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1.
J Dig Dis ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31922658

RESUMO

AIM: The main objective was to explore the effectiveness of gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) in predicting portal hypertension and high-risk esophageal varices (EVs) in hepatitis B cirrhosis patients. METHODS: In total, 71 and 30 patients comprised the training and validation groups respectively. We performed univariate and multivariate analyses to detect the risk factors of high-risk EVs to generate EV score formulae. The relationships between the relative enhancement ratio (RE) of Gd-BOPTA-enhanced MRI and portal vein pressure were further explored. RESULTS: Platelet count, portal vein width and RE were identified as independent predictors of high-risk EVs. Based on these parameters, we calculated the EV score model as: -6.483 + 15.612*portal vein width + 2.251*RE-0.176*platelet count. The area under the receiver operating characteristic curve (AUROC) was 0.903. At a cut-off value of <-2.74, the negative predictive value (NPV) was 94.00%, while the positive predictive value (PPV) was as high as 93.80% when cut-off was set at >4.00. Gd-BOPTA-enhanced MRI was effective in predicting portal pressure. The accuracy was confirmed with the validation set. CONCLUSIONS: Gd-BOPTA-enhanced MRI was successfully applied to evaluate high-risk EVs and portal hypertension. These results present an accurate non-invasive model for detecting high-risk EVs, based on which we propose a cost-effective EV management algorithm, eliminating the need to perform endoscopy in all cirrhosis patients. This article is protected by copyright. All rights reserved.

2.
J Biomed Sci ; 27(1): 12, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31907057

RESUMO

BACKGROUND: Polyethylene glycol (PEG) is widely used in industry and medicine. Anti-PEG antibodies have been developed for characterizing PEGylated drugs and other applications. However, the underlying mechanism for specific PEG binding has not been elucidated. METHODS: The Fab of two cognate anti-PEG antibodies 3.3 and 2B5 were each crystallized in complex with PEG, and their structures were determined by X-ray diffraction. The PEG-Fab interactions in these two crystals were analyzed and compared with those in a PEG-containing crystal of an unrelated anti-hemagglutinin 32D6-Fab. The PEG-binding stoichiometry was examined by using analytical ultracentrifuge (AUC). RESULTS: A common PEG-binding mode to 3.3 and 2B5 is seen with an S-shaped core PEG fragment bound to two dyad-related Fab molecules. A nearby satellite binding site may accommodate parts of a longer PEG molecule. The core PEG fragment mainly interacts with the heavy-chain residues D31, W33, L102, Y103 and Y104, making extensive contacts with the aromatic side chains. At the center of each half-circle of the S-shaped PEG, a water molecule makes alternating hydrogen bonds to the ether oxygen atoms, in a similar configuration to that of a crown ether-bound lysine. Each satellite fragment is clamped between two arginine residues, R52 from the heavy chain and R29 from the light chain, and also interacts with several aromatic side chains. In contrast, the non-specifically bound PEG fragments in the 32D6-Fab crystal are located in the elbow region or at lattice contacts. The AUC data suggest that 3.3-Fab exists as a monomer in PEG-free solution but forms a dimer in the presence of PEG-550-MME, which is about the size of the S-shaped core PEG fragment. CONCLUSIONS: The differing amino acids in 3.3 and 2B5 are not involved in PEG binding but engaged in dimer formation. In particular, the light-chain residue K53 of 2B5-Fab makes significant contacts with the other Fab in a dimer, whereas the corresponding N53 of 3.3-Fab does not. This difference in the protein-protein interaction between two Fab molecules in a dimer may explain the temperature dependence of 2B5 in PEG binding, as well as its inhibition by crown ether.

3.
Cell Prolif ; : e12763, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31925859

RESUMO

In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be controlled. Therefore, further study of the pathogenesis of DKD and improvements in DKD treatment are crucial for prognosis. Traditional studies have shown that podocyte injury plays an important role in this process. Recently, it has been found that glomerulotubular balance and tubuloglomerular feedback (TGF) may be involved in the progression of DKD. Glomerulotubular balance is the specific gravity absorption of the glomerular ultrafiltrate by the proximal tubules, which absorbs only 65% to 70% of the ultrafiltrate. This ensures that the urine volume will not change much regardless of whether the glomerular filtration rate (GFR) increases or decreases. TGF is one of the significant mechanisms of renal blood flow and self-regulation of GFR, but how they participate in the development of DKD in the pathological state and the specific mechanism is not clear. Injury to tubular epithelial cells (TECs) is the key link in DKD. Additionally, injury to glomerular endothelial cells (GECs) plays a key role in the early occurrence and development of DKD. However, TECs and GECs are close to each other in anatomical position and can crosstalk with each other, which may affect the development of DKD. Therefore, the purpose of this review was to summarize the current knowledge on the crosstalk between TECs and GECs in the pathogenesis of DKD and to highlight specific clinical and potential therapeutic strategies.

4.
Pediatr Blood Cancer ; : e28160, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31904157

RESUMO

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures were designed to assess symptoms and functioning in children and adolescents. The study goal was to evaluate the validity and responsiveness of the PROMIS Pediatric measures in a diverse cohort of children with cancer. METHODS: Children (7-18 years) from nine pediatric oncology hospitals completed surveys at 72 hours preceding treatment initiation (T1) and at follow-up (T2) approximately 7 to 17 days later for chemotherapy, and 4+ weeks later for radiation. Children completed PROMIS Pediatric measures (Mobility, Pain Interference, Fatigue, Depressive Symptoms, Anxiety, Psychological Stress), Memorial Symptom Assessment Scale (MSAS), and global impressions of change (GIC) questions on their symptoms and functioning at T2 reflecting on T1. Parents completed the Lansky Play-Performance Status (PPS) scale and medication list for their child. RESULTS: The children (n = 482) were average age 12.9 years, 46% female, 60% Caucasian, and had diverse cancers and treatments. There were moderate to strong correlations between PROMIS Pediatric and MSAS, supporting convergent validity. In support for known-groups validity, the PROMIS Pediatric average scores were statistically different (P < 0.05) for most domains by PPS and if the child was on a medication (or not) for controlling a symptom. The PROMIS Pediatric measures were responsive over time in association with the GIC. CONCLUSIONS: In a large, diverse sample of children and adolescents with cancer, there was strong evidence for the construct validity and responsiveness of the PROMIS Pediatric measures. This evidence supports PROMIS Pediatric measure use in pediatric oncology trials.

5.
Medicine (Baltimore) ; 99(2): e18467, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914018

RESUMO

BACKGROUND: Curcumin, a controversial "panacea," has been broadly studied. Its bioactivities including antioxidant, anti-inflammatory, and especially antineoplastic activities have been documented. However, due to its extensive bioactivities, some scientists hold a skeptical point of view toward curcumin and described curcumin as a "deceiver" to chemists. The objective of this study was to explore curcumin's another possibility as a potential supplementary leading compound to cancer treatments. METHODS: Literature searches were conducted using electronic databases. Search terms such as "curcumin," "curcumin analogues," and so on were used. The literatures were collected and summarized. In this article, reported targets of curcumin are reviewed. The limitations of a curcumin as a therapeutic anticancer product including low bioavailability and poor targeting are mentioned. Furthermore, modified curcumin analogues and antitumor mechanisms are listed and discussed in the aspects of cell death and tumor microenvironment including angiogenesis, tissue hypoxia status, and energy metabolism. RESULTS: Several possible modification strategies were presented by analyzing the relationships between the antitumor activity of curcumin analogues and their structural characteristics, including the introduction of hydrophilic group, shortening of redundant hydrocarbon chain, the introduction of extra chemical group, and so on. CONCLUSIONS: From our perspective, after structural modification curcumin could be more effective complementary product for cancer therapies by the enhancement of targeting abilities and the improvement of bioavailability.

6.
Org Lett ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31951145

RESUMO

An asymmetric tandem cycloisomerization and intermolecular [5+2] cycloaddition reaction of 2-ethynylphenyl-substituted nitrones with methyleneindolinones was realized. The process includes the palladium(II)-promoted in situ formation of azomethine ylide and the following chiral N,N'-dioxide-Co(II) complex-catalyzed regio-, diastereo-, and enantioselective [5+2] cycloaddition reaction. The desired spiro-tropanyl oxindoles were obtained in good yields with excellent dr and ee values. On the basis of the determination of the catalyst structure, a possible transition state model was proposed.

7.
J Ethnopharmacol ; : 112577, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31953200

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Polygoni Multiflori Radix (PMR) and Polygoni Multiflori Radix Praeparata (PMRP) that is used after processing are two well-known traditional Chinese medicines. PMRP is traditionally reported to have lipid-reducing activity as recorded in Chinese Pharmacopoeia. AIM OF THE STUDY: This study aims to observe the alleviation of Polygoni Multiflori Radix Praeparata water extract (PMRPWE) and Polygoni Multiflori Radix water extract (PMRWE) against nonalcoholic fatty liver disease (NAFLD), and its potential engaged mechanism and the main active ingredients. MATERIALS AND METHODS: The contents of 2,3,5,4'-tetrahydroxy-stilbene-2-O-ß- D-glucoside (TSG), emodin and physcion in PMRWE and PMRPWE were measured by using high-performance liquid chromatography (HPLC). NAFLD was induced in rats by high-fat diet (HFD) feeding for 8 weeks. At the same time, rats were orally given with PMRWE (70, 140, 280 mg/kg) or PMRPWE (70, 140, 280 mg/kg) every day. Serum and liver biochemical parameters, hepatic gene expression and enzymatic activity were detected. Cellular lipids accumulation in human normal liver L-02 cells was induced by 0.5 mM non-esterified fatty acid (NEFA). RESULTS: The results of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver reactive oxygen species (ROS) and hematoxylin-eosin (H&E) observation showed that PMRWE and PMRPWE both alleviated liver injury in HFD-fed rats. The results of liver triglyceride (TG), total cholesterol (TC) and NEFA amounts, and liver Oil Red O staining evaluation showed that PMRWE and PMRPWE both reduced hepatic lipids accumulation in HFD-fed rats. The results of 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorescence staining and cellular TG content showed that both PMRWE and PMRPWE reduced NEFA-induced cellular lipids accumulation in L-02 cells. PMRWE and PMRPWE increased liver mRNA expression of some signals involved in mitochondrial ß oxidation, including the key enzyme carnitine palmitoyltransferase 1A (CPT1A). Moreover, PMRWE and PMRPWE increased the decreased liver CPT1A enzymatic activity in HFD-fed rats. Etomoxir (ETO), a CPT1A inhibitor, weakened the lipid-lowering activity of PMRWE and PMRPWE in vitro. Additionally, the main compounds in PMRWE and PMRPWE including TSG, emodin, physcion and resveratrol all reduced cellular lipids accumulation induced by NEFA in L-02 cells. CONCLUSIONS: PMRWE and PMRPWE alleviated NAFLD through promoting mitochondrial ß oxidation by enhancing liver CPT1A activity. Stilbenes (including TSG, polydatin and resveratrol) and anthraquinones (including physcion, emodin and rhein) may be the main active compounds contributing to the lipid-lowering activity provided by PMRWE and PMRPWE.

8.
Toxicol Appl Pharmacol ; : 114882, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31953203

RESUMO

Pulmonary fibrosis is a prototypic chronic progressive lung disease with high morbidity and mortality worldwide. Novel effective therapeutic agents are urgently needed owing to the limited treatment options in clinic. Herein, nagilactone D (NLD), a natural norditerpenoid obtained from Podocarpus nagi, was found to suppress transforming growth factor-ß1 (TGF-ß1)-mediated fibrotic process in vitro and bleomycin (BLM)-induced pulmonary fibrosis in vivo. NLD attenuated TGF-ß1-induced expression of fibrotic markers including type I and III collagen, fibronectin, α-SMA, and CTGF in human pulmonary fibroblasts (WI-38 VA-13 and HLF-1 cells). Mechanism study indicated that NLD suppressed TGF-ß1-induced up-regulation of TßR I, and Smad2 phosphorylation, nuclear translocation, and transcriptional activation. Moreover, NLD ameliorated BLM-induced histopathological abnormalities in the lungs of experimental fibrotic mice, suppressed synthesis of relative fibrotic markers and fibroblast-to-myofibroblast transition, as well as BLM-induced up-regulation of TßR I expression and Smad signaling in mouse lungs. These data collectively support NLD to be a potential therapeutic agent for pulmonary fibrosis.

9.
Biomolecules ; 10(1)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936661

RESUMO

The main curative treatments for hepatocellular carcinoma (HCC) are surgical resection and liver transplantation, which only benefits 15% to 25% of patients. In addition, HCC is highly refractory and resistant to cytotoxic chemotherapy. Although several multi-kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for treating advanced HCC, only a short increase of median overall survival in HCC patients was achieved. Therefore, there is an urgent need to design more effective strategies for advanced HCC patients. Human ribonucleotide reductase is responsible for the conversion of ribonucleoside diphosphate to 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. In this study, mining the cancer genomics and proteomics data revealed that ribonucleotide reductase regulatory subunit M2 (RRM2) serves as a prognosis biomarker and a therapeutic target for HCC. The RNA sequencing (RNA-Seq) analysis and public microarray data mining found that RRM2 was a novel molecular target of sorafenib in HCC cells. In vitro experiments validated that sorafenib inhibits RRM2 expression in HCC cells, which is positively associated with the anticancer activity of sorafenib. Although both RRM2 knockdown and sorafenib induced autophagy in HCC cells, restoration of RRM2 expression did not rescue HCC cells from sorafenib-induced autophagy and growth inhibition. However, long-term colony formation assay indicated that RRM2 overexpression partially rescues HCC cells from the cytotoxicity of sorafenib. Therefore, this study identifies that RRM2 is a novel target of sorafenib, partially contributing to its anticancer activity in HCC cells.

10.
Sci Rep ; 10(1): 381, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942015

RESUMO

Qualitative and quantitative assessments of fluid cycling are essential to address the role and transport of deeply sourced fluids in subduction systems. In this study, sediment cores distributed across a submarine mud volcano (SMV) offshore southwestern Taiwan were investigated to determine the characteristics of fluids generated through the convergence between the Eurasian and Phillippine Sea Plates. The low dissolved chloride concentration combined with the enrichment of 18O, and depletion of 2H of pore fluids suggest the discharge of deep freshwater formed by smectite dehydration at an equilibrium temperature of 100 to 150 °C. The upward fluid velocities, decreasing from 2.0 to 5.0 cm yr-1 at the center to a negligible value at margin sites, varied with the rate and efficiency of anaerobic methanotrophy, demonstrating the impact of fluid migration on biogeochemical processes and carbon cycling. By extrapolating the velocity pattern, the flux of fluids exported from 13 SMVs into seawater amounted up to 1.3-2.5 × 107 kg yr-1, a quantity accounting for 1.1-28.6% of the smectite-bound water originally stored in the incoming sediments. Our results imply that SMVs could act as a conduit to channel the fluids produced from great depth/temperature into seafloor environments in a subduction system of the western Pacific Ocean.

11.
Gynecol Endocrinol ; : 1-5, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31928249

RESUMO

Recurrent implantation failure (RIF) remains a clinical dilemma. Helium-Neon (He-Ne) laser irradiation has recently become more popular under certain clinical conditions. Given the unique therapeutic effects, we were interested in determining whether pretreatment with He-Ne laser irradiation prior to frozen-thawed embryo transfer (FET) would improve the microcirculation and cause the release of growth factors and cytokines, thus improving endometrial receptivity and the clinical pregnancy rates. Patients chose for themselves whether to proceed with (n = 29) or without (n = 31) pretreatment with He-Ne laser irradiation prior to FET. The clinical pregnancy rate (37.9%) and implantation rate (20.3%) were higher in the laser-treatment group than in the control group (35.5% and 15.9%, respectively, p = .844 and .518, respectively). The live birth rate was higher in the laser-treatment group (27.6% vs. 25.8%, respectively, p = .876) and the miscarriage rate was lower in the laser-treatment group (18.2% and 27.3%, respectively, p = .611). No side effects or complications from laser irradiation were encountered in patients who received the laser treatment. We concluded that pretreatment with He-Ne laser prior to FET may be an alternative choice for RIF-affected women; however, additional well-designed prospective studies are necessary to determine the precise clinical value of this treatment.

12.
Medicine (Baltimore) ; 99(1): e18447, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895773

RESUMO

Prenatal examination is a pivotal measure to prevent high-risk pregnancy and to ensure the safety of both mother and infant. However, pregnant women in Linzhi Prefecture in the Tibet Autonomous Region (TAR) often cannot obtain regular prenatal examinations due to limited accessibility of healthcare facilities, shortage of medical staff, and lack of medical equipment. Health education is an important approach to solve this ever-growing issue of pregnant women in rural Tibet.To evaluate the efficacy of flexible methods of health education programs on improving compliance among pregnant women from Tibet, China.In May to November of 2018, a total of 168 pregnant women receiving prenatal examination in a tertiary referral hospital in Linzhi Prefecture were recruited and randomly assigned to a control (n = 85) and intervention group (n = 83). All pregnant women were followed up until delivery. The pregnant women in the control group received regular prenatal examination and health education programs. Other than receiving routine prenatal care, participants of the interventional group also voluntarily joined the WeChat Social Messaging platform. Online resources posted by the maternity schools provided convenience and flexibility for the pregnant woman. The number of prenatal examinations was statistically significant between the 2 groups. The effect of flexible patterns of health education programs on improving the compliance of pregnant women in Tibet was assessed.The number of prenatal examinations in the intervention group was 2.646 times, which was higher than that in the control group (P < .01). Multivariate analysis demonstrated that interventional measures and ethnicity were the influencing factors of the number of prenatal examinations for pregnant women in Linzhi after the adjustment of age, history of adverse pregnancy, education level, ethnicity, multiparity, gestational complications, and medical history. The number of prenatal examinations for the pregnant Tibetan women was 0.535 times lower compared with that of the pregnant Han women (95% CI: -0.089, 1.157, P = .091).Flexible forms of health education during the antenatal period can effectively increase the compliance of pregnant women in Tibet.


Assuntos
Educação em Saúde/métodos , Cooperação do Paciente , Cuidado Pré-Natal/estatística & dados numéricos , Adulto , Feminino , Humanos , Gravidez , Rede Social , Tibet
13.
BMC Cancer ; 20(1): 33, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937294

RESUMO

BACKGROUND: Matrix metalloproteinase 7 (MMP7), as the smallest member of the matrix metalloproteinase family, has been verified to be implicated in cancer progression, especially metastasis. However, its expression pattern and function in tongue cancer is not clear. METHODS: The expression of MMP7 in human tongue squamous cell carcinoma (TSCC) specimens compared with their respective paired nontumour tissues by real-time PCR and immunohistochemical staining. The effect of MMP7 on the proliferation, apoptosis, migration, invasion of tongue cancer cells was tested in appropriate ways after MMP7 siRNA knockdown or overexpression. The effect of MMP7 on lymph node metastasis in vivo was analyzed using a high-metastasis orthotopic nude mouse tongue transplanted tumour model. RESULTS: We found markedly elevated expression of MMP7 in human TSCC specimens compared with their respective paired nontumour tissues, and this high expression was correlated with the patients' lymph node metastasis. Furthermore, the results of molecular functional assays confirmed that MMP7 promotes cell proliferation, migration and invasion of TSCC cells. Knockdown of MMP7 inhibited lymph nodes metastasis in vivo. CONCLUSIONS: MMP7 plays an oncogenic role in carcinogenesis and metastasis of tongue cancer, and may serve as a potential therapeutic target for tongue cancer.

14.
Toxicol Lett ; 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31935479

RESUMO

1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant, but little is known about the cerebellar dysfunction induced by excessive exposure to it. To uncover 1,2-DCE-induced neurotoxicity in cerebellar granular cells (CGCs), and to investigate the underlying mechanisms, we explored this, both in vitro and in vivo. Our findings showed significant cell viability inhibition in human CGCs (HCGCs) treated with 1,2-DCE. Flow cytometry and mitochondrial membrane potential analyses discovered an increase in apoptotic-mediated cell death in HCGCs after 1,2-DCE treatment. This HCGC apoptosis was involved in the increases of protein expression in Cytochrome c, Caspase-3, Bad, Bim, transformation related protein 53, Caspase-8, tumor necrosis factor-α, and Survivin. Quantitative real-time PCR (qPCR) and western blot confirmed the increases in Cytochrome c, Caspase-3, cleaved Caspase-3, and Bad in HCGCs after 1,2-DCE treatment. Bax inhibitor peptide V5 rescued 1,2-DCE-induced HCGC apoptosis. Furthermore, 80 CD-1 male mice were exposed to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day for 4 weeks. An open field test found abnormal neurobehavioral changes in the mice exposed to 1,2-DCE. Histopathological examination showed significantly shrunken and hypereosinophilic cytoplasm with nuclear pyknosis in mouse CGCs from the 700 mg/m3 1,2-DCE group. TdT-mediated dUTP nick-end labeling assay verified significant increases in apoptotic positive cells in the mouse CGCs after 1,2-DCE exposure. We confirmed the increases in the expressions of Cytochrome c, Caspase-3, cleaved Caspase-3 and Bad in the mice exposed to 1,2-DCE. These findings suggest that 1,2-DCE exposure can induce CGC apoptosis and cerebellar dysfunction, at least in part, through mitochondrial pathway.

15.
Clin Exp Pharmacol Physiol ; 47(2): 294-301, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31631367

RESUMO

Recently both N-acetylcysteine (NAC) and Dexmedetomidine (DEX) have shown emerging roles in protection of acute lung injury (ALI). However, how their protective roles work and whether they can provide synergistic effects in ALI remain unknown. Here we explored it from the hot research viewpoint of Th1/Th2/Th17 cytokines balance. Lipopolysaccharide (LPS)-induced ALI was established and treated with NAC and/or DEX. Mice were divided into Sham group, ALI group, NAC group, DEX group and NAC+DEX group. Mice were sampled at 6, 12 and 24 hours after the model construction. Histopathology, wet to dry ratio and myeloperoxidase (MPO) activity were assessed in lung tissues. Protein concentration and cell count were assessed in bronchoalveolar lavage fluid (BALF). Th1/Th2/Th17 cytokines were assessed in plasma, BALF and lung homogenate. ALI-induced lung morphological damage, edema and aberrant MPO activity can be attenuated by NAC or DEX and mostly by NAC+DEX. NAC with DEX significantly reduced ALI-induced protein leakage and cell infiltration in BALF. Th1/Th2/Th17 cytokines imbalance aggravated with ALI progression. NAC, DEX and especially NAC+DEX can effectively correct these unbalanced cytokines. Galectin-9 and Tim-3 were transcriptionally up-regulated in ALI. Combination of NAC with DEX obtained a maximum effect on decreasing Galectin-9/Tim-3 expression. In summary, Th1/Th2/Th17 cytokines imbalance is newly found to participate in LPS-induced ALI. NAC or DEX administration can attenuate ALI by rebalancing Th1/Th2/Th17 cytokines. Their protective roles can be enhanced when co-administration, because DEX may relieve the Galectin-9/Tim-3 axis-mediated immune suppression.

16.
Neuropsychopharmacology ; 45(2): 301-308, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31394567

RESUMO

There is increasing interest in developing drugs that act at α4ß2 nicotinic acetylcholine receptors (nAChRs) to treat alcohol use disorder. The smoking cessation agent varenicline, a partial agonist of α4ß2 nAChRs, reduces alcohol intake, but its use can be limited by side effects at high therapeutic doses. There are two stoichiometric forms of α4ß2 nAChRs, (α4)3(ß2)2 and (α4)2(ß2)3. Here we investigated the hypothesis that NS9283, a positive allosteric modulator selective for the (α4)3(ß2)2 form, reduces ethanol consumption. NS9283 increased the potency of varenicline to activate and desensitize (α4)3(ß2)2 nAChRs in vitro without affecting other known targets of varenicline. In male and female C57BL/6J mice, NS9283 (10 mg/kg) reduced ethanol intake in a two-bottle choice, intermittent drinking procedure without affecting saccharin intake, ethanol-induced incoordination or ethanol-induced loss of the righting reflex. Subthreshold doses of NS9283 (2.5 mg/kg) plus varenicline (0.1 mg/kg) synergistically reduced ethanol intake in both sexes. Finally, despite having no aversive valence of its own, NS9283 enhanced ethanol-conditioned place aversion. We conclude that compounds targeting the (α4)3(ß2)2 subtype of nAChRs can reduce alcohol consumption, and when administered in combination with varenicline, may allow use of lower varenicline doses to decrease varenicline side effects.

17.
Water Res ; 170: 115351, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31810033

RESUMO

Determination of the effects of cascade dams on benthic microbial ecosystem is essential for dam regulation and ecological function protection. However, no comprehensive investigation has yet shown the ecosystem-level responses of microbiota to dam impoundments. This study conducted DNA metabarcoding and microbial food web analysis for multiple species and their interrelationships along a cascade dam-affected river. The composition, distribution and diversity of bacteria, protozoans and metazoans were obviously different between river and reservoirs, mainly controlled by hydrological (P < 0.01) and nutrient parameters (P < 0.05). Those three groups make up a co-occurrence network, with most edges direct from higher to lower trophic levels or vice versa and more than 50% keystones participate in the food web, indicating the significant role of predator-prey relationships. Based on the microbial food web analysis, the predator biomass, especially at higher trophic levels, decreased by about 10% from the riverine to the lacustrine system. The structural equation model illustrates that both bottom-up forces (environmental factors particularly velocity and nutrient concentrations) and top-down forces (higher trophic levels) critically control microbial food web patterns (P < 0.05). As a result of dam impoundments, the lower velocity in the reservoirs has direct negative effects on trophic transfer efficiencies that may be further magnified by nutrient accumulation, probably leading to an increase of eutrophication and posing a risk to water quality. The results suggest the potential ecological risk in the reservoirs and highlight the need to consider from the perspective of ecosystem during the operation of cascade dams.

18.
Small ; : e1905202, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31814302

RESUMO

Graphene has attracted great interests in various areas including optoelectronics, spintronics, and nanomechanics due to its unique electronic structure, a linear dispersion with a zero bandgap around the Dirac point. Shifts of Dirac cones in graphene creates pseudo-magnetic field, which generates an energy gap and brings a zero-magnetic-field analogue of the quantum Hall effect. Recent studies have demonstrated that graphene pseudo-magnetic effects can be generated by vacancy defects, atom adsorption, zigzag or armchair edges, and external strain. Here, a larger than 100 T pseudo-magnetic field is reported that generated on the step area of graphene; and with the ultrahigh vacuum scanning tunneling microscopy, the observed Landau levels can be effectively tailored by graphene phonons. The zero pseudo-Landau level is suppressed due to the phonon-mediated inelastic tunneling, and this is observed by the scanning tunneling spectroscopy spectrum and confirmed by the Vienna ab initio simulation package calculation, where graphene phonons modulate the flow of tunneling electrons and further mediate pseudo-Landau levels. These observations demonstrate a viable approach for the control of pseudo-Landau levels, which tailors the electronic structure of graphene, and further ignites applications in graphene valley electronics.

19.
Am J Cancer Res ; 9(11): 2314-2330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815037

RESUMO

Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDDP) in vitro and in vivo. Mechanism analysis indicated that ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus. In addition, ZEB1 as a transcription factor binds to the promoter of HDGF to stimulate HDGF transcription. Furthermore, suppression of HDGF in ZEB1-overexpressed EC cells not only reduced the expression of ß-catenin, TCF4, and ZEB1, but also repressed ß-catenin translocation from the cytoplasm into the nucleus and further downregulated the combination with TCF4. Interestingly, the ß-catenin/TCF4 signaling feedback stimulates ZEB1 transcription and therefore constitutes a positive feedback loop. In clinical samples, ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of EC. In summary, our study demonstrated that the positive feedback loop of ZEB1/HDGF/ß-catenin/TCF4 plays an unfavorable role in the metastasis of endometrial carcinoma.

20.
Sensors (Basel) ; 19(24)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817131

RESUMO

We proposed a novel kind of absolute capacitive grating displacement measuring system with both high accuracy and long range in a previous article. The measuring system includes both a MOVER and a STATOR, the contact surfaces of which are coated by a thin layer of dielectric film with a low friction coefficient and high hardness. The measuring system works in contact mode to minimize the gap changes. This paper presents a theoretical analysis of the influence of some factors, including fabrication errors, installation errors, and environment disturbance, on measurement signals. The measuring signal model was modified according to the analysis. The signal processing methods were investigated to improve the signal sensitivity and signal-to-noise ratio (SNR). The displacement calculation model shows that the design of orthogonal signals can solve the dead-zone problem. Absolute displacement was obtained by a simple method using two coarse signals and highly accurate displacement was further obtained while using two fine signals with the help of absolute information. According to the displacement calculation model and error analysis, the error in fine calculation functions mainly determines the model's accuracy and is locally affected by coarse calculation functions. It was also determined that amplitude differences, non-orthogonality, and signal offsets are not related to the accuracy of the displacement calculation model. The experiments were carried out to confirm the abovementioned theoretical analysis. The experimental results show that the displacement resolution and error in the displacement calculation model reach ±4.8 nm and ±34 nm, respectively, in the displacement range of 5 mm. The experiments and the theoretical analyses both indicate that our proposed measuring system has great potential for achieving an accuracy of tens of nanometers and a range of hundreds of millimeters.

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