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1.
Curr Opin Struct Biol ; 61: 1-8, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31629221

RESUMO

Proteolysis of amyloid precursor protein (APP), first extracellularly by ß-secretase and then within the membrane by γ-secretase, produces ß-amyloid peptides (Aß). Aß accumulates in the brain to form amyloid plaques, a hallmark of Alzheimer's disease (AD). Mutations in APP and presenilin (the catalytic subunit of γ-secretase) result in early onset of AD. Cryogenic electron microscopy (cryo-EM) structures of substrate-free and substrate-bound γ-secretase, determined at atomic resolutions, reveal the physical basis of distinct substrate specificity. These advances, together with the discovery and characterization of multiple proteins that interact with APP or presenilin, have given rise to an optimistic scenario for future mechanistic understanding of AD.

2.
Zool Res ; 40(6): 552-557, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31592584

RESUMO

A blind fish of Sinocyclocheilus (Cypriniformes: Cyprinidae) was caught in open water in the Three Gorges (Sanxia) reservoir, at a depth of 20 m in the mainstream of Yangtze River in Zigui County, Hubei Province, China. This fish can be easily distinguished from all other congeners by external morphological characteristics, and is estimated to have diverged from its sister group about 0.55 million years ago (Ma). The geologically well separated locality of this species has expanded the distribution of Sinocyclocheilus cavefish from around N25°(latitude) to above N30°. Herein, we describe this new species as Sinocyclocheilus sanxiaensis sp. nov., and discuss the possible reasons why the species appears, surprisingly, in the Three Gorges reservoir.

3.
Medicine (Baltimore) ; 98(43): e17353, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651840

RESUMO

BACKGROUND: Patients with simple obesity suffer from poor quality of life, as well as high risk of hypertension, diabetes, cardiovascular, and cerebrovascular accidents. Lots of Clinical trials suggested that acupuncture is beneficial for simple obesity, and it aims to gather solid evidence in order to provide reliable reference in establishing guidelines for acupuncture treatment of simple obesity in this study. METHODS: Relevant databases including Cochrane Library, PubMed, Cochrane Central Register of Controlled Trials, Medline University Resource Center, Chinese Biomedical Literature Service System, and China National Knowledge Infrastructure will be retrieved from January 1950 to November 2018. Two authors will screen studies independently according to the inclusion and exclusion criteria and extract the data in a form of sheet. Quality evaluations and bias risk assessments will be performed for the methodology of included studies. Dichotomous data will be analyzed using odds ratio (OR), and continuous data using mean differences. Network meta-analysis will be conducted by using Stata 14.0. The Development and Evaluation approach will be used to rate the certainty of the evidence of estimates derived from meta-analysis. The primary outcome is body mass index (BMI), and the secondary outcomes are triglycerides, total cholesterol, low-density lipoprotein-cholesterol, effective rate, adverse effects, and recurrence rate. Trial registration number is CRD42019117387. RESULTS: Based on current evidence, this review will rank the efficacy and safety of the various acupuncture regimen in decreasing BMI, triglycerides, total cholesterol of patients with simple obesity, and to summarize a prioritization regimen. CONCLUSION: This evidence may be useful for clinicians, patients, and guideline-makers to select the optimum proposal of acupuncture for the simple obesity treatment.


Assuntos
Terapia por Acupuntura/métodos , Obesidade/terapia , Adulto , Índice de Massa Corporal , Colesterol/sangue , Protocolos Clínicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Meta-Análise em Rede , Projetos de Pesquisa , Revisão Sistemática como Assunto , Resultado do Tratamento , Triglicerídeos/sangue
4.
Adv Healthc Mater ; : e1901015, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31599123

RESUMO

Tissue structural anisotropy is an important basis for heart function. Attempts to regenerate the complicated heart-tissue alignment has rarely featured macroscale 3D constructs required for myocardial tissue engineering. The feasibility of engineered scaffolds with micro/macro-architecture for guiding spatial cell alignment following complex patterns is reported. The scaffold is composed of stackable dual-structured layers with linear micro-ridge/groove patterns and macro-through-hole arrays, which enable tailorable anisotropy and interconnective free space. When human mesenchymal stem cells are seeded on the scaffold, well-organized spreading alignment showing the precise control in cellular orientation is significantly introduced over nonpatterned controls. Moreover, spatial cell distribution in the scaffold and directional changes of the layered linear patterns that made cell alignment orientations turning accordingly are observed, leading to the complex 3D pattern reconstruction of cellular alignment resembling natural myocardial tissue. This work validates the potential of micro/macro-architecture engineering for spatial cell guidance. Scaffolds with this capability can be potentially used for biomanufacturing of the structural alignment in myocardial tissue engineering.

5.
CNS Neurosci Ther ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31612615

RESUMO

AIMS: Sepsis-associated encephalopathy (SAE) is a common complication of severe sepsis. Our goal was to investigate the role of immunity-related GTPase M1 (IRGM1) in SAE and its underlying mechanism. METHODS: A mouse sepsis model was established by cecal ligation and perforation. SAE was diagnosed by behavior, electroencephalography, and somatosensory evoked potentials. Wild-type mice with SAE were treated with SB203580 to block the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We assessed hippocampal histological changes and the expression of IRGM1, interferon-γ (IFN-γ), and p38 MAPK signaling pathway-related proteins. RESULTS: Immunity-related GTPase M1 and IFN-γ levels increased in the hippocampus, with apoptosis, autophagy, and the p38 MAPK signaling pathway activated in neurons. Administration of SB203580 to mice with SAE reduced apoptosis and autophagy. Relative to wild-type mice with SAE, the general condition of Irgm1-/- mice with SAE was worsened, the p38 MAPK signaling pathway was inhibited, and neuronal apoptosis and autophagy were reduced. The absence of IRGM1 exacerbated SAE, with higher p38 MAPK signaling pathway activity and increased apoptosis and autophagy. CONCLUSIONS: During SAE, IRGM1 can at least partially regulate apoptosis and autophagy in hippocampal neurons through the p38 MAPK signaling pathway.

6.
Medicine (Baltimore) ; 98(38): e17291, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568014

RESUMO

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a clinically common chronic disease with the characteristic of recurrent attacks, difficulty of cure and high morbidity, disability, death rates. COPD exerts a great burden on patients, families and society. Acupoint Autohemotherapy (AA) is a traditional Chinese medicine (TCM) treatment by taking the patient's own venous blood and injecting them at acupoints, combined with the continuous stimulation of blood and the specific efficacy of the acupoint itself. It has been proved to be useful in pulmonary treatment and rehabilitation of COPD patients. However, the efficacy of AA on COPD patients has not been fully statistically evaluated. In this study, we aim to systematically examine the efficacy and safety of AA for COPD patients. METHODS: Data from all English and Chinese databases, including Medline, Cochrane Library, Embase, China National Knowledge Infrastructure Database, Wanfang Database, China Biomedical Literature Database and Chongqing VIP information, will be used to conduct a systematic and comprehensive literature search. The range of date is from inception to July 2019. Randomized controlled trials (RCTs) related to AA and western medicine in the treatment of COPD will be included. Quality of included trials will be assessed according to the risk of bias tool of Cochrane Handbook 5.1.0. The GRADE approach will be used to rate the certainty of the evidence of estimates derived from meta-analysis. RevMan 5.3 will be used for data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. A funnel plot will be developed to evaluate reporting bias, and Begg and Egger tests will be used to assess funnel plot symmetries. Grading of recommendations assessment, development and evaluation system will be utilized to assess the quality of evidence. RESULTS: This systematic review and meta-analysis aims to summarize the direct and indirect outcomes for AA and western medicine on COPD patients and evaluate its efficacy and safety. The results will be submitted to a peer-reviewed journal once completed. CONCLUSION: The systematic review will provide evidence to assess the efficacy and safety of AA and western medicine in the treatment of COPD patients. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019137189.


Assuntos
Pontos de Acupuntura , Transfusão de Sangue Autóloga/métodos , Medicina Tradicional Chinesa/métodos , Doença Pulmonar Obstrutiva Crônica/terapia , Transfusão de Sangue Autóloga/efeitos adversos , Humanos , Medicina Tradicional Chinesa/efeitos adversos , Resultado do Tratamento
7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 512-519, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642228

RESUMO

OBJECTIVE: To investigate the role of p38 mitogen-activated protein kinase (MAPK) signaling pathway in autophagy of neurons in hippocampus of sepsis rats. METHODS: A sepsis model was established by cecal ligation and puncture (CLP). SD rats were randomly divided into sham-operated group (sham group), model group (CLP group), vehicle-treated group (CLP+Veh group) and inhibitor-treated group (CLP+SB203580 group), and each group was divided into 3, 6, 12, 24 and 48 h subgroups. CLP+Veh group and CLP+SB203580 group were injected with 1% DMSO 5 µL and 0.1 mmol/L SB203580 5 µL respectively in the lateral ventricle, and CLP was established 30 min after injection. The sham group only turned over the cecum and closed the abdomen without other treatments. The vital signs of rats were monitored, including mean arterial pressure (MAP) and heart rate (HR). Neurobehavioral score was used to investigate the brain injury in rats. Histopathological changes in hippocampus of rats were observed by HE staining. The process of neuronal autophagy in hippocampal of rats was observed under transmission electron microscope (TEM). Western blot assay was performed to detect the expression of microtubule associated protein 1 light chain 3 (LC3)Ⅱ, LC3Ⅰ, selective autophagy adaptor protein p62/sequestosome-1 (p62/SQSTM1), MAPK-activated protein kinase 2 (MK-2) and phosphorylation MK-2 (p-MK-2) in the hippocampus. The expressions of LC3 and p62/SQSTM1 in hippocampal neurons of rats were observed by immunofluorescence. RESULTS: At different time points, MAP of CLP group was lower than sham group, while HR was higher than sham group, the change was most obvious at 12 h after molding; the neurobehavioral score of CLP group was the lowest; the histopathological changes in the hippocampus were obvious; and many autophagy vacuoles were observed under transmission electron microscope; compared with CLP group, the neurobehavioral score of CLP+SB203580 group increased; the pathological changes in the hippocampus improved; the inclusions in autophagy vacuoles were degraded under transmission electron microscopy; Western blot results showed:compared with sham group, expression of-LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 increased, and p62/SQSTM1 decreased in hippocampal tissue of CLP group in rat, the former reaches its peak at 12 h, the latter bottomed out at 12 h. Compared with the other groups, at 12 h of modeling, the expression of LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 was further increased, the expression of p62/SQSTM1 decreased further in hippocampal tissue of CLP+SB203580 group in rat (P < 0.05); immunofluorescence observation showed that localization and expression of LC3 and p62/SQSTM1 in NeuN were consistent with Western blot. CONCLUSION: Inhibition of p38 MAPK signaling pathway in sepsis rats can further activate autophagy and protect neurons in the hippocampus.

8.
Obes Surg ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31602628

RESUMO

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) could affect immunological activity after surgery. We examined the role of RYGB on the NOD-like receptor pyrin domain containing-6 (NLRP6) in the intestine after surgery in rat models. METHODS: Expression of intestinal NLRP6 in the lean, obesity, RYGB, and sham-pair fed (PF) groups was analyzed by quantitative RT-PCR, Western blotting, and immunohistochemistry. Gut microbiota abundance was determined by 16S rRNA sequencing. Cohousing experiments were conducted to analyze the effects of gut microbiota. Inflammatory cell infiltration and gut permeability were further validated. RESULTS: Obese rats had decreased intestinal NLRP6 levels, which could be restored by RYGB but not by calorie restriction. This regulation was dependent on the gut microbiota-related metabolites, taurine, and histamine. After RYGB, there were increased levels of taurine, which could positively affect NLRP6 expression. The pair-fed groups showed increased histamine, which had the opposite effects on NLRP6. Obese rats had greater intestinal permeability along with increased CD8+ T cell infiltration. However, RYGB but not calorie restriction could restore these changes in a manner, dependent on gut NLRP6 expression. CONCLUSIONS: In rat models, RYGB could efficiently restore abnormal gut permeability and reduce inflammation in the intestine, depending on reactivation of NLRP6.

9.
Microbiol Mol Biol Rev ; 83(4)2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31484691

RESUMO

SUMMARYPasteurella multocida is a highly versatile pathogen capable of causing infections in a wide range of domestic and wild animals as well as in humans and nonhuman primates. Despite over 135 years of research, the molecular basis for the myriad manifestations of P. multocida pathogenesis and the determinants of P. multocida phylogeny remain poorly defined. The current availability of multiple P. multocida genome sequences now makes it possible to delve into the underlying genetic mechanisms of P. multocida fitness and virulence. Using whole-genome sequences, the genotypes, including the capsular genotypes, lipopolysaccharide (LPS) genotypes, and multilocus sequence types, as well as virulence factor-encoding genes of P. multocida isolates from different clinical presentations can be characterized rapidly and accurately. Putative genetic factors that contribute to virulence, fitness, host specificity, and disease predilection can also be identified through comparative genome analysis of different P. multocida isolates. However, although some knowledge about genotypes, fitness, and pathogenesis has been gained from the recent whole-genome sequencing and comparative analysis studies of P. multocida, there is still a long way to go before we fully understand the pathogenic mechanisms of this important zoonotic pathogen. The quality of several available genome sequences is low, as they are assemblies with relatively low coverage, and genomes of P. multocida isolates from some uncommon host species are still limited or lacking. Here, we review recent advances, as well as continuing knowledge gaps, in our understanding of determinants contributing to virulence, fitness, host specificity, disease predilection, and phylogeny of P. multocida.

10.
Respiration ; : 1-10, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509823

RESUMO

Massive hemoptysis is one of emergency and critical diseases of the respiratory system. The definition of massive hemoptysis has always been different in the literature, which often depends on the quantitative estimation of the amount of hemoptysis, such as the amount of hemoptysis being in the range of 300-600 mL within 24 h, or hemoptysis more than 3 times within 1 week. Each amount of hemoptysis that is greater than 100 mL can be considered as massive hemoptysis, but the amount of hemoptysis is difficult to accurately estimate. Therefore, massive hemoptysis can be defined as any life-threatening hemoptysis and any hemoptysis that may cause airway obstruction and asphyxia. Massive hemoptysis accounts for approximately 5% of all hemoptysis cases and usually indicates the presence of a potentially severe respiratory or systemic disease. The mortality rate of massive hemoptysis is about 6.5-38%. The cause of death is generally shock caused by airway obstruction or excessive bleeding, and asphyxia is the main cause of death. At present, due to insufficient understanding of massive hemoptysis, there are limited technical means in the etiological diagnosis and untimely or improper treatment, resulting in high mortality of massive hemoptysis. Therefore, the diagnosis and treatment of massive hemoptysis needs to be standardized.

11.
Opt Express ; 27(18): 25943-25952, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31510456

RESUMO

High performance InGaN-based laser diodes (LDs) monolithically grown on Si is fundamentally interesting and highly desirable for photonics integration on Si platform. Suppression of point defects is of crucial importance to improve the device performance of InGaN-based LDs grown on Si. This work presents a detailed study on the impact of point defects, such as carbon (C) impurities and gallium vacancies (VGa), on the device characteristics of InGaN-based LDs grown on Si. By suppressing the VGa-related defect within the waveguide layers, reducing the thermal degradation of InGaN-based quantum wells, and controlling the C impurity concentrations within the thick p-type cladding layers, the as-fabricated InGaN-based LDs grown on Si exhibited a significantly reduced threshold current density of 2.25 kA/cm2 and an operation voltage of 4.7 V.

12.
J Periodontal Res ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31512745

RESUMO

BACKGROUND AND OBJECTIVE: Periodontitis is a multifactorial disease that can lead to the progressive destruction of dental support tissue. However, the detailed mechanisms and specific biomarkers involved in periodontitis remain to be further studied. Recently, long non-coding RNAs (lncRNAs) have been found to play a more important role than other types of RNAs. In our study, we analysed the expression of lncRNAs in periodontitis by analysing GSE16134. MATERIAL AND METHODS: We identified highly correlated genes by analysing GSE16134 with weighted gene co-expression network analysis (WGCNA) and identified 50 hub lncRNAs that were dysregulated. Then, we used the Linear Models for Microarray Data (Limma) package to identify the hub lncRNAs that were differentially expressed (DElncRNAs). The ceRNA co-expression network data were obtained from several sites, including miRcode, and were used to assess the potential WGCNA function of hub DElncRNAs in periodontitis. Besides, we divided the samples into LBX2-AS1 high and low expression group by the expression level of LBX2-AS1 and calculated DEG by Limma package. Furthermore, we performed GO function, KEGG pathway and GSEA enrichment of DEGs. RESULTS: In the analysis, we identified 50 hub lncRNAs that may play important roles in periodontitis. Then, we used the Limma package to identify 3 hub DElncRNAs (LINC00687, LBX2-AS1 and LINC01566). We elucidated the potential function of the hub DElncRNA LBX2-AS1 in periodontitis by constructing a co-expression network of lncRNA-miRNA-mRNA interactions. Totally, 573 DEGs (354 up- and 219 downregulated) in periodontitis samples were identified. DEGs were enriched in different GO terms and pathways, such as neutrophil degranulation, neutrophil activation, neutrophil activation involved in immune response, neutrophil-mediated immunity, antigen processing and presentation, JAK-STAT signalling pathway, natural killer cell-mediated cytotoxicity, EGFR tyrosine kinase inhibitor resistance, phosphatidylinositol signalling system and Vascular Endothelial Growth Factor (VEGF) signalling pathway. CONCLUSION: In our study, we found that 3 hub DElncRNAs (LINC00687, LBX2-AS1 and LINC01566) may be involved in the pathogenesis of periodontitis based on WGCNA and Limma analysis. Our study aimed to elucidate the mechanisms involved in periodontitis at the genetic and epigenetic levels by constructing a ceRNA network associated with lncRNA. Besides, identification DEGs of differential LBX2-AS1 and functional annotation showed that LBX2-AS1 might be associated with periodontitis.

13.
Inorg Chem ; 58(18): 12415-12421, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31483642

RESUMO

Many strategies to optimize molybdenum selenide based electrocatalysts for hydrogen evolution reaction (HER) have been explored; however, the modulation of molybdenum selenide on the molecular scale remains an ongoing challenge. Here, we synthesized a new molecular HER electrocatalyst based on a molybdenum-selenium cluster (Mo3Se13) and further realized its modulation by precise sulfur substitution at the molecular level to enhance the HER activity. The density functional theory (DFT) calculations demonstrated that the substituted sulfur could promote the hydrogen adsorption process and thus improve the HER performance. This work not only realizes the selective replacement of the bridging selenium atom with a sulfur atom in the molybdenum-selenium cluster for the first time but also provides a precise model for illustrating the structure-property relationship in electrocatalysis on the molecular level.

14.
Microbiol Res ; 230: 126343, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31539852

RESUMO

Identifying the direct target genes of response regulators (RRs) of a bacterial two-component system (TCS) is critical to understand the roles of TCS in bacterial environmental adaption and pathogenesis. Actinobacillus pleuropneumoniae is an important respiratory bacterial pathogen that causes considerable economic losses to swine industry worldwide. The targets of A. pleuropneumoniae NarP (nitrate/nitrite RR), which is the cognate RR of the nitrate/nitrite sensor histidine kinase NarQ, are still unknown. In the present study, a DNA-affinity-purified sequencing (DAP-Seq) approach was established. The upstream regions of a total of 131 candidate genes from the genome of A. pleuropneumoniae were co-purified with the activated NarP protein. Electrophoretic mobility shift assay (EMSA) results confirmed the interactions of NarP with the promoter regions of five selected target genes, including dmsA, pgaA, ftpA, cstA and ushA. The EMSA-confirmed target genes were significantly up-regulated in the narP-deleted mutant in the presence of additional nitrate, whilst the transcriptional changes were restored in the complemented strain. The NarP binding motif in the upstream regions of the target genes dmsA and ftpA were further identified and confirmed by EMSA using the truncated binding motif. The NarP binding sites were present in a total of 25.2% of the DNA fragments captured by DAP-Seq. These results demonstrated that the established DAP-Seq method is effective for exploring the direct targets of RRs of bacterial TCSs and that the A. pleuropneumoniae NarP could be a repressor in response to nitrate.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31480157

RESUMO

Objective: We investigated the temporal expression profiles of long noncoding RNA (lncRNA) and mRNA in the peripheral blood of pigs during development and identified the lncRNAs that are related to the blood-based immune system. Methods: Peripheral blood samples were obtained from the pigs at 0, 7, 28 and 180 days and 2 years of age. RNA sequencing was performed to survey the lncRNA and mRNA transcriptomes in the samples. Short time-series expression miner (STEM) was used to show temporal expression patterns in the mRNAs and lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to assess the genes' biological relevance. To predict the functions of the identified lncRNAs, we extracted mRNAs that were nearby loci and highly correlated with the lncRNAs. Results: In total of 5,946 lncRNA and 12,354 mRNA transcripts were identified among the samples. STEM showed that most lncRNAs and mRNAs had similar temporal expression patterns during development, indicating the expressional correlation and functional relatedness between them. The five stages were divided into two classes: the suckling period and the late developmental stage. Most genes were expressed at low level during the suckling period, but at higher level during the late stages. Expression of several T-cell-related genes increased continuously during the suckling period, indicating that these genes are crucial for establishing the adaptive immune system in piglets at this stage. Notably, lncRNA TCONS-00086451 may promote blood-based immune system development by upregulating nuclear factor of activated T-cells cytoplasmic 2 (NFATC2) expression. Conclusion: This study provides a catalog of porcine peripheral blood-related lncRNAs and mRNAs and reveals the characteristics and temporal expression profiles of these lncRNAs and mRNAs during peripheral blood development from the newborn to adult stages in pigs.

16.
Bioorg Chem ; 92: 103266, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31542716

RESUMO

In this paper, the nitrogen atom was inserted into the anthracycline system of the isocryptolepine nucleus to obtain the "Aza"-type structure benzo[4,5]imidazo[1,2-c] quinazoline. A series of "Aza"-type derivatives were designed, synthesized and evaluated for their antifungal activity against six plant fungi in vitro. Among all derivatives, compounds A-0, B-1 and B-2 showed significant antifungal activity against B. cinerea with the EC50 values of 2.72 µg/mL, 5.90 µg/mL and 4.00 µg/mL, respectively. Compound A-2 had the highest activity against M. oryzae with the EC50 values of 8.81 µg/mL, and compound A-1 demonstrated the most control efficacy against R. solani (EC50, 6.27 µg/mL). Moreover, compound A-0 was selected to investigate the in vivo tests against B. cinerea and the results indicated that the preventative efficacy of it up to 72.80% at 100 µg/mL. Preliminary mechanism studies revealed that after treatment with A-0 at 5 µg/mL, the B. cinerea mycelia appeared curved, collapsed and the cell membrane integrity may be damaged. The reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia have been changed, and the membrane function and cell proliferation of mycelia were destroyed. Compounds A-0, A-1, B-1 and B-2 presented weaker toxicities against two cells lines than isocryptolepine. This study lays the foundation for the future development of isocryptolepine derivatives as environmentally friendly and safe agricultural fungicides.

17.
Int J Pharm ; 570: 118668, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31494237

RESUMO

Tumor cell nucleus is the ultimate target of many first-line chemotherapeutics and therapeutic genes. However, nuclear drug delivery is always hampered by multiple intracellular obstacles especially low efficiency of cellular uptake and insufficient nuclear trafficking. It is urgent to establish novel nuclear drug delivery systems to simultaneously overcome barriers including cell membranes and nuclear envelope. Herein, an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-based drug delivery system was designed to achieve enhanced intracellular and intranuclear drug delivery. A biomimetic peptide (SVS-1), derived from antimicrobial peptides, which was reported to efficiently penetrate cell membranes and translocate rapidly into nucleus without decreasing cell viability, was conjugated to the HPMA copolymer backbone. The in vitro studies showed that SVS-1 could enhance the uptake and nuclei accumulation of HPMA copolymer by 4.1 and 7.0-fold on human cervical cancer cells (HeLa) separately compared with corresponding non-SVS-1 modified HPMA copolymers (P-DOX). This also transferred to greater DNA damage, more apoptosis and superior cytotoxicity (2.4-fold) of doxorubicin which was chosen as the model drug and attached to SVS-1 modified HPMA copolymer (SVS-1-P-DOX). Furthermore, the in vivo investigation revealed that compared with free doxorubicin, SVS-1-P-DOX not only showed prolonged blood circulation and preferential tumor accumulation, but also suppressed tumor growth more efficiently with tumor growth inhibition of 78.7% in HeLa tumor-bearing BALB/c nude mice without causing noticeable physiological change in major organs. These results demonstrated that the SVS-1 modification was a promising strategy for contemporaneously overcome cell membranes and nuclear envelope, which might provide new opportunities for constructing nucleus-targeted anticancer therapy.

18.
Biomacromolecules ; 20(10): 3755-3766, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31465208

RESUMO

As a major clinical tumor chemotherapeutic burden, multidrug resistance (MDR) is often a result of up-regulation of P-glycoprotein (P-gp), which strongly enhances anticancer drug efflux. The excess mitochondrial reactive oxygen species (ROS) could not only inhibit the function of P-gp through insufficient adenosine triphosphate supply but also cause apoptosis in MDR cells. Here, we designed a mitochondria targeting nanoparticulate system (GNPs-P-Dox-GA) for overcoming MDR through enhanced ROS generation, where increased cellular uptake as well as mitochondria accumulation were both realized by glycyrrhetinic acid (GA). First, doxorubicin was conjugated with GA (GA-Dox) and then grafted onto a N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer backbone via hydrazone bond (P-Dox-GA). The obtained P-Dox-GA was subsequently attached to the surface of gelatin nanoparticles (GNPs). As gelatin is a substrate of tumor extracellular metal matrix protease-2 (MMP2), GNPs-P-Dox-GA nanoparticles could be degraded and release small size P-Dox-GA to facilitate tumor tissue penetration. After P-Dox-GA internalized by tumor cells under GA mediation, Dox-GA detached from HPMA copolymer through hydrolysis of hydrazone bond and then efficiently delivered to mitochondria. Compared to non-GA modified carriers, GNPs-P-Dox-GA exhibited increased cellular uptake nearly 4-fold and mitochondria distribution 8.8-fold, and increased ROS production level nearly 3-fold, significantly decreased efflux rate (55% compared with Dox group) in drug resistant HepG2/ADR cells, and then led to improved in vitro antitumor efficiency in HepG2/ADR cells (IC50 only 19.5% of unmodified ones) as well as exciting in vivo antitumor efficiency on HepG2/ADR heterotopic tumor nude mice (1.75-fold higher tumor growth inhibition rate than free drug).

19.
Epigenomics ; 11(11): 1251-1266, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364879

RESUMO

Aim: To develop novel diagnostic tools that can predict the prognosis of gastric cancer. Material & methods: Using RNA expression data from The Cancer Genome Atlas and Gene Expression Omnibus, we established protein-coding RNAs-noncoding RNAs-tumor microenvironment type (PNM) scores, which contain signatures of tumor protein coding genes (P), tumor noncoding genes (N) and immune/stroma cells in tumor microenvironment (M) to predict the prognosis of gastric cancer. Results & conclusion: Based on PNM scores, gastric cancer patients were divided into three subgroups and Kaplan-Meier survival curves revealed significant differences among the subgroups (p < 0.001). Our study showed that the PNM scores could be used as a robust predicting tool for the prognosis of gastric cancer.

20.
Am J Pathol ; 189(11): 2233-2245, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31430464

RESUMO

Little is known about the role of the spleen in mediating systemic inflammatory responses in severe acute pancreatitis (SAP). We investigated the role played by the spleen in rats after SAP induction. Splenectomy was performed at designated time points after SAP induction. Pancreatic tissue and serum samples were collected and subjected to histologic, immunohistochemical, and immunologic analyses. After SAP induction, the splenic immune response was enhanced during SAP progression, as shown by the increased diameter of the splenic periarterial lymphatic sheath and the thickness of the splenic marginal zone. Rats with splenectomy developed acute pancreatitis more slowly than rats without splenectomy. In addition, pancreatic tissues of rats with splenectomy contained lower levels of serum amylase, tumor necrosis factor-α, and IL-6 and exhibited less acinar cell death, leukocyte infiltration, and interstitial edema than those of rats without splenectomy. Compared with splenectomy alone, cotreatment with splenectomy and the administration of splenic cells originating from a rat with SAP 12 hours after induction increased systemic inflammation in SAP rats. Splenic factors exacerbated SAP-associated liver and lung injury and accentuated intestinal mucosal barrier dysfunction. Splenectomy altered the serum cytokine profile in rats with SAP. In a rat model of SAP, the spleen exacerbated the systematic inflammatory responses and injury to multiple organs, indicating a new role for the spleen in SAP.

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