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1.
Heart Rhythm ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32068184

RESUMO

BACKGROUND: Subcutaneous nerve stimulation (ScNS) remodels the stellate ganglion and reduces stellate ganglion nerve activity (SGNA) in dogs. Acute myocardial infarction (MI) increases SGNA through nerve sprouting. OBJECTIVE: To test the hypothesis that ScNS remodels the stellate ganglion and reduces SGNA in ambulatory dogs with acute MI. METHODS: In the experimental group, a radiotransmitter was implanted during the first sterile surgery to record nerve activity and an electrocardiogram, followed by a second sterile surgery to create MI. The dogs then underwent ScNS for two months. The average SGNA (aSGNA) was compared with a historical control group (N=9) with acute MI monitored for two months without ScNS. RESULTS: In the experimental group, the baseline aSGNA and heart rate were 4.08±0.35 µV and 98±12 bpm, respectively. They increased within one week after MI to 6.91±1.91 µV (p=0.007) and 107±10 bpm (p=0.028), respectively, compared with baseline. ScNS reduced aSGNA to 3.46±0.44 µV (p<0.039) and 2.14±0.50 µV (p<0.001) at 4 and 8 weeks, respectively, after MI. In comparison, the aSGNA at 4 and 8 weeks in dogs with MI but no ScNS were 8.26±6.31 µV (p=0.005) and 10.82±7.86 µV (p=0.002), respectively. Immunostaining showed confluent areas of remodeling in bilateral stellate ganglia and high percentage of tyrosine hydroxylase-negative ganglion cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling was positive in 26.61±11.54% of ganglion cells in the left and 15.94±3.62% ganglion cells in the right stellate ganglion. CONCLUSION: ScNS remodels the stellate ganglion, reduces stellate ganglion nerve activity and suppresses cardiac nerve sprouting after acute MI.

2.
Cells ; 9(2)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019276

RESUMO

(1) Background: l-leucine (Leu) plays a positive role in regulating protein turnover in skeletal muscle in mammal. However, the molecular mechanism for the effects of Leu on muscle growth and protein deposition is not clearly demonstrated in fish. This study investigated the effects of dietary Leu on growth performance and muscle growth, protein synthesis, and degradation-related signaling pathways of hybrid catfish (Pelteobagrus vachelli♀ × Leiocassis longirostris♂). (2) Methods: A total of 630 hybrid catfish (23.19 ± 0.20 g) were fed 6 different experimental diets containing graded levels of Leu at 10.0 (control), 15.0, 20.0, 25.0, 30.0, 35.0, and 40.0 g Leu kg-1 for 8 weeks. (3) Results: Results showed that dietary Leu increased percent weight gain (PWG), specific growth rate (SGR), FI (feed intake), feed efficiency (FE), protein efficiency ratio (PER), muscle fibers diameter, and muscle fibers density; up-regulated insulin-like growth factor I (IGF-I), insulin-like growth factor I receptor (IGF-IR), proliferating cell nuclear antigen (PCNA), myogenic regulation factors (MyoD, Myf5, MyoG, and Mrf4), and MyHC mRNA levels; increased muscle protein synthesis via regulating the AKT/TOR signaling pathway; and attenuated protein degradation via regulating the AKT/FOXO3a signaling pathway. (4) Conclusions: These results suggest that Leu has potential role to improve muscle growth and protein deposition in fish, which might be due to the regulation of IGF mRNA expression, muscle growth related gene, and protein synthesis and degradation-related signaling pathways. Based on the broken-line model, the Leu requirement of hybrid catfish (23.19-54.55 g) for PWG was estimated to be 28.10 g kg-1 of the diet (73.04 g kg-1 of dietary protein). These results will improve our understanding of the mechanisms responsible for muscle growth and protein deposition effects of Leu in fish.

3.
Drug Des Devel Ther ; 14: 195-206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021104

RESUMO

Background: Osteoporosis is a chronic bone metabolism disorder affecting millions of the world population. The RANKL/RANK/OPG signaling pathway has been confirmed to be the main regulator of osteoporosis. It is of great interest to identify appropriate therapeutic agents that can regulate the RANKL/RANK/OPG pathway. Baicalin (BA) is a well-known traditional Chinese medicine formula against various inflammatory diseases with a proven role of the RANKL/RANK/OPG pathway regulation. However, the potential effect of BA on osteoporosis and the mechanisms underlying this remain unclear. In the present study, we aimed to evaluate the efficacy of BA in the prevention of dexamethasone (DEX)-induced osteoporosis in zebrafish. Methods: In this study, growth and development changes of zebrafish and calcein staining were assessed with a micrograph. The expression levels of RANKL and OPG and transcription factors in response to DEX induction and BA administration were evaluated by Western blotting and qRT-PCR. In addition, the intermolecular interactions of BA and RANKL were investigated by molecular docking. Results: Results show that BA enhances the growth and development of dexamethasone (DEX)-induced osteoporosis in zebrafish larvae. Calcein staining and calcium and phosphorus determination revealed that BA ameliorates mineralization of DEX-induced osteoporosis zebrafish larvae. BA also regulates the expression of RANKL and OPG and hampers the changes in gene expression related to bone formation and resorption under the induction of DEX in zebrafish. It can be inferred by molecular docking that BA may interact directly with the extracellular domain of RANKL. Conclusion: The findings, herein, reveal that BA ameliorates DEX-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway.

4.
J Cell Mol Med ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31930778

RESUMO

Excessive activation of pro-inflammatory M1 macrophages following acute myocardial infarction (MI) aggravates adverse cardiac remodelling and heart dysfunction. There are two break points in the tricarboxylic acid cycle of M1 macrophages, and aspartate-arginosuccinate shunt compensates them. Aminooxyacetic acid (AOAA) is an inhibitor of aspartate aminotransferase in the aspartate-arginosuccinate shunt. Previous studies showed that manipulating macrophage metabolism may control macrophage polarization and inflammatory response. In this study, we aimed to clarify the effects of AOAA on macrophage metabolism and polarization and heart function after MI. In vitro, AOAA inhibited lactic acid and glycolysis and enhanced ATP levels in classically activated M1 macrophages. Besides, AOAA restrained pro-inflammatory M1 macrophages and promoted anti-inflammatory M2 phenotype. In vivo, MI mice were treated with AOAA or saline for three consecutive days. Remarkably, AOAA administration effectively inhibited the proportion of M1 macrophages and boosted M2-like phenotype, which subsequently attenuated infarct size as well as improved post-MI cardiac function. Additionally, AOAA attenuated NLRP3-Caspase1/IL-1ß activation and decreased the release of IL-6 and TNF-α pro-inflammatory cytokines and reciprocally increased IL-10 anti-inflammatory cytokine level in both ischaemic myocardium and M1 macrophages. In conclusion, short-term AOAA treatment significantly improves cardiac function in mice with MI by balancing macrophage polarization through modulating macrophage metabolism and inhibiting NLRP3-Caspase1/IL-1ß pathway.

5.
Virus Res ; 278: 197858, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31904408

RESUMO

Avastrovirus-specific antibodies are widely detected in chickens in China. However, there are currently no commercially available vaccines for this group of viruses. To address this issue, we collected 76 tissue samples from Avastrovirus (AAstVs) antibody-positive chickens from farms across eight provinces in China from 2016 to 2018. The samples were then screened for the presence of AAstVs sequences by polymerase chain reaction analysis and a phylogenetic tree was constructed. Specific primers were designed to amplify the whole genome sequences of the viruses from four positive samples, with the genetic characteristics and structures of the resulting genomes then analyzed further. Overall, 42 (55.3 %) of the 76 samples were positive for AAstVs RNA. Phylogenetic analysis along with the ORF1b gene showed that 15 isolates were grouped in AAstV-1 and 27 of them were grouped in AAstV-2. None of the isolates was belonged to AAstV-3. Sequencing and structural analyses revealed that the genomes of the four isolates showed the typical characteristics of AAstVs genomes but were genetically distinct from other AAstVs. The results of this study will contribute to our understanding of the genetic characteristics of AAstVs in China.

6.
World Neurosurg ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31953100

RESUMO

OBJECTIVE: The present study aimed to characterize the mechanism of fluid shear stress (FSS)-induced endothelial cell (EC) injury via protein kinase C alpha (PKCα)-mediated vascular endothelial cadherin (VE-cadherin) and p120-catenin (p120ctn) expression. METHODS: We designed a T chamber system that produced stable FSS on ECs in vitro. Human umbilical vein endothelial cells (HUVECs) in which PKCα was knocked down and normal HUVECs were cultured on the coverslips. FSS was impinged on these 2 types of ECs for 0 hours and 6 hours. The morphology and density of HUVECs were evaluated, and expression levels of phosphorylated PKCα, p120-catenin (p120ctn), VE-cadherin, phosphorylated p120ctn at S879 (p-S879p120ctn), and nuclear factor kappa B (NF-κB) were analyzed by Western blot. RESULTS: HUVECs exposed to FSS were characterized by a polygonal shape and decreased cell density. The phosphorylated PKCα level was increased under FSS at 6 hours (P < 0.05). In normal HUVECs during FSS, p120ctn and VE-cadherin were decreased, whereas p-S879p120ctn and NF-κB were increased, at 6 hours (P < 0.05). In HUVECs after PKCα knockdown, p120ctn and VE-cadherin were not significantly changed (P > 0.05), p-S879p120ctn was undetectable, but NF-κB was decreased (P < 0.05) at 6 hours. CONCLUSIONS: The possible mechanism of FSS-induced EC injury may be as follows: 1) PKCα induces low expression of p120ctn, which leads to activation of NF-κB and degradation of VE-cadherin; 2) PKCα-mediated phosphorylation of p120ctn at S879 disrupts p120ctn binding to VE-cadherin.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31943606

RESUMO

Patterning multiple images within a single element without crosstalk can significantly increase the information capacity and security, but it is challenging to enable the response capability in each image. Now, the patterning of crosstalk-free yet cooperative-thermoresponse images (holographic and fluorescent images) is successfully achieved by designing a liquid crystal (LC)/AIEgen system with a unique synergy. The AIEgen's fluorescence intensity is controlled by the LC, while the LC's phase transition is in turn promoted by the AIEgen. The fluorescent image contrast is significantly boosted by efficient energy transfer (ΦET : 96 %) from the LC to the AIEgen. The AIEgen's photocyclization for fluorescent patterning occurs in a zero-order kinetic manner and can be completed within several minutes when assisted by the LC. The photocyclization conversion is quantitatively dependent on the aggregation size: α∼exp(-d), and able to reach as high as 98 %.

8.
Br J Nutr ; 123(2): 121-134, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31637992

RESUMO

The experiment was conducted to investigate the effects of dietary threonine (Thr) on growth performance and muscle growth, protein synthesis and antioxidant-related signalling pathways of hybrid catfish Pelteobagrus vachelli♀ × Leiocassis longirostris♂. A total of 1200 fish (14·19 (se 0·13) g) were randomly distributed into six groups with four replicates each, fed six diets with graded level of Thr (9·5, 11·5, 13·5, 15·4, 17·4 and 19·3 g/kg diets) for 56 d. Results showed (P < 0·05) that dietary Thr (1) increased percentage weight gain, specific growth rate, feed efficiency and protein efficiency ratio; (2) up-regulated growth hormone (GH), insulin-like growth factor 1 (IGF-1), proliferating cell nuclear antigen, myogenic regulation factors (MyoD, Myf5, MyoG and Mrf4) and myosin heavy chain (MyHC) mRNA levels; (3) increased muscle protein content via regulating the protein kinase B/target of rapamycin signalling pathway and (4) decreased malondialdehyde and protein carbonyl contents, increased catalase, glutathione-S-transferase, glutathione reductase and GSH activities, up-regulated mRNA levels of antioxidant enzymes related to NFE2-related factor 2 and γ-glutamylcysteine ligase catalytic subunit. These results suggest that Thr has a potential role to improve muscle growth and protein synthesis, which might be due to the regulation of GH-IGF system, muscle growth-related gene, antioxidative capacity and protein synthesis-related signalling pathways. Based on the quadratic regression analysis of specific growth rate, the Thr requirement of hybrid catfish (14·19-25·77 g) was estimated to be 13·77 g/kg of the diet (33·40 g/kg of dietary protein).

9.
J Sep Sci ; 43(2): 531-546, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654547

RESUMO

As a representative formulation of Radix Salviae miltiorrhizae (Danshen)-Lignum Dalbergiae odoriferae (Jiangxiang), Xiangdan injection is widely prescribed for cardio- and cerebrovascular diseases in practice. This necessitates a pharmacokinetic investigation of this formulation to make it safer and more broadly applicable. We developed and validated a sensitive, selective, and reliable high-performance liquid chromatography with tandem mass spectrometry method for the simultaneous determination of 11 phenolic compounds including danshensu plus two diterpenoid quinones like cryptotanshinone and tanshinone IIA in rat. We applied this method for the pharmacokinetic studies of the 13 compounds in a rat model of middle cerebral artery occlusion after intravenous injection of Xiangdan injection or Danshen injection. In sham-operated rats, the animals taking Xiangdan injection exhibited significant growth of the area under the curve for danshensu, protocatechuic aldehyde, and tanshinone IIA compared with the changes seen in the data of those administrated with Danshen injection. Such a pattern was also observed in middle cerebral artery occlusion rats, whereas increased the area under the curve values were observed for danshensu, protocatechuic aldehyde, caffeic acid, rosmarinic acid, and tanshinone IIA. These results demonstrated that synergistic interactions occurred between the components of Danshen and the active compounds of Jiangxiang both in sham-operated and middle cerebral artery occlusion rats, increasing the bioavailability of Danshen. The results presented herein can be used to determine a reference dose for the clinical application of Xiangdan injection, and to elucidate the synergistic mechanism of Danshen and Jiangxiang.

10.
IEEE Trans Vis Comput Graph ; 26(1): 1256-1266, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31443013

RESUMO

Visual querying is essential for interactively exploring massive trajectory data. However, the data uncertainty imposes profound challenges to fulfill advanced analytics requirements. On the one hand, many underlying data does not contain accurate geographic coordinates, e.g., positions of a mobile phone only refer to the regions (i.e., mobile cell stations) in which it resides, instead of accurate GPS coordinates. On the other hand, domain experts and general users prefer a natural way, such as using a natural language sentence, to access and analyze massive movement data. In this paper, we propose a visual analytics approach that can extract spatial-temporal constraints from a textual sentence and support an effective query method over uncertain mobile trajectory data. It is built up on encoding massive, spatially uncertain trajectories by the semantic information of the POls and regions covered by them, and then storing the trajectory documents in text database with an effective indexing scheme. The visual interface facilitates query condition specification, situation-aware visualization, and semantic exploration of large trajectory data. Usage scenarios on real-world human mobility datasets demonstrate the effectiveness of our approach.

11.
Int J Mol Sci ; 20(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816816

RESUMO

Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role of miR-451 and the therapeutic effects of genistein in the NASH mouse model. MiR-451 was downregulated in various types of liver inflammation, and subsequent experiments showed that miR-451 regulates liver inflammation via IL1ß. Genistein is a phytoestrogen with anti-inflammatory and anti-oxidant effects. Interestingly, we found that the anti-inflammatory effects of genistein were related to miR-451 and was partially antagonized by the miR-451 inhibitor. MiR-451 overexpression or genistein treatment inhibited IL1ß expression and inflammation. Taken together, this study shows that miR-451 has a protective effect on hepatic inflammation, and genistein can be used as a natural promoter of miR-451 to ameliorate NASH.

13.
Org Biomol Chem ; 18(1): 76-80, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31773124

RESUMO

Eupulcherol A (1), a novel triterpenoid with an unprecedented carbon skeleton, was isolated from Euphorbia pulcherrima. Its structure was determined by comprehensive analysis of spectroscopic data, including HRESIMS and 1D and 2D NMR, and the absolute configuration was defined by single crystal X-ray diffraction analysis. Biological studies showed that compound 1 possessed anti-Alzheimer's disease (AD) bioactivity, which could delay paralysis of transgenic AD Caenorhabditis elegans. A plausible biogenetic pathway for eupulcherol A (1) was also proposed.

14.
Medicine (Baltimore) ; 98(46): e17903, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725638

RESUMO

In this study, we aimed to develop a reliable nomogram to estimate individualized prognosis for patients with distal bile duct cancer (DBDC) and compare the predictive value with the American Joint Committee on Cancer staging system.Data of 1110 patients diagnosed with DBDC were recruited from the Surveillance, Epidemiology, and End Results database between 1973 and 2015. All patients were randomly divided into the training (n = 777) and validation (n = 333) cohorts, respectively. Multivariate Cox regression was performed to identify the independent risk factors. The Akaike information criterion was used to select covariates for constructing a nomogram. The predictive ability of the nomogram was assessed by concordance index (C-index) and area under receiver operating characteristic curve (AUROC) compared to tumor-node-metastasis (TNM) staging system.A nomogram integrating 8 risk factors was developed with a higher C-index than that of the TNM staging system (training data set, 0.70 vs 0.61; validation data set, 0.71 vs 0.57). The AUROCs of the nomogram for 1-year and 3-year overall survival (OS) predication were 0.76 and 0.78 in the training cohort, 0.78 and 0.77 in the validation cohort. However, AUROCs of the TNM stage for predicting 1-year and 3-year OS were all below 0.60. Calibration curves showed the optimal agreement in predicating OS between nomogram and actual observation. In addition, this nomogram can effectively distinguish the OS between low and high-risk groups divided by the median score (P < .01).Present study was the first one to construct a prognostic nomogram of DBDC patients, which has the potential to provide individual prediction of OS.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Nomogramas , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Programa de SEER , Fatores Sexuais , Fatores Socioeconômicos , Carga Tumoral , Adulto Jovem
15.
Medicine (Baltimore) ; 98(48): e18118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770239

RESUMO

BACKGROUND: Vitamin D is a fat-soluble vitamin that is related to the health of the human body and is an indispensable nutrient for human beings. Some studies indicated that type 2 diabetes mellitus (T2DM) with diabetic peripheral neuropathy (DPN) may be associated with vitamin D deficiency, but the current understanding of this point of view remains controversial. This study aimed to evaluate the correlation between serum 25-hydroxyl vitamin D (25 [OH] D) concentration and DPN in patients with T2DM by a meta-analysis, and to provide a reference for doctors. METHODS: Relevant studies were selected from the PubMed, Cochrane Library, China National Knowledge Infrastructure, VIP databases, and Wanfang Data Knowledge Service Platform databases dating from 2000 to December 2017. A total of 75 articles related to serum 25 (OH) D and DPN were selected from 2000 to December 2017. Based on the inclusion and exclusion criteria of the literature, a quality assessment was conducted using the Newcastle-Ottawa scale, and a meta-analysis was performed by RevMan5.3 statistical software. RESULTS: Thirteen studies that involved a total of 2814 type 2 diabetic patients were finally included into the meta-analysis. Meta-analysis results, heterogeneity test showed that, P < .000 01, I = 92%, calculation by random effect model revealed that, the serum concentration of 25 (OH) D in T2DM combined with DPN group was lower than that in the group without DPN (weighted mean difference = -0.74, 95% confidence interval: -1.03 to -0.46) CONCLUSIONS:: Vitamin D is associated with type 2 DPN (DPN), and vitamin D deficiency can lead to an increased risk of type 2 DPN. However, more high-quality research is needed.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Neuropatias Diabéticas/sangue , Doenças do Sistema Nervoso Periférico/sangue , Deficiência de Vitamina D/etiologia , Vitamina D/análogos & derivados , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/etiologia , Fatores de Risco , Vitamina D/sangue , Deficiência de Vitamina D/sangue
16.
Viruses ; 11(10)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652591

RESUMO

Some coronaviruses (CoVs) have an extra furin cleavage site (RRKR/S, furin-S2' site) upstream of the fusion peptide in the spike protein, which plays roles in virion adsorption and fusion. Mutation of the S2' site of QX genotype (QX-type) infectious bronchitis virus (IBV) spike protein (S) in a recombinant virus background results in higher pathogenicity, pronounced neural symptoms and neurotropism when compared with conditions in wild-type IBV (WT-IBV) infected chickens. In this study, we present evidence suggesting that recombinant IBV with a mutant S2' site (furin-S2' site) leads to higher mortality. Infection with mutant IBV induces severe encephalitis and breaks the blood-brain barrier. The results of a neutralization test and immunoprotection experiment show that an original serum and vaccine can still provide effective protection in vivo and in vitro. This is the first demonstration of IBV-induced neural symptoms in chickens with encephalitis and the furin-S2' site as a determinant of neurotropism.

17.
Virology ; 538: 71-85, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31580973

RESUMO

In order to confirm the existence of W protein in Avian avulavirus 1 (AAvV-1) infected cells, two monoclonal antibodies were prepared. The presence of W protein in cells infected with lentogenic genotype II strain La Sota or velogenic genotype VII strain SG10 was confirmed with immunofluorescence and western blotting assays. WSG10 localized to the cytoplasm, whereas WLa Sota localized to the nucleus. The influence of W protein was investigated in vitro and in vivo with two AAvV-1 strains defective in the W C-terminus. The growth kinetic curves and pathogenicity tests in 3-week-old SPF chickens both showed that the replication abilities of strains with C-terminally deleted W proteins were lower than that of the parental strain. Restoring the appropriate dose of W protein increased the viral titers of these strains. The expression validation and functional exploration of W protein will facilitate our understanding of pathogenic mechanism of AAvV-1.

18.
Food Sci Nutr ; 7(9): 3052-3061, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31572598

RESUMO

The aim of this study was to demonstrate the effect of arabinoxylan on colonic mucosal barrier and metabolomic profiles in high-fat diet-induced rats. A total of 20 six-week-old male rats were arranged randomly to two groups (n = 10/group), including a high-fat diet (HFD) group and a high-fat supplemented with arabinoxylan diet (AXD) group. Results showed that feeding AXD reduced serum lipopolysaccharide in rats after 5 weeks. In colonic digesta, Escherichia coli population was reduced, while Lactobacillus, Bifidobacterium, and Bacteroidetes populations were increased in AXD group. Metabolomics assay found that the different abundances of 84 metabolites were observed, involving lipid, carbohydrate, and nitrogenous metabolism in colonic digesta. In colonic mucosa, AXD up-regulated gene level of tight-junction-related proteins. Meanwhile, lower TNF-α and IL-1ß levels were related to TLR4/NF-κB/MyD88 pathway in AXD group. In conclusion, arabinoxylan could change colonic microbial metabolism and improve the colonic mucosal barrier via modulating intestinal microflora and tight junction proteins.

19.
Eur J Med Chem ; 183: 111650, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539780

RESUMO

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1ß2γ2 GABAA receptors (EC50 46.3 ±â€¯7.3 µM). Thus, 68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.


Assuntos
Anisóis/química , Anticonvulsivantes/química , Cinamatos/química , Medicamentos de Ervas Chinesas/química , Ésteres/química , L-Lactato Desidrogenase/antagonistas & inibidores , Polygala/química , Regulação Alostérica , Animais , Anisóis/farmacologia , Anticonvulsivantes/farmacologia , Carbamazepina/química , Carbamazepina/farmacologia , Cinamatos/farmacologia , Dioxolanos/química , Dioxolanos/farmacologia , Desenho de Drogas , Medicamentos de Ervas Chinesas/farmacologia , Ésteres/farmacologia , Humanos , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Neuralgia/prevenção & controle , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Ácido Valproico/química , Ácido Valproico/farmacologia
20.
Front Microbiol ; 10: 1905, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497001

RESUMO

DNA methylation serves as a vital component of restriction-modification (R-M) systems in bacteria, where it plays a crucial role in defense against foreign DNA. Recent studies revealed that DNA methylation has a global impact on gene expression. Deinococcus radiodurans, an ideal model organism for studying DNA repair and genomic stability, possesses unparalleled resistance to DNA-damaging agents such as irradiation and strong oxidation. However, details on the methylome of this bacterium remain unclear. Here, we demonstrate that N 4-cytosine is the major methylated form (4mC) in D. radiodurans. A novel methylated motif, "C4mCGCGG" was identified that was fully attributed to M.DraR1 methyltransferase. M.DraR1 can specifically bind and methylate the second cytosine at N 4 atom of "CCGCGG" motif, preventing its digestion by a cognate restriction endonuclease. Cells deficient in 4mC modification displayed higher spontaneous rifampin mutation frequency and enhanced DNA recombination and transformation efficiency. And genes involved in the maintenance of genomic stability were differentially expressed in conjunction with the loss of M.DraR1. This study provides evidence that N 4-cytosine DNA methylation contributes to genomic stability of D. radiodurans and lays the foundation for further research on the mechanisms of epigenetic regulation by R-M systems in bacteria.

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