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1.
Science ; 370(6512): 50-56, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004510

RESUMO

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.


Assuntos
Doença de Alzheimer/etiologia , Sistema Glinfático/fisiopatologia , Transtornos do Sono-Vigília/complicações , Sono , Envelhecimento , Doença de Alzheimer/fisiopatologia , Animais , Aquaporina 4/genética , Doenças Cardiovasculares/etiologia , Humanos , Sistema Linfático/fisiopatologia , Camundongos , Polimorfismo Genético , Proteínas Priônicas/metabolismo , Agregados Proteicos , Transtornos do Sono-Vigília/fisiopatologia
2.
PLoS One ; 15(5): e0233517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437405

RESUMO

Vitreo-retinal (VR) surgeries induce conjunctival changes. However, there are no study reports regarding prevalence and severity of dry eye after these surgeries. This study evaluated dry eye outcome after VR surgery. Patients undergoing VR surgery classified as scleral buckle and microincision vitrectomy surgery (n = 44, mean age: 56.09±10.2 years) were recruited. Dry eye evaluation was done before and 8 weeks after surgery (2 weeks after omitting topical eye drops). Conjunctival imprint cytology for goblet cell count and tear Mucin 5AC (MUC5AC) protein estimation was done. Gene expressions of MUC5AC, MUC4, MUC16, Aquaporin 4 (AQP4) and AQP5 were analyzed in the conjunctival imprint cells by qPCR. None of the patients exhibited clinical signs of dry eye after VR surgery. But the conjunctival goblet cell density (GCD) was significantly lowered post-VR surgery (63% cases, **p = 0.012) with no alterations in the tear MUC5AC protein. Post-VR surgery, the conjunctival cell gene expression of MUC4, MUC16 and AQP4 were significantly increased (*p = 0.025, *p = 0.05 and *p = 0.02 respectively) and AQP5 was significantly lowered (*p = 0.037), with no change in MUC5AC expression. Tear cytokines were significantly increased post-VR surgery (anti-inflammatory: IL1RA, IL4, IL5, IL9, FGF; PDGFbb and pro-inflammatory: IL2, IL6, IL15, GMCSF and IFNg). Though clinical signs of dry eye were not observed after VR surgery, ocular surface changes in the form of reduced GCD, altered MUC5AC, MUC4, MUC16, AQP4, AQP5 and cytokines are suggestive of dry eye outcome at the molecular level especially inpatients aged above 51 years, especially female gender and those who are diabetic.


Assuntos
Aquaporinas/genética , Síndromes do Olho Seco/cirurgia , Mucinas/genética , Aquaporina 4/análise , Aquaporina 4/genética , Aquaporina 5/análise , Aquaporina 5/genética , Aquaporinas/análise , Antígeno Ca-125/análise , Antígeno Ca-125/genética , Túnica Conjuntiva/química , Túnica Conjuntiva/metabolismo , Túnica Conjuntiva/patologia , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/patologia , Feminino , Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/análise , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mucina-5AC/análise , Mucina-5AC/genética , Mucina-4/análise , Mucina-4/genética , Mucinas/análise , Lágrimas/química , Lágrimas/metabolismo
3.
PLoS Biol ; 18(5): e3000623, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32369477

RESUMO

Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid eye movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis, and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep, and cognitive consequences of prolonged wakefulness.


Assuntos
Aquaporina 4/genética , Sono de Ondas Lentas/genética , Aquaporina 4/metabolismo , Eletroencefalografia , Haplótipos , Voluntários Saudáveis , Homeostase , Humanos , Vigília
4.
J Biomed Sci ; 27(1): 40, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32138732

RESUMO

BACKGROUND: The present study aimed to verify whether long noncoding RNA (lncRNA) MALAT1 is involved in brain tissue damage induced by ischemia-reperfusion injury, and to explore the mechanism by which MALAT1 regulates aquaporin 4 (AQP4). METHODS: In this study, we established glucose deprivation (OGD)/reoxygenation (RX) astrocyte cell model and middle cerebral artery occlusion (MCAO)/reperfusion mouse model in vitro and in vivo. Then cell counting kit-8 assay, flow cytometry analysis, Triphenyltetrazolium chloride (TTC) staining, and western blotting were used to determine cell viability, cell apoptosis, cerebral infarction volume, and the abundance of AQP4, respectively. RESULTS: We found that the level of MALAT1 was significantly upregulated in both the MCAO/reperfusion model and OGD/RX model. Knockdown of MALAT1 increased cell viability and reduced cell apoptosis in MA-C cells, while an AQP4 siRNA combined with a siRNA targeting MALAT1 could not enhance this effect. Further experiments showed that MALAT1 positively regulated AQP4 expression via miR-145. The MALAT1 siRNA did not alleviate the exacerbation of damage after miR-145 inhibitor action. However, an miR-145 inhibitor reversed the protection effects of MALAT1, indicating that MALAT1 silencing protects against cerebral ischemia-reperfusion injury through miR-145. TTC staining showed that the infracted area of whole brain was significantly attenuated in treated with sh-MALAT1 group in vivo. CONCLUSION: Taken together, our study confirmed that MALAT1 promotes cerebral ischemia-reperfusion injury by affecting AQP4 expression through competitively binding miR-145, indicating that MALAT1 might be a new therapeutic target for treatment cerebral ischemic stroke.


Assuntos
Aquaporina 4/genética , Regulação da Expressão Gênica , Inativação Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Traumatismo por Reperfusão/genética , Animais , Aquaporina 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para Cima
5.
PLoS One ; 15(3): e0229274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160197

RESUMO

Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognostic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblastomas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age<65, Karnofsky Performance Status> = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an independent prognostic effect in IDH-wildtype glioblastoma.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Glioblastoma/genética , Glioblastoma/mortalidade , Isocitrato Desidrogenase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4/genética , Aquaporina 4/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico , Nestina/genética , Nestina/metabolismo , Proteínas Nogo/genética , Proteínas Nogo/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Adulto Jovem
6.
Lancet Neurol ; 19(4): 298-306, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32199095

RESUMO

BACKGROUND: Pharmacological prevention against relapses in patients with neuromyelitis optica spectrum disorder (NMOSD) is developing rapidly. We aimed to investigate the safety and efficacy of rituximab, an anti-CD20 monoclonal antibody, against relapses in patients with NMOSD. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled clinical trial at eight hospitals in Japan. Patients aged 16-80 years with NMOSD who were seropositive for aquaporin 4 (AQP4) antibody, were taking 5-30 mg/day oral steroids, and had an Expanded Disability Status Scale (EDSS) score of 7·0 or less were eligible for the study. Individuals taking any other immunosuppressants were excluded. Participants were randomly allocated (1:1) either rituximab or placebo by a computer-aided dynamic random allocation system. The doses of concomitant steroid (converted to equivalent doses of prednisolone) and relapses in previous 2 years were set as stratification factors. Participants and those assessing outcomes were unaware of group assignments. Rituximab (375 mg/m2) was administered intravenously every week for 4 weeks, then 6-month interval dosing was done (1000 mg every 2 weeks, at 24 weeks and 48 weeks after randomisation). A matching placebo was administered intravenously. Concomitant oral prednisolone was gradually reduced to 2-5 mg/day, according to the protocol. The primary outcome was time to first relapse within 72 weeks. Relapses were defined as patient-reported symptoms or any new signs consistent with CNS lesions and attributable objective changes in MRI or visual evoked potential. The primary analysis was done in the full analysis set (all randomly assigned patients) and safety analyses were done in the safety analysis set (all patients who received at least one infusion of assigned treatment). The primary analysis was by intention-to-treat principles. This trial is registered with the UMIN clinical trial registry, UMIN000013453. FINDINGS: Between May 10, 2014, and Aug 15, 2017, 38 participants were recruited and randomly allocated either rituximab (n=19) or placebo (n=19). Three (16%) patients assigned rituximab discontinued the study and were analysed as censored cases. Seven (37%) relapses occurred in patients allocated placebo and none were recorded in patients assigned rituximab (group difference 36·8%, 95% CI 12·3-65·5; log-rank p=0·0058). Eight serious adverse events were recorded, four events in three (16%) patients assigned rituximab (lumbar compression fracture and infection around nail of right foot [n=1], diplopia [n=1], and uterine cancer [n=1]) and four events in two (11%) people allocated to placebo (exacerbation of glaucoma and bleeding in the right eye chamber after surgery [n=1], and visual impairment and asymptomatic white matter brain lesion on MRI [n=1]); all patients recovered. No deaths were reported. INTERPRETATION: Rituximab prevented relapses for 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This study is limited by its small sample size and inclusion of participants with mild disease activity. However, our results suggest that rituximab could be useful maintenance therapy for individuals with NMOSD who are AQP4 antibody-positive. FUNDING: Japanese Ministry of Health, Labour and Welfare, Japan Agency for Medical Research and Development, and Zenyaku Kogyo.


Assuntos
Aquaporina 4/genética , Fatores Imunológicos/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Método Duplo-Cego , Quimioterapia Combinada , Potenciais Evocados Visuais , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Infusões Intravenosas , Japão , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/genética , Prednisolona/uso terapêutico , Recidiva , Rituximab/efeitos adversos , Esteroides/uso terapêutico , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Adulto Jovem
7.
Int J Mol Sci ; 21(4)2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32102323

RESUMO

Translational readthrough (TRT) of aquaporin-4 (AQP4) has remarkably expanded the importance of this new post-transcriptional mechanism, as well as the regulation potential of AQP4. The TRT isoform of AQP4, named AQP4ex, is central for both AQP4 polarization and water channel activity in the central nervous system (CNS). Here we evaluate the relevance of the TRT mechanism by analyzing whether AQP4ex is also expressed in peripheral tissues and whether the expression of AQP4ex is necessary for its polarized expression as it occurs in perivascular astrocyte processes. To this purpose, AQP4ex null mice were used, and analysis was performed by immunolocalization and immunoblot. The results demonstrate that AQP4ex is expressed in kidney, stomach, trachea and skeletal muscle with the same localization pattern as the canonical AQP4 isoforms. AQP4ex protein levels vary from 6% to about 13% of the total AQP4 protein levels in peripheral tissues. Immunogold electron microscopy experiments demonstrated the localization of AQP4ex at the astrocytic endfeet, and experiments conducted on AQP4ex null mice CNS confirmed that the expression of AQP4ex is necessary for anchoring of the perivascular AQP4. Without the readthrough isoform, AQP4 assemblies are mis-localized, being uniformly distributed on the astrocyte processes facing the neuropile. No alteration of AQP4 polarization was found in AQP4ex null kidney, stomach, trachea or skeletal muscle, suggesting that AQP4ex does not have a role for proper membrane localization of AQP4 in peripheral tissues. We conclude that a dual role for AQP4ex is limited to the CNS.


Assuntos
Aquaporina 4/genética , Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Regulação da Expressão Gênica , Animais , Aquaporina 4/metabolismo , Astrócitos/ultraestrutura , Sistema Nervoso Central/ultraestrutura , Immunoblotting , Rim/metabolismo , Camundongos , Camundongos Knockout , Microscopia Imunoeletrônica , Músculo Esquelético/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estômago/química , Traqueia/metabolismo
8.
PLoS One ; 15(1): e0227355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990937

RESUMO

Incomplete hippocampal inversion (IHI), also called hippocampal malrotation, is an atypical presentation of the hippocampus present in about 20% of healthy individuals. Here we conducted the first genome-wide association study (GWAS) in IHI to elucidate the genetic underpinnings that may contribute to the incomplete inversion during brain development. A total of 1381 subjects contributed to the discovery cohort obtained from the IMAGEN database. The incidence rate of IHI was 26.1%. Loci with P<1e-5 were followed up in a validation cohort comprising 161 subjects from the PING study. Summary statistics from the discovery cohort were used to compute IHI heritability as well as genetic correlations with other traits. A locus on 18q11.2 (rs9952569; OR = 1.999; Z = 5.502; P = 3.755e-8) showed a significant association with the presence of IHI. A functional annotation of the locus implicated genes AQP4 and KCTD1. However, neither this locus nor the other 16 suggestive loci reached a significant p-value in the validation cohort. The h2 estimate was 0.54 (sd: 0.30) and was significant (Z = 1.8; P = 0.036). The top three genetic correlations of IHI were with traits representing either intelligence or education attainment and reached nominal P< = 0.013.


Assuntos
Encefalopatias/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipocampo/fisiopatologia , Adolescente , Aquaporina 4/genética , Encefalopatias/diagnóstico por imagem , Encefalopatias/fisiopatologia , Proteínas Correpressoras/genética , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Lobo Temporal/fisiopatologia
9.
Toxicol Lett ; 319: 160-167, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734271

RESUMO

Overexposure to 1,2-dichloroethane (1,2-DCE) can induce brain edema, but the underlying mechanisms remain largely unknown. Aquaporin 4 (AQP4) is the most prevalent water channel in the brain, and the pool of AQP4 facilitates brain edema by controlling the inflow and clearance of brain water. MicroRNAs play an important role in the regulation of brain edema via RNA silencing and post-transcriptional regulation of gene expression. To explore the regulation role of AQP4 and microRNA in 1,2-DCE-induced brain edema, Sprague-Dawley (SD) rats and AQP4 knockout CD-1 mice were exposed to 1,2-DCE by inhalation for 7 days (0, 600, 1,800 mg/m3) and 28 days (0, 100, 350, 700 mg/m3), respectively. The results showed that 1,2-DCE induces brain edema, in both rats and mice, characterized by an increase in brain water content and vacuolations in the brain parenchyma and around the vessels of the cerebral cortex. Notably, 1,2-DCE exposure can down-regulate AQP4 expression, in both rats and mice. Also, deleting AQP4 intensifies 1,2-DCE-induced brain edema in mice. Meanwhile, microRNA-29b-3p (miR-29b) expression increases with 1,2-DCE exposure, in both rats and mice. A negative correlation was found between the expression of miR-29b and AQP4 in vivo. Moreover, the negative regulation of miR-29b by direct targeting to AQP4 was confirmed by dual luciferase reporter assay in vitro. Taken together, our findings indicate that AQP4 plays an important role in balancing water content in 1,2-DCE-induced brain edema. The dysregulation of miR-29b after 1,2-DCE exposure can aggravate brain edema by directly suppressing the expression of AQP4.


Assuntos
Aquaporina 4/efeitos dos fármacos , Edema Encefálico/induzido quimicamente , Dicloretos de Etileno/toxicidade , MicroRNAs/genética , Administração por Inalação , Animais , Aquaporina 4/genética , Água Corporal/metabolismo , Química Encefálica/efeitos dos fármacos , Edema Encefálico/patologia , Feminino , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/biossíntese , Ratos , Ratos Sprague-Dawley
10.
Cell Prolif ; 53(1): e12732, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746080

RESUMO

OBJECTIVES: Temozolomide (TMZ) is one of the most commonly used clinical drugs for glioblastoma (GBM) treatment, but its drug sensitivity needs to be improved. Gamabufotalin (CS-6), the primary component of the traditional Chinese medicine "ChanSu," was shown to have strong anti-cancer activity. However, more efforts should be directed towards reducing its toxicity or effective treatment doses. METHODS: Target fishing experiment, Western blotting, PCR, confocal immunofluorescence and molecular cloning techniques were performed to search for possible downstream signalling pathways. In addition, GBM xenografts were used to further determine the potential molecular mechanisms of the synergistic effects of CS-6 and TMZ in vivo. RESULTS: Mechanistic research revealed a negative feedback loop between ATP1A3 and AQP4 through which CS-6 inhibited GBM growth and mediated the synergistic treatment effect of CS-6 and TMZ. In addition, by mutating potential amino acid residues of ATP1A3, which were predicted by modelling and docking to interact with CS-6, we demonstrated that abrogating hydrogen bonding of the amino acid Thr794 interferes with the activation of ATP1A3 by CS-6 and that the Thr794Ala mutation directly affects the synergistic treatment efficacy of CS-6 and TMZ. CONCLUSIONS: As the main potential target of CS-6, ATP1A3 activation critically depends on the hydrogen bonding of Thr794 with CS-6. The combination of CS-6 and TMZ could significantly reduce the therapeutic doses and promote the anti-cancer efficacy of CS-6/TMZ monotherapy.


Assuntos
Aquaporina 4/metabolismo , Bufanolídeos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteínas de Neoplasias/biossíntese , ATPase Trocadora de Sódio-Potássio/biossíntese , Temozolomida/farmacologia , Animais , Aquaporina 4/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Proteínas de Neoplasias/genética , ATPase Trocadora de Sódio-Potássio/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Neuroimmunol ; 339: 577121, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31786498

RESUMO

This study aimed to investigate the underlying pathological muscle damage in neuromyelitis optica spectrum disorder (NMOSD) patients without muscular symptoms. We prospectively enrolled 15 patients with aquaporin 4 (AQP4) antibody seropositive NMOSD and 16 patients with non-NMOSD diseases as a control group. Biceps biopsy samples from 18 patients were examined. Six NMOSD patients exhibited inflammatory lesions/edema in lower muscles on muscle MRI. On histopathological examination, NMOSD samples showed significantly decreased IgG-targeting AQP4 expression on sarcolemma compared with non-NMOSD samples in terms of the area of positive staining and integrated optical density. Muscle biopsy can support the differential diagnosis of NMOSD.


Assuntos
Aquaporina 4/sangue , Neuromielite Óptica/sangue , Neuromielite Óptica/diagnóstico por imagem , Sarcolema/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4/biossíntese , Aquaporina 4/genética , Diagnóstico Diferencial , Feminino , Expressão Gênica , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Neuromielite Óptica/genética , Estudos Prospectivos , Sarcolema/genética
12.
Intern Med ; 59(1): 55-60, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484905

RESUMO

Objective Oryeongsan (Goreisan), a formula composed of five herbal medicines, has long been used to treat impairments of the regulation of body fluid homeostasis. Goreisan has been revealed to have anti-inflammatory actions and inhibit a water channel, the aquaporin (AQP). We herein report the therapeutic effect of Goreisan on experimental autoimmune encephalomyelitis (EAE in, an animal model of inflammatory demyelinating diseases. Materials and Methods EAE mice immunized with MOG35-55 peptide were divided into Goreisan- and sham-treated groups. The clinical EAE score and histopathological finding of the central nervous system (CNS) were analyzed. For the proliferation assay, prepared spleen cells from immunized mice were cultured and analyzed for the [3H]-thymidine uptake and cytokine concentrations of the culture supernatant. The relative quantification of AQP4 mRNA in the CNS of EAE mice was analyzed quantitatively. Results The EAE score of the Goreisan-treated mice was significantly lower than that of the sham-treated mice. The CD4-positive cell number in the CNS of Goreisan-treated mice was lower than that of sham-treated mice. In the recall response to MOG35-55 peptide, the cell proliferation did not differ markedly between the spleen cells from Goreisan- and sham-treated mice. Furthermore, Goreisan decreased the mRNA level of AQP4 in the spinal cord during EAE. Conclusion Goreisan prevented the disease activity of EAE by inhibiting the migration of pathogenic cells into the CNS by suppressing the AQP4 expression in the CNS. Goreisan may have a therapeutic effect on inflammatory demyelinating diseases.


Assuntos
Aquaporina 4/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Medula Espinal/efeitos dos fármacos , Animais , Aquaporina 4/genética , Aquaporina 4/metabolismo , Proliferação de Células , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia
13.
J Neuroimmunol ; 339: 577112, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31765953

RESUMO

We analyzed the association of polymorphisms from the 3' untranslated region of the HLA-G gene in 70 neuromyelitis optica spectrum disorder (NMOSD) patients and 162 healthy controls. No associations were found between the polymorphisms in NMOSD when compared to healthy controls, serology of the anti-AQP4 NMOSD biomarker and Expanded Disability Status Scale (EDSS). In conclusion, the 3' untranslated region 14 bp Ins/Del and +3142C/G polymorphisms seem not to be associated with NMOSD susceptibility, autoantibody production, nor a neurological deficit in patients.


Assuntos
Aquaporina 4/genética , Autoanticorpos/genética , Pessoas com Deficiência , Antígenos HLA-G/genética , Neuromielite Óptica/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4/sangue , Autoanticorpos/sangue , Brasil/epidemiologia , Feminino , Antígenos HLA-G/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Neuromielite Óptica/epidemiologia , Regiões não Traduzidas/genética , Adulto Jovem
14.
Int J Mol Sci ; 20(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752329

RESUMO

The detection of IgG aquaporin-4 antibodies in the serum of patients with Neuromyelitis optica (NMO) has dramatically improved the diagnosis of this disease and its distinction from multiple sclerosis. Recently, a group of patients have been described who have an NMO spectrum disorder (NMOsd) and who are seronegative for AQP4 antibodies but positive for IgG aquaporin-1 (AQP1) or myelin oligodendrocyte glycoprotein (MOG) antibodies. The purpose of this study was to determine whether AQP1 and MOG could be considered new biomarkers of this disease; and if point mutations in the gDNA of AQP4, AQP1 and MOG genes could be associated with the etiology of NMOsd. We evaluated the diagnostic capability of ELISA and cell-based assays (CBA), and analyzed their reliability, specificity, and sensitivity in detecting antibodies against these three proteins. The results showed that both assays can recognize these antigen proteins under appropriate conditions, but only anti-AQP4 antibodies, and not AQP1 or MOG, appears to be a clear biomarker for NMOsd. CBA is the best method for detecting these antibodies; and serum levels of AQP4 antibodies do not correlate with the progression of this disease. So far, the sequencing analysis has not revealed a genetic basis for the etiology of NMOsd, but a more extensive analysis is required before definitive conclusions can be drawn.


Assuntos
Anticorpos/sangue , Aquaporina 1/genética , Aquaporina 4/genética , Glicoproteína Mielina-Oligodendrócito/genética , Neuromielite Óptica/sangue , Neuromielite Óptica/genética , Mutação Puntual/genética , Adulto , Biomarcadores/sangue , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Medicine (Baltimore) ; 98(42): e17591, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626131

RESUMO

BACKGROUND: Spinal cord ischemia-reperfusion injury (SCII) is a common complication of spinal surgery as well as thoracic and abdominal surgery. Acute cytotoxic edema is the key pathogenic alteration. Therefore, avoiding or decreasing cellular edema has become the major target for SCII treatment. METHODS: The antiedema activity of ginsenoside Rb1 on aquaporin (AQP) 4, nerve growth factor (NGF), and brain-derived neurotrophic factor expression was detected by western blot and real-time polymerase chain reaction under conditions of oxygen-glucose deprivation/reoxygenation (OGD/R) in a rat astrocyte model in vitro. In addition, the cellular membrane permeability of AQP4 overexpressing cells or AQP4 small interfering RNA-transfected cells was detected. RESULTS: Ginsenoside Rb1 significantly prevented OGD/R-induced AQP4 downregulation in rat astrocytes. In addition, ginsenoside Rb1 treatment or AQP4 overexpression in rat astrocytes significantly attenuated the OGD/R-induced increase of cellular membrane permeability. Moreover, ginsenoside Rb1 obviously prevented the OGD/R-induced decrease of NGF and BDNT expression in rat astrocytes. CONCLUSION: These findings demonstrate that ginsenoside Rb1 can relieve spinal cord edema and improve neurological function by increasing AQP4 expression.


Assuntos
Aquaporina 4/genética , Astrócitos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Ginsenosídeos/farmacologia , Glucose/metabolismo , Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Animais , Animais Recém-Nascidos , Aquaporina 4/biossíntese , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , RNA/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/metabolismo , Medula Espinal/patologia
16.
Pak J Pharm Sci ; 32(3 Special): 1333-1342, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551212

RESUMO

The MIC and MBC values of Shikuqin (SKQ) against 5 bacteria that readily cause diarrhea were measured by the broth micro dilution method. The castor oil-induced diarrhea method was used to evaluate the antidiarrheal activity. Intestinal transit and gastric emptying were also evaluated with normal and neostigmine-induced intestinal transit in rodents. In addition, the antidiarrheal activity of SKQ was assessed in vivo with isolated rabbit ileum. Xylene-induced ear edema was used to evaluate the anti-inflammatory activities in mice, while hot plate and writhing tests were performed to assess the analgesic effects. Senna decoction (0.3g/mL) was administered intragastrically to induce a rat model of diarrhea. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect AQP4 mRNA, and Western blot was performed to quantify the protein level of AQP4 in the colon. SKQ exhibits remarkable antidiarrheal, anti-inflammatory and analgesic effects in the gastrointestinal tract disorders, and can therefore be developed as a promising antidiarrheal agent.


Assuntos
Analgésicos/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antidiarreicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Animais , Aquaporina 4/genética , Aquaporina 4/metabolismo , Óleo de Rícino/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Edema/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Pós , Coelhos , Ratos Sprague-Dawley
17.
Sci Rep ; 9(1): 11689, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406213

RESUMO

Canine distemper virus (CDV) causes a fatal demyelinating leukoencephalitis in young dogs resembling human multiple sclerosis. Astrocytes are the main cellular target of CDV and undergo reactive changes already in pre-demyelinating brain lesions. Based on their broad range of beneficial and detrimental effects in the injured brain reactive astrogliosis is in need of intensive investigation. The aim of the study was to characterize astrocyte plasticity during the course of CDV-induced demyelinating leukoencephalitis by the aid of immunohistochemistry, immunofluorescence and gene expression analysis. Immunohistochemistry revealed the presence of reactive glial fibrillary acidic protein (GFAP)+ astrocytes with increased survivin and reduced aquaporin 4, and glutamine synthetase protein levels, indicating disturbed blood brain barrier function, glutamate homeostasis and astrocyte maladaptation, respectively. Gene expression analysis revealed 81 differentially expressed astrocyte-related genes with a dominance of genes associated with neurotoxic A1-polarized astrocytes. Accordingly, acyl-coA synthetase long-chain family member 5+/GFAP+, and serglycin+/GFAP+ cells, characteristic of A1-astrocytes, were found in demyelinating lesions by immunofluorescence. In addition, gene expression revealed a dysregulation of astrocytic function including disturbed glutamate homeostasis and altered immune function. Observed findings indicate an astrocyte polarization towards a neurotoxic phenotype likely contributing to lesion initiation and progression in canine distemper leukoencephalitis.


Assuntos
Astrócitos/virologia , Doenças Desmielinizantes/veterinária , Vírus da Cinomose Canina/patogenicidade , Cinomose/virologia , Encefalomielite Aguda Disseminada/veterinária , Proteína Glial Fibrilar Ácida/genética , Animais , Aquaporina 4/genética , Aquaporina 4/imunologia , Astrócitos/imunologia , Astrócitos/patologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/virologia , Coenzima A Ligases/genética , Coenzima A Ligases/imunologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Progressão da Doença , Cinomose/genética , Cinomose/imunologia , Cinomose/patologia , Vírus da Cinomose Canina/imunologia , Cães , Encefalomielite Aguda Disseminada/genética , Encefalomielite Aguda Disseminada/patologia , Encefalomielite Aguda Disseminada/virologia , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/imunologia , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/imunologia , Ácido Glutâmico/imunologia , Ácido Glutâmico/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Proteoglicanas/genética , Proteoglicanas/imunologia , Transdução de Sinais , Survivina/genética , Survivina/imunologia , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/imunologia
18.
PLoS One ; 14(6): e0218415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220136

RESUMO

Aquaporin-4 (AQP4) plays an important role in regulating water exchange across the blood-brain barrier (BBB) and brain-cerebrospinal fluid interface. Studies on AQP-4 knockout mice (AQP4-KO) have reported considerable protection from brain edema induced by acute water intoxication and ischemic stroke, identifying AQP4 as a potential target for therapeutic interventions. However, the long-term effects of chronic AQP4 suppression are yet to be elucidated. In the current study, we evaluated the physiological and structural changes in adult AQP4-KO mice using magnetic resonance imaging (MRI) and immunohistochemical analysis. Water exchange across BBB was assessed by tracking an intravenous bolus injection of oxygen-17 (17O) water (H217O) using 17O-MRI. Cerebral blood flow (CBF) was quantified using arterial spin-labeling (ASL) MRI. Capillary density was determined by immunohistochemical staining for glucose transporter-1 (GLUT1). Compared to wildtype control mice, AQP4-KO mice showed a significant reduction in peak and steady-state H217O uptake despite unaltered CBF. Interestingly, a 22% increase in cortical capillary density was observed in AQP4-KO mice. These results suggest that increased cerebral vascularization may be an adaptive response to chronic reduction in water exchange across BBB in AQP4-KO mice.


Assuntos
Aquaporina 4/genética , Edema Encefálico/genética , Encéfalo/irrigação sanguínea , Neovascularização Patológica/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Transporte Biológico/genética , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Neovascularização Patológica/patologia , Água/metabolismo
19.
J Cell Biochem ; 120(10): 17584-17592, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31218751

RESUMO

Brain edema is a major traumatic brain injury (TBI)-related neurological complication. In the initiation stage of TBI, brain edema is characterized by astrocyte swelling (cytotoxic edema). We studied the impact of a long noncoding RNA, Malat1, on the TBI-induced astrocyte swelling and brain edema. Our results showed that Malat1 was downregulated in both the TBI rat model and the astrocyte fluid percussion injury (FPI) model, which concurred with brain edema and astrocyte swelling. Overexpression of Malat1 significantly inhibited rat brain edema, meanwhile reducing interleukin-6 (IL-6), nuclear factor-κB (NF-κB), and aquaporin 4 (AQP4) expression after TBI. In addition, overexpression of Malat1 ameliorated FPI-induced astrocyte swelling and reduced IL-6 release. Quantitative real-time polymerase chain reaction and Western blot analysis also corroborated the inhibitory effects of Malat1 on NF-κB and AQP4 expression after FPI. Our results highlighted the protective effects of Malat1 on the TBI-induced brain edema, which were mediated through regulating IL-6, NF-κB, and AQP4 expression. Our study could provide a novel approach for TBI treatment.


Assuntos
Aquaporina 4/genética , Edema Encefálico/genética , Lesões Encefálicas Traumáticas/genética , RNA Longo não Codificante/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Edema Encefálico/fisiopatologia , Lesões Encefálicas Traumáticas/fisiopatologia , Técnicas de Cultura de Células , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Interleucina-6/genética , NF-kappa B/genética , Ratos , Transdução de Sinais/genética
20.
Acta Neuropathol Commun ; 7(1): 74, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068220

RESUMO

Redistribution of the water channel aquaporin-4 (AQP4) away from astrocyte endfeet and into parenchymal processes is a striking histological feature in mouse models of Alzheimer's disease (AD) and other neurological conditions with prominent astrogliosis. AQP4 redistribution has been proposed to impair bulk Aß clearance in AD, resulting in increased amyloid deposition in the brain; however, this finding is controversial. Here, we provide evidence in support of a different and novel role of AQP4 in AD. We found that Aqp4 deletion significantly increased amyloid deposition in cerebral cortex of 5xFAD mice, with an increase in the relative number of fibrillar vs. dense core plaques. AQP4 deficient 5xFAD mice also showed a significant reduction in the density of GFAP labeled peri-plaque astrocyte processes. Microglial plaque coverage was also significantly reduced, suggesting astrocyte involvement in organizing the peri-plaque glial response. The alterations in peri-plaque glial structure were accompanied by increased neuronal uptake of Aß and an increase in the number of dystrophic neurites surrounding plaques. On the basis of these findings, we propose that redistribution of AQP4 into the parenchymal processes facilitates astrocyte structural plasticity and the formation of a reactive glial net around plaques that protects neurons from the deleterious effects of Aß aggregates. AQP4 redistribution may thus facilitate plaque containment and reduce neuropathology in AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Animais , Aquaporina 4/genética , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Neurônios/metabolismo
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