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1.
Chemosphere ; 239: 124811, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726522

RESUMO

China has been suffering from endemic fluorosis for the past 30 years. This study investigated fluoride concentrations in 10 districts of Tianjin, China, to illustrate their spatial distribution characteristics and potential human health risks. The results showed fluoride concentration of 0.01-6.30 mg L-1 with a mean value of 0.99 mg L-1, and 78.82% of water fluoride reaches the standard for drinking water (1.5 mg L-1). Higher fluoride levels were recorded in deep well pumps supply zones, and more potential changes in fluoride occurred was positively correlated with pH in groundwater. Mean value of fluoride in drinking water in 10 districts followed the order of WQ > BC > JZ > NH > BD > BH > JN > JH > DL > XQ. Estimations of non-carcinogenic risk for drinking water indicated that mean hazard quotient values of fluoride for combined pathways (i.e., oral ingestion and dermal absorption) were >1.0 for all age groups of WQ and BC. The results also showed that the estimated risk primarily came from the ingestion pathway. Risk levels for children varied obviously, generally in the order of 1-4y > 4-7y > 7-9y (years old). In the central tendency center and reasonable maximum exposure conditions, estimated risks were 1.25, 1.12, 0.771 and 3.66, 3.29, 2.27, respectively. The results supply material information for health authorities in fluorosis areas to put forward more efficient policies to control the endemic diseases. Attention should be paid to the formulation of health promotion strategies and measures to reduce fluoride intake in order to protect the health of residents.

2.
Medicine (Baltimore) ; 98(44): e17031, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689742

RESUMO

The mechanisms underlying the potential risks of in vitro fertilization and embryo transfer (IVF-ET) have not been fully elucidated. The aim of this study was to explore changes in the complement and coagulation pathways in placentae subjected to IVF-ET in the first trimester compared to placentae from normal pregnancies. Four placenta samples in the first trimester were obtained from patients undergoing IVF-ET owing to oviductal factors only. An additional 4 control placentae were obtained from volunteers with normal pregnancies. A GeneChip Affymetrix HG-U133 Plus 2.0 Array was utilized to analyze the changes in gene expression between the normal and IVF-ET placentae. Differentially expressed genes (DEGs) were analyzed using the Database for Annotation and Visualization and Integrated Discovery bioinformatics resource, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Using real-time PCR, we confirmed the obtained microarray data in 10 dysregulated genes. Five of the gene products were further analyzed by immunohistochemistry (IHC) to determine their protein expression and localization. A total of fifty DEGs were identified in the complement and coagulation pathways in the IVF-ET treated placentae: 38 upregulated and 12 down-regulated. KEGG pathway analysis indicated that IVF-ET manipulation substantially over-activated the coagulation and complement pathways, while urokinase plasminogen activator- and urokinase plasminogen activator receptor-mediated trophoblastic invasion and tissue remodeling were inhibited. Furthermore, the 5 proteins analyzed by IHC were found to be localized specifically to the placenta. This is the first study to compare DEGs relating to the placental complement and coagulation pathways from patients undergoing IVF-ET treatment compared to those undergoing normal pregnancy. These findings identified valuable biomarkers and potential novel therapeutic targets to combat the unfavorable effects of IVF-ET.

3.
Theranostics ; 9(25): 7948-7960, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695808

RESUMO

RATIONALE: Radiotherapy combined with immunotherapy has revealed promising outcomes in both preclinical studies and ongoing clinical trials. Targeted radionuclide therapy (TRT) is a branch of radiotherapy concerned with the use of radioisotopes, radiolabeled molecules or nanoparticles that deliver particulate radiation to cancer cells. TRT is a promising approach in cases of metastatic disease where conventional treatments are no longer effective. The increasing use of TRT raises the question of how to best integrate TRT with immunotherapy. In this study, we proposed a novel therapeutic regimen that combined programmed death ligand 1 (PD-L1)-based immunotherapy with peptide-based TRT (177Lu as the radionuclide) in the murine colon cancer model. METHODS: To explore the most appropriate timing of immunotherapy after radionuclide therapy, the anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner when 177Lu TRT was given. RESULTS: The results demonstrated that TRT led to an acute increase in PD-L1 expression on T cells, and TRT in combination with αPD-L1 mAb stimulated the infiltration of CD8+ T cells, which improved local tumor control, overall survival and protection against tumor rechallenge. Moreover, our data revealed that the time window for this combination therapy may be critical to outcome. CONCLUSIONS: This therapeutic combination may be a promising approach to treating metastatic tumors in which TRT can be used. Clinical translation of the result would suggest that concurrent rather than sequential blockade of the PD-1/PD-L1 axis combined with TRT improves overall survival and long-term tumor control.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31754859

RESUMO

As the composition of animal cell culture medium becomes more complex, the identification of key variables is important for simplifying and guiding the subsequent medium optimization. However, the traditional experimental design methods are impractical and limited in their ability to explore such large feature spaces. Therefore, in this work, we developed a NRGK (nonparametric regression with Gaussian kernel) method, which aimed to identify the critical components that affect product titres during the development of cell culture media. With this nonparametric model, we successfully identified the important components that were neglected by the conventional PLS (partial least squares regression) method. The superiority of the NRGK method was further verified by ANOVA (analysis of variance). Additionally, it was proven that the selection accuracy was increased with the NRGK method because of its ability to model both the nonlinear and linear relationships between the medium components and titres. The application of this NRGK method provides new perspectives for the more precise identification of the critical components that further enable the optimization of media in a shorter timeframe.

5.
Drug Deliv ; 26(1): 1058-1067, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735064

RESUMO

Realgar and (-)-Epigallocatechin-3-gallate (EGCG) are natural medicines that inhibit cancer cell growth, resulting in inhibition of formation and development of tumors. The anticancer effects of realgar and EGCG were greatly improved following formulation as nanoparticles. EGCG has received increased attention as a drug carrier. The aim of this study was to prepare a new nanomedicine, (EGCG-RNPs), in which encapsulated nano-realgar. EGCG-RNPs were prepared by coprecipitation and characterized by transmission electron microscopy (TEM), differential scanning calorimetry (DSC), particle size and zeta potential, X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and in vitro release. Furthermore, we evaluated the antiproliferative effects of EGCG-RNPs on HL-60 cells in vitro, antitumor effect by intratumoral injection of EGCG-RNPs into solid tumors derived from APL HL-60 cells in vivo. Possible mechanisms were evaluated using uptake and efflux experiments in HL-60 cells. The results showed that the average particle size and zeta potentials of EGCG-RNPs was 200.3 ± 1.23 nm and -46.8 ± 1.31 mV. Controlled release of EGCG-RNPs was sustained and continued up to 72 h in vitro. Compared with nano-realgar and EGCG + RNPs (EGCG and nano-realgar physical mixing), EGCG-RNPs significantly inhibited growth of HL-60 cells. In a solid tumor model, EGCG-RNPs decreased tumor volumes, with an inhibitory rate of 60.18% at a dose of 70 mg · kg-1. The mechanisms of antitumor improvement may correlate with the increased uptake of realgar and prolonged the retention time of realgar in HL-60 cells due to EGCG as a carrier. EGCG-RNPs could enhance anticancer therapeutic efficacy for acute promyelocytic leukemia.

6.
EBioMedicine ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31757777

RESUMO

BACKGROUND: Alcohol intake is a well-known lifestyle risk factor for CRC, and an increasing number of studies have revealed that alcohol intake is also tightly associated with CRC metastasis. However, the effect of alcohol on CRC metastasis and its underlying mechanism remain unclear. METHODS: A retrospective cohort study was performed to investigate the characteristics of patients with alcohol-related CRC. The effects of ethanol on the biological behaviours of CRC cells were assessed through in vivo and in vitro assays using the Lieber-DeCarli ethanol liquid diet and ethanol, respectively. The ethanol-mediated signalling pathway and downstream factors were screened through ELISA, western blot, immunofluorescence and co-immunoprecipitation. FINDINGS: Most patients with alcohol-related CRC, particularly those with tumour metastasis, were characterized by a notably higher circulating ethanol level and a lower systemic acetaldehyde level. Moreover, CRC cells accumulated in ethanol, but not acetaldehyde, to notably higher levels compared with adjacent normal cells. Alcohol intake significantly promoted CRC metastasis via the ethanol-mediated TGF-ß/Smad/Snail axis, and ethanol induced the cytoplasmic mislocalization of RUNX3 and further promoted the aggressiveness of CRC by targeting Snail. Pirfenidone (PFD) significantly eliminated the effects of ethanol on CRC metastasis by specifically blocking TGF-ß signalling. INTERPRETATION: Alcohol intake plays a vital role in CRC metastasis via the ethanol-mediated TGF-ß/RUNX3/Snail axis, and PFD might be a novel therapeutic management strategy for CRC.

7.
Anal Bioanal Chem ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758198

RESUMO

A novel sensitive and selective probe for the important antibiotic vancomycin (Van) has been synthesized by integrating a coumarin and a fluorescein as dual fluorescence reporters and a Van binding peptide D-Ala-D-Ala. Only weak green fluorescence was initially observed, which was mostly attributed to fluorescence self-quenching induced by fluorophore stacking. Upon the binding of Van with the D-Ala-D-Ala peptide, the fluorescence turned on, probably due the disaggregation of fluorophores. The intensity ratio of the dual emission bands I519/I446 exhibited an excellent linear relationship with the concentration of Van increasing from 0-20 µM in synthetic urine. The lowest detection limit was calculated to be 92.8 nM in urine, which made the probe applicable in clinically relevant concentration ranges. The synthetic probe has also shown the potential for Van detection in human serum. More interestingly, this probe has been successfully applied for in vivo imaging of Van in zebrafish. Graphical Abstract.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31682014

RESUMO

Obesity plays an important role in the pathogenesis of atrial fibrillation (AF). Recently, rather than general fat distribution, epicardial adipose tissue (EAT) gains a growing concern. EAT is the local adipose deposition between myocardium and pericardium. Accumulated evidence revealed several distinguishing characteristics of EAT. It lies contiguously with the myocardium and could infiltration into myocardium, actively secrets cytokines and adipokines mediating inflammation or remodeling, and contains abundant ganglionated plexi. Clinical research also found EAT may be an independent risk factor of AF. Volume or thickness of EAT measured on CT or MRI could be applied as a predictor of presence, severity, and recurrence of AF. Some drugs, like antidiabetic drugs and lipid-lowing drugs, show ability to reduce EAT. Additional surgical ablation of EAT was also proved that it could improve outcome of pulmonary vein isolation for AF. In present review, we summarize recent epidemic, biological, and clinical findings about EAT and its possible role in AF.

9.
Science ; 366(6468): 1013-1021, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31699883

RESUMO

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.

10.
J Exp Clin Cancer Res ; 38(1): 473, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752959

RESUMO

BACKGROUND: Circulating tumour cells (CTCs), especially mesenchymal CTCs, are important determinants of metastasis, which leads to most recurrence and mortality in hepatocellular carcinoma (HCC). However, little is known about the underlying mechanisms of CTC colonisation in pre-metastatic niches. METHODS: Detection and classification of CTCs in patients were performed using the CanPatrol™ system. A lentiviral vector expressing Prrx1-targeting shRNA was constructed to generate a stable HCC cell line with low expression of Prrx1. The effect of Prrx1 knockdown on stemness, migration, and drug resistance of the cell line was assessed, including involvement of SDF-1/CXCR4 signalling. Promising clinical applications of an inhibitor of STAT3 tyrosine phosphorylation, C188-9, and specific blockade with CXCR4 antibody were explored. RESULTS: The number of mesenchymal CTCs in blood was closely associated with tumour recurrence or metastasis. Pre-metastatic niche-derived SDF-1 could downregulate Prrx1, which induced the stemness, drug resistance, and increased expression of CXCR4 in HCC cells through the STAT3 pathway in vitro. In vivo, mice bearing tumours of Prrx1 low-expressing cells had significantly shorter survival. In xenograft tumours and clinical samples, loss of Prrx1 was negatively correlated with increased expression of CXCR4 in lung metastatic sites compared with that in the primary foci. CONCLUSIONS: These findings demonstrate that decreased expression of Prrx1 stimulates SDF-1/CXCR4 signalling and contributes to organ colonisation with blood CTCs in HCC. STAT3 inhibition and specific blockade of CXCR4 have clinical potential as therapeutics for eliminating organ metastasis in advanced HCC.

11.
Sci Rep ; 9(1): 16754, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728035

RESUMO

In this paper, we propose a network-based technique to analyze bills-voting data comprising the votes of Brazilian congressmen for a period of 28 years. The voting sessions are initially mapped into static networks, where each node represents a congressman and each edge stands for the similarity of votes between a pair of congressmen. Afterwards, the constructed static networks are converted to temporal networks. Our analyses on the temporal networks capture some of the main political changes happened in Brazil during the period of time under consideration. Moreover, we find out that the bills-voting networks can be used to identify convicted politicians, who commit corruption or other financial crimes. Therefore, we propose two conviction prediction methods, one is based on the highest weighted convicted neighbor and the other is based on link prediction techniques. It is a surprise to us that the high accuracy (up to 90% by the link prediction method) on predicting convictions is achieved only through bills-voting data, without taking into account any financial information beforehand. Such a feature makes possible to monitor congressmen just by considering their legal public activities. In this way, our work contributes to the large scale public data study using complex networks.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31680339

RESUMO

OBJECTIVE: This study was to assess the esthetic and clinical outcomes of immediate implantation using the conventional flap-less approach and the Socket-Shield Technique (SST). METHODS: This study included 30 adult patients who underwent anterior teeth replacement and fulfilled the predefined criteria. Patients were randomly allocated to the SST (n=15) and conventional flap-less (control, n=15) groups. The esthetic outcomes were evaluated by assessing the degree of soft tissue recession and the pink esthetic scores (PES). Clinical parameters, including the modified plaque index (mPI), modified sulcus bleeding index (mSBI), probing depth (PD), and implant stability quotient (ISQ), were assessed. The buccal plate width (BPW) and height (BPH) were also measured. RESULTS: Implantation was clinically successful for all subjects in both groups. With a similar baseline, the SST group exhibited less reduction in the mid-facial mucosal margins and the height of the mesial and distal papillae as well as higher BPW and BPH values compared to the control group (P <0.001). The ISQ values were 76.01±1.31 for the SST group and 75.56±1.07 for the control group (P >0.05), suggesting sufficient initial stability in both groups. At the 24-month follow-up, SST group patients had statistically significant lower values of PD, mSBI, and mPLI compared to the control group. There were no significant differences in the overall and individual PES values for both groups. CONCLUSION: SST may improve functional and esthetic outcomes by maintaining alveolar bone volume and peri-implant tissues. SST seems to be a promising treatment approach for implants in the esthetic zone.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31773941

RESUMO

Conventional adjuvants (e.g., aluminum) are insufficient to trigger cell-mediate immunity, which plays crucial role in triggering specific immunity against cancer. Therefore, developing appropriate adjuvants for cancer vaccines is a central way to stimulate antitumor immune response. Hollow mesoporous silica nanoparticles (HMSNs) have been proven to stimulate Th1 antitumor immunity in vivo and promote immunological memory in the formulation of novel cancer vaccines. Yet, immune response rates of existing HMSNs for anti-cancer immunity still remain low. Here, we demonstrate the generation of polyethyleneimine (PEI)-incorporated thin shell HMSNs (THMSNs) through a facile PEI-etching strategy for cancer immunotherapy. Interestingly, incorporation of PEI and thin shell hollow structures of THMSNs not only improve the antigen-loading efficacy, sustained drug release profiles, but also enhance the phagocytosis efficiency by dendritic cells (DCs), enabled DCs maturation and Th1 immunity, and sustained immunological memory, resulting in the enhancement of the adjuvant effect of THMSNs. Moreover, THMSNs vaccines without significant side effects can significantly reduce the potentiality of tumor growth and metastasis in tumor challenge and re-challenge models, respectively. THMSNs are considered to be promising vehicles and excellent adjuvants for the formulation of cancer vaccines for immune therapy.

14.
Electrophoresis ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621929

RESUMO

Exosomes are vesicles with sizes ranging from 30 to 150 nm. The analysis and detection of blood exosomes offers an effective route for cancer diagnosis, prognosis assessment, and therapeutic evaluation of diseases. Due to the difference in separation procedure, collection method and the usage of anticoagulants, serum and plasma samples show diversity test results. In order to evaluate the isolation effect of exosomes in serum and plasma samples, two commonly used exosomal isolation methods, ultracentrifugation and polymer-based precipitation kit, were used, respectively. And the isolation effects were evaluated by comparing the composition and abundant of proteins from isolated exosomes based on MS-based proteomics analysis. The results showed that the plasma exosomes extracted by ultracentrifugation identified more exosome biomarkers, and the concentrations of these biomarkers were higher than others. And plasma exosomes could be a better sample for blood-based proteomics research of exosomes. It would be more useful for future targeted biomarker discovery.

15.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1038-1044, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640956

RESUMO

OBJECTIVE: To optimize the method for embedding multiple undecalcified mouse tibias in plastic blocks, improve the efficiency and stability of plastic embedding and reduce the detachment rate of plastic slides. METHODS: Thirty undecalcified tibias from 15 B6 mice were used for plastic embedding after calcein labeling, fixation, dehydration and infiltration. The tibias were embedded in cylindrical plastic blocks with a diameter of 4 mm. For each bone, the 1/4 proximal tibia was cut off, and the remaining 3/4 was used for re-embedding. Five bones were embedded in a single block with each bone standing closely on the surface of a flat plate. The samples were randomized into control and experimental groups in all the processes of embedding, sectioning and staining. In the 3 groups with modified embedment, flowing CO2 was added into the embedding solution, embedding solution was applied to the section surface, and the slides were heated at 95 ℃ for 15 min. The polymerization time, slide detachment rate, bone formation and osteoblast parameters were analyzed. RESULTS: We prepared 6 plastic blocks, each containing 5 tibias, whose cross sections were on the same plane. The blocks were completely polymerized and suitable for sectioning. Flowing CO2 into the embedding solution reduced the polymerization time and increased the rate of complete polymerization. Application of the embedding solution on the section surface significantly reduced the detachment rate of the sections (P < 0.05) without affecting bone formation analysis (P > 0.05). Heating the slides significantly lowered the detachment rate of the sections (P < 0.05) without affecting osteoblast analysis (P > 0.05). CONCLUSIONS: The optimized method allows effective embedding of multiple undecalcified mice tibias in the same block and can be an ideal method for histological analysis of undecalcified bones.


Assuntos
Plásticos , Tíbia , Inclusão do Tecido/métodos , Animais , Camundongos , Coloração e Rotulagem
16.
ACS Synth Biol ; 8(11): 2524-2535, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31596566

RESUMO

Chinese hamster ovary (CHO) cells are used for industrial production of protein-based therapeutics (i.e., "biologics"). Here we describe a method for combining systems-level kinetic models with a synthetic biology platform for multigene overexpression to rationally perturb N-linked glycosylation. Specifically, we sought to increase galactose incorporation on a secreted Immunoglobulin G (IgG) protein. We rationally design, build, and test a total of 23 transgenic cell pools that express single or three-gene glycoengineering cassettes comprising a total of 100 kilobases of engineered DNA sequence. Through iterative engineering and model refinement, we rationally increase the fraction of bigalactosylated glycans five-fold from 11.9% to 61.9% and simultaneously decrease the glycan heterogeneity on the secreted IgG. Our approach allows for rapid hypothesis testing and identification of synergistic behavior from genetic perturbations by bridging systems and synthetic biology.

17.
Dig Dis Sci ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31617131

RESUMO

BACKGROUND: Acute hypertriglyceridemic pancreatitis (HTGP) is more likely to be severe and complicated with extrapancreatic organ injury. NOX may be involved in the occurrence and development of high fat acute pancreatitis, but the specific mechanism is not clear. AIMS: To investigate the protective effects of apocynin, an inhibitor of NOX, on kidney injury associated with the HTGP and its potential mechanisms in a rat model. METHODS: In this study, HTGP rat model was induced by intraperitoneal injection of P-407 and L-Arg in combination. Apocynin was given by subcutaneously injection 30 min before the model was induced. The pancreatic and renal histopathology changes were analyzed. Serum AMY, BUN, Cr levels were measured by the Automatic Biochemistry Analyzer. The expression levels of protein associated with NOX/Akt pathway in the kidney were detected. ROS level in kidney and serum was measured by DHE staining and MDA, SOD kits, respectively. Serum TNF-α and IL-6 were detected by ELISA kits. RESULTS: In HTGP group, the levels of serum AMY, BUN, Cr, TNF- α, and IL-6 were significantly increased, and the injury of pancreas and kidney was aggravated. The levels of NOX4, NOX2, ROS, p-Akt, GSK-3ß, NF-κB, and TNF-α in the kidney were detected, suggesting that NOX may regulate the activity of downstream p-Akt and GSK-3ß by regulating ROS levels, thereby affecting the release of inflammatory mediators and regulating HTGP-related kidney injury. After application of apocynin, the expression of NOX4 and NOX2 and the level of ROS in the kidney were reduced, the release of inflammatory mediators decreased, and the histopathology injury of pancreas and kidney was improved obviously. CONCLUSION: NOX may play an important role in HTGP-associated kidney injury through Akt/GSK-3ß pathway. Apocynin can significantly downregulate the level of NOX and play a protective role in HTGP-related kidney injury through Akt/GSK-3ß pathway.

18.
Zhongguo Zhong Yao Za Zhi ; 44(14): 2947-2952, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602838

RESUMO

The aim of this paper was to discuss the protective effect and mechanism of Acanthopanax senticosus polysaccharides( ASPs) on immunological liver injury caused by conanavalin A( Con A). BALB/c mice were randomly divided into seven groups: control group,model group( Con A),low-,medium-,and high-dose( 36. 25,72. 5,145 mg·kg~(-1)) ASPs groups,bifendate( 200 mg·kg~(-1),positive drug) group and pyrrolidinedithiocarbamate( PDTC,NF-κB inhibitor,200 mg·kg~(-1)) group. ASPs groups and bifendate group were given with corresponding drugs by ig administration once daily for 7 d. Control group,model group and PDTC group were given with normal saline by ig administration once daily for 7 d. After the last ig administration,PDTC was given in DTC group by iv administration( 200 mg·kg~(-1)); 0. 5 h after that,Con A( 20 mg·kg~(-1)) was injected via the tail vein to induce immunological liver injury in all the mice except normal control group. The mice were killed 8 h later and their liver tissues were collected for histopathological examination. The contents of nitric oxide( NO),superoxide dismutase( SOD),malondialdehyde( MDA),reduced glutathione( GSHPX),interleukin( IL-1ß) and tumor necrosis factor( TNF-α) in liver tissues were detected by kit assay. Western blot method was used to detect TNF-α,intercellular cell adhesion molecule-1( ICAM-1),inducible nitric oxide synthase( i NOS) and nuclear factor( NF-κB) protein expression in liver tissues. As compared with model group,ASPs not only could reduce the activity of MDA,NO,IL-1ß and TNF-α,but also increase the content of GSH-PX and SOD; at the same time,the protein expression levels of TNF-α,ICAM-1,i NOS and NF-κB were reduced in liver tissues; in addition,inflammatory cell infiltration was alleviated,hepatocyte cytoplasm was loose and swollen,and nuclear condensation and staining were improved. ASPs has a protective effect on immunological liver injury,and the mechanism may be associated with regulating secretion of inflammatory cytokines and the expression of adhesion factor through NF-κB signaling pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Citocinas/metabolismo , Eleutherococcus/química , Polissacarídeos/farmacologia , Animais , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Peptídeos Cíclicos , Distribuição Aleatória , Transdução de Sinais
19.
Mol Cancer Ther ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594823

RESUMO

The carbon and nitrogen components of glutamine are used for multiple biosynthetic processes by tumors. Glutamine metabolism and the therapeutic potential of glutamine antagonists (GA), however, are incompletely understood in malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma observed in patients with neurofibromatosis type I. We investigated glutamine dependence of MPNST using JHU395, a novel orally-bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within target tissues. Human MPNST cells, compared to Schwann cells derived from healthy peripheral nerve, were selectively susceptible to both glutamine deprivation and GA dose-dependent growth inhibition. In vivo, orally administered JHU395 delivered active GA to tumors with over two-fold higher tumor-to-plasma exposure, and significantly inhibited tumor growth in a murine flank MPNST model without observed toxicity. Global metabolomics studies and stable isotope labeled flux analyses in tumors identified multiple glutamine dependent metabolites affected, including prominent effects on purine synthesis. These data demonstrate that glutamine antagonism is a potential antitumor strategy for MPNST.

20.
Ann Bot ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633171

RESUMO

BACKGROUND AND AIMS: The plant economics spectrum theory provides a useful framework to examine plant strategies by integrating the coordination of plant functional traits along a resource acquisition-conservation trade-off axis. Empirical evidences of this theory have been widely observed for seed plants (Spermatophyta). However, whether this theory can be applied to ferns (Pteridophyta), a ubiquitous and ancient group of vascular plants, has rarely been evaluated so far. METHODS: We measured eleven pairs of plant functional traits on leaves and fine roots (diameter < 2 mm) on 12 coexisting fern species in a subtropical forest. Litterbags of leaves and roots were placed in situ and exposed for 586 days to measure decomposition rates. The variation of traits across species and the coordination among traits within and between plant organs were analyzed. Finally, the influence of the traits on decomposition rates were explored. KEY RESULTS: Most leaf and root traits displayed high cross-species variation, and were aligned along a major resource acquisition-conservation trade-off axis. Many fern traits co-varied between leaves and fine roots, suggesting coordinated responses between above- and below-ground organs. Decomposition rates of leaves were significantly higher than those of fine roots, but they were significantly and positively correlated. Finally, our results highlight that the decomposition of both leaves and roots were relatively well predicted by the leaf and root economics spectra. CONCLUSIONS: Our results support the existence of an acquisition-conservation trade-off axis within ferns and indicate that traits have important 'afterlife' effects on fern litter decomposition. We conclude that the plant economics spectrum theory that is commonly observed across seed plants can be applied to ferns species, thereby extending the generality of this theory to this ancient plant lineage in our study site. Our study further suggests that the evolutionary and ecological basis for the relationships among key economics traits appear to be similar between ferns and seed plants. Future studies involving larger datasets will be required to confirm these findings across different biomes at larger spatial scales.

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