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2.
Nature ; 563(7732): 564-568, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30405245

RESUMO

Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain1,2. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine-a tryptophan metabolite that blocks antitumour immunity-inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity.


Assuntos
Doenças Autoimunes/imunologia , Biopterinas/análogos & derivados , Neoplasias/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Administração Oral , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/metabolismo , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Biopterinas/biossíntese , Biopterinas/metabolismo , Biopterinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coenzimas/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , GTP Cicloidrolase/genética , GTP Cicloidrolase/metabolismo , Humanos , Hipersensibilidade/imunologia , Ferro/metabolismo , Cinurenina/metabolismo , Cinurenina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
3.
Mol Psychiatry ; 26(12): 7257-7269, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34316004

RESUMO

We demonstrate that the rate of extracellular signal-related kinase phosphorylation (P-ERK1,2/Total-ERK1,2) in the amygdala is negatively and independently associated with anxiety symptoms in 23 consecutive patients with drug-resistant mesial temporal lobe epilepsy that was surgically treated. In naive Wistar rats, the P-ERK1,2/Total-ERK1,2 ratio in the amygdala correlates negatively with innate anxiety-related behavior on the elevated plus maze (n = 20) but positively with expression of defensive-learned behavior (i.e., freezing) on Pavlovian aversive (fear) conditioning (n = 29). The microinfusion of ERK1/2 inhibitor (FR180204, n = 8-13/group) or MEK inhibitor (U0126, n = 8-9/group) into the basolateral amygdala did not affect anxiety-related behavior but impaired the evocation (anticipation) of conditioned-defensive behavior (n = 9-11/group). In conclusion, the P-ERK1,2/Total-ERK1,2 ratio in the amygdala predicts anxiety in humans and the innate anxiety- and conditioned freezing behaviors in rats. However, the ERK1/2 in the basolateral AMY is only required for the expression of defensive-learned behavior. These results support a dissociate ERK-dependent mechanism in the amygdala between innate anxiety-like responses and the anticipation of learned-defensive behavior. These findings have implications for understanding highly prevalent psychiatric disorders related to the defensive circuit manifested by anxiety and fear. HIGHLIGHTS: The P-ERK1,2/Total-ERK1,2 ratio in the amygdala (AMY) correlates negatively with anxiety symptoms in patients with mesial temporal lobe epilepsy. The P-ERK1,2/Total-ERK1,2 in the amygdala correlates negatively with the anxiety-like behavior and positively with freezing-learned behavior in naive rats. ERK1,2 in the basolateral amygdala is required for learned-defensive but not for the anxiety-like behavior expression in rats.


Assuntos
Tonsila do Cerebelo , Ansiedade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação , Ratos , Ratos Wistar
4.
Mol Psychiatry ; 25(3): 655-665, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-29880883

RESUMO

Fear is a conscious state caused by exposure to real or imagined threats that trigger stress responses that affect the body and brain, particularly limbic structures. A sub-group of patients with mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) have seizures with fear, which is called ictal fear (IF), due to epileptic activity within the brain defensive survival circuit structures. Synaptic transmission efficacy can be bi-directionally modified through potentiation (long-term potentiation (LTP)) or depression (long-term depression (LTD)) as well as the phosphorylation state of Ser831 and Ser845 sites at the GluA1 subunit of the glutamate AMPA receptors, which has been characterized as a critical event for this synaptic plasticity. In this study, GluA1 levels and the phosphorylation at Ser845 and Ser831 in the amygdala (AMY), anterior hippocampus (aHIP) and middle gyrus of temporal neocortex (CX) were determined with western blots and compared between MTLE-HS patients who were showing (n = 06) or not showing (n = 25) IF. Patients with IF had an 11% decrease of AMY levels of the GluA1 subunit (p = 0.05) and a 21.5% decrease of aHIP levels of P-GluA1-Ser845 (p = 0.009) compared to patients not showing IF. The observed associations were not related to imbalances in the distribution of other concomitant types of aura, demographic, clinical or neurosurgical variables. The lower levels of P-GluA1-Ser845 in the aHIP of patients with IF were not related to changes in the levels of the serine/threonine-protein phosphatase PP1-alpha catalytic subunit or protein kinase A activation. Taken together, the GluA1 subunit levels in AMY and P-GluA1-Ser845 levels in the aHIP show an overall accuracy of 89.3% (specificity 95.5% and sensitivity 66.7%) to predict the presence of IF. AMY levels of the GluA1 subunit and aHIP levels of P-GluA1-Ser845 were not associated with the psychiatric diagnosis and symptoms of patients. Taken together with previous findings in MTLE-HS patients with IF who were evaluated by stereotactic implanted depth electrodes, we speculate our findings are consistent with the hypothesis that AMY is not a centre of fear but together with other sub-cortical and cortical structures integrates the defensive circuit that detect and respond to threats. This is the first report to address neuroplasticity features in human limbic structures connected to the defensive survival circuits, which has implications for the comprehension of highly prevalent psychiatric disorders and symptoms.


Assuntos
Medo/fisiologia , Receptores de Glutamato/genética , Convulsões/psicologia , Adulto , Tonsila do Cerebelo/metabolismo , Ansiedade/genética , Ansiedade/fisiopatologia , Transtornos de Ansiedade/metabolismo , Biomarcadores/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Humanos , Potenciação de Longa Duração , Masculino , Plasticidade Neuronal/fisiologia , Fosforilação , Receptores de AMPA/metabolismo , Receptores de Glutamato/metabolismo , Convulsões/metabolismo , Serina/metabolismo , Transmissão Sináptica
5.
J Toxicol Environ Health A ; 83(4): 153-167, 2020 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-32085696

RESUMO

Several investigators demonstrated that glyphosate formulations produce neurotoxicity associated with oxidative stress, alterations in glutamatergic system, inhibition of acetylcholinesterase activity and mitochondrial dysfunction. However, the underlying molecular mechanisms following exposure to this herbicide on astrocytes are unclear. Thus, the aim of the present study was to determine the activity of enzymes related to energy metabolism, in addition to oxidative stress parameters, mitochondrial mass, nuclear area, and autophagy in astrocytes treated with a glyphosate-based herbicide. Our results showed that 24 h exposure to a glyphosate-based herbicide decreased (1) cell viability, (2) activities of mitochondrial respiratory chain enzymes and creatine kinase (CK), (3) mitochondrial mass, and (4) nuclear area in rat astroglioma cell line (C6 cells). However, non-protein thiol (NPSH) levels were increased but catalase activity was not changed in cells exposed to the herbicide at non-cytotoxic concentrations. Low glyphosate concentrations elevated content of cells positive to autophagy-related proteins. Nuclear factor erythroid 2-related factor (Nrf2), NAD(P)H dehydrogenase [quinone] 1 (NQO1) and PTEN-induced kinase 1 (PINK1) labeling were not markedly altered in cells exposed to glyphosate at the same concentrations that an increase in NPSH levels and positive cells to autophagy were found. It is conceivable that mitochondria and CK may be glyphosate-based herbicides targets. Further, autophagy induction and NPSH increase may be mechanisms initiated to avoid oxidative stress and cell death. However, more studies are needed to clarify the role of autophagy in astrocytes exposed to the herbicide and which components of the formulation might be triggering the effects observed here.


Assuntos
Autofagia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicina/análogos & derivados , Herbicidas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular , Glicina/toxicidade , Humanos , Espécies Reativas de Oxigênio , Glifosato
6.
J Surg Res ; 234: 167-177, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30527470

RESUMO

BACKGROUND: Anastomotic leakage is the deadliest complication of colonic procedures. Ghrelin is an orexigenic hormone with potent actions on growth hormone release and functions in the processes of growth, tissue inflammation, repair, and oxidative stress. We evaluated the hypothesis that the exogenous administration of ghrelin causes beneficial effects on the healing of colonic anastomosis. MATERIALS AND METHODS: Sixty-four male Wistar rats were randomly assigned to eight subgroups receiving postoperative intraperitoneal administration of ghrelin (23 µg/kg/d) or saline after a colonic anastomosis. The anastomotic tissue was evaluated on the third, seventh, and 14th postoperative days. Anastomotic bursting pressure, histological parameters, hydroxyproline content, and tissue oxidative stress markers were compared. RESULTS: There was a significant increase in the mean anastomotic bursting pressure in the ghrelin subgroup on the seventh postoperative day (P = 0.035). Histological evaluation demonstrated a significant difference in the neutrophilic infiltrate (P = 0.035) on the third and 14th d and in apoptosis (P = 0.004), granulation tissue (P = 0.011) and peritoneal inflammation (P = 0.014) on the 14th postoperative day. There was a statistically significant increase in the hydroxyproline content in the ghrelin subgroup on the 14th postoperative day (P = 0.043). There were significant differences in the nitrite tissue levels (P = 0.021) on day 3 and in reactive oxygen species (P = 0.012) on day 14. CONCLUSIONS: The administration of ghrelin had beneficial anti-inflammatory and antioxidant effects, increasing the resistance of the anastomosis and the hydroxyproline tissue content in the postoperative period.


Assuntos
Fístula Anastomótica/prevenção & controle , Antioxidantes/farmacologia , Colo/cirurgia , Grelina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Cuidados Pós-Operatórios/métodos , Cicatrização/efeitos dos fármacos , Anastomose Cirúrgica , Animais , Antioxidantes/uso terapêutico , Colo/efeitos dos fármacos , Esquema de Medicação , Grelina/uso terapêutico , Injeções Intraperitoneais , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
7.
Cell Biol Toxicol ; 35(1): 49-58, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29961152

RESUMO

Developmental endochondral ossification requires constant blood supply, which is provided by the embryonic vascular network. High levels of homocysteine (Hcy) have vasculotoxic properties, but it remains unclear how Hcy disrupts blood vessel formation in endochondral ossification. Thus, we investigated the toxicity of Hcy on contents of vasculogenic factors (VEGF, VCAM-1, NOS3) and osteocalcin, using developing limbs as model. Chicken embryos were submitted to treatment with 20 µmol D-L Hcy at 12H&H and the analyses occur at 29H&H and 36H&H. We did not identify differences in the area of limb ossification in Hcy-treated (7.5 × 105 µm2 ± 3.9 × 104) and untreated embryos (7.6 × 105 µm2 ± 3.3 × 104) at 36H&H. In Hcy-treated embryos, we observed a significantly decrease of 46.8% at 29H&H and 26.0% at 36H&H in the number of VEGF-reactive cells. Also, treated embryos showed decrease of 98.7% in VCAM-1-reactive cells at 29H&H and 34.6% at 36H&H. The number of NOS3-reactive cells was reduced 54.0% at 29H&H and 91.5% at 36H&H, in the limbs of Hcy-treated embryos. Finally, in Hcy-treated embryos at 36H&H, we observed a reduction of 58.86% in the number of osteocalcin-reactive cells. Here, we demonstrated for the first time that the toxicity of Hcy is associated with a reduction in the contents of proteins involved in blood vessel formation and bone mineralization, which interferes with endochondral ossification of the limb during embryonic development. Graphical abstract.


Assuntos
Indutores da Angiogênese/metabolismo , Homocisteína/farmacologia , Osteogênese/efeitos dos fármacos , Animais , Calcificação Fisiológica/efeitos dos fármacos , Embrião de Galinha , Neovascularização Fisiológica/efeitos dos fármacos , Osteocalcina/metabolismo
8.
Mol Genet Metab ; 125(1-2): 104-111, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29935801

RESUMO

Tetrahydrobiopterin (BH4) is synthesized by the combined action of three metabolic pathways, namely de novo synthesis, recycling, and salvage pathways. The best-known function of BH4 is its mandatory action as a natural cofactor of the aromatic amino acid hydroxylases and nitric oxide synthases. Thus, BH4 is essential for the synthesis of nitric oxide, a retrograde neurotransmitter involved in learning and memory. We investigated the effect of BH4 (4-4000 pmol) intracerebroventricular administration on aversive memory, and on BH4 metabolism in the hippocampus of rodents. Memory-related behaviors were assessed in Swiss and C57BL/6 J mice, and in Wistar rats. It was consistently observed across all rodent species that BH4 facilitates aversive memory acquisition and consolidation by increasing the latency to step-down in the inhibitory avoidance task. This effect was associated with a reduced threshold to generate hippocampal long-term potentiation process. In addition, two inhibitors of memory formation (N(ω)-nitro-L-arginine methyl ester - L-Name - and dizocilpine - MK-801 -) blocked the enhanced effect of BH4 on memory, while the amnesic effect was not rescue by the co-administration of BH4 or a cGMP analog (8-Br-cGMP). The data strongly suggest that BH4 enhances aversive memory by activating the glutamatergic neurotransmission and the retrograde activity of NO. It was also demonstrated that BH2 can be converted into BH4 by activating the BH4 salvage pathway under physiological conditions in the hippocampus. This is the first evidence showing that BH4 enhances aversive memory and that the BH4 salvage pathway is active in the hippocampus.


Assuntos
Biopterinas/análogos & derivados , Hipocampo/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Óxido Nítrico/metabolismo , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Biopterinas/administração & dosagem , Feminino , GTP Cicloidrolase/genética , Hipocampo/fisiologia , Humanos , Masculino , Memória de Longo Prazo/fisiologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase/genética , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
9.
Cell Biol Int ; 42(6): 725-733, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29624777

RESUMO

Parkinson's disease (PD), the second-most prevalent neurodegenerative disease, is primarily characterized by neurodegeneration in the substantia nigra pars compacta, resulting in motor impairment. Loss-of-function mutations in parkin are the major cause of the early onset familial form of the disease. Although rodents deficient in parkin (parkin(-/-) ) have some dopaminergic system dysfunction associated with central oxidative stress and energy metabolism deficiencies, these animals only display nigrostriatal pathway degeneration under inflammatory conditions. This study investigated the impact of the inflammatory stimulus induced by lypopolisaccharide (LPS) on tetrahydrobiopterin (BH4) synthesizing enzymes (de novo and salvage pathways), since this cofactor is essential for dopamine synthesis. The mitochondrial content and architecture was investigated in the striatum of LPS-exposed parkin(-/-) mice. As expected, the LPS (0.33 mg/kg; i.p.) challenge compromised spontaneous locomotion and social interaction with juvenile parkin(-/-) and WT mice. Moreover, the genotype impacted the kinetics of the investigation of the juvenile. The inflammatory scenario did not induce apparent changes in mitochondrial ultrastructure; however, it increased the quantity of mitochondria, which were of smaller size, and provoked the perinuclear distribution of the organelle. Furthermore, the BH4 de novo biosynthetic pathway failed to be up-regulated in the LPS challenge, a well-known stimulus for its activation. The LPS treatment increased sepiapterin reductase (SPR) expression, suggesting compensation by the salvage pathway. This might indicate that dopamine synthesis is compromised in parkin(-/-) mice under inflammatory conditions. Finally, this scenario impaired the striatal expression of the transcription factor BDNF, possibly favoring cell death.


Assuntos
Biopterinas/análogos & derivados , Corpo Estriado/metabolismo , Ubiquitina-Proteína Ligases/genética , Oxirredutases do Álcool/metabolismo , Animais , Comportamento Animal , Biopterinas/biossíntese , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Lipopolissacarídeos/farmacologia , Locomoção , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Plasticidade Neuronal/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/veterinária , Ubiquitina-Proteína Ligases/deficiência , Regulação para Cima/efeitos dos fármacos
10.
Brain Behav Immun ; 61: 31-35, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27477921

RESUMO

Exercise improves mental health and synaptic function in the aged brain. However, the molecular mechanisms involved in exercise-induced healthy brain aging are not well understood. Evidence supports the role of neurogenesis and neurotrophins in exercise-induced neuroplasticity. The gene silencing transcription factor neuronal RE1-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) and an anti-inflammatory role of exercise are also candidate mechanisms. We evaluate the effect of 8weeks of physical activity on running wheels (RW) on motor and depressive-like behavior and hippocampal gene expression of brain-derived neurotrophic factor (BDNF), REST, and interleukins IL-1ß and IL-10 of adult and aged C57BL/6 mice. The aged animals exhibited impaired motor function and a depressive-like behavior: decreased mobility in the RW and open field and severe immobility in the tail suspension test. The gene expression of REST, IL-1ß, and IL-10 was increased in the hippocampus of aged mice. Physical activity was anxiolytic and antidepressant and improved motor behavior in aged animals. Physical activity also boosted BDNF and REST expression and decreased IL-1ß and IL-10 expression in the hippocampus of aged animals. These results support the beneficial role of REST in the aged brain, which can be further enhanced by regular physical activity.


Assuntos
Envelhecimento/metabolismo , Comportamento Animal/fisiologia , Depressão/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Atividade Motora/fisiologia , Condicionamento Físico Animal/fisiologia , Afeto/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Interleucina-10/sangue , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo
11.
Brain Behav Immun ; 56: 156-64, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26916218

RESUMO

Neopterin is found at increased levels in biological fluids from individuals with inflammatory disorders. The biological role of this pteridine remains undefined; however, due to its capacity to increase hemeoxygenase-1 content, it has been proposed as a protective agent during cellular stress. Therefore, we investigated the effects of neopterin on motor, emotional and memory functions. To address this question, neopterin (0.4 and/or 4pmol) was injected intracerebroventricularly before or after the training sessions of step-down inhibitory avoidance and fear conditioning tasks, respectively. Memory-related behaviors were assessed in Swiss and C57BL/6 mice, as well as in Wistar rats. Moreover, the putative effects of neopterin on motor and anxiety-related parameters were addressed in the open field and elevated plus-maze tasks. The effects of neopterin on cognitive performance were also investigated after intraperitoneal lipopolysaccharide (LPS) administration (0.33mg/kg) in interleukin-10 knockout mice (IL-10(-/-)). It was consistently observed across rodent species that neopterin facilitated aversive memory acquisition by increasing the latency to step-down in the inhibitory avoidance task. This effect was related to a reduced threshold to generate the hippocampal long-term potentiation (LTP) process, and reduced IL-6 brain levels after the LPS challenge. However, neopterin administration after acquisition did not alter the consolidation of fear memories, neither motor nor anxiety-related parameters. Altogether, neopterin facilitated cognitive processes, probably by inducing an antioxidant/anti-inflammatory state, and by facilitating LTP generation. To our knowledge, this is the first evidence showing the cognitive enhancer property of neopterin.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Inibição Psicológica , Potenciação de Longa Duração/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Neopterina/farmacologia , Nootrópicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Medo/efeitos dos fármacos , Injeções Intraventriculares , Interleucina-10 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neopterina/administração & dosagem , Nootrópicos/administração & dosagem , Ratos , Ratos Wistar
12.
Neurochem Res ; 41(1-2): 64-72, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26323504

RESUMO

INTRODUCTION: Exercise improves the motor symptoms of patients with Parkinson disease in a palliative manner. Existing evidence demonstrates that exercise induces neuroprotection based on the neurotrophic properties. We investigated the effect of exercise on mitochondrial physiology and oxidative stress in an animal model of hemiparkinsonism. METHODS: C57BL/6 mice completed a 6-week exercise program on a treadmill. We injected 6-hydroxydopamine (6-OHDA; 4 µg/2 µl) into the midstriatum. The animals progressively developed bradykinesia and R(-)-apomorphine-induced rotations that were attenuated by exercise. Transcriptional activation of protective genes is mediated by the antioxidant response element (ARE). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) binds to ARE. We investigated the Nrf2-ARE pathway in the striatum of animals. RESULTS: Exercise protected 6-OHDA-induced loss of tyrosine hydroxylase immunolabeling and activated the Nrf2-ARE pathway in the nigrostriatal pathway. Exercise stimulated mitochondrial biogenesis in the striatum of animals that was more resistant to oxidant 6-OHDA and nitric oxide donor (±)-S-nitroso-N-acetylpenicillamine. CONCLUSIONS: In mice, exercise activated Nrf2-ARE signaling in the nigrostriatal pathway that was protective against the development of hemiparkinsonism.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Oxidopamina/toxicidade , Transtornos Parkinsonianos/prevenção & controle , Condicionamento Físico Animal , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/metabolismo
13.
Neurochem Res ; 41(4): 880-91, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26586405

RESUMO

Mitochondrial respiratory chain complexes enzymatic (MRCCE) activities were successfully evaluated in frozen brain samples. Epilepsy surgery offers an ethical opportunity to study human brain tissue surgically removed to treat drug resistant epilepsies. Epilepsy surgeries are done with hemodynamic and laboratory parameters to maintain physiology, but there are no studies analyzing the association among these parameters and MRCCE activities in the human brain tissue. We determined the intra-operative parameters independently associated with MRCCE activities in middle temporal neocortex (Cx), amygdala (AMY) and head of hippocampus (HIP) samples of patients (n = 23) who underwent temporal lobectomy using multiple linear regressions. MRCCE activities in Cx, AMY and HIP are differentially associated to trans-operative mean arterial blood pressure, O2 saturation, hemoglobin, and anesthesia duration to time of tissue sampling. The time-course between the last seizure occurrence and tissue sampling as well as the sample storage to biochemical assessments were also associated with enzyme activities. Linear regression models including these variables explain 13-17 % of MRCCE activities and show a moderate to strong effect (r = 0.37-0.82). Intraoperative hemodynamic and laboratory parameters as well as the time from last seizure to tissue sampling and storage time are associated with MRCCE activities in human samples from the Cx, AMYG and HIP. Careful control of these parameters is required to minimize confounding biases in studies using human brain samples collected from elective neurosurgery.


Assuntos
Encéfalo/enzimologia , Complexo II de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Epilepsia/enzimologia , Adulto , Lobectomia Temporal Anterior , Encéfalo/patologia , Encéfalo/cirurgia , Epilepsia/patologia , Epilepsia/cirurgia , Feminino , Congelamento , Humanos , Masculino , Manejo de Espécimes/métodos , Succinato Desidrogenase/metabolismo
14.
Mol Cell Biochem ; 390(1-2): 1-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24623265

RESUMO

Interest in biochemistry of organoselenium compound has increased in the last decades, mainly due to their chemical and biological activities. Here, we investigated the protective effect of diphenyl diselenide (PhSe)2 (5 µmol/kg), in a mouse model of methylmercury (MeHg)-induced brain toxicity. Swiss male mice were divided into four experimental groups: control, (PhSe)2 (5 µmol/kg, subcutaneous administration), MeHg (40 mg/L, in tap water), and MeHg + (PhSe)2. After the treatment (21 days), the animals were killed and the cerebral cortex was analyzed. Electron microscopy indicated an enlarged and fused mitochondria leading to a reduced number of organelles, in the MeHg-exposed mice. Furthermore, cortical creatine kinase activity, a sensitive mitochondrial oxidative stress sensor, was almost abolished by MeHg. Subcutaneous (PhSe)2 co-treatment rescued from MeHg-induced mitochondrial alterations. (PhSe)2 also behaved as an enhancer of mitochondrial biogenesis, by increasing cortical mitochondria content in mouse-receiving (PhSe)2 alone. Mechanistically, (PhSe)2 (1 µM; 24 h) would trigger the cytoprotective Nrf-2 pathway for activating target genes, since astroglial cells exposed to the chalcogen showed increased content of hemeoxygenase type 1, a sensitive marker of the activation of this via. Thus, it is proposed that the (PhSe)2-neuroprotective effect might be linked to its mitoprotective activity.


Assuntos
Derivados de Benzeno/administração & dosagem , Encéfalo/metabolismo , Heme Oxigenase-1/biossíntese , Mitocôndrias/metabolismo , Compostos Organosselênicos/administração & dosagem , Animais , Encéfalo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Masculino , Intoxicação do Sistema Nervoso por Mercúrio/metabolismo , Intoxicação do Sistema Nervoso por Mercúrio/patologia , Compostos de Metilmercúrio/toxicidade , Camundongos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
15.
Brain Inj ; 28(10): 1262-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24841415

RESUMO

INTRODUCTION: Changes in hormone blood levels during the acute phase of traumatic brain injury (TBI) have been described in the literature. The objective was to investigate the association among several hormones plasma levels in the acute phase of severe TBI and the hospital mortality rate of male patients. METHODS: The independent association among plasma levels of TSH, LH, FSH, GH, free T4, cortisol, IGF-1 and total testosterone was measured 10 hours and 30 hours after severe TBI and the hospital mortality of 60 consecutive male patients was evaluated. RESULTS: At least one hormonal level abnormality was demonstrated in 3.6-73.1% of patients. The multiple logistic regressions showed a trend for an independent association among hospital mortality and normal or elevated LH levels measured at 10 hours (OR = 3.7, 95% CI = 0.8-16.3, p = 0.08) and 30 hours (OR = 3.9, 95% CI = 0.9-16.7, p = 0.06). Admission with abnormal pupils and a lower Glasgow Coma Score also were independently associated with hospital mortality. CONCLUSION: The hormonal changes are frequent in the acute phase of severe TBI. The hormones plasma levels, excepting the LH, are not highly consistent with the hospital mortality of male patients.


Assuntos
Insuficiência Adrenal/sangue , Lesões Encefálicas/sangue , Hormônios/sangue , Mortalidade Hospitalar , Hipogonadismo/sangue , Adolescente , Insuficiência Adrenal/etiologia , Insuficiência Adrenal/mortalidade , Adulto , Idoso , Biomarcadores/metabolismo , Lesões Encefálicas/complicações , Lesões Encefálicas/mortalidade , Hormônio Foliculoestimulante/sangue , Escala de Coma de Glasgow , Hormônio do Crescimento Humano/sangue , Humanos , Hidrocortisona/sangue , Hipogonadismo/etiologia , Hipogonadismo/mortalidade , Escala de Gravidade do Ferimento , Fator de Crescimento Insulin-Like I/metabolismo , Modelos Logísticos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Testosterona/sangue , Tireotropina/sangue
16.
J Sports Sci ; 32(1): 22-30, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24117160

RESUMO

The purpose of the present investigation was to identify muscle damage, inflammatory response and oxidative stress blood markers in athletes undertaking the ultra-endurance MultiSport Brazil race. Eleven well-trained male athletes (34.3 ± 3.1 years, 74.0 ± 7.6 kg; 172.2 ± 5.1 cm) participated in the study and performed the race, which consisted of about 90 km of alternating off-road running, mountain biking and kayaking. Twelve hours before and up to 15 minutes after the race a 10 mL blood sample was drawn in order to measure the following parameters: lactate dehydrogenase and creatine kinase activities, lipid peroxidation, catalase activity, protein carbonylation, respiratory chain complexes I, II and IV activities, oxygen consumption and neopterin concentrations. After the race, plasma lactate dehydrogenase and creatine kinase activities were significantly increased. Erythrocyte TBA-RS levels and plasma protein carbonylation were markedly augmented in post-race samples. Additionally, mitochondrial complex II activity and oxygen consumption in post-race platelet-rich plasma were also increased. These altered biochemical parameters were accompanied by increased plasma neopterin levels. The ultra-endurance event provoked systemic inflammation (increased neopterin) accompanied by marked oxidative stress, likely by increasing oxidative metabolism (increased oxidative mitochondrial function). This might be advantageous during prolonged exercise, mainly for efficient substrate oxidation at the mitochondrial level, even when tissue damage is induced.


Assuntos
Biomarcadores/sangue , Plaquetas/metabolismo , Neopterina/sangue , Estresse Oxidativo/fisiologia , Resistência Física/fisiologia , Ciclismo/fisiologia , Catalase/sangue , Comportamento Competitivo/fisiologia , Eritrócitos/metabolismo , Humanos , Peroxidação de Lipídeos , Masculino , Mitocôndrias/metabolismo , Músculo Esquelético/enzimologia , Músculo Esquelético/lesões , Carbonilação Proteica , Corrida/fisiologia
17.
Metabolites ; 14(3)2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38535321

RESUMO

Consumption of high-fat diets (HFD) is associated with brain alterations, including changes in feeding behavior, cognitive decline, and dementia. Astrocytes play a role in HFD-induced neuroinflammation and brain dysfunction; however, this process is not entirely understood. We hypothesized that exposure to saturated fatty acids can compromise astrocyte viability and mitochondrial function. The C6 (astrocytes) cell line was treated with palmitate or stearate (200 µM and 400 µM) for 6 h. Cell viability, morphology, inflammatory markers, and oxidative stress were evaluated. To assess mitochondrial function, various parameters were measured (membrane potential, mass, respiration, and complex activities). We observed that 6 h of treatment with 400 µM palmitate decreased cell viability, and treatment with 200 µM palmitate changed the astrocyte morphology. Palmitate increased inflammatory markers (TNF-α and IL6) but did not induce oxidative stress. Palmitate significantly decreased the mitochondrial membrane potential and mitochondrial mass. Complex I activity also decreased in palmitate-treated cells; however, no changes were observed in mitochondrial respiration. In conclusion, palmitate, a saturated fatty acid, induces inflammation and impairs mitochondrial function, leading to reduced astrocytic cell viability and changes in cellular morphology. Our study provides valuable insights into the potential mechanisms underlying the relationship between saturated fatty acids, astrocytes, and mitochondrial function in obesity-related brain dysfunction.

18.
Brain Res ; 1833: 148866, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38494098

RESUMO

Caffeine has been extensively studied in the context of CNS pathologies as many researchers have shown that consuming it reduces pro-inflammatory biomarkers, potentially delaying the progression of neurodegenerative pathologies. Several lines of evidence suggest that adenosine receptors, especially A1 and A2A receptors, are the main targets of its neuroprotective action. We found that caffeine pretreatment 15 min before LPS administration reduced the expression of Il1b in the hippocampus and striatum. The harmful modulation of caffeine-induced inflammatory response involved the downregulation of the expression of A2A receptors, especially in the hippocampus. Caffeine treatment alone promoted the downregulation of the adenosinergic receptor Adora2A; however, this promotion effect was reversed by LPS. Although administering caffeine increased the expression of the enzymes DNA methyltransferases 1 and 3A and decreased the expression of the demethylase enzyme Tet1, this effect was reversed by LPS in the hippocampus of mice that were administered Caffeine + LPS, relative to the basal condition; no significant differences were observed in the methylation status of the promoter regions of adenosine receptors. Finally, the bioinformatics analysis of the expanded network demonstrated the following results: the Adora2B gene connects the extended networks of the adenosine receptors Adora1 and Adora2A; the Mapk3 and Esr1 genes connect the extended Adora1 network; the Mapk4 and Arrb2 genes connect the extended Adora2A network with the extended network of the proinflammatory cytokine Il1ß. These results indicated that the anti-inflammatory effects of acute caffeine administration in the hippocampus may be mediated by a complex network of interdependencies between the Adora2B and Adora2A genes.


Assuntos
Cafeína , Regulação para Baixo , Hipocampo , Lipopolissacarídeos , Doenças Neuroinflamatórias , Fármacos Neuroprotetores , Receptor A2A de Adenosina , Animais , Lipopolissacarídeos/farmacologia , Receptor A2A de Adenosina/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Cafeína/farmacologia , Masculino , Regulação para Baixo/efeitos dos fármacos , Camundongos , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/induzido quimicamente , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Interleucina-1beta/metabolismo , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente
19.
Mol Genet Metab Rep ; 38: 101025, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38125072

RESUMO

Background: LBSL is a mitochondrial disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, resulting in a distinctive pattern on brain magnetic resonance imaging (MRI) and spectroscopy. Clinical presentation varies from severe infantile to chronic, slowly progressive neuronal deterioration in adolescents or adults. Most individuals with LBSL are compound heterozygous for one splicing defect in an intron 2 mutational hotspot and a second defect that could be a missense, non-sense, or splice site mutation or deletion resulting in decreased expression of the full-length protein. Aim: To present a new family with two affected members with LBSL and report a novel DARS2 mutation. Results: An 8-year-old boy (Patient 1) was referred due to headaches and abnormal MRI, suggestive of LBSL. Genetic testing revealed a previously reported c.492 + 2 T > C mutation in the DARS2 gene. Sanger sequencing uncovered a novel variant c.228-17C > G in the intron 2 hotspot. Family studies found the same genetic changes in an asymptomatic 4-year-old younger brother (Patient 2), who was found on follow-up to have an abnormal MRI. mRNA extracted from patients' fibroblasts showed that the c.228-17C > G mutation caused skipping of exon 3 resulting in lower DARS2 mRNA level. Complete absence of DARS2 protein was also found in both patients. Summary: We present a new family with two children affected with LBSL and describe a novel mutation in the DARS2 intron 2 hotspot. Despite findings of extensive white matter disease in the brain and spine, the proband in this family presented only with headaches, while the younger sibling, who also had extensive white matter changes, was asymptomatic. Our in-vitro results confirmed skipping of exon 3 in patients and family members carrying the intron 2 variant, which is consistent with previous reported mutations in intron 2 hotspots. DARS2 mRNA and protein levels were also reduced in both patients, further supporting the pathogenicity of the novel variant.

20.
J Bioenerg Biomembr ; 45(5): 449-57, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23471523

RESUMO

Interactions of chemicals with cerebral cellular systems are often accompanied by similar changes involving components in non-neural tissues. On this basis, indirect strategies have been developed to investigate neural cell function parameters by methods using accessible cells, including platelets and/or peripheral blood lymphocytes. Therefore, here it was investigated whether peripheral blood markers may be useful for assessing the central toxic effects of methylmercury (MeHg). For this purpose, we investigated platelet mitochondrial physiology in a well-established mouse model of MeHg-induced neurotoxicity, and correlated this peripheral activity with behavioural and central biochemical parameters. In order to characterize the cortical toxicity induced by MeHg (20 and 40 mg/L in drinking water, 21 days), the behavioral parameter namely, short-term object recognition, and the central mitochondrial impairment assessed by measuring respiratory complexes I-IV enzyme activities were determined in MeHg-poisoned animals. Neurotoxicity induced by MeHg exposure provoked compromised cortical activity (memory impairment) and reduced NADH dehydrogenase, complex II and II-III activities in the cerebral cortex. These alterations correlated with impaired systemic platelet oxygen consumption of intoxicated mice, which was characterized by reduced electron transfer activity and uncoupled mitochondria. The data brought here demonstrated that impaired systemic platelet oxygen consumption is a sensitive and non-invasive marker of the brain energy deficits induced by MeHg poisoning. Finally, brain and platelets biochemical alterations significantly correlated with cognitive behavior in poisoned mice. Therefore, it could be proposed the use of platelet oxygen consumption as a peripheral blood marker of brain function in a mouse model MeHg-induced neurotoxicity.


Assuntos
Plaquetas/metabolismo , Encéfalo/metabolismo , Síndromes Neurotóxicas/sangue , Consumo de Oxigênio/fisiologia , Animais , Biomarcadores/sangue , Encéfalo/patologia , Modelos Animais de Doenças , Masculino , Compostos de Metilmercúrio , Camundongos , Síndromes Neurotóxicas/metabolismo , Neurotoxinas , Distribuição Aleatória
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