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1.
Immun Ageing ; 20(1): 71, 2023 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-38042785

RESUMO

BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

2.
Bioelectromagnetics ; 43(4): 218-224, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35476263

RESUMO

Radiofrequency radiation (RFR) was classified as a "possible" human carcinogen in 2011, which caused great public concern. A carcinogenicity study by the National Toxicology Program (NTP) found Code Division Multiple Access-and Global System for Mobile Communications-modulated mobile phone RFR to be carcinogenic to the brain and heart of male rats. As part of an investigation of mobile phone carcinogenesis, and to verify the NTP study results, a 5-year collaborative animal project was started in Korea and Japan in 2019. An international animal study of this type has two prerequisites: use of the same study protocol and the same RF-exposure system. This article discusses our experience in the design of this global study on radiofrequency electromagnetic fields (RF-EMFs).© 2022 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.


Assuntos
Telefone Celular , Ondas de Rádio , Animais , Encéfalo , Carcinogênese , Campos Eletromagnéticos , Masculino , Ratos
3.
J Therm Biol ; 110: 103350, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36462859

RESUMO

Radiofrequency radiation (RFR) can generate heat in living organisms. In this study, we monitored the body temperature of healthy animals during RFR exposure in real time using an implantable iButton data logger. A reverberation chamber system for small animals was used for this radiofrequency (RF) exposure in vivo study. Healthy male Sprague-Dawley rats were divided into two groups: with versus without iButton implantation (n = 20 per group). Each group was further divided into a sham-exposed and RF-exposed group (n = 10 per subgroup). Rats were exposed to a 1,760-MHz long-term evolution (LTE) signal in the reverberation chamber system at a whole-body average specific absorption rate of 0 W/kg (sham-exposed) or 4 W/kg (RF-exposed) for 6 h. The body temperature of iButton-implanted rats was recorded using an intraperitoneally implanted iButton every minute over 6 h of RF exposure, whereas that of non-implanted rats was measured directly using a rectal thermometer immediately before and after the 6-h RF exposure period. The temperature values measured by the two types of thermometers were significantly positively correlated (r = 0.63, P < 0.01, linear regression), and changes in body temperatures recorded in iButton-implanted and non-implanted rats measured using two thermometers after 6 h of RF exposure were maintained within <1°C (P = 0.87, general linear model, followed by univariate model). Similar results were obtained for rectal thermometer measurements (P = 0.12, paired t-test). These results suggest that RF exposure at a whole-body average specific absorption rate of 4 W/kg does not induce significant changes in body temperature in healthy rats over a 6-h RF exposure period.


Assuntos
Temperatura Corporal , Ondas de Rádio , Masculino , Ratos , Animais , Ratos Sprague-Dawley , Temperatura Alta , Modelos Lineares
4.
Telemed J E Health ; 28(5): 666-674, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34757827

RESUMO

Background:Faced with the coronavirus disease 2019 (COVID-19) pandemic, Korea has allowed telemedicine use for a limited time. This study examined whether the surge in COVID-19 cases led to increased telemedicine use and the associated factors.Methods:Data from the electronic medical records of 929,753 outpatient episodes between March 4 and September 4, 2020, in a tertiary hospital in Korea were used. A comparison group was chosen by matching, adjusting for age and sex because only a small portion (1.0%) of the sample used telemedicine. The final sample comprised 57,972 episodes. Multivariable logistic regression analyses were performed to examine the association of independent variables with the dichotomous dependent variable (i.e., telemedicine visit/in-person visit).Results:The surge in confirmed COVID-19 cases led to significantly increased telemedicine use (101-300 new cases odds ratio [OR]: 3.00; 301-500 new cases OR: 5.82; and ≥501 new cases OR: 42.18; all p < 0.0001). Telemedicine use was also statistically associated with sex (female patients OR: 2.08), age ˃19 years, distance from the hospital (Incheon, Gyeonggi, region, OR: 1.30; and other regions, OR: 4.33), and the number of days from diagnosis (3-6 months OR: 1.21; 6-12 months OR: 1.56; 12-36 months OR: 1.98; and ≥36 months OR: 2.49). Medical Aid patients (OR: 0.83) were less likely to use telemedicine than those with National Health Insurance.Conclusions:Telemedicine can be effective in delivering health services during an outbreak. Policymakers and health care organizations are encouraged to use the results of this study to tailor telemedicine to meet the needs of patients.


Assuntos
COVID-19 , Telemedicina , Adulto , COVID-19/epidemiologia , Feminino , Humanos , Pacientes Ambulatoriais , Pandemias , Telemedicina/métodos , Centros de Atenção Terciária , Adulto Jovem
5.
J Cell Physiol ; 236(10): 7058-7070, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33754353

RESUMO

Diabetes mellitus (DM) characterized by hyperglycemia leads to a variety of complications, including cognitive impairment or memory loss. The hippocampus is a key brain area for learning and memory and is one of the regions that is most sensitive to diabetes. However, the pathogenesis of diabetic neuronal lesion is not yet completely understood. We focused on the association of microglia activation and brain lesions in diabetes. In this study, we investigated whether and how signal transducer and activator of transcription 3 (STAT3) activation in microglia affects neuronal lesions in diabetic brains. Using a streptozotocin-induced type 1 DM model, we showed enhanced hippocampal neuronal apoptosis that was associated with increased STAT3 activation. We found that hyperglycemia increased the expression of inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6, in the diabetic hippocampus. In particular, IFN-γ induced autocrine activation of microglia, and STAT3 activation is important for this process. We also demonstrated that STAT3 activation in microglia increased tumor necrosis factor-α (TNF-α) expression; subsequently, TNF-α increased neuronal apoptosis by increasing reactive oxygen species (ROS) levels in the neuronal cells. We also took advantage of mice lacking STAT3 in microglia and demonstrated that depletion of microglial STAT3 reduced neuronal apoptosis in the diabetic hippocampus. Taken together, these results suggest that STAT3 activation in microglia plays an important role in hyperglycemia-induced neuronal apoptosis in the diabetic hippocampus and provide a potential therapeutic benefit of STAT3 inhibition in microglia for preventing diabetic neuronal lesions.


Assuntos
Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hipocampo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Comunicação Autócrina , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Hipocampo/patologia , Humanos , Mediadores da Inflamação/metabolismo , Camundongos Knockout , Microglia/patologia , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
6.
J Pharmacol Sci ; 145(4): 308-312, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33712281

RESUMO

Astrocytes are the most abundant cell type in the central nervous system (CNS) and their major function is to maintain homeostasis of the CNS by exerting various functions. Simultaneously, reactive astrocytes are well known to be involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Reactive astrocytes, induced by amyloid beta peptide (Aß), the main component of the neuritic plaques found in AD, induce neuroinflammation, producing cytokines that lead to neuronal cell death in AD. Phloroglucinol,a polyphenol monomer and a component of phlorotannin, is found at sufficient levels in Ecklonia cava of the Laminariaceae family. Recently, several studies have reported that phloroglucinol has the ability to trap free radicals in lung fibroblasts or cancer cells. However, the effects of phloroglucinol in astrocytes have not yet been studied. Here, we found that phloroglucinol inhibits the generation of ROS induced by oligomeric Aß1-42 (oAß1-42) treatment in primary astrocytes. Futhermore, phloroglucinol was shown to ameliorate the protein expression of glial fibrillary acidic protein, a marker of reactive astrocytes, after treatment with oAß1-42. These results indicate that phloroglucinol exerts antioxidant effects in primary cultured astrocytes and attenuates the astrocytic activation induced by oAß1-42.


Assuntos
Peptídeos beta-Amiloides/efeitos adversos , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Sequestradores de Radicais Livres , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/metabolismo , Floroglucinol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Animais , Células Cultivadas , Sistema Nervoso Central/citologia , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Laminaria/química , Camundongos , Floroglucinol/isolamento & purificação
7.
Bioelectromagnetics ; 42(3): 191-199, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33527465

RESUMO

The placenta protects the fetus against excessive stress-associated maternal cortisol during pregnancy. We studied whether exposure to radiofrequency electromagnetic field (RF-EMF) radiation during pregnancy can cause changes in dams and their placentas. Pregnant Sprague-Dawley rats were divided into cage-control, sham-exposed, and RF-exposed groups. They were exposed to RF-EMF signals at a whole-body specific absorption rate of 4 W/kg for 8 h/day from gestational Day 1 to 19. Levels of cortisol in the blood, adrenal gland, and placenta were measured by enzyme-linked immunosorbent assay. Levels of adrenocorticotropic hormone and corticotropin-releasing hormone were monitored in maternal blood. Expression levels of placental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) messenger RNA (mRNA) were measured by reverse transcription polymerase chain reaction. Morphological changes in the placenta were analyzed using hematoxylin and eosin staining. Fetal parts of the placenta were measured using Zen 2.3 blue edition software. Maternal cortisol in circulating blood (RF: 230 ± 24.6 ng/ml and Sham: 156 ± 8.3 ng/ml) and the adrenal gland (RF: 58.3 ± 4.5 ng/ml and Sham: 30 ± 3.8 ng/ml) was significantly increased in the RF-exposed group (P < 0.05). Placental cortisol was stably maintained, and the level of placental 11ß-HSD2 mRNA expression was not changed in the RF-exposed group. RF-EMF exposure during pregnancy caused a significant elevation of cortisol levels in circulating blood; however, no changes in the placental barrier were observed in pregnant rats. Bioelectromagnetics. © 2021 Bioelectromagnetics Society.


Assuntos
Campos Eletromagnéticos , Placenta , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2 , Animais , Campos Eletromagnéticos/efeitos adversos , Feminino , Hidrocortisona , Gravidez , Ratos , Ratos Sprague-Dawley
8.
Cell Biol Int ; 44(9): 1831-1839, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32401383

RESUMO

Oxidative stress, an imbalance of redox homeostasis, contributes to the pathogenesis and progress of muscle atrophy. However, it is debated whether oxidative stress is a cause or consequence of muscle atrophy. In this study, we investigated the relationship between menadione-induced oxidative stress and serum starvation-induced muscle atrophy in C2C12 myotubes. We found that atrophic phenotypes including myotube diameter decrease, protein ubiquitination, and the expression of atrogenes were detected under oxidative stress as well as during serum starvation. Oxidative stress during serum starvation was assessed to confirm the correlation. Both intracellular reactive oxygen species (ROS) and protein oxidation were increased in atrophic myotubes. These results indicate that menadione-induced oxidative stress triggers muscle atrophy and vice versa. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular response to oxidative stress and it is considered to have a cytoprotective role in the mitigation of muscle atrophy. Transcription of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase-1, target genes of Nrf2, was decreased during serum starvation, which is related to decreased nuclear translocation of Nrf2. Pre-treatment of sulforaphane (SFN), a known Nrf2 inducer, before serum starvation showed a protective effect via Nrf2/HO-1 upregulation. SFN can liberate Nrf2 from Keap1, enabling the nuclear translocation of Nrf2. Consequently, the expression of HO-1 increased and intracellular ROS was significantly reduced by SFN pre-treatment. These results demonstrate that oxidative stress mediates the pathophysiology of muscle atrophy, which can be improved via upregulation of the Nrf2-mediated antioxidant response.


Assuntos
Isotiocianatos/farmacologia , Atrofia Muscular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sulfóxidos/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Isotiocianatos/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Atrofia Muscular/tratamento farmacológico , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos/metabolismo , Vitamina K 3/efeitos adversos , Vitamina K 3/farmacologia
9.
J Pharmacol Sci ; 143(4): 290-299, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32507685

RESUMO

The pathophysiological roles of astrocytes in the reactive state are thought to have important significance in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). However, the detailed mechanisms underlying the transition of astrocytes from the resting state to the reactive state during neurodegenerative disease largely remain to be defined. Here, we investigated the pathways involved in activating astrocytes from the resting state to the reactive state in primary cultured astrocytes treated with oligomeric Aß and in the hippocampus of 5XFAD mice. Treatment with oligomeric Aß induced an increase in reactive astrocytes, as assessed by the protein level of glial fibrillary acidic protein (GFAP) and this increase was caused by STAT3 phosphorylation in primary cultured astrocytes. The administration of Stattic, an inhibitor of STAT3, rescued the activation of astrocytes in primary cultured astrocytes and in the hippocampus of 6-month-old 5XFAD mice as well as impairments in learning and memory. Collectively, these results demonstrated that reactive astrocytes in the AD brain are induced via STAT3 and the impairments in learning and memory observed in 5XFAD mice are rescued by STAT3 inhibition, suggesting that the inhibition of STAT3 phosphorylation in astrocytes may be a novel therapeutic target for cognitive impairment in AD.


Assuntos
Doença de Alzheimer/genética , Inativação Gênica , Fator de Transcrição STAT3 , Doença de Alzheimer/terapia , Animais , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Camundongos Transgênicos , Terapia de Alvo Molecular , Fosforilação
10.
Bioelectromagnetics ; 41(2): 104-112, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31828817

RESUMO

Exposure to a radiofrequency (RF) signal at a specific absorption rate (SAR) of 4 W/kg can increase the body temperature by more than 1 °C. In this study, we investigated the effect of anesthesia on the body temperature of rats after exposure to an RF electromagnetic field at 4 W/kg SAR. We also evaluated the influence of body mass on rats' body temperature. Rats weighing 225 and 339 g were divided into sham- and RF-exposure groups. Each of the resulting four groups was subdivided into anesthetized and non-anesthetized groups. The free-moving rats in the four RF-exposure groups were subjected to a 915 MHz RF identification signal at 4 W/kg whole-body SAR for 8 h. The rectal temperature was measured at 1-h intervals during RF exposure using a small-animal temperature probe. The body temperatures of non-anesthetized, mobile 225 and 339 g rats were not significantly affected by exposure to an RF signal. However, the body temperatures of anesthetized 225 and 339 g rats increased by 1.9 °C and 3.3 °C from baseline at 5 and 6 h of RF exposure, respectively. Three of the five 339 g anesthetized and exposed rats died after 6 h of RF exposure. Thus, anesthesia and body mass influenced RF exposure-induced changes in the body temperature of rats. Bioelectromagnetics. 2020;41:104-112. © 2019 Bioelectromagnetics Society.


Assuntos
Anestesia , Temperatura Corporal/fisiologia , Campos Eletromagnéticos/efeitos adversos , Animais , Radiação Eletromagnética , Masculino , Ondas de Rádio/efeitos adversos , Ratos Sprague-Dawley
11.
J Clin Lab Anal ; 34(8): e23316, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32227396

RESUMO

BACKGROUND: Mild-to-moderate fibrosis is rarely diagnosed because the disease is asymptomatic in the early stage. The serum level of Mac-2 binding protein glycosylation isomer (M2BPGi) has been found to increase with the severity of liver fibrosis. The aim of this study was to determine the diagnostic performance of M2BPGi in screening liver fibrosis using magnetic resonance elastography (MRE) as a reference standard and to compare it with using the aspartate aminotransferase-to-platelet ratio (APRI) and the Fibrosis-4 index (FIB-4) in health checkups. METHODS: This cross-sectional study consecutively selected subjects at health examinations who underwent MRE and M2BPGi testing at eight health promotion centers in Korea between January and September 2019. The serum M2BPGi level was measured using the chemiluminescence enzyme immunoassay method. The measured levels were indexed using the cutoff index (COI). COI values of M2BPGi were compared with the MRE results. RESULTS: The median (interquartile) values of COI for fibrosis stages F0 (normal liver stiffness), F1 (mild fibrosis), F2 (significant fibrosis), and ≥F3 (advanced fibrosis) were 0.49 (0.34-0.61), 0.48 (0.38-0.68), 0.64 (0.43-1.03), and 1.01 (0.75-1.77), respectively (P < .0001). The AUCs of the COI for the screening of fibrosis stage ≥F1, ≥F2, and ≥F3 were 0.591, 0.698, and 0.853, respectively. Using a threshold of 0.75 for COI to exclude advanced fibrosis had a sensitivity, specificity, and negative predictive value of 80.0%, 77.9%, and 98.9%, respectively. The AUC for excluding advanced fibrosis was better for M2BPGi than for FIB-4 and APRI. CONCLUSION: Serum M2BPGi was useful for screening significant and advanced fibrosis in health checkups.


Assuntos
Antígenos de Neoplasias/sangue , Antígenos de Neoplasias/química , Cirrose Hepática/diagnóstico , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspartato Aminotransferases/sangue , Estudos Transversais , Testes Diagnósticos de Rotina , Técnicas de Imagem por Elasticidade , Feminino , Glicosilação , Humanos , Isomerismo , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Retrospectivos , Sensibilidade e Especificidade
12.
J Pharmacol Sci ; 139(3): 249-253, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30718079

RESUMO

The duplication of human chromosome 15q11-13 is known to be associated with an estimated 1.1% of autism cases. Here, we investigated whether differentiation into neurons and astrocytes is altered in fetal neural stem cells (FNSCs) isolated from the mouse model of 15q11-13 duplication syndrome (patDp/+ mice). In patDp/+ mice-derived FNSCs, multipotency was maintained for a longer period, the population of neurons was downregulated, and that of astrocytes was upregulated significantly after differentiation induction. These results suggest that the dysregulation of FNSCs differentiation could affect cortical development and behavioral deficits in the early postnatal stage shown in the patDp/+ mice.


Assuntos
Transtorno do Espectro Autista/genética , Diferenciação Celular/fisiologia , Deficiência Intelectual/fisiopatologia , Células-Tronco Neurais/citologia , Animais , Astrócitos/citologia , Transtorno do Espectro Autista/fisiopatologia , Aberrações Cromossômicas , Cromossomos Humanos Par 15 , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia
13.
Exp Cell Res ; 364(2): 224-233, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29458173

RESUMO

Duchenne muscular dystrophy (DMD) is an X chromosome-linked disorder caused by a mutation in the dystrophin gene. Many previous studies reported that the skeletal muscles of DMD patients were more susceptible to oxidative stress than those of healthy people. However, not much has been known about the responsible mechanism of the differential susceptibility. In this study, we established dystrophin knock-down (DysKD) cell lines by transfection of dystrophin shRNA lentiviral particles into C2 cells and found that DysKD myotubes are more vulnerable to menadione-induced oxidative stress than control myotubes. We focused on the nuclear erythroid 2-related factor 2 (Nrf2) which is a transcription factor that regulates the expression of phase II antioxidant enzymes by binding to the antioxidant response element (ARE). Under menadione-induced oxidative stress, the translocation of Nrf2 to the nucleus is significantly decreased in the DysKD myotubes. In addition, the binding of Nrf2 to ARE site of Bcl-2 gene as well as protein expression of Bcl-2 is decreased compared to the control cells. Interestingly, sulforaphane increased Akt activation and Nrf2 translocation to the nucleus in the DysKD myotubes. These results suggest that the Nrf2 pathway might be the responsible pathway to the oxidative stress-induced muscle damage in DMD.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Distrofina/antagonistas & inibidores , Fibras Musculares Esqueléticas/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Vitamina K 3/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Distrofina/metabolismo , Humanos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Regul Toxicol Pharmacol ; 106: 7-14, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009651

RESUMO

This study aimed to determine the safety and tolerability of the subretinal injection of hESC-derived RPE cells at higher doses than the established clinical dose (5 × 104 cells/150 µL) by using minipigs. The hESC-derived RPE cells (60 or 120 × 104 cells/150 µL) were injected in subretinal region, and minipigs were sacrificed at Weeks 4, 8, and 12 post-surgery. Time-course examination was performed by using fundus photography, optical coherence tomography (OCT), histopathology, and fluorescence in situ hybridization (FISH). After surgery, retinal bleb and pigmentation were seen and retinal bleb became smaller gradually. In histopathology, cell clusters consisting of a uniform population of the round to oval cells were seen at the subretinal injection site. In immunohistochemistry, most of the cells were positive for anti-CD3 and CD45 antibodies but negative for anti-human nuclei antibody; transplanted cells were not detectable by DNA probe in FISH assay. Cell clusters were thought to be a host immune response to trauma or transplanted cells. There were no other changes related to subretinal RPE cell injection. These results suggested that subretinal injection of hESC-derived RPE cells (60 and 120 × 104 cells/150 µL) in minipigs is well-tolerated and safe.


Assuntos
Células-Tronco Embrionárias Humanas/citologia , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/transplante , Segurança , Porco Miniatura , Animais , Humanos , Hibridização in Situ Fluorescente , Suínos , Tomografia de Coerência Óptica
15.
Chem Senses ; 43(4): 213-221, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29438489

RESUMO

Olfactory loss is known to affect both mood and quality of life. Transient anosmia was induced in mice to study the resulting changes in mood, behavior, and on a molecular level. Transient anosmia was induced by a single intranasal instillation of ZnSO4 in BALB/c mice. Hematoxylin and eosin (HE) staining, and potato chip finding test were performed to confirm olfactory loss. Tail suspension, forced swim, and splash tests were performed to evaluate depression-related behavior; while the open field, and elevated plus maze tests were used to evaluate anxiety-related behavior. The mRNA levels of amygdalar corticotropin-releasing hormone (CRH) and hypothalamic glucocorticoid receptor (GR) were quantified using real-time PCR to confirm relevant molecular change. Olfactory loss was confirmed 1-2.5 weeks after induction, and this loss was subsequently reversed over time. The results of the behavioral tests indicated increased depression-like and reduced anxiety-like behavior at week 1. Accordingly, PCR data identified decreased amygdalar CRH expression at week 1. These results suggest that transient anosmia induces both depressive and anxiolytic behavior as a result of decreased amygdalar CRH in a mouse model of anosmia.


Assuntos
Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Transtornos do Olfato/patologia , Sulfato de Zinco/toxicidade , Administração Intranasal , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/etiologia , Hormônio Liberador da Corticotropina/genética , Depressão/etiologia , Modelos Animais de Doenças , Hipotálamo/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Transtornos do Olfato/induzido quimicamente , Transtornos do Olfato/complicações , Mucosa Olfatória/patologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo
16.
Pharmacol Res ; 128: 110-121, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28823725

RESUMO

Mounting evidence suggests that the etiology of autism spectrum disorders (ASDs) is profoundly influenced by exposure to environmental factors, although the precise molecular and cellular links remain ill-defined. In this study, we examined how exposure to valproic acid (VPA) during pregnancy is associated with an increased incidence of ASD. A mouse model was established by injecting VPA at embryonic day 13, and its behavioral phenotypes including impaired social interaction, increased repetitive behaviors and decreased nociception were observed at postnatal days 21-42. VPA-treated mice showed dysregulation of synaptic structure in cortical neurons, including a reduced proportion of filopodium-type and stubby spines and increased proportions of thin and mushroom-type spines, along with a decreased spine head size. We also found that VPA-treatment led to decreased expression of phosphate and tensin homolog (PTEN) and increased levels of p-AKT protein in the hippocampus and cortex. Our data suggest that there is a correlation between VPA exposure and dysregulation of PTEN with ASD-like behavioral and neuroanatomical changes, and this may be a potential mechanism of VPA-induced ASD.


Assuntos
Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Espinhas Dendríticas/patologia , PTEN Fosfo-Hidrolase/metabolismo , Animais , Transtorno do Espectro Autista/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ácido Valproico
17.
J Pharmacol Sci ; 137(2): 146-153, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29914798

RESUMO

The amyloid precursor protein (APP) is a key molecule in Alzheimer's disease. The prevailing view is that APP is initially transported to the plasma membrane as a full-length protein. Its localization at the cell surface can trigger downstream signaling and APP cleavage. Our previous work has shown that Neuregulin 1 (NRG1) has neuroprotective effects in an Alzheimer's disease model. In the present study, we examine whether NRG1 signaling is involved in APP expression and non-amyloidogenic processing in neuronal cells. Here we show that NRG1 increased the cell surface expression of APP without changing the total amount of APP mRNA or protein expression in SH-SY5Y cells and in rat primary cortical neurons. In addition, NRG1 significantly increased the levels of the secreted form of APP, sAPPα, in the conditioned media but did not change the expression of ADAM10 on the cell surface or in the cell lysates. Furthermore, we found that the protein level of NRG1 was reduced in the hippocampus of Alzheimer's disease (AD) patients. Our results demonstrate that NRG1 increased APP expression on the cell surface and sAPPα secretion into the media of neuronal cell cultures. Taken together, these results suggest a role for NRG1 in non-amyloidogenic processing.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Neuregulina-1/fisiologia , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Membrana Celular/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Expressão Gênica/genética , Proteínas de Membrana/metabolismo , Neuregulina-1/metabolismo , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/metabolismo
18.
Bioelectromagnetics ; 39(1): 68-76, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29171038

RESUMO

We investigated whether exposure to the 915 MHz radiofrequency identification (RFID) signal affected circulating blood cells in rats. Sprague-Dawley rats were exposed to RFID at a whole-body specific absorption rate of 2 W/kg for 8 h per day, 5 days per week, for 2 weeks. Complete blood counts were performed after RFID exposure, and the CD4+ /CD8+ ratio was determined by flow cytometry. The number of red blood cells (RBCs) and the values of hemoglobin, hematocrit, and RBC indices were increased in the RFID-exposed group compared with those in the cage-control and sham-exposed groups (P < 0.05). However, the RBCs and platelet numbers were within normal physiologic response ranges. The number of white blood cells, including lymphocytes, was decreased in RFID-exposed rats. However, there was no statistically significant difference between the sham-exposed and RFID-exposed groups in terms of T-cell counts or CD4+ /CD8+ ratio (P > 0.05). Although the number of circulating blood cells was significantly altered by RFID exposure at a whole-body specific absorption rate of 2 W/kg for 2 weeks, these changes do not necessarily indicate that RFID exposure is harmful, as they were within the normal physiological response range. Bioelectromagnetics. 39:68-76, 2018. © 2017 Wiley Periodicals, Inc.


Assuntos
Células Sanguíneas/efeitos da radiação , Campos Eletromagnéticos/efeitos adversos , Dispositivo de Identificação por Radiofrequência , Animais , Células Sanguíneas/citologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos da radiação , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos da radiação , Contagem de Células , Eritrócitos/citologia , Eritrócitos/efeitos da radiação , Masculino , Ratos , Ratos Sprague-Dawley , Irradiação Corporal Total/efeitos adversos
19.
J Proteome Res ; 16(12): 4455-4467, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28960081

RESUMO

One of the major goals of the Chromosome-Centric Human Proteome Project (C-HPP) is to fill the knowledge gaps between human genomic information and the corresponding proteomic information. These gaps are due to "missing" proteins (MPs)-predicted proteins with insufficient evidence from mass spectrometry (MS), biochemical, structural, or antibody analyses-that currently account for 2579 of the 19587 predicted human proteins (neXtProt, 2017-01). We address some of the lessons learned from the inconsistent annotations of missing proteins in databases (DB) and demonstrate a systematic proteogenomic approach designed to explore a potential new function of a known protein. To illustrate a cautious and strategic approach for characterization of novel function in vitro and in vivo, we present the case of Na(+)/H(+) exchange regulatory cofactor 1 (NHERF1/SLC9A3R1, located at chromosome 17q25.1; hereafter NHERF1), which was mistakenly labeled as an MP in one DB (Global Proteome Machine Database; GPMDB, 2011-09 release) but was well known in another public DB and in the literature. As a first step, NHERF1 was determined by MS and immunoblotting for its molecular identity. We next investigated the potential new function of NHERF1 by carrying out the quantitative MS profiling of placental trophoblasts (PXD004723) and functional study of cytotrophoblast JEG-3 cells. We found that NHERF1 was associated with trophoblast differentiation and motility. To validate this newly found cellular function of NHERF1, we used the Caenorhabditis elegans mutant of nrfl-1 (a nematode ortholog of NHERF1), which exhibits a protruding vulva (Pvl) and egg-laying-defective phenotype, and performed genetic complementation work. The nrfl-1 mutant was almost fully rescued by the transfection of the recombinant transgenic construct that contained human NHERF1. These results suggest that NHERF1 could have a previously unknown function in pregnancy and in the development of human embryos. Our study outlines a stepwise experimental platform to explore new functions of ambiguously denoted candidate proteins and scrutinizes the mandated DB search for the selection of MPs to study in the future.


Assuntos
Fosfoproteínas/fisiologia , Proteogenômica/métodos , Trocadores de Sódio-Hidrogênio/fisiologia , Animais , Caenorhabditis elegans/genética , Diferenciação Celular , Movimento Celular , Bases de Dados de Proteínas , Feminino , Humanos , Immunoblotting , Espectrometria de Massas , Reprodução , Transgenes , Trofoblastos/citologia
20.
J Pharmacol Sci ; 133(4): 261-267, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28408165

RESUMO

Alzheimer's disease is the most common disease underlying dementia in humans. Two major neuropathological hallmarks of AD are neuritic plaques primarily composed of amyloid beta peptide and neurofibrillary tangles primarily composed of hyperphosphorylated tau. In addition to impaired memory function, AD patients often display neuropsychiatric symptoms and abnormal emotional states such as confusion, delusion, manic/depressive episodes and altered fear status. Brains from AD patients show atrophy of the amygdala which is involved in fear expression and emotional processing as well as hippocampal atrophy. However, which molecular changes are responsible for the altered emotional states observed in AD remains to be elucidated. Here, we observed that the fear response as assessed by evaluating fear memory via a cued fear conditioning test was impaired in 5XFamilial AD (5XFAD) mice, an animal model of AD. Compared to wild-type mice, 5XFAD mice showed changes in the phosphorylation of twelve proteins in the amygdala. Thus, our study provides twelve potential protein targets in the amygdala that may be responsible for the impairment in fear memory in AD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Tonsila do Cerebelo/metabolismo , Quinase 1 do Ponto de Checagem/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Lipoproteínas/metabolismo , Proteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Tonsila do Cerebelo/patologia , Animais , Atrofia , Quinase 1 do Ponto de Checagem/fisiologia , Quinase do Ponto de Checagem 2/fisiologia , Modelos Animais de Doenças , Emoções , Medo , Hipocampo/patologia , Lipoproteínas/fisiologia , Memória , Camundongos Transgênicos , Fosforilação/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
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