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1.
Anal Chem ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32066230

RESUMO

Six mitochondria/lysosomes self-targetable and viscosity-sensitive dyes (1a-1f) were developed via simple structure modification on cyanine-derived dyes. They all showed remarkable OFF-ON fluorescent response to viscosity in the near-infrared region (652-690 nm) and exhibited good linear relationship with solution viscosity. The transient absorption spectra were used to evaluate the excited-state lifetime of dye 1a in different viscosity environments. Furthermore, cellular imaging assays indicated that different derivatives (1a-1f) with the same chromophore core exhibited different organelle-targeting abilities. Among them, dyes 1a-1c could sense lysosomal viscosity fluctuations while dyes 1d-1f could be applied in mitochondrial viscosity detections.

2.
J Ethnopharmacol ; 252: 112635, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32004629

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Standard therapy for asthma, a highly heterogeneous disease, is primarily based on bronchodilators and immunosuppressive drugs, which confer short-term symptomatic relief but not a cure. It is difficult to discover novel bronchodilators, although potential new targets are emerging. Traditional Chinese Medicine (TCM) formulas have been used to treat asthma for more than 2000 years, forming the basis for representative asthma treatments. AIM OF THE STUDY: Based on the efficacy of TCM formulas, anti-asthmatic herbal compounds bind proteins are potential targets for asthma therapy. This analysis will provide new drug targets and discovery strategies for asthma therapy. MATERIALS AND METHODS: A list of candidate herbs for asthma was selected from the classical formulas (CFs) of TCM for the treatment of wheezing or dyspnea recorded in Treatise on Cold Damage and Miscellaneous Diseases (TCDMD) and from modern herbal formulas identified in the SAPHRON TCM Database using the keywords "wheezing" or "dyspnea". Compounds in the selected herbs and compounds that directly bind target proteins were acquired by searching the Herbal Ingredients' Targets Database (HITD), TCM Data Bank (TCMDB) and TCM Integrated Database (TCMID). Therapeutic targets of conventional medicine (CM) for asthma were collected by searching Therapeutic Target Database (TTD), DrugBank and PubMed as supplements. Finally, the enriched gene ontology (GO) terms of the targets were obtained using the Database for Annotation Visualization and Integrated Discovery (DAVID) and protein-protein interactions (PPI) networks were constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). The effects of two selected TCM compounds, kaempferol and ginkgolide A, on cellular resistance in human airway smooth muscle cells (ASMCs) and pulmonary resistance in a mouse model were investigated. RESULTS: The list of 32 candidate herbs for asthma was selected from 10 CFs for the treatment of wheezing or dyspnea recorded in TCDMD and 1037 modern herbal formulas obtained from the SAPHRON TCM Database. A total of 130 compounds from the 32 selected herbs and 68 herbal compounds directly bind target proteins were acquired from HITD and TCMDB. Eighty-eight therapeutic targets of CM for asthma were collected by searching TTD and PubMed as supplements. DAVID and STRING analyses showed targets of TCM formulas are primarily related to cytochrome P450 (CYP) family, transient receptor potential (TRP) channels, matrix metalloproteinases (MMPs) and ribosomal protein. Both TCM formulas and CM act on the same types of targets or signaling pathways, such as G protein-coupled receptors (GPCRs), steroid hormone receptors (SHRs), and JAK-STAT signaling pathway. The proteins directly targeted by herbal compounds, TRPM8, TRPA1, TRPV3, CYP1B1, CYP2B6, CYP1A2, CYP3A4, CYP1A1, PPARA, PPARD, NR1I2, MMP1, MMP2, ESR1, ESR2, RPLP0, RPLP1 and RPLP2, are potential targets for asthma therapy. In vitro results showed kaempferol (1 × 10-2 mM) and ginkgolide A (1 × 10-5 mM) significantly increased the cell index (P < 0.05 vs. histamine, n = 3) and therefore relaxed human ASMCs. In vivo results showed kaempferol (145 µg/kg) and ginkgolide A (205 µg/kg) significantly reduced pulmonary resistance (P < 0.05 vs. methacholine, n = 6). CONCLUSION: Potential target discovery for asthma treatment based on the clinical effectiveness of TCM is a feasible strategy.

3.
Bioorg Med Chem ; 28(5): 115351, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035750

RESUMO

Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 µM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32050043

RESUMO

Vibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual ß-lactone-fused bicycle is derived from an aryl ring moiety via an oxidative ring-expansion prior to an intramolecular cyclization. Here, we report the discovery of the cyclase VibC which belongs to the α/ß-hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the catalytic Ser-His-Asp triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic b-lactone. This presents a naturally occurring new enzyme reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical diversity expansion of natural products.

5.
Bioorg Med Chem Lett ; 30(7): 126996, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32033852

RESUMO

Bioactive oxazolopyridine unit was used in the synthesis of fluorescent markers for specific organelles in this paper. The compounds 1a-c are linked with double bond between oxazolopyridine ring and photogenic precursors (3a-c). Compound 1a showed higher fluorescence yield (0.86 in THF), compounds 1b-c showed larger stokes shifts in DMSO. In lipid vesicles environment, they also showed good optical properties. In addition, the three compounds are biomarkers with lower cytotoxicity. Among them, compound 1a based on oxazolopyridine and coumarin unit is a dual targetable fluorescent marker for mitochondria and lipid droplets; while the other two compounds 1b-c are only biomarkers for lipid droplets.

6.
Strahlenther Onkol ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32078694

RESUMO

Correction to: Strahlenther Onkol 2019 https://doi.org/10.1007/s00066-019-01539-1 The original version of this article unfortunately contained a mistake. The correct version of the funding information are given ….

7.
Artigo em Inglês | MEDLINE | ID: mdl-32043167

RESUMO

PURPOSE: To describe the surgical procedures, outcomes, and complications of a novel technique of subretinal injection of ranibizumab (SRR). METHODS: Between September 2012 and September 2018, 37 eyes of 26 consecutive children with vascularly active total retinal detachments in 1 or both eyes treated with SRR as primary treatment were included in this retrospective study. All included eyes received subretinal injection of ranibizumab (0.25 mg/ 0.025 ml). Data included demographics, ocular examination, and anatomic outcomes, following treatment and complications of eyes after SRR were collected. RESULTS: Eleven patients had bilateral SRR injections and 15 had monocular SRR injection. Thirteen patients were diagnosed as retinopathy of prematurity. Of all patients, the mean gestational age was 34.5 ± 5.1 weeks (range: 29.6~40.7 weeks), and birth weight was 2328.1 ± 1083.9 g (range: 940~3900 g). On 1-week postoperative follow-up, vascular activity decreased in all 37 eyes (100%). On the 1-month postoperative follow-up, vascular activity decreased but remained in 24 eyes (24/35, 68.6%) of 16 patients and vanished in 11 eyes (11/35, 31.4%) of 9 patients. No eye needed a secondary anti-VEGF therapy. Local subconjunctival hemorrhage was noted in two eyes (2/37, 5.4%). Localized wound leakage of subretinal fluid was also noted in one eye (1/37, 2.7%). CONCLUSIONS: In this very limited study, we showed that SRR in vascularly active advanced pediatric vasoproliferative disorders with total retinal detachments is effective and promising, although more extensive controlled trials will be needed to confirm its safety and efficacy.

8.
ACS Appl Mater Interfaces ; 12(5): 6727-6735, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31917536

RESUMO

Soft bilayer actuators with a simple fabrication process, diverse molecular alignment, and multistimulus response are displayed in this work. The microchannel method proposed by us can exquisitely program the molecular arrangement. Based on the mismatch in coefficient of thermal expansion (CTE) between graphene oxide (GO) and the azobenzene doped liquid crystal network (ALCN), bilayer actuators can exhibit reversible, rapid, and complex deformations under the control of heat, UV and NIR light. Furthermore, in addition to microchannels, various deformation behaviors of bilayer actuators can also be programmed by directionally arranging GO layers. Smart bilayer membranes can be customized into a range of delicate biomimetic devices, such as bionic butterfly, bionic leaf, and foot robot, promising their numerous applications in biomimetic and intelligent soft robotics fields.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31986235

RESUMO

RATIONALE: A new HPLC method was required for the determination of impurities in Rutin tablets to improve the method of the official monograph in national drug standards. METHODS: Five impurities in Rutin tablets were characterized by trap-free two-dimensional liquid chromatography coupled with ion trap/time-of-flight mass spectrometry (2D-LC/IT-TOF MS) in both positive and negative ion modes of electrospray ionization. In the first dimension, the LC column was a Thermo Acclaim 120TM C18 (4.6 mm×250 mm, 5 µm), and the mobile phase was composed of 0.1 M sodium dihydrogen phosphate aqueous solution (pH adjusted to 4.4 with phosphoric acid) and acetonitrile (80:20, v/v). In the second dimension, the column was a Shimadzu Shim-pack GISS C18 (50 mm × 2.1 mm, 1.9 µm), and the mobile phase was composed of 10 mM ammonium formate solution and methanol. RESULTS: Structures of five impurities in Rutin tablets were deduced based on the MSn data in both positive and negative ion modes, in which two impurities were unknown. Impurity 1, impurity 2 and impurity 3 were proposed as flavonol 3,7-di-O-glycosides, flavonol mono-O-triglycoside and quercetin 3-O-glycoside, respectively, and impurity 4 and impurity 5 were proposed as kaempferol 3-O-rhamnosyl-glucoside and isorhamnetin 3-O-rhamnosyl-glucoside, respectively. CONCLUSIONS: The method established in this study was simple and reliable for the routine quality control of Rutin tablets. The contradiction between non-volatile salt mobile phase and mass spectrometry was solved by means of a multiple heart-cutting 2D-LC approach and on-line desalination technology. Five impurities were separated and characterized. These results provided the scientific basis for further improving the national drug standard of Rutin tablets.

10.
Dalton Trans ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31989138

RESUMO

With the in situ-generated [Pb(MCP)4]2+ (HMCP+ = 1-methyl-4-(carboxyl)pyridinium) or [M(phen)3]2+ (M = Co, Fe and Ni; phen = 1,10-phenanthroline) complexes as structural directing agents and charge-balancing ions, we solvothermally synthesized and structurally characterized four new organic-inorganic hybrid iodoplumbates. Compound K2[Pb(MCP)4]Pb3I10 (1) represents the first K+ and [Pb(MCP)4]2+ co-templated hybrid haloplumbate, and exhibits a curve-like anionic layer of [Pb3I10]n4n-. Compounds [M(phen)3]Pb2I6·CH3CN (M = Co (2), Fe (3) and Ni (4)) have isostructural phases, and feature a one-dimensional (1D) [Pb2I6]n2n- anionic chain characteristic of pyramid-like [PbI5] units. The optical property studies show that compounds 1-4 exhibit semiconductor behaviors with the band gaps of 1.98-2.68 eV. In addition, the title compounds exhibited interesting photoelectrical responsive properties, with the photocurrent density in the order of 1 > 3 > 2 > 4. The thermal stabilities of the title compounds 1-4, as well as the theoretical band structure and density of states (DOS) of compounds 1 and 2 have also been studied.

11.
Medicine (Baltimore) ; 99(2): e18688, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914067

RESUMO

INTRODUCTION: Estrogen is a key factor in breast cancer carcinogenesis, and reductions in its synthesis can decrease breast cancer risk. Anastrozole can reduce plasma estrogen levels by inhibiting the enzyme aromatase, and is approved for adjuvant treatment of breast cancer. We report a case of pulmonary cryptococcosis in a patient who was treated with anastrozole for an early-stage tumor. This case is of special interest because the patient achieved a better curative effect after the administration of anastrozole was discontinued. PATIENT CONCERNS: A 61-year-old woman was found to have multiple pulmonary nodules on chest computed tomography (CT) after being treated for 5 months with anastrozole as an adjuvant breast cancer therapy. A biopsy of the largest lesion of the right lung showed cryptococcus fungal bodies with granulomatous inflammation, so the patient was diagnosed with pulmonary cryptococcosis. She was treated with fluconazole (400 mg/day) for 1 month, but a follow-up CT scan of chest showed no improvement. DIAGNOSIS: Pulmonary cryptococcosis. INTERVENTIONS: Because the pulmonary cryptococcosis was not improving, the administration of anastrozole was discontinued. Fluconazole was continued. OUTCOMES: The pulmonary lesions diminished in size 2 months after discontinuing anastrozole. The patient continued taking fluconazole for a total of 6 months without re-administration of anastrozole, and the lesions of pulmonary cryptococcosis almost disappeared. CONCLUSION: This case of pulmonary cryptococcosis may have been induced by a decrease in estrogen level caused by the aromatase inhibitor, anastrozole. Treatment of pulmonary cryptococcosis with concurrent anastrozole use may be ineffective, and it may be better to discontinue the aromatase inhibitor.


Assuntos
Anastrozol/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Criptococose/etiologia , Pneumopatias Fúngicas/etiologia , Anastrozol/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade
12.
Clin Chim Acta ; 503: 169-174, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991129

RESUMO

BACKGROUND: Reduced serum omentin-1 concentrations might be related to an increased risk for poor functional outcome after acute ischemic stroke. We intended to explore whether serum omentin-1 could be a promising prognostic biomarker for acute intracerebral hemorrhage. METHODS: A total of 104 consecutive patients with hemorrhagic stroke underwent 90-day follow-up. The modified Rankin scale score >2 was evaluated as worse prognosis. A multivariable logistic model was conFig.d for assessing the relationship between serum omentin-1 concentrations and functional outcome. RESULTS: Serum omentin-1 concentrations, with the median value of 147.9 ng/ml (interquartile range, 114.7-199.8 ng/ml), were substantially declined with rising modified Rankin scale scores (P < 0.001). Serum omentin-1 concentrations <147.9 ng/ml was independently related to higher risk of 90-day worse prognosis (odds ratio, 3.789; 95% confidence interval, 1.819-8.608; P = 0.018). Under receiver operating characteristic curve, an optimal value of serum omentin-1 concentrations was selected as 179.7 ng/ml, which yielded 0.88 sensitivity value and 0.70 specificity value for discriminating patients at risk of 90-day worse prognosis (area under curve, 0.82; 95% confidence interval, 0.73-0.89). CONCLUSIONS: Lower serum omentin-1 concentrations are closely associated with poor functional outcome after hemorrhagic stroke, substantializing serum omentin-1 as a potential prognostic biomarker for acute intracerebral hemorrhage.

13.
Environ Sci Technol ; 54(3): 1406-1414, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31913023

RESUMO

Water-soluble organic nitrogen (WSON) affects the formation, chemical transformations, hygroscopicity, and acidity of organic aerosols as well as biogeochemical cycles of nitrogen. However, large uncertainties exist in the origins and formation processes of WSON. Submicrometer aerosol particles were collected at a suburban forest site in Tokyo in summer 2015 to investigate the relative impacts of anthropogenic and biogenic sources on WSON formations and their linkages with aerosol liquid water (ALW). The concentrations of WSON (ave. 225 ± 100 ngN m-3) and ALW exhibited peaks during nighttime, which showed a significant positive correlation, suggesting that ALW significantly contributed to WSON formation. Further, the thermodynamic predictions by ISORROPIA-II suggest that ALW was primarily driven by anthropogenic sulfate. Our analysis, including positive matrix factorization, suggests that aqueous-phase reactions of ammonium and reactive nitrogen with biogenic volatile organic compounds (VOCs) play a key role in WSON formation in submicrometer particles, which is particularly significant in nighttime, at the suburban forest site. The formation of WSON associated with biogenic VOCs and ALW was partly supported by the molecular characterization of WSON. The overall result suggests that ALW is an important driver for the formation of aerosol WSON through a combination of anthropogenic and biogenic sources.

14.
J Sep Sci ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31957980

RESUMO

Halitosis with the main components of trace volatile sulfur compounds widely affects the quality of life. In this study, an adaptable active sampling system with two sample-collection modes of direct injection and solid-phase microextraction was developed for the rapid and precise determination of trace volatile sulfur compounds in human halitosis coupled with gas chromatography-flame photometric detection. The active sampling system was well designed and produced for efficiently sampling and precisely determining trace volatile targets in halitosis under the optimized sampling and detection conditions. The analytical method established was successfully applied for the determination of trace targets in halitosis. The limits of detection of H2 S, CH3 SH, and CH3 SCH3 by direct injection were 0.0140-23.0 µg/L with good recoveries ranging from 82.2 to 118% and satisfactory relative standard deviations of 0.4-9.5% (n = 3), respectively. The limit of detections of CH3 SH and CH3 SCH3 by solid-phase microextraction were 2.03 and 0.186 × 10-3  µg/L with good recoveries ranging from 98.3 to 108% and relative standard deviations of 5.9-9.0% (n = 3). Trace volatile targets in positive real samples could be actually found and quantified by combination of direct injection and solid-phase microextraction. This method was reliable and efficient for the determination of trace volatile sulfur compounds in halitosis.

15.
J Biol Chem ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953327

RESUMO

G protein-gated inwardly rectifying K+ (GIRK) channels are targets of Gi/o protein signaling systems that inhibit cell excitability. GIRK channels exist as homotetramers (GIRK2 and GIRK4) or heterotetramers with non-functional homomeric subunits (GIRK1 and GIRK3). Although they have been implicated in multiple conditions, the lack of selective GIRK drugs that discriminate among the different GIRK channel subtypes has hampered investigations into their precise physiological relevance and therapeutic potential. Here, we report a highly specific, potent, and efficacious activator of brain GIRK1/2 channels. Using a chemical screen and electrophysiological assays, we found that this activator, the bromothiophene-substituted small molecule GAT1508, is specific for brain-expressed GIRK1/2 channels rather than for cardiac GIRK1/4 channels. Computational models predicted a GAT1508-binding site validated by experimental mutagenesis experiments, providing insights into how urea-based compounds engage distant GIRK1 residues required for channel activation. Furthermore, we provide computational and experimental evidence that GAT1508 is an allosteric modulator of channel-phosphatidylinositol 4,5-bisphosphate (PIP2) interactions. Through brain slice electrophysiology, we show that subthreshold GAT1508 concentrations directly stimulate GIRK currents in the basolateral amygdala (BLA) and potentiate baclofen-induced currents. Of note, GAT1508 effectively extinguished conditioned fear in rodents and lacked cardiac and behavioral side effects, suggesting its potential for use in pharmacotherapy for post-traumatic stress disorder (PTSD). In summary, our findings indicate that the small molecule GAT1508 has high specificity for brain GIRK1/2 channel subunits, directly or allosterically activates GIRK1/2 channels in the BLA, and facilitates fear extinction in a rodent model.

16.
Oncol Rep ; 43(2): 662-670, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894344

RESUMO

Cullin 4A (CUL4A) is a member of the cullin family of proteins and has been demonstrated to be abnormally expressed in various types of malignancies. However, the function of CUL4A in metastasis of lung adenocarcinoma to the bone has rarely been reported. The aim of present of the study was to explore the biological functions and potential underlying molecular mechanisms of CUL4A in lung adenocarcinoma, highlighting a novel therapeutic target for the diagnosis and treatment of patients with lung adenocarcinoma. A549­CUL4A, H1299­CUL4A and H460­shCUL4A cells were created using lentiviral infection. The efficiency of knockdown or overexpression was assessed using reverse transcription­quantitative PCR and western blotting. The effects of CUL4A on proliferation, migration and invasion of lung adenocarcinoma cells in vitro and metastasis to the bone in vivo were determined using an MTT assay, colony formation assay, wound­healing assay, Transwell assay and a mouse model of bone metastasis. The relationship between CUL4A and the EMT­activator zinc finger E­box binding homeobox 1 (ZEB1) were detected by western blotting. The results showed that overexpression of CUL4A in lung adenocarcinoma cells increased proliferation, migration and invasion, and increased metastasis of A549 to the bones in vivo. Silencing of CUL4A expression in lung adenocarcinoma cells reduced proliferation, migration and invasion in vitro. Mechanistically, CUL4A transcriptionally upregulated expression of ZEB1 which resulted in epithelial­mesenchymal transition, which in turn promoted metastasis of lung adenocarcinoma to the bones. Taken together, these results suggest that CUL4A may serve an important regulatory role in the development of metastasis of lung adenocarcinoma to the bone.

17.
Talanta ; 209: 120580, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31892055

RESUMO

In this study, a mitochondria-specific fluorescent probe for efficient ratiometric detection of Cys was designed and investigated. Probe 1 is composed of a xanthylene skeleton and a benzyl group containing an acryloyl moiety. The probe showed excellent water solubility, good selectivity and sensitivity toward Cys over other analytes, and afforded an extremely low detection limit of 33.7 nM. The possible detection mechanism was ascertained by HRMS analysis. Moreover, probe 1 had excellent mitochondrial-targeting ability (the Pearson's correlation coefficient was 0.96), and was capable of monitoring endogenous Cys in living HeLa cells by dual channel ratiometric bioimaging, demonstrating its significant potential in biological applications.

18.
Int Immunopharmacol ; 80: 106196, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978803

RESUMO

Sepsis-induced liver injury is very common in intensive care units. Here, we investigated the effects of 6-gingerol on sepsis-induced liver injury and the role of the Nrf2 pathway in this process. 6-Gingerol is the principal ingredient of ginger that exerts anti-inflammatory and antioxidant effects. Using cecal ligation and puncture (CLP) to induce polymicrobial sepsis and related liver injury, we found that mice pre-treated with 6-Gingerol showed less incidences of severe liver inflammation and death than untreated CLP groups. 6-Gingerol administration also inhibited the expression of pyroptosis-related proteins, including NOD-like receptor protein 3 (NLRP3), IL-1ß, and caspase-1. Consistent with these findings, 6-gingerol reduced the effects of pyroptosis induced by lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP) in RAW 264.7 cells, as evidenced by IL-1ß and caspase-1 protein levels in the supernatant and propidium iodide (PI) staining. 6-Gingerol was shown to activate the Nrf2 pathway in vivo and in vitro. Notably, Nrf2 siRNA transfection nullified the inhibitory effects of 6-gingerol on pyroptosis in vitro. In summary, these findings suggested that 6-gingerol alleviated sepsis-induced liver injury by inhibiting pyroptosis through the Nrf2 pathway.

19.
J Magn Reson Imaging ; 51(2): 535-546, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31187560

RESUMO

BACKGROUND: White matter hyperintensity (WMH) is widely observed in aging brain and is associated with various diseases. A pragmatic and handy method in the clinic to assess and follow up white matter disease is strongly in need. PURPOSE: To develop and validate a radiomics nomogram for the prediction of WMH progression. STUDY TYPE: Retrospective. POPULATION: Brain images of 193 WMH patients from the Picture Archiving and Communication Systems (PACS) database in the A Medical Center (Zhejiang Provincial People's Hospital). MRI data of 127 WMH patients from the PACS database in the B Medical Center (Zhejiang Lishui People's Hospital) were included for external validation. All of the patients were at least 60 years old. FIELD STRENGTH/SEQUENCE: T1 -fluid attenuated inversion recovery images were acquired using a 3T scanner. ASSESSMENT: WMH was evaluated utilizing the Fazekas scale based on MRI. WMH progression was assessed with a follow-up MRI using a visual rating scale. Three neuroradiologists, who were blinded to the clinical data, assessed the images independently. Moreover, interobserver and intraobserver reproducibility were performed for the regions of interest for segmentation and feature extraction. STATISTICAL TESTS: A receiver operating characteristic (ROC) curve, the area under the curve (AUC) of the ROC was calculated, along with sensitivity and specificity. Also, a Hosmer-Lemeshow test was performed. RESULTS: The AUC of radiomics signature in the primary, internal validation cohort, external validation cohort were 0.886, 0.816, and 0.787, respectively; the specificity were 71.79%, 72.22%, and 81%, respectively; the sensitivity were 92.68%, 87.94% and 78.3%, respectively. The radiomics nomogram in the primary cohort (AUC = 0.899) and the internal validation cohort (AUC = 0.84). The Hosmer-Lemeshow test showed no significant difference between the primary cohort and the internal validation cohort (P > 0.05). The AUC of the radiomics nomogram, radiomics signature, and hyperlipidemia in all patients from the primary and internal validation cohort was 0.878, 0.848, and 0.626, respectively. DATA CONCLUSION: This multicenter study demonstrated the use of a radiomics nomogram in predicting the progression of WMH with elderly adults (an age of at least 60 years) based on conventional MRI. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:535-546.

20.
Life Sci ; 241: 117101, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31778687

RESUMO

AIMS: Ten-eleven-translocation (Tet) proteins are 5-methylcytosine oxidases and have profound impact on DNA methylation and genes expression. This study aimed to investigate the role of Tet2 and its association with Foxp3 DNA methylation in regulatory T (Treg) cell of allergic rhinitis (AR). MATERIALS AND METHODS: CD4+CD25+Treg cells were sorted from peripheral blood lymphocytes drawn from AR patients and spleen lymphocytes drawn from OVA-exposed mice by flow cytometry. Tet2 and Foxp3 expressions were studied in sorted Treg cells. DNA methylation of CpG sites in Foxp3 in Treg cells was analyzed by pyrosequencing. TET2 protein binding to Foxp3 DNA in Treg cells was detected by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR). KEY FINDINGS: Treg cells drawn from AR patients and OVA-exposed mice showed reduction in cells counts, expression of Foxp3 mRNA and protein and down-regulation of Tet2, compared with the controls. Hypermethylation of Foxp3 TSDR and decline of TET2 binding to Foxp3 TSDR, but not promoter, were noted in Treg cells of OVA-exposed mice. Significant negative correlations between Tet2 expression and Foxp3 TSDR methylation, Foxp3 TSDR methylation and Foxp3 expression, and positive correlation between Foxp3 expression and Treg cells percentage were demonstrated by correlation analysis. SIGNIFICANCE: This study demonstrated that down-regulation of Tet2 was associated with higher methylation level of Foxp3 TSDR, reduction in Foxp3 expression and Treg cells percentage in AR, suggesting that Tet2 probably modulated the function of Treg cells in AR through Foxp3 methylation.

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