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1.
Front Oncol ; 12: 885114, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574367

RESUMO

Background: Increasing evidence has demonstrated that pyroptosis exerts key roles in the occurrence, development, and prognosis of uterine corpus endometrial carcinoma (UCEC). However, the mechanism of pyroptosis and its predictive value for prognosis remain largely unknown. Methods: UCEC data were acquired from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes in UCEC vs. normal cases were selected to perform a weighted correlation network analysis (WGCNA). Forty-two UCEC-associated pyroptosis-related genes were identified via applying differential expression analysis. Protein-protein interaction (PPI) and gene correlation analyses were applied to explore the relationship between 21 UCEC key genes and 42 UCEC-associated pyroptosis-related genes. The expression of 42 UCEC-associated pyroptosis-related genes of different grades was also calculated. The immune environment of UCEC was evaluated. Furthermore, pyroptosis-related genes were filtered out by the co-expression. Univariate and a least absolute shrinkage and selection operator (LASSO) Cox analyses were implemented to yield a pyroptosis-related gene model. We also performed consensus classification to regroup UCEC samples into two clusters. A clinically relevant heatmap and survival analysis curve were implemented to explore the clinicopathological features and relationship between two clusters. Furthermore, a Kaplan-Meier survival analysis was implemented to analyze the risk model. Results: Twenty-one UCEC key genes and 42 UCEC-associated pyroptosis-related genes were identified. The PPI and gene correlation analysis showed a clear relationship. The expression of 42 UCEC-associated pyroptosis-related genes of different grades was also depicted. A risk model based on pyroptosis-related genes was then developed to forecast overall survival among UCEC patients. Finally, Cox regression analysis verified this model as an independent risk factor for UCEC patients. Conclusions: The expression of pyroptosis-related gene may influence UCEC occurrence, development, and prognosis.

2.
Mov Disord ; 37(2): 375-383, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34636445

RESUMO

BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.


Assuntos
Distonia , Distúrbios Distônicos , Paraplegia Espástica Hereditária , Distonia/genética , Distúrbios Distônicos/genética , Humanos , Mutação/genética , Paraplegia/genética , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/genética
3.
J Environ Manage ; 302(Pt B): 114116, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34794049

RESUMO

Water footprint (WF) quantifies the impact of paddy field evapotranspiration (ET) and non-point source pollution on water resources and is an evaluation index for water sustainability. However, it is difficult to measure accurately using the existing method, which is based on parameter assumption without considering the field water conditions. In this study, a generic and physically based method for blue, green, and grey water accounting in paddy rice cultivation is introduced. We conducted field experiments using the common flood irrigation (CFI) and water-saving irrigation (SWI) modes in Nanjing, East China. By tracing the sources of ET and the migration process of multiple pollutants (TN, TP, NH4+-N, and NO3--N), the characteristics of blue-green water consumption and the actual amount of water required to dilute pollutants at different growth stages of rice under CFI and SWI were analyzed. The WF of paddy rice was 1000 m3/t (49% WFgreen, 17% WFblue, 34% WFgrey) and 910 m3/t (50% WFgreen, 10% WFblue, 40% WFgrey) for CFI and SWI, respectively. The WF for paddy rice production was reduced by approximately 9% under SWI compared to CFI, with declines of 47% for WFblue and 8% for WFgreen. The SWI mode changed the ratio of blue to green water fluxes in field water by reducing irrigation during non-critical periods, and green water was used preferentially to enhance its utility. This conceptual method is the first to describe the formation mechanism of blue, green, and grey WFs in paddy systems. It can be extended to different scales and agro-ecosystems that show the influence of crop cultivation on water resources.


Assuntos
Oryza , Água , Agricultura , China , Ecossistema , Inundações , Água/análise , Recursos Hídricos
4.
Nanomaterials (Basel) ; 11(12)2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34947593

RESUMO

The nanocone-shaped carbon nanotubes field-emitter array (NCNA) is a near-ideal field-emitter array that combines the advantages of geometry and material. In contrast to previous methods of field-emitter array, laser ablation is a low-cost and clean method that does not require any photolithography or wet chemistry. However, nanocone shapes are hard to achieve through laser ablation due to the micrometer-scale focusing spot. Here, we develop an ultraviolet (UV) laser beam patterning technique that is capable of reliably realizing NCNA with a cone-tip radius of ≈300 nm, utilizing optimized beam focusing and unique carbon nanotube-light interaction properties. The patterned array provided smaller turn-on fields (reduced from 2.6 to 1.6 V/µm) in emitters and supported a higher (increased from 10 to 140 mA/cm2) and more stable emission than their unpatterned counterparts. The present technique may be widely applied in the fabrication of high-performance CNTs field-emitter arrays.

5.
Nanomaterials (Basel) ; 11(11)2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34835790

RESUMO

Silicon carbide (SiC) nanostructure is a type of promising field emitter due to high breakdown field strength, high thermal conductivity, low electron affinity, and high electron mobility. However, the fabrication of the SiC nanotips array is difficult due to its chemical inertness. Here we report a simple, industry-familiar reactive ion etching to fabricate well-aligned, vertically orientated SiC nanoarrays on 4H-SiC wafers. The as-synthesized nanoarrays had tapered base angles >60°, and were vertically oriented with a high packing density >107 mm-2 and high-aspect ratios of approximately 35. As a result of its high geometry uniformity-5% length variation and 10% diameter variation, the field emitter array showed typical turn-on fields of 4.3 V µm-1 and a high field-enhancement factor of ~1260. The 8 h current emission stability displayed a mean current fluctuation of 1.9 ± 1%, revealing excellent current emission stability. The as-synthesized emitters demonstrate competitive emission performance that highlights their potential in a variety of vacuum electronics applications. This study provides a new route to realizing scalable field electron emitter production.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34754604

RESUMO

Background: Palmaris brevis syndrome, a pseudodystonia characterized by abnormal involuntary contractions of the palmaris brevis muscle which resides in the hypothenar eminence, is believed to be due to compressive irritation of motor fibers which arise from the superficial branch of the ulnar nerve. Case report: Herein, we review the origins, differential diagnosis and pathophysiology of the palmaris brevis syndrome, and effective treatment of a patient with workplace modifications and injections of botulinum toxin type A. Discussion: Prompt diagnosis of the palmaris brevis syndrome facilitates effective treatment and resolution. Highlights: Like the task-specific hand dystonias seen in writers and musicians, palmaris brevis syndrome, a pseudodystonia, may be caused and aggravated by extreme repetitive use. Here, we report a case of palmaris brevis syndrome apparently triggered by high-volume use of a pipette and computer mouse and review relevant clinical facets from previously published cases. Treatment must include workplace modifications and may include injections of botulinum toxin.


Assuntos
Toxinas Botulínicas Tipo A , Distúrbios Distônicos , Toxinas Botulínicas Tipo A/uso terapêutico , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/tratamento farmacológico , Mãos , Humanos , Músculo Esquelético , Nervo Ulnar
8.
Cells ; 10(4)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916001

RESUMO

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1ß production in the 5xFAD gut. Consistent with our hypothesis, increased gut-microbial-inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1ß production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut-microbial-inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/microbiologia , Encéfalo/metabolismo , Microbioma Gastrointestinal , Inflamassomos/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Animais , Apoptose , Encéfalo/patologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Modelos Animais de Doenças , Trato Gastrointestinal/patologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Ligação a Fosfato/metabolismo
9.
Medicine (Baltimore) ; 100(9): e24899, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655950

RESUMO

BACKGROUNDS: Many studies have evaluated the effect of maternal fever on the development risk of congenital heart diseases (CHDs) in offspring, but the findings were inconsistent. Furthermore, a complete overview of the existing data was also missing. Therefore, we intend to provide updated epidemiologic evidence to estimate the association between maternal fever and the risk of overall CHDs and specific CHD phenotypes in offspring. METHODS: Pubmed, Embase, and Web of Science were searched through March 2020 to identify eligible studies that assessed the association between maternal fever and CHDs risk in offspring. The summary risk estimates were calculated using random-effects models. Potential heterogeneity source was explored by subgroup analyses and potential publication bias was assessed by Begg funnel plots and Begg rank correlation test. RESULTS: Sixteen studies involving 31,922 CHDs cases among 183,563 participants were included in this meta-analysis. Overall, mothers who had a fever experience during preconception and conception periods had a significantly higher risk of overall CHDs in offspring (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.21-1.73) when compared with those who did not have a fever experience. For specific CHD phenotypes in offspring, a statistically significant association was found between maternal fever and risk of conotruncal defects (CTD) (OR = 1.38, 95%CI: 1.01-1.89), atrial septal defects (ASD) (OR = 1.48, 95% CI: 1.01-2.17), transposition of the great vessels (TGA) (OR = 1.81, 95% CI: 1.14-2.88), and right ventricular outflow tract obstruction (RVOTO) (OR = 1.66, 95% CI: 1.04-2.65). Relevant heterogeneity moderators have been identified by subgroup analyses, and sensitivity analyses yielded consistent results. CONCLUSIONS: Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, our review indicates that maternal fever is significantly associated with the risk of CHDs in offspring, which highlights that preventing maternal fever during the preconception and conception periods play an important role in decreasing the risk of CHDs in offspring. However, given the limited number of current case-control studies, larger-sample prospective studies are required to further confirm our results. Besides, due to the underlying mechanisms between maternal fever and the risk of specific CHD phenotypes in offspring are still unreported, more research is needed to explore the possible mechanisms.


Assuntos
Fertilização , Febre/complicações , Cardiopatias Congênitas/etiologia , Estudos Observacionais como Assunto , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Medição de Risco/métodos , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Mães , Gravidez , Fatores de Risco
10.
Mol Neurobiol ; 58(1): 118-131, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32895786

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for a majority of dementia cases. AD is characterized by progressive neuronal death associated with neuropathological lesions consisting of neurofibrillary tangles and senile plaques. While the pathogenesis of AD has been widely investigated, significant gaps in our knowledge remain about the cellular and molecular mechanisms promoting AD. Recent studies have highlighted the role of DNA damage, particularly DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of neurodegenerative diseases. In the present study, we tested the hypothesis that accumulation of DNA DSB plays an important role in AD pathogenesis. To test our hypothesis, we examined DNA DSB expression and DNA repair function in the hippocampus of human AD and non-AD brains by immunohistochemistry, ELISA, and RT-qPCR. We observed increased DNA DSB accumulation and reduced DNA repair function in the hippocampus of AD brains compared to the non-AD control brains. Next, we found significantly increased levels of DNA DSB and altered levels of DNA repair proteins in the hippocampus of 5xFAD mice compared to non-transgenic mice. Interestingly, increased accumulation of DNA DSBs and altered DNA repair proteins were also observed in cellular models of AD. These findings provided compelling evidence that AD is associated with accumulation of DNA DSB and/or alteration in DSB repair proteins which may influence an important early part of the pathway toward neural damage and memory loss in AD.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Quebras de DNA de Cadeia Dupla , Mudanças Depois da Morte , Animais , Células CHO , Células Cultivadas , Cricetulus , Reparo do DNA , Modelos Animais de Doenças , Hipocampo/patologia , Humanos , Camundongos Transgênicos
11.
J Neuroimmune Pharmacol ; 16(3): 667-678, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33221984

RESUMO

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and loss of both motor and non-motor features. Several clinical and preclinical studies have provided evidence that estrogen therapy reduces the risk of PD but have limitations in terms of adverse peripheral effects. Therefore, we examined the potential beneficial effects of the brain-selective estrogen prodrug, 10ß, 17ß-dihydroxyestra-1,4-dien-3-one (DHED) on nigrostriatal dopaminergic neurodegeneration and behavioral abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wild-type mice were treated with daily subcutaneous injections of DHED (50 and 100 µg/kg) or vehicle for four weeks. To produce PD-like symptoms, mice were injected with MPTP (18 mg/kg in saline; intraperitoneally) four times at 2-hr intervals for one day. After behavioral examination, mice were sacrificed, and the brains were isolated for neurochemical and morphological examinations. MPTP injected mice exhibited loss of dopaminergic neurons and fibers in substantia nigra and striatum respectively, along with impaired motor function at day 7 post MPTP injection. These phenotypes were associated with significantly increased oxidative stress and inflammatory responses in the striatum regions. DHED treatments significantly mitigated behavioral impairments and dopaminergic neurodegeneration induced by MPTP. We further observed that DHED treatment suppressed oxidative stress and inflammation in the striatum of MPTP treated mice when compared to vehicle treated mice. In conclusions, our findings suggest that DHED protects dopaminergic neurons from MPTP toxicity in mouse model of PD and support a beneficial effect of brain-selective estrogen in attenuating neurodegeneration and motor symptoms in PD-related neurological disorders. Graphical Abstract.


Assuntos
Intoxicação por MPTP , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Encéfalo , Corpo Estriado , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Estrogênios/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Substância Negra
13.
Neuroscience ; 448: 272-286, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32891704

RESUMO

PRRT2 loss-of-function mutations have been associated with familial paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis, and benign familial infantile seizures. Dystonia is the foremost involuntary movement disorder manifest by patients with PKD. Using a lacZ reporter and quantitative reverse-transcriptase PCR, we mapped the temporal and spatial distribution of Prrt2 in mouse brain and showed the highest levels of expression in cerebellar cortex. Further investigation into PRRT2 localization within the cerebellar cortex revealed that Prrt2 transcripts reside in granule cells but not Purkinje cells or interneurons within cerebellar cortex, and PRRT2 is presynaptically localized in the molecular layer. Analysis of synapses in the cerebellar molecular layer via electron microscopy showed that Prrt2-/- mice have increased numbers of docked vesicles but decreased vesicle numbers overall. In addition to impaired performance on several motor tasks, approximately 5% of Prrt2-/- mice exhibited overt PKD with clear face validity manifest as dystonia. In Prrt2 mutants, we found reduced parallel fiber facilitation at parallel fiber-Purkinje cell synapses, reduced Purkinje cell excitability, and normal cerebellar nuclear excitability, establishing a potential mechanism by which altered cerebellar activity promotes disinhibition of the cerebellar nuclei, driving motor abnormalities in PKD. Overall, our findings replicate, refine, and expand upon previous work with PRRT2 mouse models, contribute to understanding of paroxysmal disorders of the nervous system, and provide mechanistic insight into the role of cerebellar cortical dysfunction in dystonia.


Assuntos
Doenças Cerebelares , Distonia , Animais , Distonia/genética , Humanos , Proteínas de Membrana/genética , Camundongos , Mutação/genética , Proteínas do Tecido Nervoso/genética
14.
Mol Neurobiol ; 57(11): 4373-4393, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32725516

RESUMO

The neurovascular system (NVS), which consisted of neurons, glia, and vascular cells, is a functional and structural unit of the brain. The NVS regulates blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), thereby maintaining the brain's microenvironment for normal functioning, neuronal survival, and information processing. Recent studies have highlighted the role of vascular dysfunction in several neurodegenerative diseases. This is not unexpected since both nervous and vascular systems are functionally interdependent and show close anatomical apposition, as well as similar molecular pathways. However, despite extensive research, the precise mechanism by which neurovascular dysfunction contributes to neurodegeneration remains incomplete. Therefore, understanding the mechanisms of neurovascular dysfunction in disease conditions may allow us to develop potent and effective therapies for prevention and treatment of neurodegenerative diseases. This review article summarizes the current research in the context of neurovascular signaling associated with neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss the potential implication of neurovascular factor as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions. Graphical Abstract.


Assuntos
Sistema Nervoso/irrigação sanguínea , Doenças Neurodegenerativas/patologia , Animais , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Circulação Cerebrovascular , Humanos , Modelos Neurológicos , Sistema Nervoso/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/terapia
15.
Chromosome Res ; 27(4): 345-364, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31707536

RESUMO

The complexity of neurodegeneration restricts the ability to understand and treat the neurological disorders affecting millions of people worldwide. Therefore, there is an unmet need to develop new and more effective therapeutic strategies to combat these devastating conditions and that will only be achieved with a better understanding of the biological mechanism associated with disease conditions. Recent studies highlight the role of DNA damage, particularly, DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases. This is not unexpected because neurons are prone to DNA damage due to their non-proliferative nature and high metabolic activity. However, it is not clear if DSBs is a primary driver of neuronal loss in disease conditions or simply occurs concomitant with disease progression. Here, we provide evidence that supports a critical role of DSBs in the pathogenesis of the neurodegenerative diseases. Among different kinds of DNA damages, DSBs are the most harmful and perilous type of DNA damage and can lead to cell death if left unrepaired or repaired with error. In this review, we explore the current state of knowledge regarding the role of DSBs repair mechanisms in preserving neuronal function and survival and describe how DSBs could drive the molecular mechanisms resulting in neuronal death in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also discuss the potential implications of DSBs as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions.


Assuntos
Quebras de DNA de Cadeia Dupla , Predisposição Genética para Doença , Doenças Neurodegenerativas/genética , Animais , Biomarcadores , Dano ao DNA , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Diagnóstico Diferencial , Estudos de Associação Genética , Testes Genéticos , Recombinação Homóloga , Humanos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/terapia
16.
Oxid Med Cell Longev ; 2019: 1301736, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31636802

RESUMO

The present study investigated the antiapoptotic and antigenotoxic capabilities of N-acetyl cysteine- (NAC-) containing polymethyl methacrylate (PMMA) resin. An in vitro Transwell insert model was used to mimic the clinical provisional restorations placed on vital teeth. Various parameters associated with cell apoptosis and genotoxicity were investigated to obtain a deeper insight into the underlying mechanisms. The exposure of human dental pulp cell (hDPC) cultures to the PMMA resin (Unifast Trad™) resulted in a rapid increase in reactive oxygen species (ROS) level beginning at 1 h, which was followed by time-dependent cell detachment and overt death. The formation of γ-H2AX and cell cycle G1 phase arrest indicated that oxidative DNA damage occurred as a result of the interactions between DNA bases and ROS, beyond the capacities of cellular redox regulation. Such oxidative DNA damage triggers the activation of p53 via the ataxia telangiectasia mutated (ATM) signaling pathway and the induction of intrinsic mitochondrial apoptosis. Oxidative stress, cell apoptosis, and DNA damage induced by the PMMA resin were recovered to almost the level of untreated controls by the incorporation of NAC. The results indicate that the PMMA resin induced the intrinsic mitochondrial apoptosis as a consequence of p53 activation via the ATM pathway in response to oxidative DNA damage. More importantly, the incorporation of NAC as a novel component into the Unifast Trad™ PMMA resin offers protective effects against cell apoptosis and genotoxicity. This procedure represents a beneficial strategy for developing more biocompatible PMMA-based resin materials.


Assuntos
Acetilcisteína/uso terapêutico , Apoptose/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Acetilcisteína/farmacologia , Adolescente , Adulto , Humanos , Adulto Jovem
17.
Mov Disord ; 34(10): 1571-1576, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31483537

RESUMO

BACKGROUND: Intronic (TTTCA)n insertions in the SAMD12, TNRC6A, and RAPGEF2 genes have been identified as causes of familial cortical myoclonic tremor with epilepsy. OBJECTIVE: To identify the cause of familial cortical myoclonic tremor with epilepsy pedigrees without (TTTCA)n insertions in SAMD12, TNRC6A, and RAPGEF2. METHODS: Repeat-primed polymerase chain reaction, long-range polymerase chain reaction, and Sanger sequencing were performed to identify the existence of a novel (TTTGA)n insertion. Targeted long-read sequencing was performed to confirm the accurate structure of the (TTTGA)n insertion. RESULTS: We identified a novel expanded intronic (TTTGA)n insertion at the same site as the previously reported (TTTCA)n insertion in SAMD12. This insertion cosegregated with familial cortical myoclonic tremor with epilepsy in 1 Chinese pedigree with no (TTTCA)n insertion. In the targeted long-read sequencing of 2 patients and 1 asymptomatic carrier in this pedigree, with 1 previously reported (TTTCA)n -insertion-carrying patient as a positive control, a respective total of 302, 159, 207, and 50 on-target subreads (predicated accuracy: ≥90%) spanning the target repeat expansion region were generated. These sequencing data revealed the accurate repeat expansion structures as (TTTTA)114-123 (TTTGA)108-116 in the pedigree and (TTTTA)38 (TTTCA)479 in (TTTCA)n -insertion-carrying patient. CONCLUSION: The targeted long-read sequencing helped us to elucidate the accurate structures of the (TTTGA)n and (TTTCA)n insertions. Our finding offers a novel possible cause for familial cortical myoclonic tremor with epilepsy and might shed light on the identification of genetic causes of this disease in pedigrees with no detected (TTTCA)n insertion in the reported causative genes. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Epilepsias Mioclônicas/genética , Proteínas do Tecido Nervoso/genética , Tremor/genética , Adulto , Epilepsias Mioclônicas/complicações , Humanos , Íntrons/fisiologia , Masculino , Linhagem , Tremor/complicações
18.
Exp Neurol ; 318: 61-70, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31034808

RESUMO

GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in Gnal+/- mice and their isogenic Gnal+/+ littermates. In comparison to Gnal+/+ littermates, Gnal+/- mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged Gnal+/- mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf) deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf) dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.


Assuntos
Antagonistas de Dopamina/farmacologia , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Instabilidade Genômica/efeitos dos fármacos , Haloperidol/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Haploinsuficiência , Masculino , Camundongos , Discinesia Tardia/genética
19.
Mol Cancer ; 17(1): 131, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30153823

RESUMO

Liquid biopsy by genotyping circulating tumor DNA (ctDNA) has provided a non-invasive approach in assessing tumor genomic alterations in clinical oncology. However, emerging evidence in clinical settings has shown significant discordance in the genomic alterations between matched tumor tissue and blood ctDNA samples, and even between the same set of blood samples analyzed on different testing platforms. Thus, it is necessary to study underlying causes of discrepancies in these studies by genotyping tumor tissue and ctDNA in parallel using next generation sequencing (NGS) panels based on the same technology. Here we enrolled 56 non-small-cell lung cancer (NSCLC) patients and evaluated tumor tissue genotyping and ctDNA based liquid biopsy by parallel NGS panel testing and compared different sample preparation conditions. Somatic mutations in plasma cell-free DNA (cfDNA) were detected in 63.6% patients with early-stage NSCLC and 60% patients with advanced-stage NSCLC. The overall concordance between matched formalin-fixed paraffin-embedded sample and cfDNA was 54.6% in early-stage NSCLC patients and 80% in advanced-stage NSCLC patients. The positive concordance rate was 44.4% and 71.4% in early-stage and advanced-stage patients, respectively. Using fresh frozen tumor samples did not improve the overall concordance rate between matched tumor tissue and cfDNA. Processing blood samples beyond 4 h after blood draw significantly decreased the detection rate of somatic mutations in cfDNA. Thus, the concordance rate between tumor tissue-based and ctDNA-based genotyping in clinical samples can be affected by multiple pre-analytical, analytical and biologic factors. Parallel NGS panel testing on both sample types for each patient may be warranted for effective guidance of cancer targeted therapies and possible early detection of cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Mutação , Análise de Sequência de DNA/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Biópsia Líquida , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
20.
FEBS Lett ; 592(18): 3101-3110, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30098009

RESUMO

CIZ1 plays a role in DNA synthesis at the G1/S checkpoint. Ciz1 gene-trap null mice manifest motor dysfunction, cell-cycle abnormalities, and DNA damage. In contrast, it has previously been reported that mouse embryonic fibroblasts derived from presumed Ciz1 knock-out mice (Ciz1tm1.1Homy/tm1.1Homy ) generated by crossing Cre-expressing mice with exon 5-floxed mice (Ciz1tm1Homy/tm1Homy ) do not exhibit evidence of enhanced DNA damage following γ-irradiation or cell-cycle defects. Here, we report that Ciz1tm1.1Homy/tm1.1Homy mice show loss of Ciz1 exon 5 but are neurologically normal and express abnormal transcripts (Ciz1ΔE5/ΔE5 mice) that are translated into one or more proteins of approximate wild-type size. Therefore, Ciz1tm1.1Homy/tm1.1Homy mice (Ciz1ΔE5/ΔE5 ) lose residues encoded by exon 5 but may gain function from novel amino acid sequences.


Assuntos
Ciclo Celular/genética , Dano ao DNA , Éxons/genética , Proteínas Nucleares/genética , Animais , Células Cultivadas , Embrião de Mamíferos/citologia , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Integrases/genética , Integrases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/genética , Proteínas Nucleares/metabolismo
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