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1.
Neurosci Bull ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32072450

RESUMO

To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer's disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aß42, Aß42/Aß40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aß42, Aß42/Aß40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.

2.
Spectrochim Acta A Mol Biomol Spectrosc ; 231: 118110, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-32007906

RESUMO

A morpholine-functionalized pyrrole-cyanine probe was synthesized via a simple condensation reaction in high yield. This probe exhibits high selectivity toward ClO- on fluorescence and UV-vis spectra in neat aqueous solution. The strong green emission of the probe solution was quenched and the yellow color faded immediately upon the addition of ClO-. The detection limit of the probe for ClO- was 0.165 µM. The mechanism of hypochlorite-induced CC breakage was supposed on the basis of EIS-MS, NMR, and density functional theory (DFT) calculation. Finally, the probe was utilized to image ClO- in lysosomes of living cells.

3.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(1): 80-85, 2020 Feb 01.
Artigo em Chinês | MEDLINE | ID: mdl-32037771

RESUMO

The relationship between areca nut as a primary carcinogen and oral cancer has been widely concerned. Areca can change the levels of reactive oxygen species (ROS) and autophagy in cells, and the levels of ROS and autophagy are closely related to the occurrence and development of tumors. This paper reviewed the relationships among areca nut, intracellular ROS, and autophagy.


Assuntos
Autofagia , Neoplasias Bucais , Fibrose Oral Submucosa , Areca , Humanos , Nozes , Espécies Reativas de Oxigênio
4.
Adv Healthc Mater ; : e1901706, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052565

RESUMO

Preventing cancer metastasis is one of the remaining challenges in cancer therapy. As an efficient natural product, alpha-tocopheryl succinate (α-TOS), the most effective form of vitamin E, holds great anticancer potential. To improve its efficacy and bioavailability, lipid-coated calcium carbonate/phosphate (LCCP) nanoparticles (NPs) with folic acid and PEG modification are synthesized for efficient delivery of α-TOS to 4T1 cancer cells. The optimized LCCP-FA NPs (NP-TOS15) show an α-TOS loading efficiency of around 60%, and enhanced uptake by 4T1 metastatic cancer cells. Consequently, NP-TOS15 significantly enhance the anticancer effect in combination with interferon-gamma (IFN-γ) in terms of apoptosis facilitation and migration inhibition. Importantly, NP-TOS15 upregulate the anticancer immunity via downregulating program death ligand 1 (PD-L1) expression that is initially induced by IFN-γ, and remarkably prevent the lung metastasis, particularly in combination with IFN-γ. Further investigation reveals that this combination therapy also modulates the cytotoxic lymphocyte infiltration into the tumor microenvironment for tumor elimination. Taken together, the NP delivery of α-TOS in combination with IFN-γ provides an applicable strategy for cancer therapy.

5.
Transl Psychiatry ; 10(1): 30, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-32066657

RESUMO

In order to determine the role of single nucleotide variants (SNVs) in modulating antidepressant response, we conducted a study, consisting of 929 major depressive disorder (MDD) patients, who were treated with antidepressant drugs (drug-only) or in combination with a repetitive transcranial magnetic stimulation (plus-rTMS), followed by targeted exome sequencing analysis. We found that the "plus-rTMS" patients presented a more effective response to the treatment when compared to the 'drug-only' group. Our data firstly demonstrated that the SNV burden had a significant impact on the antidepressant response presented in the "drug-only" group, but was limited in the "plus-rTMS" group. Further, after controlling for overall SNV burden, seven single nucleotide polymorphisms (SNPs) at five loci, IL1A, GNA15, PPP2CB, PLA2G4C, and GBA, were identified as affecting the antidepressant response at genome-wide significance (P < 5 × 10-08). Additional multiple variants achieved a level of correction for multiple testing, including GNA11, also shown as a strong signal for MDD risk. Our study showed some promising evidence on genetic variants that could be used as individualized therapeutic guides for MDD patients.

6.
Inorg Chem ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32077694

RESUMO

The MnII(HCO3-)-H2O2 (MnII-BAP) system shows high reactivity toward oxidation of electron-rich organic substrates; however, the predominant oxidizing species and its formation pathways involved in the MnII-BAP system are still under debate. In this study, we used the MnII-BAP system to oxidize As(III) in that As(III), Mn2+, and HCO3- are common components in As(III)-contaminated groundwater. Kinetic results show that MnII(HCO3-)n [including MnII(HCO3)+ and MnII(HCO3)2] is a key factor in the MnII-BAP system to oxidize As(III). Quenching experiments rule out contributions of OH• and 1O2 to As(III) oxidation and reveal that O2•- and the oxidizing species generated from O2•- play predominant roles in the oxidation of As(III). We further reveal that the MnO2+(HCO3-)n intermediate generated in the reaction between MnII(HCO3-)n and O2•-, instead of O2•-, is the predominant oxidizing species. Although CO3•- also contributes to As(III) oxidation, the high reaction rate constant between CO3•- and O2•- indicates that CO3•- is not the predominant oxidizing species in the As(III)-MnII-BAP system. In addition, the presence of Mn(III) further indicates the important Mn(II)-Mn(III) cycling in the MnII-BAP system. We therefore suggest two important roles of MnII(HCO3-)n in the MnII-BAP system: (i) MnII(HCO3-)n reacts with H2O2 to form the MnIII(HCO3)3 intermediate, followed by a subsequent reaction between MnIII(HCO3)3 and H2O2 to produce O2•-; (ii) MnII(HCO3-)n can also stabilize O2•- with the formation of MnO2+(HCO3-)n. MnO2+(HCO3-)n is an electrophilic reagent and plays the predominant role in the oxidation of As(III) to As(V).

7.
Chem Commun (Camb) ; 56(14): 2210, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32031562

RESUMO

Correction for 'One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction' by Jie Lei et al., Chem. Commun., 2020, DOI: .

8.
Ital J Pediatr ; 46(1): 21, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050988

RESUMO

INTRODUCTION: Fetal arrhythmias are a common phenomenon with rather complicated etiologies. Debates remain regarding prenatal diagnosis and treatment of fetal arrhythmias. METHODS: The literature reporting on prenatal diagnosis and treatment of fetal arrhythmias published in the recent two decades were retrieved, collected and analyzed. RESULTS: Both fetal magnetocardiogram and electrocardiogram provide information of cardiac time intervals, including the QRS and QT durations. M-mode ultrasound detects the AV and VA intervals, fetal heart rate, and AV conduction. By using Doppler ultrasound, simultaneous recording of the atrial and ventricular waves can be obtained. Benign fetal arrhythmias, including premature contractions and sinus tachycardia, do not need any treatment before and after birth. Sustained fetal arrhythmias that predispose to the occurrence of hydrops fetalis, cardiac dysfunction or eventual fetal demise require active treatments. Intrauterine therapy of fetal tachyarrhythmias has been carried out by the transplacental route. If maternal transplacental treatment fails, intraumbilical, intraperitoneal, or direct fetal intramuscular injection of antiarrhythmic agents can be attempted. CONCLUSIONS: The outcomes of intrauterine therapy of fetal tachyarrhythmias depend on the types or etiology of fetal arrhythmias and fetal conditions. Most are curable to a transplacental treatment by the first-line antiarrhythmic agents. Fetal cardiac pacings are effective methods to restore sinus rhythm in drug-resistant or hemodynamically compromised cases. Immediate postnatal pacemaker implantation is warranted in refractory cases.

9.
Anal Chim Acta ; 1103: 156-163, 2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32081180

RESUMO

Gasotransmitter hydrogen sulfide (H2S), produced enzymatically in body, has important functions in biological signaling and metabolic processes. An abnormal level of H2S expression is associated with different diseases, therefore, development of novel bioanalytical methods for rapid and effective detection of H2S in biological conditions is of great importance. In this work, we report the development of a new responsive nanosensor for ratiometric luminescence detection of H2S in aqueous solution and live cells. The nanosensor (Ru@FITC-MSN) was prepared by immobilizing a luminescent ruthenium(II) (Ru(II)) complex into a fluorescein isothiocyanate (FITC) conjugated water-dispersible mesoporous silica nanoparticle (MSN), showing dual emission bands at 520 nm (FITC) and 600 nm (Ru complex). The red luminescence of the formed Ru@FITC-MSN was quenched in the presence of Cu2+. The in-situ generated Ru-Cu@FITC-MSN responded to H2S rapidly and selectively, showing a linear ratiometric luminescence change in FITC and Ru(II) channels with the H2S concentration (0.5-4 µM). Limit of detection (LoD) and limit of quantification (LoQ) were determined to be 0.36 and 1.21 µM. Followed by investigation of cellular uptake processes, the utility of the nanosensor for ratiometric imaging of H2S in live cells and its capability to monitor H2S levels in inflammatory breast cancer cells were then demonstrated. This study provides a powerful approach for detection of highly reactive and unstable H2S biomolecules in live systems.

10.
Plant Biotechnol J ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910327

RESUMO

Purple carrots, the original domesticated carrots, accumulate highly glycosylated and acylated anthocyanins in root and/or petiole. Previously, a quantitative trait locus (QTL) for root-specific anthocyanin pigmentation was genetically mapped to chromosome 3 of carrot. In this study, an R2R3-MYB gene, namely DcMYB113, was identified within this QTL region. DcMYB113 expressed in the root of 'Purple haze', a carrot cultivar with purple root and nonpurple petiole, but not in the roots of two carrot cultivars with a purple root and petiole (Deep purple and Cosmic purple) and orange carrot 'Kurodagosun', which appeared to be caused by variation in the promoter region. The function of DcMYB113 from 'Purple haze' was verified by transformation in 'Cosmic purple' and 'Kurodagosun', resulting in anthocyanin biosynthesis. Transgenic 'Kurodagosun' carrying DcMYB113 driven by the CaMV 35S promoter had a purple root and petiole, while transgenic 'Kurodagosun' expressing DcMYB113 driven by its own promoter had a purple root and nonpurple petiole, suggesting that root-specific expression of DcMYB113 was determined by its promoter. DcMYB113 could activate the expression of DcbHLH3 and structural genes related to anthocyanin biosynthesis. DcUCGXT1 and DcSAT1, which were confirmed to be responsible for anthocyanins glycosylation and acylation, respectively, were also activated by DcMYB113. The WGCNA identified several genes co-expressed with anthocyanin biosynthesis and the results indicated that DcMYB113 may regulate anthocyanin transport. Our findings provide insight into the molecular mechanism underlying root-specific anthocyanin biosynthesis and further modification in carrot and even other root crops.

11.
Eur Respir J ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949115

RESUMO

BACKGROUND: Gefapixant has previously demonstrated efficacy in the treatment refractory chronic cough at a high, daily dose. OBJECTIVES: The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose escalation approach. MATERIALS AND METHODS: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50-200 mg, study 2: 7.5-50 mg) or placebo for 16 days, then crossed-over after washout. The primary endpoint was awake cough frequency assessed using a 24 h ambulatory cough monitor at baseline and on day 4 of each dose. Patient reported outcomes included a cough severity visual analogue scale (VAS) and Cough Severity Diary (CSD). RESULTS: In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg. CONCLUSIONS: P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Longer duration studies are warranted.

12.
Protoplasma ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31982943

RESUMO

Carotenoids are a group of natural pigments that are widely distributed in various plants. Carrots are plants rich in carotenoids and have fleshy roots with different colors. Carotenoid accumulation is a complex regulatory process with important guiding significance for carrot production. In this work, three carrot cultivars with different taproot colors, Hongxinqicun (orange), Benhongjinshi (red), and Tianzi (purple) were chosen as experimental materials to explore the molecular mechanism of carotenoid accumulation in carrot. Results showed that the three carotenoids, namely, α-carotene, ß-carotene, and lutein, had accumulated in orange carrot cultivar Hongxinqicun. Lycopene was only detected in the taproots of Benhongjinshi. Lutein was the main carotenoid in Tianzi. Comparison of the carotenoid contents in different tissues of carrot showed that leaf blade was the tissue with the highest carotenoid accumulation. Expression analysis of carotenoid biosynthesis genes and its correlation with carotenoid accumulation confirmed the regulatory role of structural genes in carrots. The high expression of five lycopene synthesis-related genes, DcPSY2, DcPDS, DcZDS1, DcCRT1, DcCRT2, and low expression of DcLCYE may result in the lycopene accumulation in Benhongjinshi. However, the function of certain genes, such as DcPSY1 that was lowly expressed in red carrot, requires further investigation. Our results provided potential insights into the mechanism of carotenoid accumulation in three carrot cultivars with different taproot colors.

13.
Eur J Ophthalmol ; : 1120672120901702, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31984763

RESUMO

PURPOSE: To present a relatively uncommon case with a secondary iris cyst in the anterior chamber and its successful management with an anterior chamber mass excision surgery. CASE REPORT: A 46-year-old Chinese woman presented with a dark shadow in her left eye for 6 months without any other discomfort. She had a history of blunt ocular trauma by a badminton strike 3 years ago. Slit-lamp examination showed a small, nearly circular, sharply demarcated, and movable mass in the anterior chamber OS, which could change its position with head tilt. The anterior segment optical coherence tomography revealed a well-circumscribed cystic lesion in the anterior chamber with higher reflective outer layer and lower internal reflectivity. An anterior chamber mass removal surgery was performed without recurrence up to 1 year. CONCLUSION: Secondary free-floating iris cyst following a blunt trauma is rarely reported. It is relatively stable and nonprogressive so it may remain asymptomatic for a long time. Appropriate imaging techniques are necessary for facilitating diagnosis and therapy. Therapeutic management should be considered if visual symptoms arise, especially when complications occur.

14.
Arch Pharm (Weinheim) ; : e1900299, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31985855

RESUMO

Dimerization is a promising strategy to develop novel drug candidates that could extend the biological spectrum, enhance the activity, overcome drug resistance, as well as improve pharmacological, pharmacokinetic, and physicochemical profiles. Isatin dimers possess a broad spectrum of biological properties and the isatin dimer indirubin has already been used in the clinic, revealing the potential of isatin dimers as putative drugs. This review covers the recent advances of isatin dimers as pharmacologically significant scaffolds and the structure-activity relationship to set up the direction for the design and development of isatin dimers with higher efficiency and lower toxicity.

15.
Langmuir ; 36(3): 742-753, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31895574

RESUMO

The linear shrinkage behavior in thermoresponsive diblock copolymer films and its potential application in temperature sensors are investigated. The copolymer is composed of two thermoresponsive blocks with different transition temperatures (TTs): di(ethylene glycol) methyl ether methacrylate (MEO2MA; TT1 = 25 °C) and poly(ethylene glycol) methyl ether methacrylate (OEGMA300; TT2 = 60 °C) with a molar ratio of 1:1. Aqueous solutions of PMEO2MA-b-POEGMA300 show a three-stage transition upon heating as seen with optical transmittance and small-angle X-ray scattering: dissolution (T < TT1), self-assembled micelles with core-shell structure (TT1 < T < TT2), and aggregation of collapsed micelles (T > TT2). Due to the restrictions in the polymer chain arrangement introduced by the solid Si substrate, spin-coated PMEO2MA-b-POEGMA300 films exhibit an entirely different internal structure and transition behavior. Neutron reflectivity shows the absence of an ordered structure normal to the Si substrate in as-prepared PMEO2MA-b-POEGMA300 films. After exposure to D2O vapor for 3 h and then increasing the temperature above its TT1 and TT2, the ordered structure is still not observed. Only a D2O enrichment layer is formed close to the hydrophilic Si substrate. Such PMEO2MA-b-POEGMA300 films show a linear shrinkage between TT1 and TT2 in a D2O vapor atmosphere. This special behavior can be attributed to the synergistic effect between the restrained collapse of the PMEO2MA blocks by the still swollen POEGMA300 blocks and the impedance of chain arrangement by the Si substrate. Based on this unique behavior, spin-coated PMEO2MA-b-POEGMA300 films are further prepared into a temperature sensor by implementing Ag electrodes. Its resistance decreases linearly with temperature between TT1 and TT2.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31912568

RESUMO

Supramolecular structures with strain-stiffening properties are ubiquitous in nature but remain rare in the lab. Herein, we report on strain-stiffening supramolecular hydrogels that are entirely produced through the self-assembly of synthetic molecular gelators. The involved gelators self-assemble into semi-flexible fibers, which thereby crosslink into hydrogels. Interestingly, these hydrogels are capable of stiffening in response to applied stress, resembling biological intermediate filaments system. Furthermore, strain-stiffening hydrogel networks embedded with liposomes are constructed through orthogonal self-assembly of gelators and phospholipids, mimicking biological tissues in both architecture and mechanical properties. This work furthers the development of biomimetic soft materials with mechanical responsiveness and presents potentially enticing applications in diverse fields, such as tissue engineering, artificial life, and strain sensors.

17.
EMBO Rep ; : e48860, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31930677

RESUMO

Toll-like receptors (TLRs) are important pattern recognition receptors (PRRs) that are critical for the defense against invading pathogens. IL-1ß is an important pro-inflammatory cytokine that also plays pivotal roles in shaping the adaptive immune response. TLRs and interleukin-1 receptor (IL-1R) share similar cytosolic domains and signaling processes. In this study, we identify the E3 ubiquitin ligase RNF152 as a positive regulator of TLR/IL-1R-mediated signaling. Overexpression of RNF152 potentiates IL-1ß- and LPS-induced NF-κB activation in an ubiquitination-independent manner, whereas knockdown of RNF152 has the opposite effects. RNF152-deficient mice produce less inflammatory cytokines in response to LPS and are more resistant to LPS-induced lethal endotoxemia. Mechanistically, RNF152 interacts with the adaptor protein MyD88 and enhances oligomerization of MyD88, which is essential for the recruitment of downstream signaling components and activation of TLR/IL-1R-mediated signal transduction. Our findings suggest that RNF152-mediated oligomerization of MyD88 is important for TLR/IL-1R-mediated inflammatory response.

18.
EMBO Rep ; : e48328, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31930681

RESUMO

Overexpressing Tau counteracts apoptosis and increases dephosphorylated ß-catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate ß-catenin at K49 in a concentration-, time-, and pH-dependent manner. ß-catenin K49 acetylation inhibits its phosphorylation and its ubiquitination-associated proteolysis, thus increasing ß-catenin protein levels. K49 acetylation further promotes nuclear translocation and the transcriptional activity of ß-catenin, and increases the expression of survival-promoting genes (bcl2 and survivin), counteracting apoptosis. Mutation of Tau's acetyltransferase domain or co-expressing non-acetylatable ß-catenin-K49R prevents increased ß-catenin signaling and abolishes the anti-apoptotic function of Tau. Our data reveal that Tau preserves ß-catenin by acetylating K49, and upregulated ß-catenin/survival signaling in turn mediates the anti-apoptotic effect of Tau.

19.
J Exp Bot ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31990970

RESUMO

The transcription factor Woolly (Wo) and its downstream gene CycB2 have been shown to regulate trichome development in tomato (Solanum lycopersicum). It has been demonstrated that only the gain-of-function allele of Slwo (SlWoV, the Slwo woolly motif mutant allele) can increase the trichome density; however, it remains unclear why the two alleles function differently in trichome development. In this study, we used Nicotiana benthamiana as a model and cloned the homologues of Slwo and SlCycB2 (named Nbwo and NbCycB2). We also constructed a Nbwo gain-of-function allele with the same mutation site as SlWoV (named NbWoV). We found that both Nbwo and NbWoV directly regulate NbCycB2 and their own expression by binding to the promoter of NbCycB2 and their own genomic sequences. As form of a feedback regulation, NbCycB2 negatively regulates trichome formation by repressing Nbwo activity at the protein level. We also found that mutations in the Nbwo woolly motif can prevent repression of NbWoV by NbCycB2, which results in a significant increase in the amount of active Nbwo proteins and in increases in trichome density and the number of branches. Our results reveal a novel reciprocal regulation mechanism between NbCycB2 and Nbwo during trichome formation in N. benthamiana.

20.
Curr Top Med Chem ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31994464

RESUMO

Fourteen moxifloxacin-isatin hybrids 5, 6 and 13 tethered via 1,2,3-triazole were designed, and synthesized in this paper. The in vitro activities of the synthesized hybrids against a panel of cancer cell lines including HepG2 liver cancer cells, MCF-7, doxorubicin-resistant MCF-7 (MCF-7/DOX) breast cancer cells, DU-145 and multidrug-resistant DU-145 (MDR DU-145) prostate cancer cells were evaluated. The results indicated that most of them were active against the five cancer cells, whereas the parent moxifloxacin was devoid of activity. In particular, the hybrid 5b (IC50: 31.3-76.8µM) with the anticancer activity higher than Vorinostat (IC50: 96.7->100µM) also showed potential tubulin polymerization inhibitory activity. The structure-activity relationship was summarized for further rational design of more efficient anticancer candidates.

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