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1.
Plant Physiol ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690709

RESUMO

The phytochrome B (phyB) photoreceptor stimulates light responses in plants in part by inactivating repressors of light responses, such as PHYTOCHROME-INTERACTING FACTOR3 (PIF3). Activated phyB inhibits PIF3 by rapid protein degradation and decreased transcription. PIF3 protein degradation is mediated by EIN3-BINDING F-BOX PROTEIN (EBF) and LIGHT-RESPONSE BTB (LRB) E3 ligases, the latter of which simultaneously targets phyB for degradation. In this study, we show PIF3 levels are additionally regulated by alternative splicing and protein translation in Arabidopsis (Arabidopsis thaliana). Overaccumulation of photo-activated phyB, which occurs in the mutant defective for LRB genes under continuous red light, induces a specific alternative splicing of PIF3 that results in retention of an intron in the 5' untranslated region (5' UTR) of PIF3 mRNA. In turn, the upstream open reading frames (uORFs) contained within this intron inhibit PIF3 protein synthesis. The phyB-dependent alternative splicing of PIF3 is diurnally regulated under the short-day light cycle. We hypothesize this reversible regulatory mechanism may be utilized to fine tune the level of PIF3 protein in light-grown plants and may contribute to the oscillation of PIF3 protein abundance under the short-day environment.

2.
Biol Res ; 52(1): 56, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699158

RESUMO

BACKGROUND: ADP-glucose pyrophosphorylase (AGPase), the key enzyme in plant starch biosynthesis, is a heterotetramer composed of two identical large subunits and two identical small subunits. AGPase has plastidial and cytosolic isoforms in higher plants, whereas it is mainly detected in the cytosol of grain endosperms in cereal crops. Our previous results have shown that the expression of the TaAGPL1 gene, encoding the cytosolic large subunit of wheat AGPase, temporally coincides with the rate of starch accumulation and that its overexpression dramatically increases wheat AGPase activity and the rate of starch accumulation, suggesting an important role. METHODS: In this study, we performed yeast one-hybrid screening using the promoter of the TaAGPL1 gene as bait and a wheat grain cDNA library as prey to screen out the upstream regulators of TaAGPL1 gene. And the barley stripe mosaic virus-induced gene-silencing (BSMV-VIGS) method was used to verify the functional characterization of the identified regulators in starch biosynthesis. RESULTS: Disulfide isomerase 1-2 protein (TaPDIL1-2) was screened out, and its binding to the TaAGPL1-1D promoter was further verified using another yeast one-hybrid screen. Transiently silenced wheat plants of the TaPDIL1-2 gene were obtained by using BSMV-VIGS method under field conditions. In grains of BSMV-VIGS-TaPDIL1-2-silenced wheat plants, the TaAGPL1 gene transcription levels, grain starch contents, and 1000-kernel weight also significantly increased. CONCLUSIONS: As important chaperones involved in oxidative protein folding, PDIL proteins have been reported to form hetero-dimers with some transcription factors, and thus, our results suggested that TaPDIL1-2 protein could indirectly and negatively regulate the expression of the TaAGPL1 gene and function in starch biosynthesis.

3.
Nanoscale ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31667484

RESUMO

Lanthanide-based coordination polymers (CPs) have received great attention due to their tuneable structures and excellent luminescence properties. However, limited by the stability and micro/nanoscale morphology, a very small number of lanthanide-based CPs have been used for photonic applications. Herein, we present the synthesis of Eu-based CPs (compound 2) with highly regular one-dimensional (1D) microrod morphology by in situ structure transformation from compound 1. Moreover, the Eu-based CP microrods have an excellent stability and a high photoluminescence quantum yield (PLQY), and the distance-dependent PL spectra also exhibited typical characteristics of photoactive waveguides with a low optical-loss coefficient (0.00894 dB µm-1) during propagation. These intriguing behaviors not only extend the research field of optical waveguides through lanthanide-based CPs, but also provide an opportunity for further application in optical communication systems.

4.
BMC Plant Biol ; 19(1): 459, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666019

RESUMO

BACKGROUND: Long non-coding (lnc) RNAs are a class of functional RNA molecules greater than 200 nucleotides in length, and lncRNAs play important roles in various biological regulatory processes and response to the biotic and abiotic stresses. LncRNAs associated with salt stress in cotton have been identified through RNA sequencing, but the function of lncRNAs has not been reported. We previously identified salt stress-related lncRNAs in cotton (Gossypium spp.), and discovered the salt-related lncRNA-lncRNA973. RESULTS: In this study, we identified the expression level, localization, function, and preliminary mechanism of action of lncRNA973. LncRNA973, which was localized in the nucleus, was expressed at a low level under nonstress conditions but can be significantly increased by salt treatments. Here lncRNA973 was transformed into Arabidopsis and overexpressed. Along with the increased expression compared with wild type under salt stress conditions in transgenic plants, the seed germination rate, fresh weights and root lengths of the transgenic plants increased. We also knocked down the expression of lncRNA973 using virus-induced gene silencing technology. The lncRNA973 knockdown plants wilted, and the leaves became yellowed and dropped under salt-stress conditions, indicating that the tolerance to salt stress had decreased compared with wild type. LncRNA973 may be involved in the regulation of reactive oxygen species-scavenging genes, transcription factors and genes involved in salt stress-related processes in response to cotton salt stress. CONCLUSIONS: LncRNA973 was localized in the nucleus and its expression was increased by salt treatment. The lncRNA973-overexpression lines had increased salt tolerance compared with the wild type, while the lncRNA973 knockdown plants had reduced salt tolerance. LncRNA973 regulated cotton responses to salt stress by modulating the expression of a series of salt stress-related genes. The data provides a basis for further studies on the mechanisms of lncRNA973-associated responses to salt stress in cotton.

5.
J Med Genet ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704776

RESUMO

BACKGROUND: Abnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in female infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in female infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown. OBJECTIVE: We aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest. METHODS: Whole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay. RESULTS: We identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation. CONCLUSIONS: Our study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human female meiosis and fertility.

6.
J Neurovirol ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654372

RESUMO

This case report presents a 1-year-old boy from China, with sudden onset of fever, convulsion, and sleepiness, screened for viral DNA in blood and cerebrospinal fluid (CSF) sample using next-generation sequencing (NGS) to diagnose herpes simplex virus type 1 (HSV-1) encephalitis, further validated by PCR. After acyclovir treatment, the patient's symptom disappeared and HSV-1 DNA unique reads decreased from 4290 to zero in CSF, and from 23 to zero in blood detected by NGS. The clinical presentation and outcome were consistent with the pathogenic diagnostic results of NGS. NGS of CSF samples can be used as a diagnostic assay for HSV-1 encephalitis and also might be a semi-quantitative method for evaluation of treatment effect.

7.
Biomolecules ; 9(10)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614550

RESUMO

Histamine (HA) is an important food contaminant generated during food fermentation or spoilage. However, an immunoassay for direct (derivatization free) determination of HA has rarely been reported due to its small size to induce the desired antibodies by its current hapten-protein conjugates. In this work, despite violating the classical hapten design criteria which recommend introducing a linear aliphatic (phenyl free) linker into the immunizing hapten, a novel haptens, HA-245 designed and synthesized with a phenyl-contained linker, exhibited significantly enhanced immunological properties. Thus, a quality-improved monoclonal antibody (Mab) against HA was elicited by its hapten-carrier conjugates. Then, as the linear aliphatic linker contained haptens, Hapten B was used as linker-heterologous coating haptens to eliminate the recognition of linker antibodies. Indirect competitive ELISA (ic-ELISA) was developed with a 50% inhibition concentration (IC50) of 0.21 mg/L and a limit of detection (LOD) of 0.06 mg/L in buffer solution. The average recoveries of HA from spiked food samples for this ic-ELISA ranged from 84.1% and 108.5%, and the analysis results agreed well with those of referenced LC-MS/MS. This investigation not only realized derivatization-free immunoassay for HA, but also provided a valuable guidance for hapten design and development of immunoassay for small molecules.

8.
J Agric Food Chem ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31617717

RESUMO

Because Monascus pigments (MPs) predominantly accumulate in the cytoplasm during submerged fermentation, many biotechnologies are applied to enhance the production of extracellular MPs (exMPs) to reduce the downstream processing costs. In this study, the genes monascus_7017 and monascus_8018, identified as ERG4 genes, were knocked out to disrupt the ergosterol biosynthetic pathway and enhance the production of exMPs in Monascus purpureus LQ-6. Double-deletion of EGR4 in M. purpureus LQ-6 reduced ergosterol concentration by 57.14% and enhanced exMPs production 2.06-fold. In addition, integrated transcriptomic and proteomic analyses were performed to elucidate the trans-membrane secretion mechanism of exMPs based on the relationship between ergosterol synthesis and membrane permeability, which revealed that several metabolic pathways were noticeably dynamic, including fatty acid degradation, amino acid metabolism, energy metabolism, carbohydrate metabolism, and transport. These findings therefore clarified the secretion mechanism of exMPs and provide a novel strategy for further enhancement of exMPs production in submerged fermentation.

9.
Elife ; 82019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566565

RESUMO

Nanobodies (nAbs) are small, minimal antibodies that have distinct attributes that make them uniquely suited for certain biomedical research, diagnostic and therapeutic applications. Prominent uses include as intracellular antibodies or intrabodies to bind and deliver cargo to specific proteins and/or subcellular sites within cells, and as nanoscale immunolabels for enhanced tissue penetration and improved spatial imaging resolution. Here, we report the generation and validation of nAbs against a set of proteins prominently expressed at specific subcellular sites in mammalian brain neurons. We describe a novel hierarchical validation pipeline to systematically evaluate nAbs isolated by phage display for effective and specific use as intrabodies and immunolabels in mammalian cells including brain neurons. These nAbs form part of a robust toolbox for targeting proteins with distinct and highly spatially-restricted subcellular localization in mammalian brain neurons, allowing for visualization and/or modulation of structure and function at those sites.

10.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3454-3459, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602909

RESUMO

The present study was aimed to explore the dose-toxicity-effect relationship of Tripterygium wilfordii Hook f( TW) processed by liquorice,to establish the safe and effective therapeutic window,and further to provide scientific reference for the clinical use of TW. The toxicity and anti-inflammatory effect of six doses of raw TW and TW processed by liquorice( 0. 78,1. 56,3. 12,6. 24,12. 48,15. 60 g·kg-1) in 1-fluoro-2,4-dinitrobenzene( DNFB)-induced allergic contact dermatitis( ACD) model were mainly examined by histopathology and serum biochemistry. The liver biochemical parameters including ALT and AST,related inflammatory factors including TNF-α and IL-2,together with liver index,kidney index and the other pharmacodynamic indicators,were examined and compared. The results showed that compared with the control group,the serum levels of TNF-α and IL-2 of the model group were significantly increased( P<0. 01),which proved that the ACD model was successful. The comprehensive analysis of liver biochemical indexes,serum inflammatory factors and the other indexes showed that the safe and effective therapeutic window of TW processed by liquorice was 3. 12-12. 48 g·kg-1. The results showed the therapeutic window of TW processed by liquorice was much broader than that of raw TW. And it could provide scientific reference for the clinical rational use of TW.


Assuntos
Dermatite Alérgica de Contato/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Glycyrrhiza/química , Extratos Vegetais/farmacologia , Tripterygium/química , Animais , Citocinas/sangue
11.
J Nephrol ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31643008

RESUMO

BACKGROUND: Uremic toxins have been suspected as potential contributors for cognitive impairment in peritoneal dialysis (PD) patients. However, associations between the clearance of serum small and middle molecules and the change of cognitive function were not fully explored and then we explored this issue in the present study. METHOD: A total of clinically-stable 222 patients on PD were enrolled and then followed up for 2 years in this single-center prospective cohort study. Small and middle molecules clearances were examined by urea clearance (Kt/V), creatinine clearance (Ccr) and beta-2 microglobulin (B2M) clearance via dialysate and urine at baseline and after 2 years. Global and specific cognitive impairment were measured at baseline and after 2 years. Modified Mini-Mental State Examination (3MS) was assessed for global cognitive function, trail-making tests A and B for executive function and subtests of the battery for the assessment of neuropsychological status for immediate and delayed memory, visuospatial skills and language ability. RESULTS: The median of total Kt/V, Ccr and B2M clearance were 1.89, 53.2 l/w/1.73 m2 and 17.5 l/w/1.73 m2, respectively at baseline. The prevalence of global cognitive impairment was 12.3% for 222 patients and 15.4% for the remained 130 patients after 2 years. At baseline, total Kt/V was independently positively associated with delayed memory function. Total and dialysate beta-2 microglobulin clearance was positively associated with 3MS scores and negatively with completion time on trail A after multivariate adjustment. At 2 years, we observed a significant difference in the changing trend of 3MS scores between groups divided by total B2M clearance (P = 0.033), which still maintained to be meaningful after multivariate adjustment (P = 0.024). Patients with total B2M clearance > 19.0 l/w/1.73 m2 got significant improvement on their 3MS scores (P = 0.005). Patients divided by total Kt/V or Ccr were not significantly different in the trends of general and any specific cognitive function during the follow up. CONCLUSION: The higher middle molecules clearance independently correlated to better performance on general cognitive and executive function in PD patients, which also predict an improvement in general cognitive function during the follow up.

12.
Biomolecules ; 9(10)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591300

RESUMO

Nanobodies are one-tenth the size of conventional antibodies and are naturally obtained from the atypical heavy-chain-only antibodies present in camelids. Their small size, high solubility, high stability, and strong resilience to organic solvents facilitate their use as novel analytical reagents in immunochemistry. In this study, specific nanobodies against pesticide carbofuran were isolated and characterized from an immunized library via phage display platform. We further established an indirect competitive enzyme-linked immunosorbent assay (ELISA) using nanobody Nb316 to detect carbofuran in vegetable and fruit samples. The results showed a half-maximal inhibitory concentration (IC50) of 7.27 ng/mL and a detection limit of 0.65 ng/mL. A simplified sample pretreatment procedure omitting the evaporation of organic solvent was used. The averaged recovery rate of spiked samples ranged between 82.3% and 103.9%, which correlated with that of standard UPLC-MS/MS method. In conclusion, a nanobody with high specificity for carbofuran was characterized, and a nanobody-based sensitive immunoassay for simple and rapid detection of carbofuran in real samples was validated.

13.
Chin Med J (Engl) ; 132(19): 2278-2285, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31567379

RESUMO

BACKGROUND: Clinical assessment and treatment guidance for heart failure depends on a variety of biomarkers. The objective of this study was to investigate the prognostic predictive value of growth differentiation factor-15 (GDF-15) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in assessing hospitalized patients with acute heart failure (AHF). METHODS: In total, 260 patients who were admitted for AHF in the First Affiliated Hospital of Nanjing Medical University were enrolled from April 2012 to May 2016. Medical history and blood samples were collected within 24 h after the admission. The primary endpoint was the all-cause mortality within 1 year. The patients were divided into survival group and death group based on the endpoint. With established mortality risk factors and serum GDF-15 level, receiver-operator characteristic (ROC) analyses were performed. Cox regression analyses were used to further analyze the combination values of NT-proBNP and GDF-15. RESULTS: Baseline GDF-15 and NT-proBNP were significantly higher amongst deceased than those in survivors (P < 0.001). In ROC analyses, area under curve (AUC) for GDF-15 to predict 1-year mortality was 0.707 (95% confidence interval [CI]: 0.648-0.762, P < 0.001), and for NT-proBNP was 0.682 (95% CI: 0.622-0.738, P < 0.001). No statistically significant difference was found between the two markers (P = 0.650). Based on the optimal cut-offs (GDF-15: 4526.0 ng/L; NT-proBNP: 1978.0 ng/L), the combination of GDF-15 and NT-proBNP increased AUC for 1-year mortality prediction (AUC = 0.743, 95% CI: 0.685-0.795, P < 0.001). CONCLUSIONS: GDF-15, as a prognostic marker in patients with AHF, is not inferior to NT-proBNP. Combining the two markers could provide an early recognition of high-risk patients and improve the prediction values of AHF long-term prognosis. CLINICAL TRIAL REGISTRATION: ChiCTR-ONC-12001944, http://www.chictr.org.cn.

14.
Hum Brain Mapp ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31571320

RESUMO

Machine learning has increasingly been applied to classification of schizophrenia in neuroimaging research. However, direct replication studies and studies seeking to investigate generalizability are scarce. To address these issues, we assessed within-site and between-site generalizability of a machine learning classification framework which achieved excellent performance in a previous study using two independent resting-state functional magnetic resonance imaging data sets collected from different sites and scanners. We established within-site generalizability of the classification framework in the main data set using cross-validation. Then, we trained a model in the main data set and investigated between-site generalization in the validated data set using external validation. Finally, recognizing the poor between-site generalization performance, we updated the unsupervised algorithm to investigate if transfer learning using additional unlabeled data were able to improve between-site classification performance. Cross-validation showed that the published classification procedure achieved an accuracy of 0.73 using majority voting across all selected components. External validation found a classification accuracy of 0.55 (not significant) and 0.70 (significant) using the direct and transfer learning procedures, respectively. The failure of direct generalization from one site to another demonstrates the limitation of within-site cross-validation and points toward the need to incorporate efforts to facilitate application of machine learning across multiple data sets. The improvement in performance with transfer learning highlights the importance of taking into account the properties of data when constructing predictive models across samples and sites. Our findings suggest that machine learning classification result based on a single study should be interpreted cautiously.

15.
Nanotoxicology ; 13(9): 1244-1274, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31537143

RESUMO

Carbon nanotubes (CNTs) are nanomaterials with unique physicochemical properties that are targets of great interest for industrial and commercial applications. Notwithstanding, some characteristics of CNTs are associated with adverse outcomes from exposure to pathogenic particulates, raising concerns over health risks in exposed workers and consumers. Indeed, certain forms of CNTs induce a range of harmful effects in laboratory animals, among which inflammation, fibrosis, and cancer are consistently observed for some CNTs. Inflammation, fibrosis, and malignancy are complex pathological processes that, in summation, underlie a major portion of human disease. Moreover, the functional interrelationship among them in disease pathogenesis has been increasingly recognized. The CNT-induced adverse effects resemble certain human disease conditions, such as pneumoconiosis, idiopathic pulmonary fibrosis (IPF), and mesothelioma, to some extent. Progress has been made in understanding CNT-induced pathologic conditions in recent years, demonstrating a close interconnection among inflammation, fibrosis, and cancer. Mechanistically, a number of mediators, signaling pathways, and cellular processes are identified as major mechanisms that underlie the interplay among inflammation, fibrosis, and malignancy, and serve as pathogenic bases for these disease conditions in CNT-exposed animals. These studies indicate that CNT-induced pathological effects, in particular, inflammation, fibrosis, and cancer, are mechanistically, and in some cases, causatively, interrelated. These findings generate new insights into CNT adverse effects and pathogenesis and provide new targets for exposure monitoring and drug development against inflammation, fibrosis, and cancer caused by inhaled nanomaterials.

16.
Bioresour Technol ; 294: 122133, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31525583

RESUMO

Enzymatic hydrolysis of lignocellulose to produce bioethanol by cellulase is an important method to alleviate the energy crisis. In this paper, in order to overcome the shortcomings of low efficiency, high cost and easy deactivation of cellulase in the process of bio-refinery, pH-responsive lignin-based magnetic nanoparticles (Fe3O4/LSQA) were synthesized to immobilize and recover cellulase. It was shown that a high immobilization ratio of 55.52% for cellulase was obtained. Meanwhile, the desorption ratio was 68.27% by adjusting the pH of the system. After five reusing cycles, the desorbed cellulase retained 31.79% of the relative activity due to the pH responsiveness of Fe3O4/LSQA. These results not only provide a new idea for the recycling of cellulase, but also broaden the application of industrial lignin and increase the extra value.


Assuntos
Celulase , Nanopartículas de Magnetita , Concentração de Íons de Hidrogênio , Hidrólise , Lignina
17.
Placenta ; 86: 4-10, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31491693

RESUMO

OBJECTIVE: In the mouse model, manipulations of assisted reproductive technology (ART) can lead to enlarged placentas and influence the expression of glucose transporters (GLUTs) in placentas during mid-to late-gestation. Expression of imprinted genes which plays a vital role in placental growth and function, is also vulnerable to be affected by ART. However, it is uncertain whether those abnormal changes presented in ART mouse placentas also occur in human ART placentas. METHODS: We compared the expression of GLUT family genes (SLC2A1- SLC2A13), mTOR activity, the expression of four imprinted genes (H19, IGF2, CDKN1C and PHLDA2), and KCNQ1OT1 methylation in human placentas conceived naturally or by ART. RESULTS: Our data showed that the placental weight and birthweight were similar between NC (n = 20) and ART group (n = 20). We found that up-regulated mRNA expression of GLUTs and elevated GLUT1 protein level occurred in human ART placentas with unchanged mTOR activity. And we found that mRNA and protein expression of PHLDA2 were significantly increased in ART placentas compared with placentas from natural pregnancies. Additionally, we revealed that ART placentas had increased expression of KCNQ1OT1 which negatively controls PHLDA2 expression. CONCLUSION: This study reveals that the increased expression of GLUTs occurs in human ART placentas with normal mTOR activity. The down-regulated expression of imprinted gene PHLDA2 may account for the up-regulation of GLUTs. Those adaptive changes in ART placentas may explain why most of ART offspring have normal birth weight at born.

18.
Sensors (Basel) ; 19(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505871

RESUMO

The authors wish to make the following corrections to this paper [1]: [...].

19.
Kidney Blood Press Res ; 44(5): 1115-1127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31537006

RESUMO

BACKGROUND: Patients with chronic kidney disease experience a high burden of sleep disorders, and there are associations between sleep disorders and cognitive impairment. OBJECTIVES: Based on our previous cross-sectional survey on cognitive impairment in peritoneal dialysis, we further explored the relationship between sleep disorders and cognitive impairment, and predictors for declining cognitive function. METHOD: We conducted a multicenter prospective cohort study enrolling 458 clinically stable patients on peritoneal dialysis who were then followed up for 2 years.Demographic data, comorbidities, depression, and biochemistry data were collected at baseline. Sleep disorders including insomnia, restless legs syndrome, sleep apnea syndrome, excessive daytime sleepiness, possible narcolepsy, sleep walking and nightmares, and possible rapid eye movement behavior disorders were assessed using a panel of specific sleep questionnaires at baseline and in a second survey. Global cognitive function was measured at baseline and in a second survey, using the Modified Mini-Mental State Examination. Specific cognitive domains were evaluated using Trail-Making Test Forms A and B for executive function, and subtests of the Battery for the Assessment of Neuropsychological Status were used to asses immediate and delayed memory, visuospatial skills, and language ability. RESULTS: Sleep disorders were common among peritoneal dialysis patients. The prevalence of cognitive impairment evaluated by the Modified Mini-Mental State Examination (3MS) increased from 19.8 to 23.9%. Possible narcolepsy was associated with decreased Modified Mini-Mental State Examination scores at baseline. During follow-up, sleepwalking and nightmares were associated with higher risks of declined delayed memory in the longitudinal study. CONCLUSIONS: Possible narcolepsy was associated with general cognitive dysfunction, and sleep walking and nightmares were risk factors for impaired delayed memory.

20.
J Pineal Res ; 67(4): e12611, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541591

RESUMO

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.

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