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1.
Am J Hum Genet ; 105(5): 974-986, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668702

RESUMO

The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.

2.
Oncol Lett ; 18(5): 5654, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31666816

RESUMO

[This corrects the article DOI: 10.3892/ol.2019.10123.].

3.
Int J Biol Macromol ; 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31593722

RESUMO

The effects of native starch (NS), acetylated starch (AS), and acetylated distarch phosphate (ADSP) on the gel properties of soybean protein thermal gel were investigated using texture analysis, low-field nuclear magnetic resonance (LF-NMR) spectroscopy, dynamic rheometry and scanning electron microscopy. The results of the textural profile analysis showed that 10% ADSP increased the hardness and chewiness of the mixed gel, while NS and AS led to decreases in the textural properties. The results of the LF-NMR analysis indicated that the AS improved the water-holding capacity of the mixed gel due to the transformation of weakly bound water to strongly bound water. During heating and cooling, the rheological profiles of the elastic (G') and viscous modulus (G'') of all the samples exhibited a two-stage pattern of decrease and then increase, and the final values of G' and G'' reached maxima when the ADSP content was 10%. The scanning electron microscopy images showed that the ADSP granules dispersed in the gel network. Theintegrity of the starch granules was crucial for regulating the properties of the soybean protein gel. These results provided information about the further design and preparation of soybean protein foods containing modified starch.

4.
Int J Biol Macromol ; 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31593726

RESUMO

Corn/octenylsuccinated starch (C/OS) composite films incorporated with soybean oil (SO) at 0, 0.5%, 1.0%, 1.5% and 2.0% (w/w) were prepared to investigate their physicochemical properties. Fourier transform infrared analysis indicated that low concentrations of SO could facilitate molecular interaction and the formation of hydrogen bonds between starch molecules. All the films exhibited similar diffractograms and lower relative crystallinity values. Scanning electron microscopy and atomicforcemicroscopy showed that the irregular and coarse surface structures of the films were obtained more frequently with increasing SO concentration. A higher contact angle of 76.14° and lower water vapor permeability of 2.46×10-12 g.cm/cm2. s. Pa were obtained with increasing SO content, with the exception of the 2.0% SO sample. The highest tensile strength value of 6.54 MPa was obtained by the C/OS-1.0% SO composite film, while the optimumelongation at break of 71.84% was exhibited by the C/OS-1.5% SO composite film.

5.
J Biol Chem ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628195

RESUMO

The nuclear factor (erythroid 2)-like (NRF) transcription factors are a subset of cap'n'collar (CNC) transcriptional regulators. They consist of three members, NRF1, NRF2, and NRF3, that regulate the expression of genes containing antioxidant response elements (AREs) in their promoter regions. Although all NRF members regulate ARE-containing genes, each is associated with distinct roles. A comprehensive study of differential and overlapping DNA-binding and transcriptional activities of the NRFs has not yet been conducted. Here, we performed ChIP-exo sequencing, an approach that combines ChIP with exonuclease treatment to pinpoint regulatory elements in DNA with high precision, in conjunction with RNA-Seq to define the transcriptional targets of each NRF member. Our approach, done in three U2OS cell lines, identified 31 genes that were regulated by all three NRF members, 27 of which were regulated similarly by all three, whereas 4 genes were differentially regulated by at least one NRF member. We also found genes that were up- or down-regulated by only one NRF member, with 84, 84, and 22 genes that were regulated by NRF1, NRF2, and NRF3, respectively. Analysis of ARE motifs identified in ChIP peaks revealed that NRF2 prefers binding to AREs flanked by GC-rich regions and that NRF1 prefers AT-rich flanking regions. Thus, sequence preference, likely in combination with upstream signaling events, determines NRF member activation under specific cellular contexts. Our analysis provides a comprehensive description of differential and overlapping gene regulation by the transcriptional regulators NRF1, NRF2, and NRF3.

6.
Cancer Med ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31663688

RESUMO

COX7A1 is a subunit of cytochrome c oxidase, and plays an important role in the super-assembly that integrates peripherally into multi-unit heteromeric complexes in the mitochondrial respiratory chain. In recent years, some researchers have identified that COX7A1 is implicated in human cancer cell metabolism and therapy. In this study, we mainly explored the effect of COX7A1 on the cell viability of lung cancer cells. COX7A1 overexpression was induced by vector transfection in NCI-H838 cells. Cell proliferation, colony formation and cell apoptosis were evaluated in different groups. In addition, autophagy was analyzed by detecting the expression level of p62 and LC3, as well as the tandem mRFP-GFP-LC3 reporter assay respectively. Our results indicated that the overexpression of COX7A1 suppressed cell proliferation and colony formation ability, and promoted cell apoptosis in human non-small cell lung cancer cells. Besides, the overexpression of COX7A1 blocked autophagic flux and resulted in the accumulation of autophagosome via downregulation of PGC-1α and upregulation of NOX2. Further analysis showed that the effect of COX7A1 overexpression on cell viability was partly dependent of the inhibition of autophagy. Herein, we identified that COX7A1 holds a key position in regulating the development and progression of lung cancer by affecting autophagy. Although the crosstalk among COX7A1, PGC-1α and NOX2 needs further investigation, our study provides a novel insight into the therapeutic action of COX7A1 against human non-small cell lung cancer.

7.
Adv Mater ; : e1904408, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31617644

RESUMO

To improve the photovoltaic performance (both efficiency and stability) in hybrid organic-inorganic halide perovskite solar cells, perovskite lattice distortion is investigated with regards to residual stress (and strain) in the polycrystalline thin films. It is revealed that residual stress is concentrated at the surface of the as-prepared film, and an efficient method is further developed to release this interfacial stress by A site cation alloying. This results in lattice reconstruction at the surface of polycrystalline thin films, which in turn results in low elastic modulus. Thus, a "bone-joint" configuration is constructed within the interface between the absorber and the carrier transport layer, which improves device performance substantially. The resultant photovoltaic devices exhibit an efficiency of 21.48% with good humidity stability and improved resistance against thermal cycling.

8.
Bioconjug Chem ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31597042

RESUMO

The interaction between light and tissue such as absorption and scattering limits the penetration depth and spatiotemporal resolution of in vivo fluorescence bioimaging in a noninvasive manner. The near-infrared window (NIR) between 700 and 1700 nm, generally emphasized as the NIR-II (1000-1700 nm) window, has been developed into a promising bio-optical solution chosen as the lower interaction effect in this spectrum. Besides, the beam shaping techniques used in microscopy can also optimize the image quality making the combination change NIR imaging. In this Review, we summarize the recent progress developed on NIR fluorescence including inorganic molecules, small organic molecules, and fluorescence proteins. We also cover the recent advanced beam shaped microscopy techniques to provide options to combine with the emitters introduced previously. Combined with the developed advanced techniques, the improvement potential of current challenges is also discussed.

9.
Environ Sci Technol ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31593442

RESUMO

The uptake of gas-phase dicarboxylic acids to organic particulate matter (PM) was investigated to probe the role of the PM physical state in exchange processes between gas-phase semivolatile organic molecules and organic PM. A homologous series of probe molecules, specifically isotopically labeled 13C-dicarboxylic acids, was used in conjunction with aerosol mass spectrometry to obtain a quantitative characterization of the uptake to organic PM for different relative humidities (RHs). The PM was produced by the dark ozonolysis of unlabeled α-pinene. The uptake of 13C-labeled oxalic, malonic, and α-ketoglutaric acids increased stepwise by 5 to 15 times with increases in RH from 15 to 80%. The enhanced uptake with increasing RH was explained primarily by the higher molecular diffusivity in the particle phase, as associated with changes in the physical state of the organic PM from a nonliquid state to a progressively less-viscous liquid state. At high RH, the partitioning of the probe molecules to the particle phase was more associated with physicochemical interactions with the organic PM than that with the co-absorbed liquid water. Uptake of the probe molecules also increased with a decrease in volatility along the homologous series. This study quantitatively shows the key roles of the particle physical state in governing the interactions of organic PM with semivolatile organic molecules.

10.
Sci Rep ; 9(1): 14337, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586081

RESUMO

To identify clinical characteristics and mutation spectra in Chinese patients with renal angiomyolipoma (AML) associated with the tuberous sclerosis complex (TSC, TSC-AML), examined the efficacy and safety of short-term everolimus therapy (12 weeks). We analyzed the frequency distribution of each TSC-related clinical feature and investigated gene mutations by genetic testing. Some subjects received everolimus for 12 weeks at a dose of 10 mg/day, and the efficacy and safety of short-term everolimus therapy were examined. Finally, 82 TSC-AML patients were enrolled for analysis in this study. Of the 47 patients who underwent genetic testing, 22 patients (46.81%) had at least one detectable mutation in the TSC1 or TSC2 gene: 7 were TSC1 gene mutations, 13 were TSC2 gene mutations, and 2 were found in both TSC1 and TSC2. Everolimus treatment had a statistically significant effect on the renal AML volume reduction during follow-up (P < 0.05), and the mean reduction rate of volume for all cases was 56.47 ± 23.32% over 12 weeks. However, 7 patients (7/25; 28.00%) experienced an increase in renal AML tumor volume within 12 weeks after discontinuation of the everolimus treatment. Although most patients (27/30, 90.00%) experienced some adverse events during the treatment period, all such events were mild, and no patients discontinued or needed dose reduction because of adverse events. Overall, in this study, the mutation rate of TSC-AML patients is much lower than other reports. Short-term everolimus treatment for TSC-AML is effective and safe, but the stability is much lower than long-term therapy.

11.
Chin Med J (Engl) ; 132(21): 2621-2627, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31651519

RESUMO

BACKGROUND: Hypobaric hypoxia (HH) exposure at high altitudes can result in a decline in cognitive function, which may have a serious impact on the daily life of people who migrate to high altitudes. However, the specific HH-induced changes in brain function remain unclear. This study explored changes in brain activity in rats exposed to a sustained HH environment using functional magnetic resonance imaging (fMRI). METHODS: Healthy male rats (8 weeks old) were randomly divided into a model group and a control group. A rat model of cognitive impairment induced by sustained HH exposure was established. The control and model groups completed training and testing in the Morris water maze (MWM). A two-sample t-test for between-group difference comparisons was performed. Repeated measures analyses of variance for within-group comparisons were performed and post-hoc comparisons were made using the Tukey test. Between-group differences in spontaneous brain activity were assessed using a voxel-wise analysis of resting-state fMRI (rs-fMRI), combined with analyses of the fractional amplitude of low frequency fluctuations (fALFF) in statistical parametric mapping. RESULTS: In the MWM test, the escape latencies of the model group were significantly longer compared with those of the control group (control group vs. model group, day 1: 21.6 ± 3.3 s vs. 40.5 ±â€Š3.4 s, t = -11.282; day 2: 13.5 ±â€Š2.2 s vs. 28.7 ±â€Š5.3 s, t = -7.492; day 3: 10.5 ±â€Š2.8 s vs. 22.6 ±â€Š6.1 s, t = -5.099; day 4: 9.7 ±â€Š2.5 s vs. 18.6 ±â€Š5.2 s, t = -4.363; day 5: 8.8 ±â€Š2.7 s vs. 16.7 ±â€Š5.0 s, t = -3.932; all P < 0.001). Within both groups, the escape latency at day 5 was significantly shorter than those at other time points (control group: F = 57.317, P < 0.001; model group: F = 50.718, P < 0.001). There was no within-group difference in average swimming speed (control group, F = 1.162, P = 0.956; model group, F = 0.091, P = 0.880). Within the model group, the time spent within the original platform quadrant was significantly shorter (control group vs. model group: 36.1 ±â€Š5.7 s vs. 17.8 ±â€Š4.3 s, t = 7.249, P < 0.001) and the frequency of crossing the original platform quadrant was significantly reduced (control group vs. model group: 6.4 ±â€Š1.9 s vs. 2.0 ±â€Š0.8 s, t = 6.037, P < 0.001) compared with the control group. In the rs-fMRI study, compared with the control group, rats in the model group showed widespread reductions in fALFF values throughout the brain. CONCLUSIONS: The abnormalities in spontaneous brain activity indicated by the fALFF measurements may reflect changes in brain function after HH exposure. This widespread abnormal brain activity may help to explain and to provide new insights into the mechanism underlying the impairment of brain function under sustained exposure to high altitudes.

12.
Nanoscale ; 11(42): 19923-19932, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31599910

RESUMO

Monolayer SnP3 is a novel two-dimensional (2D) semiconductor material with high carrier mobility and large optical absorption coefficient, implying its potential applications in the photovoltaic and thermoelectric (TE) fields. Herein, we report on the TE properties of monolayer SnP3 utilizing first principles density functional theory (DFT) together with semiclassical Boltzmann transport theory. Results indicate that it exhibits a low lattice thermal conductivity of ∼4.97 W m-1 K-1 at room temperature, mainly originating from its small average acoustic group velocity (∼1.18 km s-1), large Grüneisen parameters (∼7.09), strong dipole-dipole interactions, and strong phonon-phonon scattering. A large in-plane charge transfer is observed, which results in a non-ignorable bipolar effect on the lattice thermal conductivity. The exhibited mixed mode between in-plane and out-of-plane vibrations enhances the complexity of the phonon phase space, which enhances the possibility of phonon scattering processes and results in suppression of thermal conductivity. A highly twofold degeneracy appearing at the K point gives a high Seebeck coefficient. Our calculated figure of merit (ZT) for optimal p-type doping at 500 K can approach 3.46 along the armchair direction, which is better than the theoretical value of 1.94 reported in the well-known TE material SnSe. Our studies here shed light on monolayer SnP3 in use as a TE material and supply insights to further optimize the TE properties in similar systems.

13.
Hum Mutat ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31471994

RESUMO

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

14.
Phys Rev Lett ; 123(9): 096401, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31524481

RESUMO

As a paradigmatic phenomenon in condensed matter physics, the quantum anomalous Hall effect (QAHE) in stoichiometric Chern insulators has drawn great interest for years. Using model Hamiltonian analysis and first-principles calculations, we establish a topological phase diagram and map different 2D configurations to it, which are taken from the recently grown magnetic topological insulators MnBi_{4}Te_{7} and MnBi_{6}Te_{10} with superlatticelike stacking patterns. These configurations manifest various topological phases, including the quantum spin Hall effect with and without time-reversal symmetry and QAHE. We then provide design principles to trigger the QAHE by tuning experimentally accessible knobs, such as the slab thickness and magnetization. Our work reveals that superlatticelike magnetic topological insulators with tunable exchange interactions are an ideal platform to realize the long-sought QAHE in pristine compounds, paving a new path within the area of topological materials.

15.
J Neurointerv Surg ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401562

RESUMO

BACKGROUND: Genetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown. OBJECTIVE: To investigate potential FIA-causing genetic variants by rare variant interrogation and a family-based genomics approach in a large family with an extensive multigenerational pedigree with FIAs. METHOD: Exome sequencing (ES) was performed in a dominant likely family with intracranial aneurysms (IAs). Variants were analyzed by an in-house developed pipeline and prioritized using various filtering strategies, including population frequency, variant type, and predicted variant pathogenicity. Sanger sequencing was also performed to evaluate the segregation of the variants with the phenotype. RESULTS: Based on the ES data obtained from five individuals from a family with 7/21 living members affected with IAs, a total of 14 variants were prioritized as candidate variants. Familial segregation analysis revealed that NFX1 c.2519T>C (p.Leu840Pro) segregated in accordance with Mendelian expectations with the phenotype within the family-that is, present in all IA-affected cases and absent from all unaffected members of the second generation. This missense variant is absent from public databases (1000genome, ExAC, gnomAD, ESP5400), and has damaging predictions by bioinformatics tools (Gerp ++ score = 5.88, CADD score = 16.43, MutationTaster score = 1, LRT score = 0). In addition, 840Leu in NFX1 is robustly conserved in mammals and maps in a region before the RING-type zinc finger domain. CONCLUSION: NFX1 c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.

16.
Plant Dis ; 103(10): 2541-2547, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432772

RESUMO

To prevent the spread of anthracnose in strawberry plants and characterize the metabolic changes occurring during plant-pathogen interactions, we developed a method for the early diagnosis of disease based on an analysis of the metabolome by gas chromatography-mass spectrometry. An examination of the metabolic profile revealed 189 and 202 total ion chromatogram peaks for the control and inoculated plants, respectively. A partial least squares discriminant analysis (PLS-DA) model was conducted for the reliable and accurate discrimination between healthy and diseased strawberry plants, even in the absence of disease symptoms (e.g., early stages of infection). ANOVA (analysis of variance) and orthogonal partial least squares analysis (OPLS) identified 20 metabolites as tentative biomarkers of Colletotrichum theobromicola infection (e.g., citric acid, d-xylose, erythrose, galactose, gallic acid, malic acid, methyl α-galactopyranoside, phosphate, and shikimic acid). At least some of these potential biomarkers may be applicable for the early diagnosis of anthracnose in strawberry plants. Moreover, these metabolites may be useful for characterizing pathogen infections and plant defense responses. This study confirms the utility of metabolomics research for developing diagnostic tools and clarifying the mechanism underlying plant-pathogen interactions. Furthermore, the data presented herein may be relevant for developing new methods for preventing anthracnose in strawberry seedlings cultivated under field conditions.


Assuntos
Biomarcadores , Colletotrichum , Fragaria , Cromatografia Gasosa-Espectrometria de Massas , Metabolômica , Biomarcadores/análise , Colletotrichum/fisiologia , Fragaria/microbiologia
17.
Int J Chron Obstruct Pulmon Dis ; 14: 1517-1526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371937

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is a disease of continuous progress and environmental factors may affect the progress. COPD patients' activity tolerance and quality of life are associated with air quality. COPD exacerbation from the perspective of geographical air quality has not been reported. Objectives: To explore environmental effect of two different geographical places on COPD exacerbation and the effect of cigarette smoke extract and carbon particles on bronchial epithelial cell viability. Methods: Total 139 COPD patients, who lived in Beijing during summer and temporarily migrated to Sanya city in winter, have been enrolled. Respiratory symptoms and lung function data were collected when they were living in Beijing or Sanya, respectively. Effect of cigarette smoke extract plus ultrafine carbon particles on airway epithelial cells were studied. Measurements and main results: Air pollution as measured by air quality index (AQI) in Beijing summer (113.1±14.2) was significantly worse than that in Sanya winter (49.4±8.9, p<0.001). The COPD Assessment Test (CAT) score was significantly higher in Beijing (26.4±7.1) than that in Sanya (20.0±8.0, p=0.019). Modified Medical Research Council dyspnea scale was also significantly higher in Beijing (2.9±0.9) than that in Sanya (1.9±0.8, p<0.001). FEV1 was significantly improved when the patients were in Sanya (48.88±24.78%) compared to that in Beijing (41.79±20.06%, p<0.01). Compared with Beijing and Sanya, the relative risk (RR) of hospitalization and acute exacerbation were 1.64 and 3.36, respectively. In vitro study demonstrated that apoptosis of BEAS2B cells in response to cigarette smoke extract plus ultrafine carbon particles (25.50±2.10%) was significantly higher than that of control culture (2.30±1.05%, p<0.01). Conclusion: These findings suggested that ambient air pollution cause COPD exacerbation, and that air pollutants particle matters induce apoptosis of airway epithelial cells.

18.
Am J Med Genet A ; 179(10): 2056-2066, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407851

RESUMO

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

19.
Cell Chem Biol ; 26(10): 1427-1435.e5, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31402317

RESUMO

The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all NRF2 inducers are electrophilic molecules that possess unwanted off-target effects due to their reactive nature. Here, we report a group of NRF2 inducers, ent-kaurane diterpenoid geopyxins, with and without C151 reactive electrophilic moieties. Among 16 geopyxins, geopyxin F, a non-electrophilic NRF2 activator, showed enhanced cellular protection relative to an electrophilic NRF2 activator, geopyxin C. To our knowledge, this is the first detailed structure-activity relationship study of covalent versus non-covalent NRF2 activators, showing the promise of non-covalent NRF2 activators as potential therapeutic compounds.

20.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(7): 916-919, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31441423

RESUMO

OBJECTIVE: With advances in intensive care, more patients are surviving from critical illness, and post-intensive care syndrome (PICS) began to get people's attention. Early detection and intervention of PICS can improve the quality of life of intensive care unit (ICU) survivors and reduce the rate of re-hospitalization. However, effective, reliable, and easy-to-use assessment tools are the basis for early detection and evaluation of intervention outcomes. Thus, we introduce the evaluation tools for PICS from the perspective of universality or specificity, aim to provide reference for doctors or nurses to choose suitable assessment tools for PICS, and to provide reference for the development of localized assessment tools for PICS in China, so as to promote the related research of PICS.


Assuntos
Cuidados Críticos , Unidades de Terapia Intensiva , Qualidade de Vida , China , Estado Terminal , Humanos
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