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1.
Proc Natl Acad Sci U S A ; 118(19)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33952697

RESUMO

Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.

2.
Food Chem ; 358: 129843, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33915425

RESUMO

The inhibitory effects of seven polyphenols on 3-chloropropane-1,2-diol fatty acid esters (3-MCPDE) formation were investigated in palm oil models. Results showed that there was not a positive significant correlation between the free-radical scavenging activities of the tested compounds and their 3-MCPDE-formation inhibitory activities; puerarin, with weak antioxidant activity, showed the highest inhibitory capacity. Moreover, puerarin reduced the content of glycidol and glycidyl esters (GEs), two key intermediates of 3-MCPDE formation in the oil models; and a puerarin-adduct was discovered in the oil fortified with glycidol or GEs, with its structure elucidated by LC-MS/MS and comparison with newly synthesized ones. Based on its chemical structure, we proposed that puerarin, at least in part, reacted with glycidol and GEs to inhibit 3-MCPDE formation. In addition, the formed compound, puerarin-7-O-propanediol was identified in the potato chips frying system, further confirming reacting with glycidol/GEs as a key mechanism of puerarin to inhibit 3-MCPDE formation.

3.
Molecules ; 26(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917726

RESUMO

This paper studies the influence of hydroxyethyl methyl cellulose (HEMC) on the properties of calcium sulfoaluminate (CSA) cement mortar. In order to explore the applicability of different HEMCs in CSA cement mortars, HEMCs with higher and lower molar substitution (MS)/degree of substitution (DS) and polyacrylamide (PAAm) modification were used. At the same time, two kinds of CSA cements with different contents of ye'elimite were selected. Properties of cement mortar in fresh and hardened states were investigated, including the fluidity, consistency and water-retention rate of fresh mortar and the compressive strength, flexural strength, tensile bond strength and dry shrinkage rate of hardened mortar. The porosity and pore size distribution were also analyzed by mercury intrusion porosimetry (MIP). Results show that HEMCs improve the fresh state properties and tensile bond strength of both types of CSA cement mortars. However, the compressive strength of CSA cement mortars is greatly decreased by the addition of HEMCs, and the flexural strength is decreased slightly. The MIP measurement shows that HEMCs increase the amount of micron-level pores and the porosity. The HEMCs with different MS/DS have different effects on the improvement of tensile bond strength in different CSA cement mortars. PAAm modification can improve the tensile bond strength of HEMC-modified CSA cement mortar.

4.
Medicine (Baltimore) ; 100(15): e25447, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847650

RESUMO

BACKGROUND: High pretreatment level of D-dimer in small cell lung cancer (SCLC) is commonly encountered, but the impact of high pretreatment D-dimer level on the prognosis of SCLC patients remains undetermined. Therefore, we conducted this meta-analysis focusing specifically on the prognostic value of high pretreatment D-dimer level in SCLC patients comprehensively. METHODS: We searched systematically in PubMed, Embase, and Web of Science for relevant studies published before January 28, 2019. Outcomes including 1-year overall survival (OS), progression-free survival (PFS) rates, and hazard ratios (HRs) of OS and PFS from multivariate analysis were extracted and analyzed. RESULTS: A total of 5 cohort studies consisting of 813 SCLC patients (473 patients with high pretreatment level of D-dimer and 340 with normal level of D-dimer) were finally included for meta-analysis. We found that patients with high pretreatment level of D-dimer had significantly shorter 1-year OS (47.6% vs 79.9%; fixed effects: risk ratio [RR] = 2.506; 95% confidence interval [CI] = [1.948, 3.224]; P < .001) and PFS (15.8% vs 34.0%; random effects: RR = 1.294; 95% CI = [1.060, 1.579]; P = .011) rates than those with normal level of D-dimer. Moreover, high pretreatment D-dimer level was further proved to remain as an unfavorable predictor of OS (fixed effects: HR = 1.865; 95% CI = [1.469, 2.367]; P < .001; I2 = 7.6%) and PFS (fixed effects: HR = 1.513; 95% CI = [1.183, 1.936]; P = .001; I2 = 0.0%) in patients with SCLC. CONCLUSION: High pretreatment level of D-dimer was found to be an independent unfavorable prognostic factor in SCLC patients. However, more studies with sufficient adjustment for confounding factors are encouraged to confirm our conclusions.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Carcinoma de Pequenas Células do Pulmão/terapia , Taxa de Sobrevida
5.
Nanoscale ; 13(14): 6780-6785, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33885480

RESUMO

Plasmonic nanolasers based on the spatial localization of surface plasmons (SPs) have attracted considerable interest in nanophotonics, particularly in the desired application of optoelectronic and photonic integration, even breaking the diffraction limit. Effectively confining the mode field is still a basic, critical and challenging approach to improve optical gain and reduce loss for achieving high performance of a nanolaser. Here, we designed and fabricated a semiconductor/metal (ZnO/Al) core-shell nanocavity without an insulator spacer by simple magnetron sputtering. Both theoretical and experimental investigations presented plasmonic lasing behavior and SP-exciton coupling dynamics. The simulation demonstrated the three-dimensional optical confinement of the light field in the core-shell nanocavity, while the experiments revealed a lower threshold of the optimized ZnO/Al core-shell nanolaser than the same-sized ZnO photonic nanolaser. More importantly, the blue shift of the lasing mode demonstrated the SP-exciton coupling in the ZnO/Al core-shell nanolaser, which was also confirmed by low-temperature photoluminescence (PL) spectra. The analysis of the Purcell factor and PL decay time revealed that SP-exciton coupling accelerated the exciton recombination rate and enhanced the conversion of spontaneous radiation into stimulated radiation. The results indicate an approach to design a real nanolaser for promising applications.

6.
Nat Prod Res ; : 1-8, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33858273

RESUMO

The ethanol extract of the roots of Codonopsis pilosula was subjected to chromatographic fractionation, which result in the isolation and characterization of two new aromatic derivatives 2,3-dihydroxypropyl 2,4-dihydroxy-3,6-dimethylbenzoate (1) and 2-oxopropyl 3-hydroxy-4-methoxybenzoate (2), along with three known compounds pilosulinene A (3), pollenfuran B (4) and (+)-pinoresinol (5). Their structures were demonstrated by HRESIMS and spectroscopic methods including NMR and IR. It is worth noting that compound 4 was isolated for the first time from the genus Codonopsis. The potential hypoglycemic properties of compounds 2-5 were evaluated by measuring their α-glucosidase inhibitory effects. As a result, compounds 2 and 3 showed weak α-glucosidase inhibitory activities with IC50 values of 154.8 ± 11.0 µM and 24.0 ± 2.2 µM, respectively.

7.
J Agric Food Chem ; 69(10): 3124-3133, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33683879

RESUMO

Stilbenes are phytoalexins with health-promoting benefits for humans. Here, we boost stilbenes' production, and in particular the resveratrol dehydrodimer viniferin, with significant pharmacological properties, by overexpressing stilbene synthase (STS) under unlimited phenylalanine (Phe) supply. Vitis vinifera cell cultures were co-transformed with a feedback-insensitive E. coli DAHP synthase (AroG*) and STS genes, under constitutive promoters. All transgenic lines had increased levels of Phe and stilbenes (74-fold higher viniferin reaching 0.74 mg/g DW). External Phe feeding of AroG* + STS lines caused a synergistic effect on resveratrol and viniferin accumulation, achieving a 26-fold (1.33 mg/g DW) increase in resveratrol and a 620-fold increase (6.2 mg/g DW) in viniferin, which to date is the highest viniferin accumulation reported in plant cultures. We suggest that this strategy of combining higher Phe availability and STS expression generates grape cell cultures as potential factories for sustainable production of stilbenes with a minor effect on the levels of flavonoids.

8.
J Nanobiotechnology ; 19(1): 77, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741008

RESUMO

BACKGROUND: Although many treatments for breast cancer are available, poor tumour targeting limits the effectiveness of most approaches. Consequently, it is difficult to achieve satisfactory results with monotherapies. The lack of accurate diagnostic and monitoring methods also limit the benefits of cancer treatment. The aim of this study was to design a nanocarrier comprising porous gold nanoshells (PGNSs) co-decorated with methoxy polyethylene glycol (mPEG) and trastuzumab (Herceptin®, HER), a therapeutic monoclonal antibody that binds specifically to human epidermal receptor-2 (HER2)-overexpressing breast cancer cells. Furthermore, a derivative of the microtubule-targeting drug maytansine (DM1) was incorporated in the PGNSs. METHODS: Prepared PGNSs were coated with mPEG, DM1 and HER via electrostatic interactions and Au-S bonds to yield DM1-mPEG/HER-PGNSs. SK-BR-3 (high HER2 expression) and MCF-7 (low HER2) breast cancer cells were treated with DM1-mPEG/HER-PGNSs, and cytotoxicity was evaluated in terms of cell viability and apoptosis. The selective uptake of the coated PGNSs by cancer cells and subsequent intracellular accumulation were studied in vitro and in vivo using inductively coupled plasma mass spectrometry and fluorescence imaging. The multimodal imaging feasibility and synergistic chemo-photothermal therapeutic efficacy of the DM1-mPEG/HER-PGNSs were investigated in breast cancer tumour-bearing mice. The molecular mechanisms associated with the anti-tumour therapeutic use of the nanoparticles were also elucidated. RESULT: The prepared DM1-mPEG/HER-PGNSs had a size of 78.6 nm and displayed excellent colloidal stability, photothermal conversion ability and redox-sensitive drug release. These DM1-mPEG/HER-PGNSs were taken up selectively by cancer cells in vitro and accumulated at tumour sites in vivo. Moreover, the DM1-mPEG/HER-PGNSs enhanced the performance of multimodal computed tomography (CT), photoacoustic (PA) and photothermal (PT) imaging and enabled chemo-thermal combination therapy. The therapeutic mechanism involved the induction of tumour cell apoptosis via the activation of tubulin, caspase-3 and the heat shock protein 70 pathway. M2 macrophage suppression and anti-metastatic functions were also observed. CONCLUSION: The prepared DM1-mPEG/HER-PGNSs enabled nanodart-like tumour targeting, visibility by CT, PA and PT imaging in vivo and powerful tumour inhibition mediated by chemo-thermal combination therapy in vivo. In summary, these unique gold nanocarriers appear to have good potential as theranostic nanoagents that can serve both as a probe for enhanced multimodal imaging and as a novel targeted anti-tumour drug delivery system to achieve precision nanomedicine for cancers.

9.
Bioorg Chem ; 110: 104734, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33689976

RESUMO

Seventeen new prenylated C6-C3 derivatives, namely, illifargeins A-M (1-13), including three pairs of enantiomers (1, 5, and 12) and one norillifargeal A (14), together with eight known analogues (15-22), were isolated from the stems and leaves of Illicium fargesii. The structures of the new compounds were elucidated using spectroscopic data (UV, IR, 1D and 2D NMR, and HRESIMS). Their absolute configurations were determined by using experimental and calculated ECD data analysis, as well as a modified Mosher's method. Compounds 1a, 1b, 2, 3, 5a, 7, 10, 11, 15, 16, 19, and 20 showed potential activity against Coxsackie virus B3, with IC50 values ranging from 6.23 to 33.33 µM. Compounds 9 and 15 exhibited potential activity against influenza virus A, with IC50 values of 11.11 and 19.24 µM, respectively. Compounds 2, 3, and 18 exhibited potential anti-oxidant activity, with IC50 values ranging from 1.43 to 6.71 µM.

10.
Chemosphere ; 275: 130109, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33677267

RESUMO

In this study, an cadmium (Cd)-immobilizing and arginine decarboxylase-producing endophytic Sphingomonas sp. strain C40 obtained from the seeds of Oryza sativa Cliangyou 513 was characterized for its Cd availability and Cd uptake in host rice using hydroponic and soil experiments. The Cd concentration decreased by 51-95% compared to the control, while the spermidine concentration increased by 19-25% with Cd compared with no Cd in the strain C40-inoculated solution. Strain C40 decreased the above-ground tissue Cd content by 27-37% and increased spermine and spermidine contents by 28-67% and the expression levels of genes involved in spermine and spermidine production by 29-217% in rice roots compared to the controls. Furthermore, correlation analyses showed the significantly negative correlation between rice root spermine and spermidine contents and above-ground tissue Cd content. In the Cd-added soil, strain C40 promoted the rice biomass by 29-36% and decreased rice root, above-ground tissue, and grain Cd contents by 18, 16, and 33% and total grain Cd uptake by 14% compared with the controls at the maturity stage. Strain C40 decreased the exchangeable Cd content by 27% and increased the Fe and Mn oxides-bound Cd content by 45% in the rice rhizosphere soils at the maturity stage compared with the controls. These results suggested that the endophytic bacterial strain C40 increased rice root polyamine production and their related gene expression and the transformation of available Cd to unavailable Cd, leading to reduced Cd accumulation and translocation from the rice roots to grains.

11.
Sheng Li Xue Bao ; 73(1): 10-16, 2021 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-33665655

RESUMO

The aim of the present study was to observe the activation of microglia in the prefrontal cortex of type 1 diabetes mellitus (T1DM) mice, and the expression of the marker genes of the disease-associated microglia (DAM) associated with neurodegenerative diseases. Sixty healthy adult male C57BL/6J mice were randomly divided into two groups, normal control (CON) group and T1DM group. Streptozocin (STZ) was injected intraperitoneally to induce T1DM mice. The spatial learning and memory function of mice was detected by Morris water maze at the 8th week after the successful model establishment. The number and activation of microglia in the prefrontal cortex of mice were detected by immunofluorescence staining and Western blot. Changes in the mRNA level of several DAM molecular markers were detected by RT-FQ-PCR. The results showed that, compared with CON mice, the fasting blood glucose of T1DM mice increased significantly, while the body weight of T1DM mice decreased remarkably (P < 0.05). The escape latency of water maze in T1DM mice was longer than that in CON mice (P < 0.05). Compared with CON group, the Iba1 protein expression and the number of microglia in prefrontal cortex of T1DM group increased significantly (P < 0.05). In addition, the mRNA levels of several DAM markers in prefrontal cortex of T1DM group were increased significantly (P < 0.05). These results suggest that the microglia are activated and transformed to DAM type in the prefrontal cortex of T1DM mice.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Animais , Hipocampo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia , Córtex Pré-Frontal
12.
Heart Lung Circ ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33642173

RESUMO

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the world. Although much technological progress in the treatment of AF has been made, there is an urgent need for better treatment of AF due to its high rates of morbidity and mortality. The anti-arrhythmic drugs currently approved for marketing have significant limitations and side effects such as life-threatening ventricular arrhythmias and hypotension. The small conductance Ca2+-activated K+ channels (SK channels) are dependent on intracellular Ca2+ concentrations, which tightly integrate with membrane potential. Given the predominant expression in the atria of many species, including humans, they are now emerging as a therapeutic target for treating AF. This review aimed to illustrate the characteristics and function of SK channels. Moreover, it discussed the regulation of SK channels and their potential as a therapeutic target of AF.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33682046

RESUMO

PURPOSE: The aim of the study is to identify a reliable gene panel to predict the prognosis of HNSCC patients by integrated genomic analysis. METHODS: Co-expression gene networks were constructed by WGCNA using GSE113282 gene expression profile. The biological functional investigation was performed by GO and KEGG function enrichment analysis. The hub gene module was screened by PPI. The prognostic gene panel was established by Lasso regression analysis, and further progression-free survival (PFS) analysis was validated by Kaplan-Meier survival analysis using GSE102995 data. RESULTS: We identified 195 genes associated with the overall survival (OS) status (correlation coefficients: - 0.42, and p value: 2e-05) by WGCNA. These genes were enriched in immune-related cytokines and pathways analyzed by GO and KEGG. Among the 195 genes, the module (42 genes) with the highest score was screened by PPI. A novel seven-gene predictive panel (CD19, CD40LG, CD5, CXCR6, FPR2, NCAM1, and SELL) was established by Lasso regression analysis, and the area under ROC curve (AUC) for 3-year OS status was 0.8298 and 0.7571, respectively, in the training set and the test set. The PFS time of the low-risk patients was significantly longer than the high-risk patients (p < 0.0001; log-rank test) by further validation using GSE102995 data. CONCLUSION: The seven-gene panel may serve as a reliable predictive tool for HNSCC patients treated with platinum-based radio (chemo) therapy, and may be potential therapeutic targets for HNSCC patients.

14.
Huan Jing Ke Xue ; 42(4): 1660-1667, 2021 Apr 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742801

RESUMO

Coal-fired power plants (CFPPs) and waste incineration power plants (WIPPs) represent a large portion of polycyclic aromatic hydrocarbons (PAHs) sources in the environment, among which halogenated PAHs (HPAHs) are more toxic to the human body compared with their corresponding parent PAHs. In the current work, we investigated the occurrence, formation mechanism, and toxicity effects of HPAHs in the coal and waste combustion products from three CFPPs and one WIPP. The results indicate that the contents of chlorinated PAHs (Cl-PAHs) in the fly ash from the CFPPs and WIPP were 1.06-1.67 ng·g-1 and 2.76 ng·g-1, respectively, and the contents of brominated PAHs (Br-PAHs) in the fly ash from the CFPPs and WIPP were 26.4-44.2 ng·g-1 and 6.31 ng·g-1, respectively. The HPAH contents in the fly ash from the WIPP were significantly higher than those from the CFPPs primarily due to the abundant plastics in the domestic waste, represented by polyvinyl chloride, resulting in the formation of Cl-PAHs during combustion. The HPAH contents in the fly ash from the pulverized coal-fired (PC) boiler were significantly higher than those from the circulating fluidized bed (CFB) boiler mostly due to the higher combustion temperature operated in the PC boiler. The HPAHs in the fly ash from coal combustion were predominantly 7-BrBaA and 9-ClPhe, and those from domestic combustion were predominantly 9-BrPhe and 2-ClAnt. In addition, the contents of 7-BrBaA and 9,10-Br2 Ant in the coal combustion fly ash were significantly higher than those in domestic waste combustion fly ash, whereas 2-BrFle exhibited a contrasting profile. The content of Br-PAHs in the fly ash treated by semi-dry deacidification was twice that in dust removal fly ash but significantly increased in the chelating agent stabilization fly ash. The Pearson correlation analysis indicated the the formation mechanism of Cl-PAHs and Br-PAHs were the same but a secondary formation of HPAHs during the chelating agent stabilization of the fly ash was deduced. The TEQ values of the HPAHs in the fly ash (8.87×10-3-15.0×10-3 ng·g-1) from the WIPP were similar to those in the fly ash from the CFPPs (10.0×10-3 ng·g-1), which were significantly reduced in the fly ash treated by semi-dry deacidification due to the removal of 7-BrBaA. Moreover, the TEQ values of the HPAHs in the fly ash increased 5.4 times after the chelating agent stabilization. The ecological risk should be considered for the CFPP fly ash due to their massive amount of discharge and high TEQ values.


Assuntos
Incineração , Hidrocarbonetos Policíclicos Aromáticos , Carvão Mineral/toxicidade , Cinza de Carvão/análise , Cinza de Carvão/toxicidade , Humanos , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Centrais Elétricas
15.
Int J Cardiol ; 330: 186-193, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33581175

RESUMO

BACKGROUND: This study aimed to investigate the trend of cardiovascular disease (CVD)-specific mortality in patients with non-small cell lung cancer (NSCLC) and identify prognostic factors for CVD-specific death in stage NSCLC patients. METHODS: In this study, 270,618 NSCLC patients were collected from the Surveillance, Epidemiology, and End Results database. CVD- and NSCLC-specific cumulative mortality and proportion of death were calculated and graphically displayed to describe the probability of specific endpoints. Prognostic factors for CVD-specific mortality were evaluated by cause-specific hazard ratios (HR) with 95% confidence intervals (CI) using the competing risk model with non-cardiovascular death as competing risks. RESULTS: Among all competing causes of death, lung cancer resulted in the highest cumulative mortality, followed by CVDs and other causes. In the proportion of cause-specific death, heart diseases accounted for approximately 5.3% of the total death, only secondary to primary cancer. In all three stages, higher age, squamous cell carcinoma, and no-or-unknown chemotherapy and/or radiotherapy were associated with a higher risk of CVD-specific death, while surgery treatment seemed to be a protective factor. Female gender was statistically related to CVD-specific death in stage I and III patients with HRs of 0.84 (0.78-0.91) and 0.84 (0.77-0.93), respectively. Interestingly, right-sided laterality was correlated with lower CVD-specific mortality with HR of 0.82 (0.74-0.90) in stage III. CONCLUSIONS: This study illustrated the historical trend of CVD-specific death in NSCLC patients and assesses potential prognostic risk factors, highlighting the involvement of cardio-oncology teams in cancer treatment to provide optimal comprehensive care and long-term surveillance for cancer patients.

16.
Am J Pathol ; 191(3): 503-514, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33608066

RESUMO

Long noncoding RNAs play critical roles in cellular homeostasis, and long noncoding RNA H19 (H19) is implicated in several pathologic conditions. The putative role of H19 in the pathogenesis and progression of hypoxic-ischemic brain damage (HIBD) is not yet understood. Therefore, a series of in vivo and in vitro experiments were designed to investigate the potential roles of H19 in neuronal apoptosis and cognitive dysfunction in HIBD. H19 expression was decreased in HIBD rat models established by partial occlusion of carotid artery. H19 bound to and decreased the expression of miR-107, which also increased VEGF expression. H19 overexpression reduced neuronal apoptosis and alleviated cognitive dysfunction in HIBD rats. The up-regulation of miR-107 reversed the protective effects conferred by H19. In addition, the cell model of HIBD was established by oxygen-glucose deprivation in neuronal cells used. H19 overexpression in oxygen-glucose deprivation neurons increased B-cell lymphoma-2 and decreased B-cell lymphoma-2-associated X, total and cleaved caspase-3 expressions. Taken together, the results showed that H19 expresses at a low level in HIBD. H19 overexpression decreased miR-107 and increased VEGF expression, which resulted in repressed neuronal apoptosis and alleviated cognitive dysfunction. Thus, H19 may serve as a molecular target for translational research for HIBD therapy.


Assuntos
Regulação da Expressão Gênica , Hipóxia-Isquemia Encefálica/prevenção & controle , MicroRNAs/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Comportamento Animal , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/patologia , Masculino , MicroRNAs/genética , Fármacos Neuroprotetores , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/genética
17.
J Pathol ; 254(2): 185-198, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33638154

RESUMO

Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)-positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR-32-5p/ER-α36 axis. We found that upregulation of CUL4B correlated with decreased TAM sensitivity of breast cancer cells, and knockdown of CUL4B or expression of a dominant-negative CUL4B mutant restored the response to TAM in TAM-resistant MCF7-TAMR and T47D-TAMR cells. Mechanistically, we demonstrated that CUL4B renders breast cancer cells TAM-resistant by upregulating ER-α36 expression, which was mediated by downregulation of miR-32-5p. We further showed that CRL4B epigenetically represses the transcription of miR-32-5p by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes to promote trimethylation at H3K27 at the promoter of miR-32-5p. Pharmacologic or genetic inhibition of CRL4B/PRC2/HDAC complexes significantly increased TAM sensitivity in breast cancer cells in vitro and in vivo. Taken together, our findings thus establish a critical role for the CUL4B-miR-32-5p-ER-α36 axis in the regulation of TAM resistance and have important therapeutic implications for combined application of TAM and the inhibitors of CRL4B/PRC2/HDAC complex in breast cancer treatment. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

18.
Fitoterapia ; 151: 104867, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33621655

RESUMO

Salvia castanea (Family Labiatae), a perennial fragrant herb with castaneous flowers, is mainly distributed in areas with an altitude of 2500-3750 m. The roots of this plant were used as a tea drink by local residents to strengthen physical health. The aim of present study was to acquire secondary metabolites of the ethanol extract obtained from the whole plant of S. castanea and to evaluate their potential anti-Alzheimer's disease. Six new sesquiterpene lactones, salcastanins A-F (1-6), together with three known guaiane-type sesquiterpenoids nubiol (7), nubdienolide (8), and nubenolide (9), were separated from the whole plant of S. castanea. The structures of these compounds were determined by HRESIMS and NMR experiments. The absolute configurations of 1-6 were ascertained by electronic circular dichroism (ECD) experiments. The humanized Caenorhabditis elegans AD pathological model was used to evaluate anti-Alzheimer's disease (AD) activities of 1-9. The results showed the compounds 1-3 and 7 significantly delayed AD-like symptoms of worm paralysis phenotype, which could be used as novel anti-AD candidates.

19.
Plant Physiol Biochem ; 161: 65-73, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33578286

RESUMO

Mulberry (Morus sp., Moraceae) is an important economic crop plant and mulberry fruits are rich in anthocyanidins. Chalcone isomerase (CHI) catalyzes the conversion of chalcones to flavanones providing precursors for biosynthesis of anthocyanidins. In this study, bona fide CHIs were cloned and characterized from different Morus species with differently colored fruits (Morus multicaulis, Mm and Morus alba variety LvShenZi, LSZ). Enzymatic assay of MmCHI1 and MmCHI2 showed that they can utilize naringenin chalcone as substrate. The catalytic efficiency of MmCHI2 and LSZCHI2 are approximately 200 and 120-fold greater than that of MmCHI1 respectively. Phylogenetic analysis showed the two mulberry CHIs belonged to different sub-clade of Type I CHI1 named type IA (CHI2) and type IB (CHI1). Type IB CHIs are mulberry specific. MmCHI1 and MmCHI2 had similar expression profiles and showed preferred expression in fruits. In addition, both mulberry CHI1 and CHI2 played roles in the response to excess zinc stress and sclerotiniose pathogen infection. Both MmCHI1 and MmCHI2 expression levels showed positive close relationship with anthocyanins content during fruit ripening process. The co-expression of MmCHI1 and MmCHI2 was observed during fruit ripening process and in transgenic mulberry. VIGS (virus induced gene silence) targeting on MmCHI1 and MmCHI2 showed significant down-regulation of MmCHI2 instead of MmCHI1 would result in significant (about 50%) decrease in anthocyanins content. MmCHI2 is the dominant CHI for anthocyanins accumulation in mulberry. The results presented in this work provided insight on bona fide CHIs in mulberry and reveal their roles in anthocyanins accumulation.


Assuntos
Morus , Antocianinas , Frutas , Liases Intramoleculares , Filogenia
20.
Int Immunopharmacol ; 94: 107455, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33582592

RESUMO

OBJECTIVE: The aim of this study was to examine the effect of gingival mesenchymal stem cells derived exosomes (GMSC-Exos) on lipopolysaccharide/interferon-gamma (LPS/INF-γ)-induced inflammatory macrophages in a high-lipid microenvironment. MATERIALS AND METHODS: Exosomes were obtained by culturing gingival mesenchymal stem cells (GMSCs) in alpha-MEM with exosome-free fetal bovine serum for 48 h. The control group was produced in vitro by inducing human acute monocytic leukemia cells (THP-1 cells) into naïve macrophages (M0). Inflammatory macrophages (M1) were made by activating M0 macrophages with LPS/IFN-γ. These M1 macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to create the high-lipid group, of which some macrophages were further treated with GMSC-Exos for 24 h to form the GMSC-Exos group. Supernatants were collected, and total RNA were extracted for downstream analysis. The expression of surface markers in macrophages were analyzed by flow cytometry. The lipid accumulation level was assessed by oil red O staining. RESULTS: Exosomes were successfully isolated from GMSC medium. The GMSC-Exos group showed lower Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and cluster of differentiation 86 (CD86) expression levels than the high-lipid group, and the highest levels of Interleukin-10 (IL-10) among all groups. The GMSC-Exos group showed significant reductions in TNF-α levels than the high-lipid group, and significant escalations in IL-10 levels than the other two groups. Oil red o Staining showed that lipid accumulation in macrophages was inhibited in the GMSC-Exos group. CONCLUSIONS: GMSC-Exos reduce the release level and expression of inflammatory factors, inhibit lipid accumulation, and promote the polarization of pro-inflammatory macrophages into anti-inflammatory phenotype in a high-lipid microenvironment.

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