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2.
J Chin Med Assoc ; 82(6): 495-499, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31180948

RESUMO

BACKGROUND: Exercise is an effective therapy for the management of diabetes because it helps regulate glucose and magnesium homeostasis. Nevertheless, the mechanisms by which exercise exerts effects on magnesium transport remain unclear. This study investigated the expression of genes encoding magnesium transporters (GMTs) after a three-month exercise program in diabetic patients. METHODS: This study was conducted with a within-subject pre-post design. A total of 15 adult patients with type 2 diabetes mellitus (T2DM) were recruited and underwent a three-month indoor bicycle exercise program. The expression of five GMTs (CNNM2, TRPM6, TRPM7, SLC41A1, and SLC41A3) was determined in blood samples. Relevant anthropometric values and biochemical parameters were also determined. RESULTS: Although the body weight and body mass index decreased after three months exercise, there were no significant differences. Fasting blood glucose, glycated hemoglobin (HbA1c), waist circumference, and magnesium levels decreased after the exercise program (p < 0.05). The expression of SLC41A1 and SLC41A3 were downregulated after exercise, but only CNNM2, TRPM6, and TRPM7 showed significantly decreased expression levels compared with those before the exercise program (p < 0.05). CONCLUSION: The three-month exercise program ameliorated blood glucose levels and downregulated the expression of magnesium-responsive genes in patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/genética , Terapia por Exercício , Magnésio/metabolismo , Proteínas de Membrana Transportadoras/genética , Glicemia/análise , Proteínas de Transporte de Cátions/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Regulação para Baixo , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Canais de Cátion TRPM/genética
3.
Sci Rep ; 9(1): 8135, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31148574

RESUMO

Previous studies have shown that the geometric development of femoral trabecular bone is affected by insufficient dietary intake of magnesium. However, it is not clear whether the development of femoral cortical bone can be quantitatively evaluated according to a diet with inadequate magnesium supplementation. Therefore, we used a micro computed tomography (CT) imaging approach with a laboratory mouse model to explore the potential application of texture analysis for the quantitative assessment of femoral cortical bones. C57BL/6J male mice were divided into two groups, where one group was fed a normal diet and the other group was fed a low-magnesium diet. We used a micro CT scanner for image acquisition, and the subsequent development of cortical bone was examined by texture analysis based on the statistical distribution of gray-scale intensities in which seven essential parameters were extracted from the micro CT images. Our calculations showed that the mean intensity increased by 7.20% (p = 0.000134), sigma decreased by 29.18% (p = 1.98E-12), skewness decreased by 19.52% (p = 0.0000205), kurtosis increased by 9.62% (p = 0.0877), energy increased by 24.19% (p = 3.32E-09), entropy decreased by 6.14% (p = 3.00E-10), and the Nakagami parameter increased by 104.32% (p = 4.13E-12) in the low-magnesium group when compared to the normal group. We found that the statistical parameters extracted from the gray-scale intensity distribution were able to differentiate between femoral cortical bone developments in the two different diet groups.


Assuntos
Osso Cortical/diagnóstico por imagem , Dieta , Fêmur/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Magnésio/farmacologia , Animais , Engenharia Biomédica , Densidade Óssea , Diferenciação Celular , Modelos Animais de Doenças , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Estatísticos , Imagens de Fantasmas , Software , Tomografia Computadorizada por Raios X , Microtomografia por Raio-X
4.
Neurosurgery ; 84(4): 965-976, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29672725

RESUMO

BACKGROUND: Magnesium supplementation has potential for use in nerve regeneration. The expression of some magnesium transporter genes is reflective of the intracellular magnesium levels. OBJECTIVE: To assess the expression of various magnesium transporter genes as they relate to neurological alterations in a sciatic nerve injury model. METHODS: Sciatic nerve injury was induced in rats, which were then fed either basal or high magnesium diets. Magnesium concentrations and 5 magnesium transporter genes (SLC41A1, MAGT1, CNNM2, TRPM6, and TRPM7) were measured in the tissue samples. RESULTS: The high magnesium diet attenuated cytoskeletal loss in a dose-dependent manner in isolated nerve explants. The high magnesium diet augmented nerve regeneration and led to the restoration of nerve structure, increased S-100, and neurofilaments. This increased regeneration was consistent with the improvement of neurobehavioral and electrophysiological assessment. The denervated muscle morphology was restored with the high magnesium diet, and that was also highly correlated with the increased expression of desmin and acetylcholine receptors in denervated muscle. The plasma magnesium levels were significantly elevated after the animals consumed a high magnesium diet and were reciprocally related to the down-regulation of CNNM2, MagT1, and SCL41A1 in the blood monocytes, nerves, and muscle tissues of the nerve crush injury model. CONCLUSION: The increased plasma magnesium levels after consuming a high magnesium diet were highly correlated with the down-regulation of magnesium transporter genes in monocytes, nerves, and muscle tissues after sciatic nerve crush injury. The study findings suggest that there are beneficial effects of administering magnesium after a nerve injury.


Assuntos
Proteínas de Transporte de Cátions , Regulação para Baixo/efeitos dos fármacos , Magnésio , Nervo Isquiático , Administração Oral , Animais , Proteínas de Transporte de Cátions/análise , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Dieta , Modelos Animais de Doenças , Magnésio/administração & dosagem , Magnésio/metabolismo , Magnésio/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/metabolismo , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões
5.
Sci Rep ; 8(1): 15625, 2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-30353027

RESUMO

Diet and exercise are conventional methods for controlling body weight and are linked to alterations in gut microbiota. However, the associations of diet, exercise, and gut microbiota in the control of obesity remain largely unknown. In the present study, using 16S rRNA amplicon sequencing and fecal microbiota transplantation (FMT), normal fat diet (NFD), exercise and their combination resulted in improved metabolic profiles in comparison to sedentary lifestyle with high fat diet (HFD). Moreover, diet exerted more influence than exercise in shaping the gut microbiota. HFD-fed mice receiving FMT from NFD-exercised donors not only showed remarkably reduced food efficacy, but also mitigated metabolic profiles (p < 0.05). The transmissible beneficial effects of FMT were associated with bacterial genera Helicobacter, Odoribacter and AF12 and overrepresentation of oxidative phosphorylation and glycolysis genes. Our findings demonstrate that the beneficial effects of diet and exercise are transmissible via FMT, suggesting a potential therapeutic treatment for obesity.


Assuntos
Dieta Hiperlipídica , Transplante de Microbiota Fecal , Condicionamento Físico Animal , Animais , Comportamento Alimentar , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Inflamação/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Análise de Componente Principal
6.
BMC Neurosci ; 19(1): 37, 2018 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-29940857

RESUMO

BACKGROUND: High-frequency transcutaneous neuromuscular electrical nerve stimulation (TENS) is currently used for the administration of electrical current in denervated muscle to alleviate muscle atrophy and enhance motor function; however, the time window (i.e. either immediate or delayed) for achieving benefit is still undetermined. In this study, we conducted an intervention of sciatic nerve crush injury using high-frequency TENS at different time points to assess the effect of motor and sensory functional recovery. RESULTS: Animals with left sciatic nerve crush injury received TENS treatment starting immediately after injury or 1 week later at a high frequency(100 Hz) or at a low frequency (2 Hz) as a control. In SFI gait analysis, either immediate or late admission of high-frequency electrical stimulation exerted significant improvement compared to either immediate or late administration of low-frequency electrical stimulation. In an assessment of allodynia, immediate high frequency electrical stimulation caused a significantly decreased pain threshold compared to late high-frequency or low-frequency stimulation at immediate or late time points. Immunohistochemistry staining and western blot analysis of S-100 and NF-200 demonstrated that both immediate and late high frequency electrical stimulation showed a similar effect; however the effect was superior to that achieved with low frequency stimulation. Immediate high frequency electrical stimulation resulted in significant expression of TNF-α and synaptophysin in the dorsal root ganglion, somatosensory cortex, and hippocampus compared to late electrical stimulation, and this trend paralleled the observed effect on somatosensory evoked potential. The CatWalk gait analysis also showed that immediate electrical stimulation led to a significantly high regularity index. In primary dorsal root ganglion cells culture, high-frequency electrical stimulation also exerted a significant increase in expression of TNF-α, synaptophysin, and NGF in accordance with the in vivo results. CONCLUSION: Immediate or late transcutaneous high-frequency electrical stimulation exhibited the potential to stimulate the motor nerve regeneration. However, immediate electrical stimulation had a predilection to develop neuropathic pain. A delay in TENS initiation appears to be a reasonable approach for nerve repair and provides the appropriate time profile for its clinical application.


Assuntos
Lesões por Esmagamento/terapia , Regeneração Nervosa/fisiologia , Neuralgia/fisiopatologia , Nervo Isquiático/lesões , Estimulação Elétrica Nervosa Transcutânea , Animais , Estimulação Elétrica/métodos , Potenciais Somatossensoriais Evocados/fisiologia , Masculino , Ratos Sprague-Dawley , Neuropatia Ciática/metabolismo , Estimulação Elétrica Nervosa Transcutânea/métodos
7.
Nanoscale Res Lett ; 13(1): 109, 2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-29675727

RESUMO

In this study, alpha nickel sulfide (α-NiS) nanosphere films have been successfully synthesized by electroplating the nickel nanosheet film on the indium tin oxide (ITO) glass substrate and sulfuring nickel-coated ITO glass substrate. First, we electrodeposited the nickel nanosheet films on the ITO glass substrates which were cut into a 0.5 × 1 cm2 size. Second, the nanosheet nickel films were annealed in vacuum-sealed glass ampoules with sulfur sheets at different annealing temperatures (300, 400, and 500 °C) for 4 h in vacuum-sealed glass ampoules. The α-NiS films were investigated by using X-ray diffraction (XRD), variable vacuum scanning electron microscopy (VVSEM), field emission scanning electron microscopy/energy dispersive spectrometer (FE-SEM/EDS), cyclic voltammogram (CV), electrochemical impedance spectroscopy (EIS), ultraviolet/visible/near-infrared (UV/Visible/NIR) spectra, and photoluminescence (PL) spectra. Many nanospheres were observed on the surface of the α-NiS films at the annealing temperature 400 °C for 4 h. We also used the high-resolution transmission electron microscopy (HR-TEM) for the analysis of the α-NiS nanospheres. We demonstrated that our α-NiS nanosphere film had a linear current response to different glucose concentrations. Additionally, our α-NiS nanosphere films were preserved at room temperature for five and a half years and were still useful for detecting glucose at low concentration.

8.
Life Sci ; 191: 236-244, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28986095

RESUMO

PURPOSE: Parkinson's disease (PD) is a progressive degenerative central nervous system disorder that particularly impairs motor function. As PD advances, gait disorders become more pronounced and are often difficult to treat with current pharmacological therapies. Physical activity improves both mobility in and the daily living activities of patients with PD. Mitochondrial alterations and oxidative stress contribute to PD progression. Therefore, the association between mitochondria and exercise in PD and the implicated regulation of mitochondrial proteins was explored in this study. METHODS: In this study, we developed a unilateral 6-hydroxydopamine rat model of PD and executed 4weeks of treadmill training. Motor behavior was evaluated through gait change analysis (the CatWalk method) and rotational testing. The viability of dopaminergic neurons, mitochondrial function, and oxidative stress in the substantia nigra and striatum were investigated through Western blot and immunohistochemical staining. KEY FINDINGS: Treadmill training improved the performance of gait parameters in terms of maximal area, swing speed, stride length, and stance phase; treadmill training also reduced methamphetamine-induced rotation. This training not only improved dopaminergic neuron viability but also recovered mitochondrial function and attenuated oxidative stress in PD rats. The mechanism may be associated with the facilitation of mitochondrial turnover, including facilitation of mitochondrial fusion, fission, and clearance accompanying increased quantities of mitochondria. SIGNIFICANCE: Treadmill exercise improved gait speed and balance, reduced oxidative stress, improved mitochondrial fusion and fission, increased mitochondrial amounts, and potentially attenuated dopaminergic neuron degeneration. Consequently, mitochondrial quality was improved in PD rats.


Assuntos
Terapia por Exercício , Marcha , Dinâmica Mitocondrial , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Animais , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Feminino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Atividade Motora , Estresse Oxidativo , Doença de Parkinson/metabolismo , Condicionamento Físico Animal , Ratos , Ratos Sprague-Dawley , Substância Negra/metabolismo , Substância Negra/fisiopatologia
9.
Sci Rep ; 7(1): 10710, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28878349

RESUMO

The cell penetrating peptide, Pep-1, has been shown to facilitate cellular uptake of foreign mitochondria but further research is required to evaluate the use of Pep-1-mediated mitochondrial delivery (PMD) in treating mitochondrial defects. Presently, we sought to determine whether mitochondrial transplantation rescue mitochondrial function in a cybrid cell model of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) disease. Following PMD, recipient cells had internalized donor mitochondria after 1 h, and expressed higher levels of normal mitochondrial DNA, particularly at the end of the treatment and 11 days later. After 4 days, mitochondrial respiratory function had recovered and biogenesis was evident in the Pep-1 and PMD groups, compared to the untreated MELAS group. However, only PMD was able to reverse the fusion-to-fission ratio of mitochondrial morphology, and mitochondria shaping proteins resembled the normal pattern seen in the control group. Cell survival following hydrogen peroxide-induced oxidative stress was also improved in the PMD group. Finally, we observed that PMD partially normalized cytokine expression, including that of interleukin (IL)-7, granulocyte macrophage-colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF), in the MELAS cells. Presently, our data further confirm the protective effects of PMD as well in MELAS disease.


Assuntos
Peptídeos Penetradores de Células/metabolismo , Síndrome MELAS/genética , Síndrome MELAS/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , Autofagia , Linhagem Celular Tumoral , Respiração Celular , Sobrevivência Celular , Citocinas/biossíntese , Técnicas de Genotipagem , Humanos , Síndrome MELAS/terapia , Mitocôndrias/transplante , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo , Oxigênio/metabolismo , Coloração e Rotulagem
10.
PLoS One ; 12(4): e0174806, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28369124

RESUMO

OBJECTIVE: The literature shows that bone mineral density (BMD) and the geometric architecture of trabecular bone in the femur may be affected by inadequate dietary intake of Mg. In this study, we used microcomputed tomography (micro-CT) to characterize and quantify the impact of a low-Mg diet on femoral trabecular bones in mice. MATERIALS AND METHODS: Four-week-old C57BL/6J male mice were randomly assigned to 2 groups and supplied either a normal or low-Mg diet for 8weeks. Samples of plasma and urine were collected for biochemical analysis, and femur tissues were removed for micro-CT imaging. In addition to considering standard parameters, we regarded trabecular bone as a cylindrical rod and used computational algorithms for a technical assessment of the morphological characteristics of the bones. BMD (mg-HA/cm3) was obtained using a standard phantom. RESULTS: We observed a decline in the total tissue volume, bone volume, percent bone volume, fractal dimension, number of trabecular segments, number of connecting nodes, bone mineral content (mg-HA), and BMD, as well as an increase in the structural model index and surface-area-to-volume ratio in low-Mg mice. Subsequently, we examined the distributions of the trabecular segment length and radius, and a series of specific local maximums were identified. The biochemical analysis revealed a 43% (96%) decrease in Mg and a 40% (71%) decrease in Ca in plasma (urine excretion). CONCLUSIONS: This technical assessment performed using micro-CT revealed a lower population of femoral trabecular bones and a decrease in BMD at the distal metaphysis in the low-Mg mice. Examining the distributions of the length and radius of trabecular segments showed that the average length and radius of the trabecular segments in low-Mg mice are similar to those in normal mice.


Assuntos
Dieta , Fêmur/diagnóstico por imagem , Deficiência de Magnésio/diagnóstico por imagem , Deficiência de Magnésio/etiologia , Microtomografia por Raio-X , Animais , Densidade Óssea , Cálcio/sangue , Cálcio/urina , Modelos Animais de Doenças , Lâmina de Crescimento/diagnóstico por imagem , Imageamento Tridimensional , Magnésio/sangue , Magnésio/urina , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Imagens de Fantasmas , Fósforo/sangue , Fósforo/urina , Distribuição Aleatória , Microtomografia por Raio-X/instrumentação
11.
BMC Musculoskelet Disord ; 18(1): 171, 2017 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-28438150

RESUMO

BACKGROUND: Intermittent parathyroid hormone (PTH) can be used to treat osteoporosis of the spine and hip. However, whether it can be used to treat osteoporosis of the mandible is unclear. The purpose of this study was to explore the influence of applying intermittent PTH to ovariectomized rats on the trabecular bone microarchitecture of the mandible and femoral head. METHODS: Eighteen female rats were divided into three groups: the healthy group, ovariectomized (OVX) group, and OVX + PTH group. The OVX group and OVX + PTH group had an OVX at 8 weeks of age. The OVX + PTH group received intermittent PTH therapy for 12 weeks. The mandibles and femurs of all rats were removed at 20 weeks and were then scanned using microcomputed tomography (micro-CT). RESULTS: From the micro-CT analysis, the trabecular bone microarchitecture of the mandible and femoral head are offered as follows: (1) The bone volume fraction and trabecular thickness in the OVX group were lower than those in the healthy group. (2) The bone volume fraction and trabecular thickness in the OVX + PTH group approximated those in the healthy group. CONCLUSION: The conclusions of this study regarding the trabecular bone microarchitecture of the mandible and femoral head are offered as follows: (1) The BV/TV and TbTh in the OVX group were lower than those in the healthy group. (2) The BV/TV and TbTh in the OVX + PTH group approximated those in the healthy group, therefore, intermittent PTH displayed high efficacy for treating femoral or mandibular deterioration of bone microstructure resulting from loss of ovarian function. Osteoporosis of the femur or mandible in the rats was ameliorated by intermittent PTH therapy.


Assuntos
Cabeça do Fêmur/efeitos dos fármacos , Cabeça do Fêmur/diagnóstico por imagem , Mandíbula/efeitos dos fármacos , Mandíbula/diagnóstico por imagem , Ovariectomia/efeitos adversos , Hormônio Paratireóideo/administração & dosagem , Animais , Feminino , Ovariectomia/tendências , Ratos , Ratos Wistar , Microtomografia por Raio-X/métodos
12.
Neurosurgery ; 80(3): 475-488, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28362972

RESUMO

Background: Axon degeneration leads to cytoskeletal disassembly, metabolism imbalance, and mitochondrial dysfunction during neurodegeneration or nerve injury. Objective: In this study, we assess the possibility of mitigating axon degeneration by local injection of mitochondria in a crushed sciatic nerve. Methods: Sciatic nerve explants cocultured with mitochondria were assessed for the optimal dosage in local injection and nerve regeneration potential. The left sciatic nerve was crushed in Sprague-Dawley rats and then local injection of mitochondria into the distal end of the injured nerve was conducted for further assessment. Results: Mitochondrial coculture attenuated cytoskeletal loss and oxidative stress in isolated nerve explants. In Vivo analyses also showed that mitochondrial transplantation improved animal neurobehaviors, electrophysiology of nerve conduction, and muscle activities. Mitochondria injection significantly attenuated the oxidative stress and increased the expression of neurotrophic factors both in injured nerves and denervated muscles, as well as restored muscular integrity, and increased the pool of muscular progenitor cells and total muscle weight. Conclusion: Mitochondria injection can protect injured nerves from axonal degeneration both in Vitro and in Vivo. This improvement was accompanied with the expression of neurotrophic factors as well as the reduction of oxidative stress, which may account for the functional recovery of both injured nerves and denervated muscles.


Assuntos
Axônios/patologia , Mitocôndrias/metabolismo , Compressão Nervosa , Degeneração Neural/prevenção & controle , Traumatismos dos Nervos Periféricos/patologia , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/lesões , Neuropatia Ciática/patologia , Animais , Axônios/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Neuropatia Ciática/metabolismo
13.
Environ Toxicol ; 32(2): 456-468, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26919256

RESUMO

Cinnamomum cassia essential oil (CC-EO) has various functional properties, such as anti-microbial, hypouricemic, anti-tyrosinase and anti-melanogenesis activities. The present study aimed to evaluate the anti-cancer activities of CC-EO and its major constituent, cinnamaldehyde, in human oral squamous cell carcinoma HSC-3 cells. Determination of the cell viability, apoptotic characteristics, DNA damage, cell cycle analysis, reactive oxygen species (ROS) production, mitochondrial membrane potential, cytosolic Ca2+ level and intracellular redox status were performed. Our results demonstrated that CC-EO and cinnamaldehyde significantly decreased cell viability and caused morphological changes. The cell cycle analysis revealed that CC-EO and cinnamaldehyde induced G2/M cell cycle arrest in HSC-3 cells. The apoptotic characteristics (DNA laddering and chromatin condensation) and DNA damage were observed in the CC-EO-treated and cinnamaldehyde-treated HSC-3 cells. Moreover, CC-EO and cinnamaldehyde promoted an increase in cytosolic Ca2+ levels, induced mitochondrial dysfunction and activated cytochrome c release. The results of ROS production and intracellular redox status demonstrated that CC-EO and cinnamaldehyde significantly increased the ROS production and thiobarbituric acid reactive substance levels, and the cellular glutathione content and glutathione peroxidase activity were significantly reduced in HSC-3 cells. Our results suggest that CC-EO and cinnamaldehyde may possess anti-oral cancer activity in HSC-3 cells. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 456-468, 2017.


Assuntos
Acroleína/análogos & derivados , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cinnamomum/química , Óleos Voláteis/farmacologia , Acroleína/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Espécies Reativas de Oxigênio/metabolismo
14.
J Pathol ; 241(3): 337-349, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27801527

RESUMO

Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-d-aspartate receptor (NMDAR) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF-1α mainly regulates the cystine-glutamate transporter (system xc- ) subunit xCT by directly binding to its promoter; xCT and its function are up-regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR) or CIR-mediated glutamate excitotoxicity in vitro and in vivo. Pharmaceutical inhibition of system xc- by a clinically approved anti-cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF-1α plays a role in CIR-induced glutamate excitotoxicity via the long-lasting activation of system xc- -dependent glutamate outflow and suggest that system xc- is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Hipóxia Celular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Separação Celular/métodos , Ácido Glutâmico/metabolismo , Camundongos , Ativação Transcricional/fisiologia , Regulação para Cima
15.
Transl Res ; 170: 40-56.e3, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26730494

RESUMO

Although restoration of mitochondrial function in mitochondrial diseases through peptide-mediated allogeneic mitochondrial delivery (PMD) has been demonstrated in vitro, the in vivo therapeutic efficacy of PMD in Parkinson's disease (PD) has yet to be determined. In this study, we compared the functionality of mitochondrial transfer with or without Pep-1 conjugation in neurotoxin (6-hydroxydopamine, 6-OHDA)-induced PC12 cells and PD rat models. We injected mitochondria into the medial forebrain bundle (MFB) of the PD rats after subjecting the nigrostriatal pathway to a unilateral 6-OHDA lesion for 21 days, and we verified the effectiveness of the mitochondrial graft in enhancing mitochondrial function in the soma of the substantia nigra (SN) neuron through mitochondrial transport dynamics in the nigrostriatal circuit. The result demonstrated that only PMD with allogeneic and xenogeneic sources significantly sustained mitochondrial function to resist the neurotoxin-induced oxidative stress and apoptotic death in the rat PC12 cells. The remaining cells exhibited a greater capability of neurite outgrowth. Furthermore, allogeneic and xenogeneic transplantation of peptide-labeled mitochondria after 3 months improved the locomotive activity in the PD rats. This increase was accompanied by a marked decrease in dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and consistent enhancement of tyrosine hydroxylase-positive immunoreaction of dopaminergic neurons in the SNc and striatum. We also observed that in the SN dopaminergic neuron in the treated PD rats, mitochondrial complex I protein and mitochondrial dynamics were restored, thus ameliorating the oxidative DNA damage. Moreover, we determined signal translocation of graft allogeneic mitochondria from the MFB to the calbindin-positive SN neuron, which demonstrated the regulatory role of mitochondrial transport in alleviating 6-OHDA-induced degeneration of dopaminergic neurons.


Assuntos
Cisteamina/análogos & derivados , Mitocôndrias/transplante , Oxidopamina/efeitos adversos , Doença de Parkinson/terapia , Peptídeos/química , Animais , Calbindinas/metabolismo , Transplante de Células , Cisteamina/química , Neurônios Dopaminérgicos/patologia , Feminino , Humanos , Mitocôndrias/fisiologia , Estresse Oxidativo , Oxidopamina/química , Células PC12 , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Transplante Heterólogo/métodos , Transplante Homólogo/métodos
16.
Cell Transplant ; 25(5): 913-27, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26555763

RESUMO

Transferring exogenous mitochondria has therapeutic effects on damaged heart, liver, and lung tissues. Whether this protective effect requires the symbiosis of exogenous mitochondria in host cells remains unknown. Here xenogenic mitochondria derived from a hamster cell line were applied to ischemic rat brains and rat primary cortical neurons. Isolated hamster mitochondria, either through local intracerebral or systemic intra-arterial injection, significantly restored the motor performance of brain-ischemic rats. The brain infarct area and neuronal cell death were both attenuated by the exogenous mitochondria. Although internalized mitochondria could be observed in neurons and astrocytes, the low efficacy of mitochondrial internalization could not completely account for the high rate of rescue of the treated neural cells. We further illustrated that disrupting electron transport or ATPase synthase in mitochondria significantly attenuated the protective effect, suggesting that intact respiratory activity is essential for the mitochondrial potency on neural protection. These results emphasize that nonsymbiotic extracellular mitochondria can provide an effective cell defense against acute injurious ischemic stress in the central nervous system.


Assuntos
Isquemia Encefálica/terapia , Infarto da Artéria Cerebral Média/terapia , Mitocôndrias/transplante , Neuroproteção/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Transplante Heterólogo , Animais , Encéfalo/patologia , Isquemia Encefálica/patologia , Morte Celular/fisiologia , Linhagem Celular , Sobrevivência Celular , Cricetinae , Transporte de Elétrons/fisiologia , Infarto da Artéria Cerebral Média/patologia , Injeções Intra-Arteriais , Masculino , Neurônios/citologia , Ratos , Ratos Sprague-Dawley
17.
Int J Endocrinol ; 2015: 380247, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26273297

RESUMO

The aim of this study is to investigate the impact of serum Mg on bone mineral metabolism in chronic kidney disease (CKD) patients with or without diabetes. A total of 56 CKD patients not receiving dialysis were recruited and divided into two groups, one group of 27 CKD patients with diabetes and another group of 29 CKD patients without diabetes. Biochemical determinations were made, and the estimated glomerular filtration rate (eGFR) was measured. Bone mineral density was measured by dual-energy X-ray absorptiometry. Serum Mg was inversely correlated with serum Ca (P = 0.023) and positively correlated with serum parathyroid hormone (PTH) (P = 0.020), alkaline phosphatase (P = 0.044), and phosphate (P = 0.040) in the CKD patients with diabetes. The CKD patients with diabetes had lower serum albumin and a higher proportion of hypomagnesemia and osteoporosis than the nondiabetic patients did (P < 0.05). Serum Mg was inversely correlated with eGFR in the CKD patients with or without diabetes (P < 0.05). Serum Mg showed an inverse correlation with 25-hydroxyvitamin D in CKD patients without diabetes (P = 0.006). Furthermore, the diabetic CKD patients with low serum Mg had a lower iPTH (P = 0.007) and a higher serum Ca/Mg ratio (P < 0.001) than the other CKD patients. The lower serum Mg subgroup showed a higher incidence of osteoporosis than the moderate and higher serum Mg subgroups did (66.7%, 39.4%, and 29.4%, resp.). In conclusion, low serum Mg may impact iPTH and exacerbates osteoporosis in CKD patients, particularly with diabetes.

18.
PLoS One ; 10(5): e0124624, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25945496

RESUMO

PURPOSE: The skeletal muscle develops various degrees of atrophy and metabolic dysfunction following nerve injury. Neurotrophic factors are essential for muscle regeneration. Human amniotic fluid derived stem cells (AFS) have the potential to secrete various neurotrophic factors necessary for nerve regeneration. In the present study, we assess the outcome of neurological function by intramuscular injection of AFS in a muscle denervation and nerve anastomosis model. MATERIALS AND METHODS: Seventy two Sprague-Dawley rats weighing 200-250 gm were enrolled in this study. Muscle denervation model was conducted by transverse resection of a sciatic nerve with the proximal end sutured into the gluteal muscle. The nerve anastomosis model was performed by transverse resection of the sciatic nerve followed by four stitches reconnection. These animals were allocated to three groups: control, electrical muscle stimulation, and AFS groups. RESULTS: NT-3 (Neurotrophin 3), BDNF (Brain derived neurotrophic factor), CNTF (Ciliary neurotrophic factor), and GDNF (Glia cell line derived neurotrophic factor) were highly expressed in AFS cells and supernatant of culture medium. Intra-muscular injection of AFS exerted significant expression of several neurotrophic factors over the distal end of nerve and denervated muscle. AFS caused high expression of Bcl-2 in denervated muscle with a reciprocal decrease of Bad and Bax. AFS preserved the muscle morphology with high expression of desmin and acetylcholine receptors. Up to two months, AFS produced significant improvement in electrophysiological study and neurological functions such as SFI (sciatic nerve function index) and Catwalk gait analysis. There was also significant preservation of the number of anterior horn cells and increased nerve myelination as well as muscle morphology. CONCLUSION: Intramuscular injection of AFS can protect muscle apoptosis and likely does so through the secretion of various neurotrophic factors. This protection furthermore improves the nerve regeneration in a long term nerve anastomosis model.


Assuntos
Líquido Amniótico/citologia , Fatores de Crescimento Neural/metabolismo , Regeneração Nervosa/fisiologia , Neuropatia Ciática/terapia , Transplante de Células-Tronco , Anastomose Cirúrgica , Animais , Células do Corno Anterior/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Fator Neurotrófico Ciliar/metabolismo , Desmina/biossíntese , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Injeções Intramusculares , Denervação Muscular , Músculo Esquelético/inervação , Atrofia Muscular/terapia , Neurotrofina 3 , Ratos , Ratos Sprague-Dawley , Receptores Colinérgicos/biossíntese , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Neuropatia Ciática/fisiopatologia , Células-Tronco/metabolismo , Transplante Heterólogo , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo
19.
Stem Cells Dev ; 24(15): 1740-50, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25923707

RESUMO

Human neural stem cells (NSCs) are particularly valuable for the study of neurogenesis process and have a therapeutic potential in treating neurodegenerative disorders. However, current progress in the use of human NSCs is limited due to the available NSC sources and the complicated isolation and culture techniques. In this study, we describe an efficient method to isolate and propagate human NSCs from the amniotic fluid with diagnosed neural tube defects (NTDs), specifically, anencephaly. These amniotic fluid-derived NSCs (AF-NSCs) formed neurospheres and underwent long-term expansion in vitro. In addition, these cells showed normal karyotypes and telomerase activity and expressed NSC-specific markers, including Nestin, Sox2, Musashi-1, and the ATP-binding cassette G2 (ABCG2). AF-NSCs displayed typical morphological patterns and expressed specific markers that were consistent with neurons, astrocytes, oligodendrocytes, and dopaminergic neurons after proper induction conditions. Furthermore, grafted AF-NSCs improved the physiological functions in a rat stroke model. The ability to isolate and bank human NSCs from this novel source provides a unique opportunity for translational studies of neurological disorders.


Assuntos
Líquido Amniótico/metabolismo , Células-Tronco Neurais/metabolismo , Defeitos do Tubo Neural/metabolismo , Adulto , Animais , Antígenos de Diferenciação/metabolismo , Feminino , Xenoenxertos , Humanos , Células-Tronco Neurais/patologia , Células-Tronco Neurais/transplante , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/patologia , Gravidez , Ratos , Ratos Sprague-Dawley , Transplante de Células-Tronco , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/terapia
20.
Eur Arch Otorhinolaryngol ; 272(10): 3051-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25726166

RESUMO

We aimed to investigate expression of magnesium transporter genes in patients with head and neck cancer who underwent cisplatin-based neoadjuvant chemotherapy and their association with serum magnesium level. Head and neck cancer patients scheduled to undergo neoadjuvant cisplatin-based chemotherapy were eligible for enrollment. Blood samples were obtained at three time points: prior to, during, and after completion of chemotherapy. Expression levels of magnesium transporter genes were determined by quantitative real-time PCR. A total of 23 patients were included in the final analysis. The average serum magnesium levels dropped 6.98 and 5.20% during and after completion of chemotherapy. There were neither significant associations between serum magnesium level and demographic variables nor tumor-related variables. SLC41A1 expression level was positively correlated with serum magnesium whereas TRPM6 expression level was negatively correlated with serum magnesium. Serum magnesium level decreased during cisplatin-based chemotherapy in head and neck cancer patients. Further studies are warranted to investigate optimal magnesium measurement and substitution protocol.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Proteínas de Transporte de Cátions/metabolismo , Cisplatino , Neoplasias de Cabeça e Pescoço , Canais de Cátion TRPM/metabolismo , Desequilíbrio Hidroeletrolítico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Monitoramento de Medicamentos/métodos , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Desequilíbrio Hidroeletrolítico/sangue , Desequilíbrio Hidroeletrolítico/induzido quimicamente , Desequilíbrio Hidroeletrolítico/fisiopatologia
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