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1.
Mol Ther Nucleic Acids ; 18: 627-637, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31689617

RESUMO

Despite surgery and adjuvant therapy, early-stage lung adenocarcinoma (LUAD) treatment often fails due to local or metastatic recurrence. However, the mechanism is largely unknown. Here, we report that increased expression levels of miR-134-5p and decreased levels of disabled-2 (DAB2) were significantly correlated with recurrence in stage I LUAD patients. Our data show that miR-134-5p overexpression or DAB2 silencing strongly stimulated LUAD cell metastasis and chemoresistance. In contrast, inhibition of miR-134-5p or overexpression of DAB2 strongly suppressed LUAD cell metastasis and overcame the insensitivity of chemoresistant LUAD cells to chemotherapy. In addition, we demonstrated that DAB2 is a target of miR-134-5p and that miR-134-5p stimulates chemoresistance and metastasis through DAB2 in LUAD. Taken together, these findings suggest that miR-134-5p and its target gene DAB2 have potential as a biomarker for predicting recurrence in stage I LUAD patients. Additionally, miR-134-5p inhibition or DAB2 restoration may be a novel strategy for inhibiting LUAD metastasis and overcoming LUAD cell resistance to chemotherapy.

2.
Expert Rev Clin Immunol ; 15(12): 1287-1302, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674254

RESUMO

Introduction: The development of childhood asthma is caused by a combination of genetic factors and environmental exposures. Epigenetics describes mechanisms of (heritable) regulation of gene expression that occur without changes in DNA sequence. Epigenetics is strongly related to aging, is cell-type specific, and includes DNA methylation, noncoding RNAs, and histone modifications.Areas covered: This review summarizes recent epigenetic studies of childhood asthma in humans, which mostly involve studies of DNA methylation published in the recent five years. Environmental exposures, in particular cigarette smoking, have significant impact on epigenetic changes, but few of these epigenetic signals are also associated with asthma. Several asthma-associated genetic variants relate to DNA methylation. Epigenetic signals can be better understood by studying their correlation with gene expression, which revealed higher presence and activation of blood eosinophils in asthma. Strong associations of nasal methylation signatures and atopic asthma were identified, which were replicable across different populations.Expert commentary: Epigenetic markers have been strongly associated with asthma, and might serve as biomarker of asthma. The causal and longitudinal relationships between epigenetics and disease, and between environmental exposures and epigenetic changes need to be further investigated. Efforts should be made to understand cell-type-specific epigenetic mechanisms in asthma.

3.
Radiat Oncol ; 14(1): 208, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752910

RESUMO

BACKGROUND: Despite increasing clinical data suggest that internal mammary node (IMN) irradiation would improve local-regional control and overall survival in breast cancer, its role remains controversial due to increased risk of cardiac and pulmonary toxicity. The current study aims to determine the high risk areas of IMN metastases by collecting and analyzing the axial imaging of IMN involvement, in order to optimize IMN delineation for breast cancer. METHODS: Breast cancer patients with IMN involvement were retrospectively identified from single-center database. All available imaging modalities including thoracic CT, breast MRI, ultrasound and PET/CT were used to diagnose IMN metastases. Anatomical characteristics from axial imaging, including distribution of involved ribs and distance from the internal mammary vessels (IMV), were collected for each metastatic IMN. What's more,the natural infiltration tendency of IMNs from IMV was calculated in this study. RESULTS: In total, 83 metastatic IMNs from 70 breast cancer patients (initial diagnosed:34 and recurrence: 36) were located from axial CT image in this study. The second intercostal space was the most likely involved in patients with single(n = 35, 53.0%) and multiple intercostal space (n = 31, 47.0%) involvement. The percentage of including IMN with a 5 mm, 6 mm and 7 mm medial/lateral distance to the IMV were 75.9% (63/83), 89.2.6% (74/83) and 92.3% (77/83) respectively. While in maximal dorsal/ventral distance, nearly 95% of the nodes were encompassed into 6 mm depth to the IMV. Over 65% of IMN adenopathy (32/49,65.3%) were found to have a growth direction close to the sternum. By retrospective reviewing diagnostic reports, MRI demonstrated a high diagnostic performance in diagnosis of IMN disease (90.3%, 28/31), while CT had a higher misdiagnosis rate (22/63, 34.9%). The diagnostic efficiency of IMN could be improved if different methods were combined. CONCLUSIONS: For patients with indications of prophylactic IMN irradiation, a 7 mm medial and 6 mm dorsal distance to the IMV on axial CT would be optimal to cover the clinical volume of IMN; and it would be reasonable to extend clinical tumor volume (CTV) coverage towards sternum for patients with evident IMN disease. Multi-imaging modalities are recommended to improve the diagnostic specificity and sensitivity of IMN metastases.

4.
Sci Total Environ ; 699: 134380, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31678878

RESUMO

The oral health of preschool children in an electronic waste (e-waste) area is susceptible to lead (Pb) exposure increasing the risk of dental caries and causing periodontitis and other oral diseases. The aim of the present study is to investigate the relationship between chronic exposure to Pb and oral anti-inflammatory potential of preschool children. For this analysis, 574 preschool children from 2.5 to 6 years of age were recruited between November and December 2017, in which 357 preschool children were from Guiyu (n = 357), an e-waste-contaminated town, and 217 from Haojiang Shantou. We measured the levels of child blood Pb, salivary sialic acid, serum interleukin-6 (IL-6) and serum tumor necrosis factor-α (TNF-α), and investigated the prevalence of dental caries in deciduous teeth. The medians of blood Pb levels, serum IL-6 and TNF-α were significantly higher in the Guiyu children than in Haojiang children. Concomitantly, salivary sialic acids were lower in the Guiyu children [9.58 (3.97, 18.42) mg/dL] than in Haojiang [17.57 (5.95, 24.23) mg/dL]. Additionally, the prevalence of dental caries in deciduous teeth was significantly higher in the Guiyu children than in Haojiang (62.5% vs. 53.9%). Blood Pb levels were negatively correlated with salivary sialic acids, in which IL-6 played as a mediator of the association between blood Pb levels and saliva sialic acid concentrations according to the mediation model. To our knowledge, this is the first report on the potential association between chronic Pb exposure and the anti-inflammatory ability of oral sialic acids among preschool children. These results suggest that the chronic Pb exposure can reduce salivary sialic acid levels, attenuate oral anti-inflammatory potential and increase the potential risk of dental caries in deciduous teeth among preschool children in an e-waste site.

5.
Eur Respir J ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31699840

RESUMO

About 40% of asthmatics experience remission of asthma symptoms. A better understanding of biological pathways leading to asthma remission may provide insight into new therapeutic targets for asthma. As an important mechanism of gene regulation, investigation of DNA methylation provides a promising approach. Our objective was to identify differences in epigenome wide DNA methylation levels in bronchial biopsies between subjects with asthma remission and subjects with persistent asthma or healthy controls.We analysed differential DNA methylation in bronchial biopsies from 26 subjects with persistent asthma, 39 remission subjects and 70 healthy controls, using the limma package. The comb-p tool was used to identify differentially methylated regions. DNA methylation of CpG-sites was associated to expression of nearby genes from the same biopsies to understand function.Four CpG-sites and 42 regions were differentially methylated between persistent asthma and remission. DNA methylation at two sites was correlated in cis with gene expression at ACKR2 and DGKQ, respectively. Between remission subjects and healthy controls 1163 CpG-sites and 328 regions were differentially methylated. DNA methylation was associated with expression of a set of genes expressed in ciliated epithelium.CpGs differentially methylated between remission and persistent asthma identify genetic loci associated with resolution of inflammation and airway responsiveness. Despite the absence of symptoms, remission subjects have a DNA methylation profile that is distinct from that of healthy controls, partly due to changes in cellular composition, with a higher gene expression signal related to ciliated epithelium in remission versus healthy controls.

6.
Nat Prod Bioprospect ; 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31734866

RESUMO

Nine new gastrodin derivatives, including seven p-hydroxybenzyl-modified gastrodin ethers (1-7), 6'-O-acetylgastrodin (8), and 4-[α-D-glucopyranosyl-(1 →6)-ß-D-glucopyranosyloxy]benzyl alcohol (9), together with seven known derivatives, were isolated from an aqueous extract of Gastrodia elata ("tian ma") rhizomes. Their structures were determined by spectroscopic and chemical methods as well as single crystal X-ray diffraction. Compounds 1-4, 7, 10, and 11 were also isolated from a reaction mixture by refluxing gastrodin and p-hydroxybenzyl alcohol in H2O. As both gastrodin and p-hydroxybenzyl alcohol exist in the plant, the reaction results provide evidence for the production and increase/decrease of potential effective/toxic components when "tian ma" is decocted solely or together with ingredients in Chinese traditional medicine formulations, though the isolates were inactive in the preliminarily cell-based assays at concentrations of 10 µM. Moreover, using ultra-performance liquid chromatography high-resolution electrospray ionization mass spectrometry (UPLC-HRESIMS), 4, 7, 10, and 11, as well as component variations, were detectable in the freshly prepared extracts of different types of samples, including the freeze-dried fresh G. elata rhizomes.

7.
Mol Cancer Res ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31662449

RESUMO

Pancreatic cancer (PC) is a highly lethal malignancy with poor prognosis due to the lack of early symptoms and resultant late diagnosis. Thus, it is extremely urgent to establish a simple and effective method for the early diagnosis of PC. Although some studies have provided positive evidence for the use of exosomal surface protein glypican-1 (GPC1) as a biomarker for early screening, its clinical application is still controversial. Here, we systematically verified the role of exosomal GPC1 as a potential screening biomarker. First, bottleneck problems of a stable detection method and an identification standard were systematically studied, and a Python based standardized data processing method was established to analyse exosomal GPC1 expression. Second, a detection panel consisting of exosomal GPC1, exosomal CD82 (Cluster of Differentiation 82), and serum carbohydrate antigen 19-9 (CA19-9) was employed for PC detection. This panel exhibited excellent diagnostic results (area under the curve (AUC): 0.942) and could effectively distinguish healthy people from PC patients (P-value threshold: 0.2282) and pancreatitis patients from PC patients (P-value threshold: 0.5467). Implications: These results indicate that the combined detection of exosomal GPC1, exosomal CD82 and serum CA19-9 shows great promise as a standard method for PC detection and that this panel could be further applied for screening PC in Chinese populations.

9.
Sci Rep ; 9(1): 14118, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575964

RESUMO

Chronic hepatitis B virus (HBV) infection may follow four different consecutive phases, which are defined by virology as well as biochemical markers and differ in terms of prognosis and need for antiviral treatment. Currently, host responses reflected by immune markers are not considered in this definition. We aimed to study soluble immune markers and their distribution in different phases of chronic HBV infection. In this cross-sectional retrospective study, we investigated a panel of 14 soluble immune markers (SIM) including CXCL10 in 333 patients with chronic HBV infection. In a small cohort of HBeAg positive patients we analyzed SIM before and after HBeAg seroconversion and compared seroconverters to patients with unknown outcome. Significant differences were documented in the levels of several SIM between the four phases of chronic HBV infection. The most pronounced difference among all investigated SIM was observed for CXCL10 concentrations with highest levels in patients with hepatitis. TGF-ß and IL-17 revealed different levels between HBeAg negative patients. HBeAg positive patients with HBeAg seroconversion presented higher amounts of IL-12 before seroconversion compared to HBeAg positive patients with unknown follow up. SIM such as CXCL10 but also IL-12, TGF-ß and IL-17 may be useful markers to further characterize the phase of chronic HBV infection.

10.
J Cell Mol Med ; 2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31657123

RESUMO

Radiation-induced lung injury (RILI) is the major complication of thoracic radiation therapy, and no effective treatment is available. This study explored the role of high-mobility group box 1 (HMGB1) in acute RILI and the therapeutic effect of glycyrrhizin, an inhibitor of HMGB1, on RILI. C57BL/6 mice received a 20 Gy dose of X-ray radiation to the whole thorax with or without administration of glycyrrhizin. Severe lung inflammation was present 12 weeks after irradiation, although only a mild change was noted at 2 weeks and could be alleviated by administration of glycyrrhizin. Glycyrrhizin decreased the plasma concentrations of HMGB1 and sRAGE as well as TNF-α, IL-1ß and IL-6 levels in the bronchoalveolar lavage fluid (BALF). The expression of RAGE was decreased while that of TLR4 was significantly increased at 12 weeks, but not 2 weeks, after irradiation in mouse lung tissue. In vitro, the expression of TLR4 increased in RAW 264.7 cells after conditioning with the supernatant from the irradiated MLE-12 cells containing HMGB1 but showed no change when conditioned medium without HMGB1 was used. However, conditioned culture had no effect on RAGE expression in RAW 264.7 cells. Glycyrrhizin also inhibited the related downstream transcription factors of HMGB/TLR4, such as NF-κB, JNK and ERK1/2, in lung tissue and RAW 264.7 cells when TLR4 was activated. In conclusion, the HMGB1/TLR4 pathway mediates RILI and can be mitigated by glycyrrhizin.

11.
Eur Radiol ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650266

RESUMO

OBJECTIVES: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0-2 and T1-4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0-2 and T1-4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). METHODS: We included 3107 patients with stage IVa NPC disease (1871 with T4N0-2 and 1236 with T1-4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0-2 and T1-4N3 patients were compared. RESULTS: T1-4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis-free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse-free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0-2 patients. Multivariate analysis showed that T1-4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274-1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100-1.572, p = 0.003), whereas T4N0-2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158-2.158, p = 0.004). CONCLUSIONS: In terms of the OS, T4N0-2 patients had better prognosis compared with T1-4N3 patients, and the patterns of failure differed between T4N0-2 and T1-4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0-2 from T1-4N3. KEY POINTS: • In nasopharyngeal carcinoma, T4N0-2 patients tended to develop local relapse, whereas T1-4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0-2 patients had better prognosis than T1-4N3 patients. • T4N0-2 should be separated from T1-4N3 in the UICC/AJCC staging system.

12.
Environ Res ; 178: 108666, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472363

RESUMO

Studies have shown that persistent organic pollutants (POPs) can have various health effects. However, little is known about the effects of multiple chemicals with possible common sources of exposure on walking speed, a proxy index reflecting lower limb neuromuscular function and physical function. We simultaneously applied multiple linear and nonlinear statistical models to explore the complex exposure-response relationship between a mixture of 22 selected POPs and walking speed. A total of 14 polychlorinated biphenyls (PCBs), 3 polychlorinated dibenzo-p-dioxins (PCDDs), and 5 polychlorinated dibenzofurans (PCDFs) were measured in the serum of participants in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002. Walking speed was measured during a physical examination. Linear regression (LR), least absolute shrinkage and selection operator (LASSO), and group LASSO were used to evaluate the linearity of mixtures, while restricted cubic spline (RCS) regression, random forest (RF), and Bayesian kernel machine regression (BKMR) models were used to evaluate the nonlinearity of mixtures. Potential confounders were adjusted in the above models. A total of 436 subjects were included in our final analysis. The results of the LR model did not identify any POP exposure that was significantly associated with walking speed. The LASSO results revealed an inverse association of one PCDD congener and two PCDF congeners with walking speed, while the group LASSO analysis identified PCDFs at the exposure level and at the group level. In the RCS analysis, two PCB congeners presented significant overall associations with walking speed. The PCB congener PCB194 showed statistically significant effects on the outcome (P = 0.01) when a permutation-based RF was used. The BKMR analysis suggested that PCBs and PCDFs (probabilities = 0.887 and 0.909, respectively) are potentially associated with walking speed. Complex statistical models, such as RCS regression, RF and BKMR models, can detect the nonlinear and nonadditive relationships between PCBs and walking speed, while LASSO and group LASSO can identify only the linear relationships between PCDFs and walking speed. Fully considering the influence of collinearity in each method during modelling can increase the comprehensiveness and reliability of conclusions in studies of multiple chemicals.

13.
Appl Opt ; 58(23): 6455-6463, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31503795

RESUMO

Optical axis pointing accuracy is an important index of airborne electro-optical (EO) platforms. In this work, we aim to correct the optical axis pointing angle of an airborne EO platform by digital compensation. First, a basic parameter model (BPM) of pointing error with clear physical significance is established by analyzing the physical structure and error source of the EO platform. Then, to suppress the nonlinear factors in the error, we propose an improved algorithm of a semi-parametric regression model based on the BPM. Numerical simulation analysis shows that the improved algorithm inherits the advantages of the BPM, such as fewer model parameters and clear physical significance, and can improve the correction effect. Finally, experimental results show that the mean square error of the azimuth angle is reduced from more than 110'' to less than 4'', and that of the elevation angle is reduced from more than 75'' to less than 3''. According to the results obtained, the proposed correction model can improve the optical axis pointing accuracy of an airborne EO platform quickly and effectively, which has significant application value.

14.
Epigenomics ; 11(13): 1487-1500, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31536415

RESUMO

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

15.
Chemosphere ; 226: 915-923, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31509921

RESUMO

Fine particulate matter ≤2.5 µm (PM2.5) is a prominent global public health risk factor that can cause respiratory infection by downregulating the amounts of antimicrobial proteins and peptides (AMPs). Both salivary agglutinin (SAG) and surfactant protein D (SPD) are important AMPs in respiratory mucosal fluid, providing protection against airway pathogen invasion and infection by inducing microbial aggregation and enhancing pathogen clearance. However, the relationship between PM2.5 and these AMPs is unclear. To better understand the relationship between PM2.5 and airway innate immune defenses, we review the respiratory antimicrobial activities of SAG and SPD, as well as the adverse effects of PM2.5 on airway innate antimicrobial defense. We speculate there exists a dual effect between PM2.5 and respiratory antimicrobial activity, which means that PM2.5 suppresses respiratory antimicrobial activity through downregulating airway AMPs, while airway AMPs accelerate PM2.5 clearance by inducing PM2.5 microbial aggregation. We propose further research on the relationship between PM2.5 and these AMPs.


Assuntos
Aglutininas/farmacologia , Antibacterianos/farmacologia , Imunidade Inata/efeitos dos fármacos , Material Particulado/efeitos adversos , Proteína D Associada a Surfactante Pulmonar/farmacologia , Sistema Respiratório/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Peptídeos Catiônicos Antimicrobianos/farmacologia , Humanos , Infecções Respiratórias/induzido quimicamente
16.
ACS Nano ; 13(10): 12148-12161, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31556987

RESUMO

Photodynamic therapy (PDT) is an effective, noninvasive therapeutic modality against local tumors that are accessible to the source of light. However, it remains challenging to apply PDT for the treatment of disseminated, metastatic cancer. On the other hand, cancer immunotherapy offers a promising approach for generating systemic antitumor immune responses against disseminated cancer. Here we report a multifunctional nanomaterial system for the combination of PDT and personalized cancer immunotherapy and demonstrate their potency against local as well as disseminated tumors. Specifically, we have synthesized uniform and biodegradable mesoporous silica nanoparticles (bMSN) with an average size of ∼80 nm and large pore size of 5-10 nm for theranostic positron emission tomography (PET)-guided PDT and neoantigen-based cancer vaccination. Multiple neoantigen peptides, CpG oligodeoxynucleotide adjuvant, and photosensitizer chlorin e6 were coloaded into a bMSN nanoplatform, and PET imaging revealed effective accumulation of bMSN in tumors (up to 9.0% ID/g) after intravenous administration. Subsequent PDT with laser irradiation recruited dendritic cells to PDT-treated tumor sites and elicited neoantigen-specific, tumor-infiltrating cytotoxic T-cell lymphocytes. Using multiple murine models of bilateral tumors, we demonstrate strong antitumor efficacy of PDT-immunotherapy against locally treated tumors as well as distant, untreated tumors. Our findings suggest that the bMSN is a promising platform for combining imaging and PDT-enhanced personalized immunotherapy for the treatment of advanced cancer.

17.
ACS Appl Mater Interfaces ; 11(39): 35667-35674, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31502826

RESUMO

Spinel LiNi0.5Mn1.5O4 (LNMO) has been considered as one of the most promising candidate cathode materials for power lithium-ion batteries. However, its cycle performance suffers from the increasing impedance of the LNMO-cathode/electrolyte interface (LNMO-CEI) layer caused by parasitic reactions on the electrode surface at high operating potentials. To address the capacity degradation upon cycling, we present a feasible way to realize electrode modification by electrophoretically deposited graphene ultrathin films on the exterior surface of the LNMO cathodes without decreasing the electrode density. A p-phenylene diamine reduced graphene oxide (pPD-rGO) film with an area density of 20 µg/cm2 not only increases the capacity retention rate of the 1000th cycle at 4.2-5.2 V from 71.7 to 81.7% but also boosts the specific capacity from 110.6 to 122.4 mAh/g. X-ray photoelectron spectroscopy (XPS) spectra reveal that the pPD-rGO film with Lewis-base nature increases the content of LiF and reduces the number of RCFx groups in the cycled electrode, indicating the consumption of high-potential-generated F radicals by the pPD-rGO film. Such consumption favors the formation of a robust interphase between the pPD-rGO film and the electrolyte, which could hinder the sustained production of F radicals, consequently stabilize the LNMO-CEI layer, and improve the cycle performance. An electrophoretically deposited Lewis-acid GO film of 20 µg/cm2 reduces the specific capacity and fails to work as the pPD-rGO film. The chemical process for the formation of interphase on the GO film is similar to that on the bare LNMO electrode.

18.
World J Gastroenterol ; 25(34): 5120-5133, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31558861

RESUMO

BACKGROUND: Allyl isothiocyanate (AITC), a classic anti-inflammatory and antitumorigenic agent, was recently identified as a potential treatment for obesity and insulin resistance. However, little is known about its direct impact on the liver. AIM: To investigate the effect and underlying mechanism of AITC in nonalcoholic fatty liver disease (commonly referred to as NAFLD). METHODS: To establish a mouse and cellular model of NAFLD, C57BL/6 mice were fed a high fat diet (HFD) for 8 wk, and AML-12 cells were treated with 200 µM palmitate acid for 24 h. For AITC treatment, mice were administered AITC (100 mg/kg/d) orally and AML-12 cells were treated with AITC (20 µmol/L). RESULTS: AITC significantly ameliorated HFD-induced weight gain, hepatic lipid accumulation and inflammation in vivo. Furthermore, serum alanine aminotransferase and aspartate aminotransferase levels were markedly reduced in AITC-treated mice. Mechanistically, AITC significantly downregulated the protein levels of sterol regulatory element-binding protein 1 (SREBP1) and its lipogenesis target genes and upregulated the levels of proteins involved in fatty acid ß-oxidation, as well as the upstream mediators Sirtuin 1 (Sirt1) and AMP-activated protein kinase α (AMPKα), in the livers of HFD-fed mice. AITC also attenuated the nuclear factor kappa B (NF-κB) signaling pathway. Consistently, AITC relieved palmitate acid-induced lipid accumulation and inflammation in AML-12 cells in vitro through the Sirt1/AMPK and NF-κB signaling pathways. Importantly, further studies showed that the curative effect of AITC on lipid accumulation was abolished by siRNA-mediated knockdown of either Sirt1 or AMPKα in AML-12 cells. CONCLUSION: AITC significantly ameliorates hepatic steatosis and inflammation by activating the Sirt1/AMPK pathway and inhibiting the NF-κB pathway. Therefore, AITC is a potential therapeutic agent for NAFLD.

19.
Environ Sci Pollut Res Int ; 26(30): 31384-31391, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473923

RESUMO

Little is known regarding the effects of environmental mercury (Hg) exposure on liver dysfunction in adolescents. We aimed to explore the association between Hg exposure and the risk of nonalcoholic fatty liver disease (NAFLD) in the adolescent population. The cross-sectional associations between blood Hg concentrations and serum alanine aminotransferase (ALT) levels, a surrogate for suspected NAFLD, were evaluated using data from adolescents (aged 12-17 years old) who participated in the National Health and Nutrition Examination Survey (NHANES), 1999-2014. A final sample of 6389 adolescents was analysed. Elevated ALT was defined as > 25 IU/L and > 22 IU/L for boys and girls ≤ 17 years old, respectively. Odds ratios (ORs) of Hg levels in association with serum ALT levels were estimated using a logistic regression after adjusting for gender, age, ethnicity, serum cotinine, body mass index, the poverty income ratio, and NHANES cycles. The median blood Hg level was 0.73 ± 0.91 µg/L amongst US adolescents. In the adjusted model, the ORs of elevated ALT levels of those in the 4th quartile were higher amongst non-Hispanic white adolescents (OR = 1.76, 95% CI 1.20, 2.59; P = 0.035) and those who were normal or underweight (OR = 1.41, 95% CI 1.08, 1.85; P = 0.020). No association was observed for the other variables. Our results indicate that the positive association between blood Hg exposure and the risk of NAFLD in US adolescents is the highest amongst non-Hispanic white and those who are normal or underweight, regardless of ethnicity. More research is necessary to confirm this association and to clarify the potential mechanisms.

20.
J Immunol ; 203(8): 2141-2149, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31541023

RESUMO

Foxo3 acts as an important central regulator that integrates signaling pathways and coordinates cellular responses to environmental changes. Recent studies show the involvement of Foxo3 in osteoclastogenesis and rheumatoid arthritis, which prompted us to further investigate the FOXO3 locus. Several databases document FOXO3 isoform2, an N-terminal truncated mutation of the full-length FOXO3 However, the biological function of FOXO3 isoform2 is unclear. In this study, we established a conditional allele of Foxo3 in mice that deletes the full-length Foxo3 except isoform2, a close ortholog of the human FOXO3 isoform2. Expression of Foxo3 isoform2 specifically in macrophage/osteoclast lineage suppresses osteoclastogenesis and leads to the osteopetrotic phenotype in mice. Mechanistically, Foxo3 isoform2 enhances the expression of type I IFN response genes to RANKL stimulation and thus inhibits osteoclastogenesis via endogenous IFN-ß-mediated feedback inhibition. Our findings identify, to our knowledge, the first known biological function of Foxo3 isoform2 that acts as a novel osteoclastic inhibitor in bone remodeling.

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