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1.
Biosens Bioelectron ; 183: 113208, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33839535

RESUMO

Currently, there are no approved therapeutics for Dengue virus (DENV) infection, even though it can cause fatal complications. Understanding DENV infection and its propagation process in host cells is necessary to develop specific antiviral therapeutics. Here, we developed a graphene oxide-based fluorescent system (Graphene Oxide-based Viral RNA Analysis system, GOViRA) that enables sensitive and quantitative real-time monitoring of the intracellular viral RNA level in living cells. The GOViRA system consists of a fluorescent dye-labeled peptide nucleic acid (PNA) with a complementary sequence to the DENV genome and a dextran-coated reduced graphene oxide nanocolloid (DRGON). When the dye labeled PNA is adsorbed onto DRGON, the fluorescence of the dye is effectively quenched. The quenched fluorescence signal is recovered when the dye labeled PNA forms interaction with intracellular viral RNA in DENV infected host cells. We demonstrated the successful use of the GOViRA platform for high-throughput screening to discover novel antiviral compounds. Through a cell-based high-throughput screening of FDA-approved small-molecule drugs, we identified ulipristal, a selective progesterone receptor modulator (SPRM), as a potent inhibitor against DENV infection. The anti-DENV activity of ulipristal was confirmed both in vitro and in vivo. Moreover, we suggest that the mode of action of ulipristal is mediated by inhibiting viral entry into the host cells.

2.
J Korean Med Sci ; 36(14): e90, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33847081

RESUMO

BACKGROUND: Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL). METHODS: BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis. RESULTS: Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B. CONCLUSION: These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.

3.
Sensors (Basel) ; 21(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800415

RESUMO

Physiological signals are immediate and sensitive to neural and cardiovascular change resulting from brain stimulation, and are considered as a quantifying tool with which to evaluate the association between brain stimulation and cognitive performance. Brain stimulation outside a highly equipped, clinical setting requires the use of a low-cost, ambulatory miniature system. The purpose of this double-blind, randomized, sham-controlled study is to quantify the physiological biomarkers of the neural and cardiovascular systems induced by a microwave brain stimulation (MBS) device. We investigated the effect of an active MBS and a sham device on the cardiovascular and neurological responses of ten volunteers (mean age 26.33 years, 70% male). Electroencephalography (EEG) and electrocardiography (ECG) were recorded in the initial resting-state, intermediate state, and the final state at half-hour intervals using a portable sensing device. During the experiment, the participants were engaged in a cognitive workload. In the active MBS group, the power of high-alpha, high-beta, and low-beta bands in the EEG increased, and the power of low-alpha and theta waves decreased, relative to the sham group. RR Interval and QRS interval showed a significant association with MBS stimulation. Heart rate variability features showed no significant difference between the two groups. A wearable MBS modality may be feasible for use in biomedical research; the MBS can modulate the neurological and cardiovascular responses to cognitive workload.

4.
Clin Chim Acta ; 518: 116-122, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33775700

RESUMO

Gitelman syndrome (GS) is an autosomal recessive disorder caused by loss-of-function mutations in SLC12A3, which encodes the Na-Cl cotransporter (NCC). Osteogenesis imperfecta (OI) is an autosomal dominant disorder caused by the inheritance of mutations mainly in the COL1A1 gene, resulting in bone fragility and deformity. In this study, we aimed to investigate the clinical and genetic manifestations in a 7-year-old boy with OI, who had electrolyte abnormalities and his four family members. Complete sequence analysis of COL1A1 revealed a novel mutation, c.268G>T, p.Glu90del. The gene mutation of OI in the patient's older brother was inherited from his mother, and the younger brother had no mutation. Two pathogenic mutations (c.179C>T, p.Thr60Met and c.1763C>T, p.Ala588Val) in SLC12A3 resulting in GS were also identified in the patient. The OI-related genetic mutation in the patient was consistent with that in the patient's mother. The GS-related genetic mutations were inherited from each parent. This study is the first to identify compound heterozygous variants in the SLC12A3 gene and a novel mutation in the COL1A1 gene in patients with OI and GS. Our findings indicate that genetic analysis is recommended to differentiate GS from BS, as clinical manifestations do not provide an accurate diagnosis.

5.
Scand J Trauma Resusc Emerg Med ; 29(1): 26, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33516239

RESUMO

BACKGROUND: Systolic blood pressure (SBP) and shock index (SI) are accurate indicators of hemodynamic instability and the need for transfusion in trauma patients. We aimed to determine whether the utility and cutoff point for SBP and SI are affected by age and antihypertensives. METHODS: This was a retrospective observational study of a level 1 trauma center between January 2017 and December 2018. We analyzed the utility and cutoff points of SBP and SI for predicting massive transfusion (MT) and 30-day mortality according to patients' age and whether they were taking antihypertensives. A multivariable logistic regression analysis was conducted to estimate the association of age and antihypertensives on primary and secondary outcomes. RESULTS: We analyzed 4681 trauma cases. There were 1949 patients aged 65 years or older (41.6%), and 1375 hypertensive patients (29.4%). MT was given to 137 patients (2.9%). The 30-day mortality rate was 6.3% (n = 294). In geriatric trauma patients taking antihypertensives, a prehospital SBP less than 110 mmHg was the cutoff value for predicting MT in multivariate logistic regression analyses; packed red blood cell transfusion volume decreased abruptly based on prehospital SBP of 110 mmHg. Emergency Department SI greater than 1.0 was the cutoff value for predicting MT in patients who were older than 65 years and were not taking antihypertensives. CONCLUSIONS: The triage of trauma patients is based on the identification of clinical features readily identifiable by first responders. However, age and medications may also affect the accurate evaluation. In initial trauma management, we must apply SBP and SI differently depending on age, whether a patient is taking antihypertensives, and the time at which the indicators are measured.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33503946

RESUMO

There are many epidemiological studies asserting that fine dust causes lung cancer, but the biological mechanism is not clear. This study was conducted to investigate the effect of PM10 (particulate matter less than 10 µm) on single nucleotide variants through whole genome sequencing in lung epithelial cancer cell lines (HCC-827, NCI-H358) that have been exposed to PM10. The two cell lines were exposed to PM10 for 15 days. We performed experimental and next generation sequencing analyses on experimental group that had been exposed to PM10 as well as an unexposed control group. After exposure to PM10, 3005 single nucleotide variants were newly identified in the NCI-H358 group, and 4402 mutations were identified in the HCC-827 group. We analyzed these single nucleotide variants with the Mutalisk program. We observed kataegis in chromosome 1 in NCI-H358 and chromosome 7 in HCC-827. In mutational signatures analysis, the COSMIC mutational signature 5 was highest in both HCC-827 and NCI-H358 groups, and each cosine similarity was 0.964 in HCC-827 and 0.979 in the NCI-H358 group. The etiology of COSMIC mutational signature 5 is unknown at present. Well-designed studies are needed to determine whether environmental factors, such as PM10, cause COSMIC mutational signature 5.

7.
Eur J Radiol ; 135: 109405, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33441267

RESUMO

PURPOSE: To analyze the quantitative and qualitative image quality of computed tomography (CT) of the extremities (shoulder, wrist, pelvis, and ankle joints) with low-dose radiation and standard-dose radiation. MATERIALS AND METHODS: In this study, we included 400 individuals who underwent CT of the extremities, comprising 50 cases of each joint (shoulder, wrist, pelvis, and ankle) at low and standard dose regimens. Low-dose CTs were performed using identical voltage and parameters with the exception of decreased (half of standard dose) tube current. Low-dose and standard-dose images were compared in terms of radiation dose, objective image quality according to the standard deviation (SD) of the Hounsfield unit value of the medulla, cortex, muscle, subcutaneous fat, and air, and subjective image quality according to noise, sharpness, diagnostic acceptability, and artifacts. RESULTS: In the shoulder and pelvis, the mean value of the SD for all tissue on low dose CT images was significantly higher than that of standard dose CT, except for the SD of cortex in the shoulder joint and marrow in the pelvis. In the wrist, the mean value of the SD for all tissue was not significantly different between low dose and standard CT (p > 0.05). In the ankle, the mean value of the SD of the medulla and cortex was not different (p > 0.05), but the remaining measurements were significantly higher in low dose CT. Subjective image quality in the shoulder and pelvis were significantly reduced in low dose CT. In the wrist, all categories of subjective image quality except artifacts were similar. In the ankle, all categories of subjective image quality except for artifacts were degraded in low dose CT. CONCLUSIONS: Objective image noise is more increased in low dose CT images of the shoulder and pelvis. Although diagnostic performance was acceptable, mean subjective image quality also decreased. In the wrist, objective image noise and subjective image quality were not degraded in low dose CT. In the ankle, some measurements of objective and subjective image quality were similar between low dose and standard dose CT.


Assuntos
Interpretação de Imagem Radiográfica Assistida por Computador , Humanos , Tomografia Computadorizada Multidetectores , Doses de Radiação , Padrões de Referência
8.
Inhal Toxicol ; : 1-7, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33283556

RESUMO

Introduction: Particulate matter (PM) has various systemic effects. We researched the effects of PM on lung epithelial cells with next generation sequencing (NGS) and validated this with quantitative real-time polymerase chain reaction (qRT-PCR). Methods: We cultured the group exposed to PM10 (Particulate matter less than 10 µm)-like fine dust (ERM® CZ120 fine dust) at a concentration of 50 µg/mL and the untreated group for seven days in one normal lung epithelial cell line (BEAS-2B) and four lung cancer epithelial cell lines (NCI-H358, HCC-827, A549, NCI-H292). Then, we extracted the RNA from the sample and performed NGS. As a result of NGS, various gene expressions were upregulated or downregulated. Among them, we selected the gene whose mean fold change was more than doubled and changed in the same direction in all five cell lines. Based on these genes, we selected the top 10 genes, either upregulated or downregulated, to validate with the qRT-PCR. Results: There were the four genes that matched the NGS and qRT-PCR results, all of which were upregulated genes. The four genes are CYP1A1, CYP1B1, LINC01816, and BPIFA2. All four genes that matched the two results were upregulated genes and none of the downregulated genes matched. Conclusion: CYP1A1 and CYP1B1 are known to cause lung cancer by metabolizing polycyclic aromatic hydrocarbons, and long noncoding RNA is also known to play an important role in lung cancer. Considering this, we thought PM10 might be associated with lung cancer by activating CYP1A1, CYP1B1, and LINC01816.

9.
Sensors (Basel) ; 20(24)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371378

RESUMO

Chromatic confocal microscopy (CCM) has been intensively developed because it can exhibit effective focal position scanning based on the axial chromatic aberration of broadband light reflected from a target. To improve the imaging speed of three-dimensional (3D) surface profiling, we have proposed the novel concept of swept-source-based CCM (SS-CCM) and investigated the usefulness of the corresponding imaging system. Compared to conventional CCM based on a broadband light source and a spectrometer, a swept-source in the proposed SS-CCM generates light with a narrower linewidth for higher intensity, and a single photodetector employed in the system exhibits a fast and sensitive response by immediately obtaining spectrally encoded depth from a chromatic dispersive lens array. Results of the experiments conducted to test the proposed SS-CCM system indicate that the system exhibits an axial chromatic focal distance range of approximately 360 µm for the 770-820 nm swept wavelength range. Moreover, high-speed surface profiling images of a cover glass and coin were successfully obtained with a short measurement time of 5 ms at a single position.

10.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322202

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid ß (Aß) in the brain. Although several studies reported possible mechanisms involved in Aß pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aß-responsive gene involved in Aß cytotoxicity. However, we still do not know how Aß increases the level of REDD1 and whether REDD1 mediates Aß-induced synaptic dysfunction. To elucidate this, we examined the effect of Aß on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aß-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aß-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aß injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aß-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aß may increase REDD1 translation rather than transcription. Aß activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aß-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aß blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aß-induced synaptic deficits. REDD1 shRNA also blocked Aß-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aß pathology and could be a target for AD therapy.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/farmacologia , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transtornos da Memória/metabolismo , Sinapses/metabolismo , Fatores de Transcrição/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Anisomicina/farmacologia , Dactinomicina/farmacologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Transtornos da Memória/genética , Transtornos da Memória/patologia , Testes de Memória e Aprendizagem , Camundongos , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , RNA Interferente Pequeno , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/genética , Sinapses/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Regulação para Cima
11.
Noncoding RNA Res ; 5(4): 201-207, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33251387

RESUMO

O-GlcNAc Transferase (OGT) is a complementary enzyme that regulates O-linked N-acetylglucosaminylation(O-GlcNAcylation) and plays a critical role in various cancer phenotypes, including invasion, migration, and metabolic reprogramming. In our previous study we found that miR-7-5p was downregulated at lung cancer cells with highly metastatic capacity. In the in-silico approach, OGT is the predicted target of miR-7-5p. To identify miR-7-5p's role in cell growth and metabolism, we transfected various lung cancer cell lines with miR-7-5p. The expression level of miR-7-5p was confirmed by qRT-PCR in lung cancer cell lines. Western blot assays and qRT-PCR were performed to demonstrate miR-7-5p's effect. Bioinformatic analysis indicated that OGT is a direct target of miR-7-5p. The binding sites of miR-7-5p in the OGT 3' UTR were verified by luciferase reporter assay. To investigate the role of miR-7-5p in the cancer metabolism of non-small cell lung cancer (NSCLC) cells, mimic of miR-7-5p was transfected into NSCLC cells, and the effect of miR-7-5p on cancer metabolism was analyzed by LDH assays, glucose uptake, and mitochondrial ATP synthase inhibitor assay. O-GlcNAcylated protein level was determined by Western blot. The role of miR-7-5p in lung cancer growth was measured by MTS assays. To identify the delivery of miR-7-5p via PLGA, an in vitro release assay of PLGA-miR-7-5p was done. miR-7-5p was highly expressed whereas OGT showed low expression in H358, H827. However, miR-7-5p exhibited low expression while OGT had high expression in H522, H460, and H1299 cell lines. OGT were repressed by binding of miR-7a-5p to the 3'-UTR. Overexpression of miR-7-5p also diminished anaerobic glycolysis. miR-181a-5p transfection induced expression levels of OGT were diminished compared to those in the control group. O-GlcNAcylation was suppressed by miR-7-5p. Moreover, the overexpression of miR-7-5a suppressed lung cancer cell growth. miR-7-5p was released via PLGA for up to 10 days. In the present study, inhibition of OGT by miR-7-5p decreased the growth and cancer metabolism of lung cancer.

12.
Nanomedicine ; 32: 102316, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33068744

RESUMO

Among various strategies to treat neurodegenerative disorders, cell replacement therapies have drawn much attention recently. Such a trend led to the increase in demand for the rare and specialized cells, followed by the outburst development of various cell reprogramming strategies. However, several limitations on these conventional methods remain to be solved, including the genetic instability of the viral vectors and the high cytotoxicity or poor performance of the non-viral carriers. Therefore, non-viral methods need to be developed to ensure safe and efficient cell reprogramming. Here, we introduce a polymer-modified nano-reagent (Polymer-functionalized Nanodot, PolyN) for the safe and efficient, non-viral direct cell reprogramming. PolyN facilitated the highly efficient contemporary overexpression of the transgene compared to the conventional reagent. With our nano-reagent, we demonstrated the SOX2-mediated cell reprogramming and successfully generated the neuron-like cell from the human fibroblast.

13.
J Psychiatr Res ; 131: 152-159, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32971359

RESUMO

The aim of this study was to determine whether the driving-related cognitive performance differs among adults with schizophrenia taking different types of antipsychotics. Neurocognitive performance was assessed using the Cognitive Perceptual Assessment for Driving (CPAD), a computerized battery of tests of visual perception, attention, working memory, reaction time, and inhibitory control for driving ability. One hundred and two adults with schizophrenia who were on antipsychotic monotherapy participated in the study. Of these, 15 were on haloperidol, 28 on risperidone, 14 on olanzapine, 28 on aripiprazole, and 17 on paliperidone. Sixty-four (63%) of the 102 subjects were regarded as competent to drive. Of the subjects taking haloperidol, 33% passed the CPAD, while the passing rates of subjects taking risperidone, olanzapine, aripiprazole, and paliperidone were 57%, 57%, 75%, and 82%, respectively, with a significant difference between the haloperidol and aripiprazole groups (p = 0.005) and between the haloperidol and paliperidone groups (p = 0.001). Additionally, scores on CPAD depth perception (number of correct responses), divided attention, digit span test, and trail-making test B subtests were significantly better for the aripiprazole and paliperidone groups than for the haloperidol and risperidone groups. In this cross-sectional design study, adults with schizophrenia treated with aripiprazole or paliperidone antipsychotic monotherapy demonstrated superior driving-related cognitive performance than those treated with haloperidol or risperidone antipsychotic monotherapy.

14.
J Affect Disord ; 276: 616-622, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871693

RESUMO

BACKGROUND: The precise relationships among depression, risk factors for cardiovascular disease (CVD), and incident CVD remain uncertain. This study examined the joint effect of depression and other CVD risk factors on the incidence of CVD. METHODS: We conducted a prospective cohort study using South Korea's National Health Insurance Service-National Sample Cohort (NHIS-NSC). To estimate incident CVD, 199,544 participants without CVD diagnosed with depression between 2003 and 2005 were followed through 2013. The clinician's diagnosis used measurements for depression, CVD risk factors, and CVD. RESULTS: Controlling for other CVD risk factors, depressed individuals had a higher risk for ischemic heart disease (AHR, 1.01; 99%%CI, 1.01-1.50) and other forms of heart disease likely related to atherosclerosis (AHR, 1.43; 99%%CI, 1.13-1.82). There were no statistically significant interactions between depression and CVD risk factors. However, when depression was comorbid with overweight or diabetes, there was a higher risk for incident ischemic heart disease, as compared to depression or CVD risk factors alone. For other forms of heart disease likely related to atherosclerosis, the coexistence of depression and physical inactivity or overweight showed a similar pattern to that shown in ischemic heart disease. LIMITATIONS: The severity of depression was not reported for depressed patients, and our dataset provided a limited number of covariates. Also, the self-reported health behavior data may be biased. CONCLUSION: As depression could be a significant predictor of incident CVD independently with other CVD risk factors, professionals should recognize and manage depression as a major CVD risk factor.

15.
Brain Commun ; 2(2): fcaa058, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32766549

RESUMO

Aggregation of amyloid beta and loss of cholinergic innervation in the brain are predominant components of Alzheimer's disease pathology and likely underlie cognitive impairment. Acetylcholinesterase inhibitors are one of the few treatment options for Alzheimer's disease, where levels of available acetylcholine are enhanced to counteract the cholinergic loss. However, these inhibitors show limited clinical efficacy. One potential explanation for this is a concomitant dysregulation of cholinergic receptors themselves as a consequence of the amyloid beta pathology. We tested this hypothesis by examining levels of M1 muscarinic acetylcholine receptors in the temporal cortex from seven Alzheimer's disease and seven non-disease age-matched control brain tissue samples (control: 85 ± 2.63 years old, moderate Alzheimer's disease: 84 ± 2.32 years old, P-value = 0.721; eight female and six male patients). The samples were categorized into two groups: 'control' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'No Alzheimer's disease', and Braak staging pathology of I-II) and 'moderate Alzheimer's disease' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'possible/probable Alzheimer's disease', and Braak staging pathology of IV). We find that in comparison to age-matched controls, there is a loss of M1 muscarinic acetylcholine receptors in moderate Alzheimer's disease tissue (control: 2.17 ± 0.27 arbitrary units, n = 7, Mod-AD: 0.83 ± 0.16 arbitrary units, n = 7, two-tailed t-test, t = 4.248, P = 0.00113). Using a functional rat cortical brain slice model, we find that postsynaptic muscarinic acetylcholine receptor function is dysregulated by aberrant amyloid beta-mediated activation of metabotropic glutamate receptor 5. Crucially, blocking metabotropic glutamate receptor 5 restores muscarinic acetylcholine receptor function and object recognition memory in 5XFAD transgenic mice. This indicates that the amyloid beta-mediated activation of metabotropic glutamate receptor 5 negatively regulates muscarinic acetylcholine receptor and illustrates the importance of muscarinic acetylcholine receptors as a potential disease-modifying target in the moderate pathological stages of Alzheimer's disease.

16.
Sci Adv ; 6(22): eaaz8201, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32523995

RESUMO

Direct-acting agents against viral components are considered as the most promising candidates for the successful antiviral therapeutics. To date, no direct-acting drugs exist for the treatment against dengue virus (DV) infection, which can develop into life-threatening diseases. RNA-dependent RNA polymerase (RdRp), an RNA virus-specific enzyme highly conserved among various viral families, has been known as the broad-range antiviral drug target. Here, we developed an RNA-based graphene biosensor system [RNA nano-graphene oxide system (RANGO)] to enable the fluorescence-based quantitative analysis of the RdRp enzyme activity. We used the RANGO system to a high-throughput chemical screening to identify novel direct-acting antiviral drug candidates targeting DV RdRp from the FDA-approved small-molecule library. RANGO accelerated the massive selection of drug candidates. We found that one of the selected hit compounds, montelukast, showed antiviral activity in vitro and in vivo by directly inhibiting replication of DV and thus relieved related symptoms.

17.
Cells ; 9(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532027

RESUMO

Receptor-mediated lysophosphatidic acid (LPA) signaling has come to be considered an important event for various diseases. In cerebral ischemia, LPA1 has recently been identified as a receptor subtype that mediates brain injury, but the roles of other LPA receptor subtypes remain unknown. Here, we investigated the potential role of LPA5 as a novel pathogenic factor for cerebral ischemia using a mouse model of transient middle cerebral artery occlusion (tMCAO). LPA5 was upregulated in the ischemic core region after tMCAO challenge, particularly in activated microglia. When TCLPA5, a selective LPA5 antagonist, was given to tMCAO-challenged mice immediately after reperfusion, brain damage, including brain infarction, functional neurological deficit, and neuronal and non-neuronal apoptosis, was reduced in mice. Similarly, delayed TCLPA5 administration (at three hours after reperfusion) reduced brain infarction and neurological deficit. The histological results demonstrated that TCLPA5 administration attenuated microglial activation, as evidenced by the decreased Iba1 immunoreactivities, the number of amoeboid cells, and proliferation in an injured brain. TCLPA5 administration also attenuated the upregulation of the expression of pro-inflammatory cytokines at mRNA levels in post-ischemic brain, which was also observed in lipopolysaccharide-stimulated BV2 microglia upon LPA5 knockdown. Overall, this study identifies LPA5 as a novel pathogenic factor for cerebral ischemia, further implicating it as a promising target for drug development to treat this disease.

18.
Int J Mol Sci ; 21(10)2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32414166

RESUMO

The aim of this study was to examine whether rubrofusarin, an active ingredient of the Cassia species, has an antidepressive effect in chronic restraint stress (CRS) mouse model. Although acute treatment using rubrofusarin failed, chronic treatment using rubrofusarin ameliorated CRS-induced depressive symptoms. Rubrofusarin treatment significantly reduced the number of Fluoro-Jade B-positive cells and caspase-3 activation within the hippocampus of CRS-treated mice. Moreover, rubrofusarin treatment significantly increased the number of newborn neurons in the hippocampus of CRS-treated mice. CRS induced activation of glycogen synthase kinase-3ß and regulated development and DNA damage responses, and reductions in the extracellular-signal-regulated kinase pathway activity were also reversed by rubrofusarin treatment. Microglial activation and inflammasome markers, including nod-like receptor family pyrin domain containing 3 and adaptor protein apoptosis-associated speck-like protein containing CARD, which were induced by CRS, were ameliorated by rubrofusarin. Synaptic plasticity dysfunction within the hippocampus was also rescued by rubrofusarin treatment. Within in vitro experiments, rubrofusarin blocked corticosterone-induced long-term potentiation impairments. These were blocked by LY294002, which is an Akt inhibitor. Finally, we found that the antidepressant effects of rubrofusarin were blocked by an intracerebroventricular injection of LY294002. These results suggest that rubrofusarin ameliorated CRS-induced depressive symptoms through PI3K/Akt signaling.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32428535

RESUMO

The γ-aminobutyric acid A (GABAA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABAA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABAA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABAA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABAA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32260265

RESUMO

The purpose of the present study was to compare the health behaviors, general health, and mental health of South Korean employees according to their employment status, and to examine how these associations vary across genders using the latest Korean National Examination Health and Nutrition Survey data. Logistic regression analyses were performed using employment status-permanent job, temporary job, and unemployed-as predictor variables and health-related variables as the outcome variables. Results indicated that temporary workers and the unemployed have higher odds of poor mental health regardless of gender. On the other hand, only male permanent workers were found to have a higher risk of problematic drinking compared to precarious workers and the unemployed. Meanwhile, only women showed a higher risk of current smoking in the temporary job and unemployed groups compared with permanent employees. Regarding general health, women, not men, in the temporary job group reported poorer general health (i.e., low health-related quality of life and higher self-perceived poor health) than those in other groups. These findings suggest that the development and implementation of intervention services, as well as organizational actions, need to consider differential impacts of unfavorable employment status on health issues according to gender.


Assuntos
Comportamentos Relacionados com a Saúde , Saúde Mental , Qualidade de Vida , Adolescente , Adulto , Emprego , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Adulto Jovem
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