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Alzheimer's disease (AD) is the most common neurodegenerative disorder, and amyloid beta oligomers (AßO), which are pathological markers of AD, are known to be highly toxic. AßO increase mitochondrial dysfunction, which is accompanied by a decrease in mitochondrial fusion. Although mitofusin (Mfn) 1 and Mfn2 are mitochondrial fusion proteins, Mfn2 is known to regulate endoplasmic reticulum (ER) function, as it is located in the ER. Several studies have shown that AßO exacerbates ER stress, however, the exact mechanism requires further elucidation. In this study, we used mouse neuroblastoma cells stably overexpressing the amyloid precursor protein (APP) with the Swedish mutation (N2a APPswe cells) to investigate the role of Mfn in ER stress. Our results revealed that amyloid beta (Aß) caused cellular toxicity in N2a APPswe cells, upregulated ER stress-related proteins, and promoted ER expansion. The AßO-mediated ER stress was reduced when Mfn1 and Mfn2 were overexpressed. Moreover, Mfn1 and Mfn2 overexpressed resulted in reduced apoptosis of N2a APPswe cells. In conclusion, our results indicate that both Mfn1 and Mfn2 reduce ER stress and apoptosis. Our data provide a foundation for future studies on the roles of Mfn1 and Mfn2 in the molecular mechanisms underlying AßO-mediated ER stress and the pathogenesis of AD.
Assuntos
Peptídeos beta-Amiloides , Apoptose , Estresse do Retículo Endoplasmático , GTP Fosfo-Hidrolases , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , GTP Fosfo-Hidrolases/metabolismo , GTP Fosfo-Hidrolases/genética , Mitocôndrias/metabolismoRESUMO
INTRODUCTION: Our previously developed blood-based transcriptional risk scores (TRS) showed associations with diagnosis and neuroimaging biomarkers for Alzheimer's disease (AD). Here, we developed brain-based TRS. METHODS: We integrated AD genome-wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization. We calculated TRS using brain transcriptome data of two independent cohorts (N = 878) and performed association analysis of TRS with diagnosis, amyloidopathy, tauopathy, and cognition. We compared AD classification performance of TRS with polygenic risk scores (PRS). RESULTS: Higher TRS values were significantly associated with AD, amyloidopathy, tauopathy, worse cognition, and faster cognitive decline, which were replicated in an independent cohort. The AD classification performance of PRS was increased with the inclusion of TRS up to 16% with the area under the curve value of 0.850. DISCUSSION: Our results suggest brain-based TRS improves the AD classification of PRS and may be a potential AD biomarker. HIGHLIGHTS: Transcriptional risk score (TRS) is developed using brain RNA-Seq data. Higher TRS values are shown in Alzheimer's disease (AD). TRS improves the AD classification power of PRS up to 16%. TRS is associated with AD pathology presence. TRS is associated with worse cognitive performance and faster cognitive decline.
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Doença de Alzheimer , Tauopatias , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Cognição , Fatores de Risco , Biomarcadores , Estratificação de Risco GenéticoRESUMO
INTRODUCTION: Alzheimer's disease (AD) involves the complement cascade, with complement component 3 (C3) playing a key role. However, the relationship between C3 and amyloid beta (Aß) in blood is limited. METHODS: Plasma C3 and Aß oligomerization tendency (AßOt) were measured in 35 AD patients and 62 healthy controls. Correlations with cerebrospinal fluid (CSF) biomarkers, cognitive impairment, and amyloid positron emission tomography (PET) were analyzed. Differences between biomarkers were compared in groups classified by concordances of biomarkers. RESULTS: Plasma C3 and AßOt were elevated in AD patients and in CSF or amyloid PET-positive groups. Weak positive correlation was found between C3 and AßOt, while both had strong negative correlations with CSF Aß42 and cognitive performance. Abnormalities were observed for AßOt and CSF Aß42 followed by C3 changes. DISCUSSION: Increased plasma C3 in AD are associated with amyloid pathology, possibly reflecting a defense response for Aß clearance. Further studies on Aß-binding proteins will enhance understanding of Aß mechanisms in blood.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Amiloide , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Complemento C3 , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/líquido cefalorraquidianoRESUMO
Autosomal recessive spastic ataxia in Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder caused by mutations in the sacsin molecular chaperone protein (SACS) gene. Since the first report from Quebec in 1978, many pathogenic ARSACS variants with significantly reduced chaperone activities have been reported worldwide in adolescents, with presumably altered protein folding. In this study, a novel SACS mutation (p.Val1335IIe, Heterozygous) was identified in a Korean patient in their 50s with late-onset ARSACS characterized by cerebellar ataxia and spasticity without peripheral neuropathy. The mutation was confirmed via whole exome sequencing and Sanger sequencing and was predicted to likely cause disease using prediction software. RT-PCR and ELISA showed decreased SACS mRNA expression and sacsin protein concentrations in the proband, supporting its implications in diseases with pathogenicity and reduced chaperone function from haploinsufficiency. Our results revealed the pathogenicity of the SACS Val1335IIe mutation in the proband patient's disease manifestation, even though the symptoms had a limited correlation with the typical ARSACS clinical triad, which could be due to the reduced chaperon function from haploinsufficiency. Furthermore, our study suggests that variants of SACS heterozygosity may have diverse symptoms, with a wide range of disease onsets for late-onset sacsinopathy.
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Obesity is caused by the accumulation of excess lipids due to an energy imbalance. Differentiation of pre-adipocytes induces abnormal lipid accumulation, and reactive oxygen species (ROS) generated in this process promote the differentiation of pre-adipocytes through mitogen-activated protein kinase (MAPK) signaling. Peroxiredoxin (Prx) is a potent antioxidant enzyme, and peroxiredoxin 5 (Prx5), which is mainly expressed in cytosol and mitochondria, inhibits adipogenesis by regulating ROS levels. Based on previous findings, the present study was performed to investigate whether cytosolic Prx5 (CytPrx5) or mitochondrial Prx5 (MtPrx5) has a greater effect on the inhibition of adipogenesis. In this study, MtPrx5 decreased insulin-mediated ROS levels to reduce adipogenic gene expression and lipid accumulation more effectively than CytPrx5. In addition, we found that p38 MAPK mainly participates in adipogenesis. Furthermore, we verified that MtPrx5 overexpression suppressed the phosphorylation of p38 during adipogenesis. Thus, we suggest that MtPrx5 inhibits insulin-induced adipogenesis more effectively than CytPrx5.
Assuntos
Adipogenia , Insulina , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Camundongos , Células 3T3-L1 , Diferenciação Celular , Insulina/metabolismo , Lipídeos/farmacologia , Mitocôndrias/metabolismo , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Peroxirredoxinas/farmacologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Asivatrep is a potent and selective antagonist of transient receptor potential vanilloid subfamily V member 1 (TRPV1), which plays an important role in itch and inflammation in atopic dermatitis (AD). OBJECTIVE: This current study aimed to evaluate the efficacy and safety of asivatrep cream in patients with AD. METHODS: For this phase 3 double-blind, vehicle-controlled study, patients aged ≥12 years with mild to moderate AD were enrolled and randomly assigned 2:1 to the 1.0% asivatrep or vehicle group for 8 weeks of twice-daily application (n = 240). The primary end point was the proportion of patients with an Investigator's Global Assessment score (IGA) of 0 or 1 at week 8. Standard safety assessments were conducted. RESULTS: At week 8, significantly more patients in the asivatrep group (36.0%) than in the vehicle group (12.8%) had IGA scores of 0 or 1 (P < .001); significantly more had ≥2 points of improvement on the IGA from baseline score (20.3% vs 7.7%; P = .01). The mean percentage reduction in the Eczema Area and Severity Index (EASI) score was 44.3% for the asivatrep group and 21.4% for the vehicle group at week 8 (P < .001). Significantly more asivatrep-treated patients experienced an improvement of at least 50%, 75%, and 90% on the EASI than the vehicle group. The mean ± SD change in the pruritus visual analog scale score at week 8 was -2.3 ± 2.4 for the asivatrep group and -1.5 ± 2.4 for the vehicle group (P = .02). No significant safety issues were reported. CONCLUSION: Asivatrep improved clinical signs and symptoms of AD and was well tolerated.
Assuntos
Dermatite Atópica , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Método Duplo-Cego , Emolientes/uso terapêutico , Excipientes , Humanos , Imunoglobulina A , Prurido/tratamento farmacológico , Índice de Gravidade de Doença , Canais de Cátion TRPV , Resultado do TratamentoRESUMO
A pathogenic mutation in presenilin-1 (PSEN1), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer's disease (EOAD). PSEN1 His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aß) oligomerization tendency with blood. The PSEN1 His214 amino acid position plays a significant role in the gamma-secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid-extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma-secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aß was reflected in the increased Aß oligomerization tendency and the accumulations of Aß in the brain from amyloid-PET, leading to EOAD.
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Doença de Alzheimer , Histidina , Humanos , Masculino , Histidina/genética , Triptofano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Presenilina-1/genética , Secretases da Proteína Precursora do Amiloide , Mutação , Proteínas Amiloidogênicas , Cátions , República da CoreiaRESUMO
BACKGROUND: Although individuals with dementia have a high risk of developing seizures, whether seizures are associated with cholinesterase inhibitors, which are commonly prescribed to treat individuals with dementia, remains unknown. This study investigated the risk of incident seizure following cholinesterase inhibitor use in patients with dementia. METHODS: A nationwide, nested case-control study was conducted using data from the Korean Health Insurance Review and Assessment Service (HIRA) from 2014 through 2018. A total of 13,767 participants aged 65-95 years who experienced incident seizure were propensity score-matched for medical comorbidities and drug exposure at a 1:3 ratio with a control group of 39,084 participants. The study examined the incidence of seizures in patients diagnosed with dementia within one year after receiving cognitive enhancers. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for seizure incidence according to cholinesterase inhibitor use were analyzed using a multivariable conditional logistic regression model. RESULTS: There was no statistically significant association between duration of cholinesterase inhibitors use and seizure risk. Although there was slight increased seizure risk in patient after receiving donepezil for 1 year compared to memantine, subgroup analyses stratified age and sex did not reveal any significant association between cholinesterase inhibitors use and late-onset seizure. CONCLUSIONS: Our findings suggest no immediate increase in seizure risk is associated with cholinesterase inhibitor use, although the risk of seizure in patients with dementia did increase after one year of continued medication intake. Further study is required to obtain confirmatory results on the seizure-related safety of cognitive enhancers in patients with dementia.
Assuntos
Demência , Nootrópicos , Estudos de Casos e Controles , Inibidores da Colinesterase/efeitos adversos , Demência/diagnóstico , Demência/tratamento farmacológico , Demência/epidemiologia , Humanos , Nootrópicos/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/epidemiologiaRESUMO
The CRISPR-Cas9 system is widely used for target-specific genome engineering. CRISPR-Cas12a (Cpf1) is one of the CRISPR effectors that controls target genes by recognizing thymine-rich protospacer adjacent motif (PAM) sequences. Cas12a has a higher sensitivity to mismatches in the guide RNA than does Cas9; therefore, off-target sequence recognition and cleavage are lower. However, it tolerates mismatches in regions distant from the PAM sequence (TTTN or TTN) in the protospacer, and off-target cleavage issues may become more problematic when Cas12a activity is improved for therapeutic purposes. Therefore, we investigated off-target cleavage by Cas12a and modified the Cas12a (cr)RNA to address the off-target cleavage issue. We developed a CRISPR-Cas12a that can induce mutations in target DNA sequences in a highly specific and effective manner by partially substituting the (cr)RNA with DNA to change the energy potential of base pairing to the target DNA. A model to explain how chimeric (cr)RNA guided CRISPR-Cas12a and SpCas9 nickase effectively work in the intracellular genome is suggested. Chimeric guide-based CRISPR- Cas12a genome editing with reduced off-target cleavage, and the resultant, increased safety has potential for therapeutic applications in incurable diseases caused by genetic mutations.
Assuntos
Proteínas de Bactérias/genética , Proteínas Associadas a CRISPR/genética , Sistemas CRISPR-Cas/genética , DNA/genética , Endodesoxirribonucleases/genética , RNA Guia de Cinetoplastídeos/genética , Pareamento Incorreto de Bases/genética , Clivagem do DNA , Edição de Genes , Humanos , Modelos Moleculares , Mutação/genética , Conformação de Ácido Nucleico , RNA/genética , RNA Circular/genéticaRESUMO
BACKGROUND: The tendency of amyloid-ß to form oligomers in the blood as measured with Multimer Detection System-Oligomeric Amyloid-ß (MDS-OAß) is a valuable biomarker for Alzheimer's disease and has been verified with heparin-based plasma. The objective of this study was to evaluate the performance of ethylenediaminetetraacetic acid (EDTA)-based MDS-OAß and to develop machine learning algorithms to predict amyloid positron emission tomography (PET) positivity. METHODS: The performance of EDTA-based MDS-OAß in predicting PET positivity was evaluated in 312 individuals with various machine learning models. The models with various combinations of features (i.e., MDS-OAß level, age, apolipoprotein E4 alleles, and Mini-Mental Status Examination [MMSE] score) were tested 50 times on each dataset. RESULTS: The random forest model best-predicted amyloid PET positivity based on MDS-OAß combined with other features with an accuracy of 77.14 ± 4.21% and an F1 of 85.44 ± 3.10%. The order of significance of predictive features was MDS-OAß, MMSE, Age, and APOE. The Support Vector Machine using the MDS-OAß value only showed an accuracy of 71.09 ± 3.27% and F-1 value of 80.18 ± 2.70%. CONCLUSIONS: The Random Forest model using EDTA-based MDS-OAß combined with the MMSE and apolipoprotein E status can be used to prescreen for amyloid PET positivity.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Ácido Edético , Peptídeos beta-Amiloides , Doença de Alzheimer/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Biomarcadores , Aprendizado de Máquina , Algoritmos , Disfunção Cognitiva/diagnósticoRESUMO
In the mammalian female reproductive tract, physiological oxygen tension is lower than that of the atmosphere. Therefore, to mimic in vivo conditions during in vitro culture (IVC) of mammalian early embryos, 5% oxygen has been extensively used instead of 20%. However, the potential effect of hypoxia on the yield of early embryos with high developmental competence remains unknown or controversial, especially in pigs. In the present study, we examined the effects of low oxygen tension under different oxygen tension levels on early developmental competence of parthenogenetically activated (PA) and in vitro-fertilized (IVF) porcine embryos. Unlike the 5% and 20% oxygen groups, exposure of PA embryos to 1% oxygen tension, especially in early-phase IVC (0-2 days), greatly decreased several developmental competence parameters including blastocyst formation rate, blastocyst size, total cell number, inner cell mass (ICM) to trophectoderm (TE) ratio, and cellular survival rate. In contrast, 1% oxygen tension did not affect developmental parameters during the middle (2-4 days) and late phases (4-6 days) of IVC. Interestingly, induction of autophagy by rapamycin treatment markedly restored the developmental parameters of PA and IVF embryos cultured with 1% oxygen tension during early-phase IVC, to meet the levels of the other groups. Together, these results suggest that the early development of porcine embryos depends on crosstalk between oxygen tension and autophagy. Future studies of this relationship should explore the developmental events governing early embryonic development to produce embryos with high developmental competence in vitro.
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Autofagia , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário , Fertilização in vitro/veterinária , Hipóxia/fisiopatologia , Oxigênio/administração & dosagem , Suínos/embriologia , Animais , Blastocisto/citologia , Blastocisto/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Feminino , GravidezRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease associated with the accumulation of amyloid-beta oligomers (AßO). Recent studies have demonstrated that mitochondria-specific autophagy (mitophagy) contributes to mitochondrial quality control by selectively eliminating the dysfunctional mitochondria. Mitochondria motility, which is regulated by Miro1, is also associated with neuronal cell functions. However, the role played by Miro1 in the mitophagy mechanism, especially relative to AßO and neurodegenerative disorders, remains unknown. In this study, AßO induced mitochondrial dysfunction, enhanced Parkin-mediated mitophagy, and reduced mitochondrial quantities in hippocampal neuronal cells (HT-22 cells). We demonstrated that AßO-induced mitochondrial fragmentation could be rescued to the elongated mitochondrial form and that mitophagy could be mitigated by the stable overexpression of Miro1 or by pretreatment with N-acetylcysteine (NAC)-a reactive oxygen species (ROS) scavenger-as assessed by immunocytochemistry. Moreover, using time-lapse imaging, under live cell-conditions, we verified that mitochondrial motility was rescued by the Miro1 overexpression. Finally, in hippocampus from amyloid precursor protein (APP)/presenilin 1 (PS1)/Tau triple-transgenic mice, we noted that the co-localization between mitochondria and LC3B puncta was increased. Taken together, these results indicated that up-regulated ROS, induced by AßO, increased the degree of mitophagy and decreased the Miro1 expression levels. In contrast, the Miro1 overexpression ameliorated AßO-mediated mitophagy and increased the mitochondrial motility. In AD model mice, AßO induced mitophagy in the hippocampus. Thus, our results would improve our understanding of the role of mitophagy in AD toward facilitating the development of novel therapeutic agents for the treatment of AßO-mediated diseases.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Mitofagia , Neurônios/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Animais , Linhagem Celular , Humanos , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas rho de Ligação ao GTP/genéticaRESUMO
Wireless sensor networks (WSN) are widely used to provide users with convenient services such as health-care, and smart home. To provide convenient services, sensor nodes in WSN environments collect and send the sensing data to the gateway. However, it can suffer from serious security issues because susceptible messages are exchanged through an insecure channel. Therefore, secure authentication protocols are necessary to prevent security flaws in WSN. In 2020, Moghadam et al. suggested an efficient authentication and key agreement scheme in WSN. Unfortunately, we discover that Moghadam et al.'s scheme cannot prevent insider and session-specific random number leakage attacks. We also prove that Moghadam et al.'s scheme does not ensure perfect forward secrecy. To prevent security vulnerabilities of Moghadam et al.'s scheme, we propose a secure and lightweight mutual authentication protocol for WSNs (WSN-SLAP). WSN-SLAP has the resistance from various security drawbacks, and provides perfect forward secrecy and mutual authentication. We prove the security of WSN-SLAP by using Burrows-Abadi-Needham (BAN) logic, Real-or-Random (ROR) model, and Automated Verification of Internet Security Protocols and Applications (AVISPA) simulation. In addition, we evaluate the performance of WSN-SLAP compared with existing related protocols. We demonstrate that WSN-SLAP is more secure and suitable than previous protocols for WSN environments.
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Segurança Computacional , Confidencialidade , Simulação por Computador , LógicaRESUMO
BACKGROUND: Fibrinogen is considered a marker of vascular pathology, indicating a weakened blood-brain barrier, and has a causative role in neuroinflammation and neurodegeneration. Little is known about the relationship between fibrinogen levels and cognitive function in patients with mild cognitive impairment (MCI). We aimed to investigate differences in cognitive profiles according to plasma fibrinogen levels in patients with MCI and the influence of plasma fibrinogen levels on cognitive decline. METHODS: This retrospective cohort study included 643 patients with MCI: 323 patients in the high fibrinogen (high fib) group and 320 patients in the low fibrinogen (low fib) group. A multiple linear regression model was performed to compare cognitive test performance between groups. The Cox proportional hazard model was used to analyze the hazard ratio of fibrinogen level for disease progression. RESULTS: The high fib group demonstrated poorer performance in attention, executive function, and confrontation naming than the low fib group. After adjustment for APOE genotype, the high fib group was associated with poor attention and executive function. After adjustment for vascular risk factors including body mass index, hypertension, diabetes mellitus, dyslipidemia, and smoking history, the high fib group showed declined attention and confrontation naming ability. High fibrinogen levels did not predict disease progression to CDR 1. CONCLUSION: High plasma fibrinogen levels were associated with poor performance in attention in patients with MCI, regardless of APOE genotype or vascular risk factors.
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Cognição/fisiologia , Disfunção Cognitiva , Fibrinogênio/análise , Testes Neuropsicológicos , Idoso , Atenção/fisiologia , Biomarcadores/análise , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Correlação de Dados , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: The aim of this study was to assess the cognitive function of patients over 60 years old with meningioma using a domain-specific neuropsychological test and to investigate the relevant factors affecting pre-operative cognitive decline in different subdomains. METHODS: We retrospectively investigated 46 intracranial meningioma patients between the ages of 60 and 85 years. All patients underwent brain MRI and neuropsychological test. Tumor size, location, peritumoral edema, and medial temporal atrophy (MTA) were examined to determine the association with cognitive impairment. We performed a logistic regression analysis to examine the odds ratios (ORs) for cognitive decline of four subdomains: verbal memory, language, visuospatial, and executive functions. RESULTS: Tumor size and age were associated with executive dysfunction (OR 1.083, 95% confidence interval (CI) 1.006-1.166, and OR 1.209, 95% CI 1.018-1.436, respectively). There was no statistically significant association in other cognitive domains (language, verbal memory, and visuospatial function) with variables in regression analysis. CONCLUSIONS: We conclude that tumor size and age are positively related with executive function in pre-operative meningioma patients over 60 years old.
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Cognição , Disfunção Cognitiva/epidemiologia , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Atrofia , Função Executiva , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos RetrospectivosRESUMO
Multiple neurological complications have been associated with the coronavirus disease-19 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2. This is a narrative review to gather information on all aspects of COVID-19 in elderly patients with cognitive impairment. First, the following three mechanisms have been proposed to underlie the neurological complications associated with COVID-19: 1) direct invasion, 2) immune and inflammatory reaction, and 3) hypoxic brain damage by COVID-19. Next, because the elderly dementia patient population is particularly vulnerable to COVID-19, we discussed risk factors and difficulties associated with cognitive disorders in this vulnerable population. We also reviewed the effects of the patient living environment in COVID-19 cases that required intensive care unit (ICU) care. Furthermore, we analyzed the impact of stringent social restrictions and COVID-19 pandemic-mediated policies on dementia patients and care providers. Finally, we provided the following strategies for working with elderly dementia patients: general preventive methods; dementia care at home and nursing facilities according to the activities of daily living and dementia characteristics; ICU care after COVID-19 infection; and public health care system and government response. We propose that longitudinal follow-up studies are needed to fully examine COVID-19 associated neurological complications, such as dementia, and the efficacy of telemedicine/telehealth care programs.
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Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Demência/epidemiologia , Serviços de Saúde para Idosos , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Atividades Cotidianas , Idoso , Betacoronavirus , Encéfalo/fisiopatologia , COVID-19 , Cuidadores , Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , Infecções por Coronavirus/complicações , Cuidados Críticos , Demência/complicações , Humanos , Hipóxia , Sistema Imunitário , Inflamação , Casas de Saúde , Pneumonia Viral/complicações , Medicina Preventiva , Saúde Pública , Fatores de Risco , SARS-CoV-2 , Isolamento Social , TelemedicinaRESUMO
Triclosan (TCS) is included in various healthcare products because of its antimicrobial activity; therefore, many humans are exposed to TCS daily. While detrimental effects of TCS exposure have been reported in various species and cell types, the effects of TCS exposure on early embryonic development are largely unknown. The aim of this study was to determine if TCS exerts toxic effects during early embryonic development using porcine parthenogenetic embryos in vitro. Porcine parthenogenetic embryos were cultured in in vitro culture medium with 50 or 100 µM TCS for 6 days. Developmental parameters including cleavage and blastocyst formation rates, developmental kinetics, and the number of blastomeres were assessed. To determine the toxic effects of TCS, apoptosis, oxidative stress, and mitochondrial dysfunction were assessed. TCS exposure resulted in a significant decrease in 2-cell rate and blastocyst formation rate, as well as number of blastomeres, but not in the cleavage rate. TCS also increased the number of apoptotic blastomeres and the production of reactive oxygen species. Finally, TCS treatment resulted in a diffuse distribution of mitochondria and decreased the mitochondrial membrane potential. Our results showed that TCS exposure impaired porcine early embryonic development by inducing DNA damage, oxidative stress, and mitochondrial dysfunction.
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Blastocisto/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Suínos/embriologia , Triclosan/toxicidade , Animais , Apoptose/efeitos dos fármacos , Blastômeros/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
In recent decades, many studies on the treatment and prevention of pancreatic cancer have been conducted. However, pancreatic cancer remains incurable, with a high mortality rate. Although mouse models have been widely used for preclinical pancreatic cancer research, these models have many differences from humans. Therefore, large animals may be more useful for the investigation of pancreatic cancer. Pigs have recently emerged as a new model of pancreatic cancer due to their similarities to humans, but no pig pancreatic cancer cell lines have been established for use in drug screening or analysis of tumor biology. Here, we established and characterized an immortalized miniature pig pancreatic cell line derived from primary pancreatic cells and pancreatic cancer-like cells expressing K-rasG12D regulated by the human PTF1A promoter. Using this immortalized cell line, we analyzed the gene expression and phenotypes associated with cancer cell characteristics. Notably, we found that acinar-to-ductal transition was caused by K-rasG12D in the cell line constructed from acinar cells. This may constitute a good research model for the analysis of acinar-to-ductal metaplasia in human pancreatic cancer.
Assuntos
Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Linhagem Celular , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Pâncreas/patologia , Ductos Pancreáticos/metabolismo , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Transdução de Sinais/genética , Suínos , Porco MiniaturaRESUMO
The developmental competence of in vitro-matured oocytes is still lower than that of the in vivo-matured oocytes due to precocious meiotic resumption and inappropriate cytoplasmic maturation. Although numerous efforts have been attempted to accomplish better in vitro maturation (IVM) condition, only limited progress has been achieved. Thus, a current study was conducted to examine the effects of 6-diazo-5-oxo-l-norleucine (DON, an inhibitor of hyaluronan synthesis) during the first half period of IVM on nuclear/cytoplasmic maturation of porcine oocytes and subsequent embryonic development. Based on the observation of the nucleus pattern, metaphase II (MII) oocyte production rate in 1 µM DON group was significantly higher than other groups at 44 h of IVM. The 1 µM of DON was suggested to be optimal for porcine IVM and was therefore used for further investigation. Meiotic arrest effect of DON was maximal at 6 h of IVM, which was supported by the maintenance of significantly higher intra-oocyte cAMP level. In addition, increased pERK1/2 levels and clear rearrangement of cortical granules in membrane of MII oocytes matured with DON provided the evidence for balanced meiosis progression between nuclear and cytoplasmic maturation. Subsequently, DON significantly improved blastocyst formation rate, total cell numbers, and cellular survival in blastocysts after parthenogenetic activation, in vitro fertilization, and somatic cell nuclear transfer. Altogether, our results showed for the first time that 1 µM DON can be used to increase the yield of developmentally competent MII oocytes by synchronizing nuclear/cytoplasmic maturation, and it subsequently improves embryo developmental competence.