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1.
J Clin Neurol ; 20(2): 194-200, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38171500

RESUMO

BACKGROUND AND PURPOSE: Performing the differential diagnosis of Parkinson's disease (PD) and multiple-system atrophy of parkinsonian type (MSA-P) is challenging. The oculomotor performances of patients with PD and MSA-P were investigated to explore their potential role as a biomarker for this differentiation. METHODS: Reflexive saccades and smooth pursuit were examined in 56 patients with PD and 34 with MSA-P in the off-medication state. RESULTS: Patients with PD and MSA-P had similar oculomotor abnormalities of prolonged and hypometric reflexive saccades. The incidence rates of decreased reflexive saccadic velocity and saccadic smooth pursuit were significantly higher in MSA-P than in PD (p<0.05 for both). Multiple logistic regression analysis indicated that slowed reflexive saccades (odds ratio [OR]=8.14, 95% confidence interval [CI]=1.45-45.5) and saccadic smooth pursuit (OR=5.27, 95% CI=1.24-22.43) were significantly related to MSA-P. CONCLUSIONS: The distinctive oculomotor abnormalities of saccadic smooth pursuit and slowed reflexive saccades in MSA-P may serve as useful biomarkers for discriminating MSA-P from PD.

2.
PeerJ ; 11: e15920, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37663290

RESUMO

Objectives: Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification. We aimed to assess the utility of immunohistochemistry (IHC) staining for MMR protein expression and polymerase chain reaction (PCR)-based MSI assays in EC and the correlation between MMR/MSI status and various clinicopathological parameters. Methods: We reviewed the clinical and pathological information of 333 patients with EC. MMR protein expression was assessed as retained or lost to determine MMR status by IHC staining, and MSI status was identified by PCR capillary electrophoresis (PCR-CE) testing with a National Cancer Institute (NCI) panel. The correlation of MMR/MSI status with clinicopathological features was determined by statistical analysis. Discrepant results were further analyzed using an alternative PCR-CE MSI (Promega panel) method, MLH1 promoter methylation assays, and next-generation sequencing (NGS). Results: Among the EC patients, the overall percentage of dMMR was 25.2%, and the overall percentage of MSI-H was 24%. Among the dMMR patients, 50 (59.5%) showed loss of MLH1 and PMS2 expression, 19 (22.6%) loss of MSH2 and MSH6 expression, and seven (8.3%) and eight (9.5%) loss of PMS2 and MSH6 expression, respectively. The dMMR subgroup was significantly younger than the pMMR subgroup, especially for <60-years-old patients (p = 0.038). In addition, we identified a strong correlation between MMR/MSI status and high-grade endometrioid or nonendometrioid components (p = 0.004 or p = 0.003). IHC staining and PCR-CE assay results showed a high level of overall concordance (98.8%, Cohen's κ = 0.98). Four patients were found to have dMRR/MSS in both examinations. We reanalyzed them with additional methods. One case showed MLH1 promotor methylation, and the other three cases harbored MSH6 germline pathogenic variations. One of the cases with MSH6 deficiency was reanalyzed as MSI-H by alternative PCR-CE assay or NGS testing. Conclusions: This study indicates that the combined use of MMR-IHC and PCR-CE MSI analyses may effectively avoid misdiagnoses of EC patients with dMMR/MSI-H. However, use of PCR-CE alone to evaluate MMR/MSI status may lead to missed diagnosis, especially for EC patients with MSH6 deficiency and presenting MSS.


Assuntos
Neoplasias do Endométrio , Instabilidade de Microssatélites , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias do Endométrio/diagnóstico , Imuno-Histoquímica , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Estudos Retrospectivos
3.
Front Neurol ; 13: 945201, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090872

RESUMO

Objective: Dementia is a common and serious non-motor symptom in Parkinson's disease (PD). We aimed to investigate the reflexive saccade in PD patients and explore its potential role as a biomarker for cognitive decline. Methods: Using an infrared video-based eye tracker, we investigated reflexive saccades in 94 PD patients and 115 healthy controls (HCs). Saccadic parameters were compared between PD patients and HCs, and also among PD subgroups. The correlation of saccadic performance with disease duration, severity and cognition were further investigated. Results: Compared with healthy controls, PD patients had prolonged and hypometric reflexive saccades even in early disease stage. Univariate and multivariate analysis showed that there was significant inverse relation between prolonged latency and MMSE in PD patients (P < 0.05); tremor dominant PD patients were more likely to have decreased velocity than non-tremor-dominant PD patients (P < 0.05); saccadic accuracy was found to have no significant relation with disease duration, H&Y staging or MMSE. Conclusion: Reflexive saccadic performance was abnormal in PD and worsened with cognitive decline. The negative correlation between prolonged latency and MMSE scores may make the reflexive saccade a potential predictor for cognitive decline in Parkinson's disease.

4.
Front Oncol ; 12: 888695, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35860568

RESUMO

In this study, we demonstrated that the expression of FK506 binding protein 51 (FKBP51) is upregulated in acute monocytic leukemia (AML-M5) cells by dexamethasone and aimed to investigate the possible effects of FKBP51 on the growth and cytarabine sensitivity of AML-M5 cells. THP-1 and U937cells were used to establish AML-M5 cell models with FKBP51 overexpression and knockdown, respectively. Cell proliferation, apoptosis and response to cytarabine were investigated by cell cycle, CCK-8 and Flow cytometry analyses. The mice experiment was conducted to detect the role of FKBP51 on AML-M5 cells proliferation and antileukemia effect of Ara-C/Dexamethasone co-therapy in vivo. Western blots were employed to determine protein expression levels. FKBP51 upregulation significantly attenuated THP-1 cell proliferation and sensitized the cells to cytarabine treatment which was further enhanced by dexamethasone. These effects were indicated by decreases in cell viability, S-G2/M phase cell cycle distribution, cytarabine 50% inhibitory concentration (IC50) values and increases in apoptosis and were supported by decreased phosphorylation levels of AKT, GSK3ß and FOXO1A and decreased levels of BCL-2 and increased levels of P21 and P27. In contrast, FKBP51 knockdown led to excessive U937 cell proliferation and cytarabine resistance, as indicated by increased cell viability and S-G2/M phase cell cycle distribution, decreased apoptosis, increased phosphorylation levels of AKT, GSK3ß and FOXO1A, and increased BCL-2 and decreased P21 and P27 expression. In addition, an AKT inhibitor blocked cell cycle progression and reduced cell viability in all groups of cells. Furthermore, SAFit2, a specific FKBP51 inhibitor, increased U937 cell viability and cytarabine resistance as well as AKT phosphorylation. In conclusion, FKBP51 decelerates proliferation and improves the cytarabine sensitivity of AML-M5 cells by inhibiting AKT pathways, and dexamethasone in combination with Ara-C improves the chemosensitivity of AML-M5.

5.
Front Immunol ; 13: 837336, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309301

RESUMO

Although the variation in chromatin architecture during adaptive immune responses has been thoroughly investigated, the 3D landscape of innate immunity is still unknown. Herein, chromatin regulation and heterogeneity among human primary monocytes were investigated. Peripheral blood was collected from two healthy persons and two patients with systemic lupus erythematosus (SLE), and CD14+ monocytes were selected to perform Hi-C, RNA-seq, ATAC-seq and ChIP-seq analyses. Raw data from the THP1 cell line Hi-C library were used for comparison. For each sample, we constructed three Hi-C libraries and obtained approximately 3 billion paired-end reads in total. Resolution analysis showed that more than 80% of bins presented depths greater than 1000 at a 5 kb resolution. The constructed high-resolution chromatin interaction maps presented similar landscapes in the four individuals, which showed significant divergence from the THP1 cell line chromatin structure. The variability in chromatin interactions around HLA-D genes in the HLA complex region was notable within individuals. We further found that the CD16-encoding gene (FCGR3A) is located at a variable topologically associating domain (TAD) boundary and that chromatin loop dynamics might modulate CD16 expression. Our results indicate both the stability and variability of high-resolution chromatin interaction maps among human primary monocytes. This work sheds light on the potential mechanisms by which the complex interplay of epigenetics and spatial 3D architecture regulates chromatin in innate immunity.


Assuntos
Cromatina , Monócitos , Cromatina/genética , Sequenciamento de Cromatina por Imunoprecipitação , Cromossomos , Epigênese Genética , Humanos
6.
Biomed Res Int ; 2021: 6108999, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327232

RESUMO

Protocatechualdehyde (PCA), an important component of Salvia miltiorrhiza, has many activities, such as anti-inflammatory and antisepsis activities. However, the role of PCA in osteoclasts is not clear. We used RAW264.7 cells (a mouse leukemic monocyte/macrophage cell line) and bone marrow macrophages (BMMs) to probe the role of PCA in osteoclasts and the underlying mechanism. The effects of PCA on cell activity were evaluated with CCK-8 assays. TRAP staining detected mature osteoclasts. Corning Osteo Assay Surface plates were used to examine absorption. The levels of RNA and protein were analyzed, respectively, using RT-PCR and Western blotting. PCA (5 µg/ml) was not toxic to the two cell types but reduced the formation of osteoclasts and bone absorption. Furthermore, PCA restrained the expression of mRNAs encoding proteins associated with osteoclasts and reduced the phosphorylation of proteins in important signaling pathways. The results indicate that PCA inhibits osteoclast differentiation by suppressing NF-κB and MAPK activity.


Assuntos
Benzaldeídos/farmacologia , Catecóis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/enzimologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/enzimologia , Actinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Osteoclastos/efeitos dos fármacos , Ligante RANK/farmacologia , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Cell Death Dis ; 12(6): 602, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112753

RESUMO

FKBP4 belongs to the family of immunophilins, which serve as a regulator for steroid receptor activity. Thus, FKBP4 has been recognized to play a critical role in several hormone-dependent cancers, including breast and prostate cancer. However, there is still no research to address the role of FKBP4 on lung adenocarcinoma (LUAD) progression. We found that FKBP4 expression was elevated in LUAD samples and predicted significantly shorter overall survival based on TCGA and our cohort of LUAD patients. Furthermore, FKBP4 robustly increased the proliferation, metastasis, and invasion of LUAD in vitro and vivo. Mechanistic studies revealed the interaction between FKBP4 and IKK kinase complex. We found that FKBP4 potentiated IKK kinase activity by interacting with Hsp90 and IKK subunits and promoting Hsp90/IKK association. Also, FKBP4 promotes the binding of IKKγ to IKKß, which supported the facilitation role in IKK complex assembly. We further identified that FKBP4 TPR domains are essential for FKBP4/IKK interaction since its association with Hsp90 is required. In addition, FKBP4 PPIase domains are involved in FKBP4/IKKγ interaction. Interestingly, the association between FKBP4 and Hsp70/RelA favors the transport of RelA toward the nucleus. Collectively, FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to potentiate the transcriptional activity and nuclear translocation of NF-κB, thereby promoting LUAD progression. Our findings suggest that FKBP4 may function as a prognostic biomarker of LUAD and provide a newly mechanistic insight into modulating IKK/NF-κB signaling.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Proteínas de Ligação a Tacrolimo/fisiologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Fator de Transcrição RelA/metabolismo
8.
Exp Ther Med ; 20(2): 968-977, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32742340

RESUMO

Primary congenital glaucoma (PCG) is one of the primary causes of blindness in children and is characterized by congenital trabecular meshwork and anterior chamber angle dysplasia. While being a rare condition, PCG severely impairs the quality of life of affected patients. However, the pathogenesis of PCG remains to be fully elucidated. It has previously been indicated that genetic factors serve a critical role in the pathogenesis of PCG, although patients with PCG exhibit significant genetic heterogeneity. Mutations in the cytochrome P450 family 1 subfamily B member 1 gene have been implicated in PCG and further genes that have been reported to be involved in PCG are myocilin, forkhead box C1, collagen type I α1 chain and latent transforming growth factor ß binding protein 2. The present review aims to provide an up to date understanding of the genes associated with PCG and the use of molecular technologies in the identification of such genes and mutations. This may pave the way for the development of preventative methods, early diagnosis and improved therapeutic strategies in PCG.

9.
PLoS Biol ; 16(4): e2002909, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29652889

RESUMO

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.


Assuntos
Movimentos Oculares/fisiologia , Vias Neurais/fisiologia , Receptores Muscarínicos/genética , Sono/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Núcleo Dorsal da Rafe/anatomia & histologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/fisiologia , Eletrodos Implantados , Eletroencefalografia , Genes Reporter , Ácido Ibotênico/toxicidade , Locus Cerúleo/anatomia & histologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Mesencéfalo/anatomia & histologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/fisiologia , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Optogenética , Parte Compacta da Substância Negra/anatomia & histologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/metabolismo , Privação do Sono/fisiopatologia , Técnicas Estereotáxicas , Área Tegmentar Ventral/anatomia & histologia , Área Tegmentar Ventral/efeitos dos fármacos , Vigília/fisiologia , Ácido gama-Aminobutírico/metabolismo , Proteína Vermelha Fluorescente
10.
Sleep Biol Rhythms ; 15(2): 107-115, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28386207

RESUMO

The ventral tegmental area (VTA) is crucial for brain functions, such as voluntary movement and cognition; however, the role of VTA in sleep-wake regulation when directly activated or inhibited remains unknown. In this study, we investigated the effects of activation or inhibition of VTA neurons on sleep-wake behavior using the pharmacogenetic "designer receptors exclusively activated by designer drugs (DREADD)" approach. Immunohistochemistry staining was performed to confirm the microinjection sites, and combined with electrophysiological experiments, to determine whether the VTA neurons were activated or inhibited. The hM3Dq-expressing VTA neurons were excited confirmed by clozapine-N-oxide (CNO)-driven c-Fos expression and firing in patch-clamp recordings; whereas the hM4Di-expressing VTA neurons inhibited by reduction of firing. Compared with controls, the activation of VTA neurons at 9:00 (inactive period) produced a 120.1% increase in the total wakefulness amount for 5 h, whereas NREM and REM sleep were decreased by 62.5 and 92.2%, respectively. Similarly, when VTA neurons were excited at 21:00 (active period), the total wakefulness amount increased 81.5%, while NREM and REM sleep decreased 64.6 and 93.8%, respectively, for 8 h. No difference of the amount and EEG power density of the NREM sleep was observed following the arousal effects of CNO. The inhibition of VTA neurons during active or inactive periods gave rise to no change in the time spent in the wakefulness, REM, and NREM sleep compared with control. The results indicated that VTA neurons activated pharmacogentically played important roles in promoting wakefulness.

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