations in diabetic retinopathy. Previous studies have shown that pterostilbene, a natural antioxidant polyphenol, is an effective therapy against diabetic retinopathy development, although its protective effects on lipid peroxidation are not well known. Plasma, urine and retinas from diabetic rabbits, control and diabetic rabbits treated daily with pterostilbene were analyzed. Lipid peroxidation was evaluated through the determination of derivatives from arachidonic, adrenic and docosahexaenoic acids by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Diabetes increased lipid peroxidation in retina, plasma and urine samples and pterostilbene treatment restored control values, showing its ability to prevent early and main alterations in the development of diabetic retinopathy. Through our study, we are able to propose the use of a derivative of adrenic acid, 17(RS)-10-epi-SC-Δ15-11-dihomo-IsoF, for the first time, as a suitable biomarker of diabetic retinopathy in plasmas or urine.

6.
Oxid Med Cell Longev ; 2020: 1452696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215168

RESUMO

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.


Assuntos
Inflamação/metabolismo , Síndrome Metabólica/metabolismo , Estresse Oxidativo/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Antioxidantes/metabolismo , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/patologia , Mitocôndrias/metabolismo , Especificidade de Órgãos , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética
7.
Front Pediatr ; 8: 12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32083039

RESUMO

Fetal to neonatal transition entails cardiorespiratory, hemodynamic, and metabolic changes coinciding with the switch from placental to airborne respiration with partial pressures of oxygen of 4-5 kPa in utero raising to 8-9 kPa ex utero in few minutes. Preterm infants have immature lung and antioxidant defense system. Very preterm infants (<32 weeks' gestation) frequently require positive pressure ventilation and oxygen to establish lung aeration, a functional residual capacity, and overcome a tendency toward hypoxemia and bradycardia in the first minutes after birth. Recent studies have shown that prolonged bradycardia (heart rate <100 beats per minute) and/or hypoxemia (oxygen saturation <80%) are associated with increased mortality and/or intracranial hemorrhage. However, despite the accumulated evidence, the way in which oxygen should be supplemented in the first minutes after birth still has not yet been clearly established. The initial inspired fraction of oxygen and its adjustment within a safe arterial oxygen saturation range measured by pulse oximetry that avoids hyper-or-hypoxia is still a matter of debate. Herewith, we present a current summary aiming to assist the practical neonatologist who has to aerate the lung and establish an efficacious respiration in very preterm infants in the delivery room.

8.
Nutrients ; 12(1)2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31892189

RESUMO

Oxidative stress generated by diabetes plays a key role in the development of diabetic retinopathy (DR), a common diabetic complication. DR remains asymptomatic until it reaches advanced stages, which complicate its treatment. Although it is known that good metabolic control is essential for preventing DR, knowledge of the disease is incomplete and an effective treatment with no side effects is lacking. Pterostilbene (Pter), a natural stilbene with good antioxidant activity, has proved to beneficially affect different pathologies, including diabetes. Therefore, our study aimed to analyse the protective and/or therapeutic capacity of Pter against oxidant damage by characterising early retinal alterations induced by hyperglycaemia, and its possible mechanism of action in a rabbit model of type 1 diabetes mellitus. Pter reduced lipid and protein oxidative damage, and recovered redox status and the main activities of antioxidant enzymes. Moreover, the redox regulation by Pter was associated with activation of the PI3K/AKT/GSK3ß/NRF2 pathway. Our results show that Pter is a powerful protective agent that may delay early DR development.


Assuntos
Antioxidantes/uso terapêutico , Retinopatia Diabética/prevenção & controle , Estilbenos/uso terapêutico , Animais , Retinopatia Diabética/etiologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Hiperglicemia/complicações , Masculino , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Transdução de Sinais/efeitos dos fármacos , Estilbenos/toxicidade
9.
Antioxidants (Basel) ; 7(12)2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30558164

RESUMO

Aerobic metabolism is highly efficient in providing energy for multicellular organisms. However, even under physiological conditions, an incomplete reduction of oxygen produces reactive oxygen species and, subsequently, oxidative stress. Some of these chemical species are highly reactive free radicals capable of causing functional and structural damage to cell components (protein, lipids, or nucleotides). Oxygen is the most used drug in ill-adapted patients during the newborn period. The use of oxygen may cause oxidative stress-related diseases that increase mortality and cause morbidity with adverse long-term outcomes. Conditions such as prematurity or birth asphyxia are frequently treated with oxygen supplementation. Both pathophysiological situations of hypoxia⁻reoxygenation in asphyxia and hyperoxia in premature infants cause a burst of reactive oxygen species and oxidative stress. Recently developed analytical assays using mass spectrometry have allowed us to determine highly specific biomarkers with minimal samples. The detection of these metabolites will help improve the diagnosis, evolution, and response to therapy in oxidative stress-related conditions during the newborn period.

10.
Acta investigación psicol. (en línea) ; 6(2): 2395-2403, ago. 2016. tab
Artigo em Espanhol | LILACS | ID: biblio-949430

RESUMO

Resumen Se analizan datos de la Encuesta Nacional de Bienestar Autorreportado (BIARE), elaborada por el Instituto Nacional de Estadística y Geografía (INEGI) para obtener indicadores de bienestar subjetivo y felicidad. El objetivo es conocer las características y establecer diferencias entre aquellas personas que reportan una baja y una alta percepción de bienestar. El indicador de felicidad fue seleccionado a partir de las preguntas: «¿Qué tan satisfecha se encuentra usted con su vida?¼ y «¿Qué tan feliz diría que es usted?¼, ambas con una escala de respuesta de 10 puntos. Se seleccionó al grupo de personas más felices entre las que eligieron el punto 10 = «totalmente satisfechos¼ La gente infeliz se seleccionó desde el punto 0 = «Nada satisfecho¼ y el punto 1 = «Un poco satisfecho¼. Se llevó a cabo estadística descriptiva y prueba de hipótesis para evaluar diferencias entre grupos utilizando chi cuadrada y U de Mann-Whitney. Se concluye que las personas infelices, comparadas con las felices, perciben menor felicidad durante toda su vida, tienen baja cantidad de logros y reconocimientos obtenidos, perciben mayores dificultades en sus vidas, mayor presencia de padecimientos, reportan menor cantidad de recursos económicos, menor contacto con familiares y amigos, menor capacidad para brindar apoyo a otros y menor percepción sobre su capacidad de afrontamiento.


Abstract The present analysis is made about the National Survey Well-being (BIARE, for its acronym in Spanish) constructed by National Institute of Statistics and Geography (INEGI) for obtain subjective indicators well-being and happiness. The objective it's to know the characteristics and differences between the people who report the lowest well-being and the highest well-being perception. The happiness indicator was selected from the questions: «How satisfied are you? ¼ and «How many happy are you?¼, which have a ten-point responding scale, happy people was selected from point 10 (totally satisfied). People unhappy was selected from point 0 = «Nothing satisfied¼ and point 1 = «A little satisfied¼. Descriptive statistics and hypothesis test was performed for evaluate group differences using chi-square and U Mann-Whitney test. The conclusion it's that the unhappy people, compared with the happy people, perceive unhappiness during long time, obtained achievements and recognition were lowest for unhappy people, more presence of diseases, few economic resources, few social contact with family and friends, lower capacity to give support to people and a lower perception of coping capacities.

11.
Cell Mol Life Sci ; 71(20): 4043-54, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24687423

RESUMO

The retrograde transport of endosomes within axons proceeds with remarkable uniformity despite having to navigate a discontinuous microtubule network. The mechanisms through which this navigation is achieved remain elusive. In this report, we demonstrate that access of SxIP motif proteins, such as BPAG1n4, to the microtubule plus end is important for the maintenance of processive and sustained retrograde transport along the axon. Disruption of this interaction at the microtubule plus end significantly increases endosome stalling. Our study thus provides strong insight into the role of plus-end-binding proteins in the processive navigation of cargo within the axon.


Assuntos
Axônios/metabolismo , Proteínas do Citoesqueleto/química , Microtúbulos/metabolismo , Motivos de Aminoácidos , Animais , Transporte Axonal , Células COS , Células Cultivadas , Chlorocebus aethiops , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Endossomos/metabolismo , Células HEK293 , Humanos , Microtúbulos/química , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética
12.
EMBO Rep ; 13(11): 1021-9, 2012 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-22995871

RESUMO

Microtubules (MTs) are integral to numerous cellular functions, such as cell adhesion, differentiation and intracellular transport. Their dynamics are largely controlled by diverse MT-interacting proteins, but the signalling mechanisms that regulate these interactions remain elusive. In this report, we identify a rapid, calcium-regulated switch between MT plus end interaction and lattice binding within the carboxyl terminus of BPAG1n4. This switch is EF-hand dependent, and mutations of the EF-hands abolish this dynamic behaviour. Our study thus uncovers a new, calcium-dependent regulatory mechanism for a spectraplakin, BPAG1n4, at the MT plus end.


Assuntos
Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Proteínas do Citoesqueleto/metabolismo , Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Células COS , Proteínas de Transporte/química , Proteínas de Transporte/genética , Chlorocebus aethiops , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Distonina , Motivos EF Hand , Células HEK293 , Humanos , Microtúbulos/química , Mutação , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética
13.
PLoS One ; 7(4): e33094, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22523538

RESUMO

In neurons, a highly regulated microtubule cytoskeleton is essential for many cellular functions. These include axonal transport, regional specialization and synaptic function. Given the critical roles of microtubule-associated proteins (MAPs) in maintaining and regulating microtubule stability and dynamics, we sought to understand how this regulation is achieved. Here, we identify a novel LisH/WD40 repeat protein, tentatively named nemitin (neuronal enriched MAP interacting protein), as a potential regulator of MAP8-associated microtubule function. Based on expression at both the mRNA and protein levels, nemitin is enriched in the nervous system. Its protein expression is detected as early as embryonic day 11 and continues through adulthood. Interestingly, when expressed in non-neuronal cells, nemitin displays a diffuse pattern with puncta, although at the ultrastructural level it localizes along the microtubule network in vivo in sciatic nerves. These results suggest that the association of nemitin to microtubules may require an intermediary protein. Indeed, co-expression of nemitin with microtubule-associated protein 8 (MAP8) results in nemitin losing its diffuse pattern, instead decorating microtubules uniformly along with MAP8. Together, these results imply that nemitin may play an important role in regulating the neuronal cytoskeleton through an interaction with MAP8.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Microtúbulos/metabolismo , Sequência de Aminoácidos , Animais , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Proteínas dos Microfilamentos/química , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/efeitos dos fármacos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso , Neurônios/metabolismo
14.
PLoS Genet ; 8(3): e1002537, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22396657

RESUMO

Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.


Assuntos
Transporte Axonal , Proteínas de Drosophila/genética , Drosophila , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas rho de Ligação ao GTP/genética , Animais , Autofagia/genética , Transporte Axonal/genética , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neurônios Motores/metabolismo , Proteínas Mutantes/metabolismo , Doença de Parkinson/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ionóforos de Próton/farmacologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo
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