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1.
J Nat Prod ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193933

RESUMO

Eight new nitrogenated azaphilones (1-8) and two known compounds (chaetoviridin A and chaetoviridin E, 9, 10) were isolated from the culture of the deep-sea-derived fungus Chaetomium globosum MP4-S01-7. The absolute configurations of new compounds were elucidated by HSQC-HECADE NMR data, J-based configuration analysis, and modified Mosher's method and finally verified by comparison of recorded and computed NMR chemical shifts from quantum chemical calculations coupled with a statistical procedure (DP4+). All of the compounds were evaluated for their in vitro cytotoxicities against the gastric cancer cell lines MGC803 and AGS, and most of them showed significant inhibition on cancer cell viability at 10 µM. Among them, compounds 1, 2, and 5 exerted the most potent cytotoxic activities, with IC50 values less than 1 µM. Further studies showed that compound 2 inhibited cell cycle progression, and both compounds 1 and 2 induced apoptosis of gastric cancer cells in a concentration-dependent manner.

2.
Carbohydr Polym ; 236: 116065, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32172880

RESUMO

The present study aimed at investigating the structural features and antitumor properties of a novel heteropolysaccharide (CSP-W-2) obtained from the fruit of Chaenomeles Speciosa (Sweet) Nakai. CSP-W-2 demonstrate that they mainly contain glucose, galactose, arabinose, mannose, xylose in a ratio of 3.7: 3.2: 1.7: 0.9: 0.4, with the molecular weight of 8.7 kDa. Its backbone is predominantly composed of 1,4 linked ß-D-Galp, 1,4 linked α-D-Glcp, 1,4 linked ß-D-Glcp, and 1,4,6-ß-D-Glcp, additionally some branches contained 1,5 linked α-L-Araf, 1,4 linked ß-D-Glcp, 1,3 linked α-L-Araf, and T linked ß-D-Manp according to the results of partial acid hydrolysis analysis, methylation analysis, IR and NMR spectra. The antitumor properties study results demonstrated that CSP-W-2 had an inhibitory effect on HepG2 growth by enhancing the nucleus shrinkage and apoptosis. These findings indicate that CSP-W-2 had antitumor potential in the treatment of human liver tumor.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32197838

RESUMO

Photodynamic therapy (PDT) is an effective oncotherapy and has been approved for clinical application. Unfortunately, its therapeutic efficacy is usually overshadowed by tumor angiogenesis. Thus, a detailed understanding of the tumor angiogenesis upon PDT is imperative. This study aimed to investigate the potential contribution and mechanism of P-21-activated kinase 1 (PAK1) in PDT-induced tumor angiogenesis. Firstly, we found that PAK1 was upregulated upon PDT and associated with tumor angiogenesis. Then, we elucidated the underlying molecular mechanism. Activation of PAK1 prevents hypoxia-inducible factor 1 alpha (HIF-1α) protein from ubiquitin-mediated degradation. Thereafter, HIF-1α accumulation results in the upregulation of vascular endothelial growth factor (VEGF), thus promoting tumor angiogenesis. More importantly, we determined that PAK1 knockdown effectually repressed tumor angiogenesis, which contributes to enhance the therapeutic effect of PDT. Together, PAK1 is a potential novel pharmaceutical target for inhibiting PDT-induced tumor angiogenesis, and PAK1 suppression in combination with PDT may be a potentially effective strategy for anti-tumor therapy.

5.
Epigenomics ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32180433

RESUMO

Aim: To identify patients with colorectal cancer (CRC) who are at a truly higher risk of progression, which is key for individualized approaches to precision therapy. Materials & methods: We developed a predictor associated with progression-free interval (PFI) using The Cancer Genome Atlas CRC methylation data. Results: The risk score was associated with PFI in the whole cohort (p < 0.001). A nomogram consisting of the risk score and other significant clinical features was generated to predict the 3- and 5-year PFI in the whole set (area under the curve: 0.79 and 0.71, respectively). Conclusion: The risk score based on 23 DNA-methylation sites may serve as the basis for improved prediction of progression in patients with CRC in future clinical practice.

6.
BMC Bioinformatics ; 21(1): 51, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041517

RESUMO

BACKGROUND: CRISPR/Cas9 system, as the third-generation genome editing technology, has been widely applied in target gene repair and gene expression regulation. Selection of appropriate sgRNA can improve the on-target knockout efficacy of CRISPR/Cas9 system with high sensitivity and specificity. However, when CRISPR/Cas9 system is operating, unexpected cleavage may occur at some sites, known as off-target. Presently, a number of prediction methods have been developed to predict the off-target propensity of sgRNA at specific DNA fragments. Most of them use artificial feature extraction operations and machine learning techniques to obtain off-target scores. With the rapid expansion of off-target data and the rapid development of deep learning theory, the existing prediction methods can no longer satisfy the prediction accuracy at the clinical level. RESULTS: Here, we propose a prediction method named CnnCrispr to predict the off-target propensity of sgRNA at specific DNA fragments. CnnCrispr automatically trains the sequence features of sgRNA-DNA pairs with GloVe model, and embeds the trained word vector matrix into the deep learning model including biLSTM and CNN with five hidden layers. We conducted performance verification on the data set provided by DeepCrispr, and found that the auROC and auPRC in the "leave-one-sgRNA-out" cross validation could reach 0.957 and 0.429 respectively (the Pearson value and spearman value could reach 0.495 and 0.151 respectively under the same settings). CONCLUSION: Our results show that CnnCrispr has better classification and regression performance than the existing states-of-art models. The code for CnnCrispr can be freely downloaded from https://github.com/LQYoLH/CnnCrispr.

7.
Circ Res ; 126(6): e15-e29, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32078488

RESUMO

RATIONALE: Atherosclerotic cardiovascular diseases are the leading cause of mortality worldwide. Atherosclerotic cardiovascular diseases are considered as chronic inflammation processes. In addition to risk factors associated with the cardiovascular system itself, pathogenic bacteria such as the periodontitis-associated Porphyromonas gingivalis (P gingivalis) are also closely correlated with the development of atherosclerosis, but the underlying mechanisms are still elusive. OBJECTIVE: To elucidate the mechanisms of P gingivalis-accelerated atherosclerosis and explore novel therapeutic strategies of atherosclerotic cardiovascular diseases. METHODS AND RESULTS: Bmal1-/- (brain and muscle Arnt-like protein 1) mice, ApoE-/- mice, Bmal1-/-ApoE-/- mice, conditional endothelial cell Bmal1 knockout mice (Bmal1fl/fl; Tek-Cre mice), and the corresponding jet-legged mouse model were used. P gingivalis accelerates atherosclerosis progression by triggering arterial oxidative stress and inflammatory responses in ApoE-/- mice, accompanied by the perturbed circadian clock. Circadian clock disruption boosts P gingivalis-induced atherosclerosis progression. The mechanistic dissection shows that P gingivalis infection activates the TLRs-NF-κB signaling axis, which subsequently recruits DNMT-1 to methylate the BMAL1 promoter and thus suppresses BMAL1 transcription. The downregulation of BMAL1 releases CLOCK, which phosphorylates p65 and further enhances NF-κB signaling, elevating oxidative stress and inflammatory response in human aortic endothelial cells. Besides, the mouse model exhibits that joint administration of metronidazole and melatonin serves as an effective strategy for treating atherosclerotic cardiovascular diseases. CONCLUSIONS: P gingivalis accelerates atherosclerosis via the NF-κB-BMAL1-NF-κB signaling loop. Melatonin and metronidazole are promising auxiliary medications toward atherosclerotic cardiovascular diseases.

8.
Drug Resist Updat ; 49: 100681, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014648

RESUMO

The presence of multidrug resistance (MDR) in malignant tumors is one of the primary causes of treatment failure in cancer chemotherapy. The overexpression of the ATP binding cassette (ABC) transporter, P-glycoprotein (P-gp), which significantly increases the efflux of certain anticancer drugs from tumor cells, produces MDR. Therefore, inhibition of P-gp may represent a viable therapeutic strategy to overcome cancer MDR. Over the past 4 decades, many compounds with P-gp inhibitory efficacy (referred to as first- and second-generation P-gp inhibitors) have been identified or synthesized. However, these compounds were not successful in clinical trials due to a lack of efficacy and/or untoward toxicity. Subsequently, third- and fourth-generation P-gp inhibitors were developed but dedicated clinical trials did not indicate a significant therapeutic effect. In recent years, an extraordinary array of highly potent, selective, and low-toxicity P-gp inhibitors have been reported. Herein, we provide a comprehensive review of the synthetic and natural products that have specific inhibitory activity on P-gp drug efflux as well as promising chemosensitizing efficacy in MDR cancer cells. The present review focuses primarily on the structural features, design strategies, and structure-activity relationships (SAR) of these compounds.

9.
Biotechniques ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32066262

RESUMO

Nucleic acid precipitation is important for virtually all molecular biology investigations. However, despite its crucial role, a systematic study of the influence factors of nucleic acid precipitation has not been reported. In the present work, via rational experimental design, key factors of nucleic acid precipitation, including the type of nucleic acid, temperature and time of incubation, speed and time of centrifugation, volume ratio of ethanol/isopropanol to nucleic acid solution, type of cation-containing salt solution and type of coprecipitator, were comprehensively evaluated in an attempt to maximize the efficiency of nucleic acid precipitation. Our results indicate that the optimal conditions of each influence factor of nucleic acid precipitation may vary in accordance with the chemistry, structure and length of nucleic acids.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32089017

RESUMO

Introduction: While back translation has been widely used in medical research surveying linguistically diverse populations, research literature often fails to document this complex translation process. Our study examines inadequacies in the use of back translation, suggests improvements, as well as suggesting where other translation strategies may be more appropriate.Areas covered: This paper cites numerous metastudies showing how back translation is often uncritically adopted in validation of research instruments, pointing to potential methodological failings, before examining the back-translation processes in an Australian study of non-English speaking cancer patients. Our study of back translation applied to patient self-report questionnaires demonstrates that appropriate renditions of items are critically dependent upon both translator and researcher awareness of item purpose, overall project specifications and identification of linguistic ambiguities in source test items. The poor implementation and documentation of back-translation processes in many studies indicate alternatives to back translation may be appropriate.Expert opinion: Where translations are used in research, translation processes need to be made explicit in research protocols and reports, and translation experts need to be part of the research team, with translation guidance and advice integrated into all stages of research design.

11.
Int J Biol Macromol ; 149: 359-370, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31981662

RESUMO

The present study aimed to explore the effect of an anti-inflammatory RG-II type polysaccharide (KMPS) purified from Aconitum coreanum (Le'vl.) on glucose metabolism in high-fat diet-induced obese (DIO) mice. Treatment with KMPS for 4 weeks significantly reduced the fasting blood glucose, increased the sensitivity to insulin and improved glucose tolerance. Concurrently, KMPS supplementation also markedly inhibited inflammatory cytokine expression in serum and insulin target tissues and decreased the proportion of M1-type macrophages in adipose tissue, which was considered as the potential hypoglycaemic mechanism. In mechanism study, it was found that KMPS reduced the serine phosphorylation of IRS-1 by inhibiting the activation of the NF-κB pathway, thereby restoring the utilization of glucose by the PI3K/AKT pathway. These results suggested that KMPS may be a potential component for targeting inflammation in the treatment of type 2 diabetes.

12.
FASEB J ; 34(2): 3224-3238, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31917470

RESUMO

Myocardial ischemia-reperfusion injury (MIRI) is common clinical complication, which represents significant challenge in the treatment of acute myocardial infarction (AMI) diseases. Interleukin 35 (IL-35) exhibits anti-inflammatory properties via the engagement of the gp130, IL-12Rß2 and IL-27Rα receptors. However, whether IL-35 plays a beneficial role in the treatment of MIRI and potential underling mechanism are unclear. We showed that IL-35 conferred protection from MIRI as demonstrated by reduced infarct size and cardiac troponin T, improved cardiac function and decreased cardiomyocyte apoptosis in a mouse model. Despite activation of both STAT3 and STAT5 phosphorylation in the heart by IL-35, signal transducers and activators of transcription 3 (STAT3) was essential for mediating the IL-35-mediated protective effect on MIRI using cardiomyocyte-specific STAT3 deficient mice. Furthermore, gp130 was required for the STAT3 activation and cardio-protection induced by IL-35. Interestingly, IL-35 induced gp130 homodimer and gp130/IL-12Rß2 heterodimers in cardiomyocyte. Our results indicate that IL-35 can execute a protective role against MIRI through a novel signaling pathway, IL-35-gp130-STAT3 pathway, in cardiomyocytes, which may be beneficial for the development of novel and effective therapeutic approaches to treat the MIRI.

13.
Pestic Biochem Physiol ; 163: 271-279, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31973867

RESUMO

In this work, a total of 36 novel 5-(nicotinamido)-1-phenyl-1H-pyrazole-4-carboxylic acid derivatives were designed and synthesized successfully by introducing a carboxyl group based on the N-(1-(4-chlorophenyl)-4-cyano-1H-pyrazol-5-yl)-6-methoxynicotinamide. Among them, the growth inhibition assays on agar plates showed that compound 5IV-d(5-(2-chloronicotinamido)-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid) exhibited the significant antifungal activity against four important fruit and main crop disease fungi (i.e., Valsa mali Miyabe et Yamada, Botryosphaeria dothidea, Helminthosporium maydis and Rhizoctonia cerealis) with EC50 values of 22.6, 14.5, 17.6 and 18.2 µM, respectively. In addition, 5IV-d showed the excellent inhibitory effect against SDH enzymes with IC50 values ranging from 9.4 to 15.6 µM. In vivo bioassay and molecular docking were applied to explore the potential in practical application and combination of modified structure and SDH. The results of structure-activity relationships indicates that the methoxy substitution at the benzene ring attached to the pyrazole ring and a wide variety of substituents could be responsible for the promising antifungal efficacy of the designed compounds. This study demonstrated that the compound 5IV-d can act as the most potent SDH inhibitor in the reported series of compounds.


Assuntos
Rhizoctonia , Succinato Desidrogenase , Antifúngicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
Sensors (Basel) ; 20(2)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31941119

RESUMO

External deformation monitoring of high core rock-fill dams (HCRFDs) is an important and difficult part of safety monitoring. The traditional method of external deformation monitoring and data analysis for HCRFDs is to use a total station for small angle observations and establish a regression model to analyze the results. However, the small angle method has low accuracy and a low automation degree, and there is multicollinearity between the independent variables, which affects the parameter estimation and leads to the failure of model establishment. The angle forward intersection method is adopted in this paper for observation, and an improved partial least squares method (IPLS) is proposed to eliminate the multicollinearity of the independent variables. Compared to the traditional method, the improved observation method exhibits high accuracy and a high automation degree. The new data analysis method can not only eliminate multicollinearity but also improve the interpretation ability of the model. The data from the initial stage of water storage shows that the displacement increases with the increase in the upstream water level and time, and the speed of water storage is proportional to the displacement. The water level and time are the main influencing factors. This conclusion provides a theoretical basis for reservoir management departments to control water levels and gate opening and closing. The method in this paper can be applied to arch dams, gravity dams, and other types of waterpower engineering systems.

15.
Soft Matter ; 16(5): 1323-1332, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31934701

RESUMO

Sudden release of energy in an explosion creates craters in granular media. In comparison with well-studied impact cratering in granular media, our understanding of explosion cratering is still primitive. Here, we study low-energy lab-scale explosion cratering in 3D granular media using controlled pulses of pressurized air. We identify four regimes of explosion cratering at different burial depths, which are associated with distinct explosion dynamics and result in different crater morphologies. We propose a general relation between the dynamics of granular flows and the surface structures of the resulting craters. Moreover, we measure the diameter of explosion craters as a function of explosion pressure, duration and burial depth. We find that the size of the craters is non-monotonic with increasing burial depth, reaching a maximum at an intermediate burial depth. In addition, the crater diameter shows a weak dependence on explosion pressure and duration at small burial depths. We construct a simple model to explain this finding. Finally, we explore the scaling relations of the size of explosion craters. Despite the huge difference in energy scales, we find that the diameter of explosion craters in our experiments follows the same cube root energy scaling as explosion cratering at high energies. We also discuss the dependence of rescaled crater sizes on the inertial number of granular flows. These results shed light on the rich dynamics of 3D explosion cratering and provide new insights into the general physical principles governing granular cratering processes.

16.
BMC Vet Res ; 16(1): 23, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992293

RESUMO

BACKGROUND: Marek's disease (MD) is caused by the oncogenic Marek's disease virus (MDV), and is a highly contagious avian infection with a complex underlying pathology that involves lymphoproliferative neoplasm formation. MicroRNAs (miRNAs) act as oncogenes or tumor suppressors in most cancers. The gga-miR-155 is downregulated in the MDV-infected chicken tissues or lymphocyte lines, although its exact role in tumorigenesis remains unclear. The aim of this study was to analyze the effects of gga-miR-155 on the proliferation, apoptosis and invasiveness of an MDV-transformed lymphocyte line MSB1 and elucidate the underlying mechanisms. RESULTS: The expression level of gga-miR-155 was manipulated in MSB1 cells using specific mimics and inhibitors. While overexpression of gga-miR-155 increased proliferation, decreased the proportion of G1 phase cells relative to that in S and G2 phases, reduced apoptosis rates and increased invasiveness. However, its downregulation had the opposite effects. Furthermore, gga-miR-155 directly targeted the RORA gene and downregulated its expression in the MSB1 cells. CONCLUSION: The gga-miR-155 promotes the proliferation and invasiveness of the MDV-transformed lymphocyte line MSB1 and inhibits apoptosis by targeting the RORA gene.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31903642

RESUMO

In this study, effects of different single biomass derived inhibitors on acetone-butanol-ethanol (ABE) production by Clostridium acetobutylicum CICC 8016 were first investigated. The results showed that formic acid, coumaric acid, and furfural at 0.5 g/L (sodium formate equivalent) inhibited ABE production. Furthermore, corn stover hydrolysate media were prepared following dilute acid pretreatment, enzymatic hydrolysis, and detoxification with different methods. Among overliming, steam stripping, acetone-ethyl ether extraction, and ion exchange with five anion resins, adsorption with resin D301 showed the highest efficiency for inhibitor removal (99-100% of phenolics and 87-99% of sugar degradation products). Without detoxification, ABE production was lower than 1.0 g/L from 28.1 g/L sugars whereas ABE production with medium detoxified by D301 resin achieved higher ABE concentrations and yields than control with synthetic medium. Correlation analysis further revealed that formic acid, coumaric acid, and total phenolics were the major compounds inhibiting ABE production. The results also showed that the single detoxification method was sufficient to detoxify the hydrolysate for ABE production at the pretreatment conditions used in this study.

18.
Chemosphere ; 242: 125235, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31698209

RESUMO

A core-shell structured zero-valent iron@carbon (ZVI@C) nanocompoiste was designed to improve the electron utilization of ZVI in the Cr(VI) reduction. The porosity of carbon layer in ZVI@C was optimized for improving the efficiency of electron utilization of ZVI in the Cr(VI) reduction process. The porous structure of carbon layer was controllably synthesized by adjusting the carbon source and the ratio of C/Fe in the precursor. The glucose was suggested as the optimal carbon source, and a high specific surface area (37.067 m2/g) was reached for the prepared ZVI@C when the ratio of C/Fe was controlled at 20. These ZVI@C performed well on Cr(VI) reduction, e.g. a complete reduction of Cr(VI) (2 mg/L) to Cr(III) within 10 min. The removal capacity (800 mg/g) exceeded previously recorded ZVI based adsorbents. The pH and initial Cr(VI) concentration were demonstrated as the key factors for the efficient electron utilization of ZVI. Furthermore, the efficiency of electron utilization of the ZVI increased up to 80% when the concentration of Cr(VI) was 2000 mg/L and the pH was controlled at 3, which was much higher than 8% of the naked ZVI.


Assuntos
Carbono , Cromo/química , Elétrons , Ferro/química , Nanopartículas/química , Concentração de Íons de Hidrogênio , Oxirredução
19.
Oncogene ; 39(9): 1944-1956, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31754211

RESUMO

Interpreting disease-causing variants, especially in noncoding regions by genome-wide association studies (GWAS), has become one of the most challenging and demanding tasks. We hypothesized that functional lncRNAs variants in GWAS-identified loci might alter expression level of genes associated with persistent HBV infection and hepatocellular carcinoma (HCC). Integrated bioinformatics approaches were used to prioritize potentially functional variants and a two-stage case-control study (2473 HBV positive HCC patients, 2248 persistent HBV carriers and 2294 spontaneously recovered subjects) was performed to assess the roles of these variants. The rs2844512 G > C variant in LINC01149 was identified to facilitate HBV spontaneous recovery (OR = 0.84, 95% CI = 0.77-0.92) but increase the risk of HCC (OR = 1.21, 95% CI = 1.11-1.32) in combined samples. Subsequent biological assays indicated this variant created a binding site for miR-128-3p and upregulated MICA expression by serving as a miRNA sponge, which might recruit NK-cells to lyse infected cells, but release highly soluble MICA by shedding to induce NK-cells exhaustion and tumor immune evasion. These findings highlight a regulatory circuit between LINC01149 and MICA, mediating by miR-128-3p, and the important role of upregulated MICA in conferring susceptibility to persistent HBV infection and HCC.

20.
Nanomedicine (Lond) ; 15(2): 145-161, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31782335

RESUMO

Aim: The dual-ligand glycyrrhetinic acid and galactose-modified chitosan nanoparticles were designed to further improve the targeting capability to hepatocellular carcinoma (HCC). Materials & methods: The dual-ligand glycyrrhetinic acid and galactose-modified chitosan nanoparticles were fabricated by using ionic gelation method and their characteristics have been measured. Furthermore, the biodistribution and biocompatibility of this targeting vehicle were investigated in vitro and in vivo, respectively. Results: The targeting vehicle was specifically internalized into hepatoma cells in vitro and accumulated into tumor tissue in vivo with high efficacy. Moreover, the vehicle did not induce inflammation reaction and affect morphologies and organ functions. Conclusion: The targeting accumulation in HCC tissue and great biocompatibility of the dual-ligand modified chitosan nanoparticles highlight the potential of delivering anticancer agents into HCC cells.

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