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1.
Cell Death Dis ; 11(2): 96, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029708

RESUMO

Cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. However, the effect of CRAMP on pressure overload-induced cardiac hypertrophy was unknown. This study explored the role of CRAMP on cardiac hypertrophy. A cardiac hypertrophy mouse model was induced by aortic banding surgery. Seven days after surgery, mice were given mCRAMP by intraperitoneal injection (8 mg/kg/d) for 7 weeks. Cardiac hypertrophy was evaluated by the hypertrophic response and fibrosis level as well as cardiac function. Mice were also injected with AAV9-shCRAMP to knockdown CRAMP in the mouse heart. CRAMP levels first increased and then reduced in the remodeling heart, as well as in angiotensin II-stimulated endothelial cells but not in cardiomyocytes and fibroblasts. mCRAMP protected against the pressure overload-induced cardiac remodeling process, while CRAMP knockdown accelerated this process. mCRAMP reduced the inflammatory response and oxidative stress in the hypertrophic heart, while mCRAMP deficiency deteriorated the pressure overload-induced inflammatory response and oxidative stress. mCRAMP inhibited the angiotensin II-stimulated hypertrophic response and oxidative stress in neonatal rat cardiomyocytes, but mCRAMP did not help the angiotensin II-induced inflammatory response and oxidative stress in endothelial cells. Mechanistically, we found that mCRAMP suppressed the cardiac hypertrophic response by activating the IGFR1/PI3K/AKT pathway via directly binding to IGFR1. AKT knockout mice completely reversed the anti-hypertrophic effect of mCRAMP but not its anti-oxidative effect. We also found that mCRAMP ameliorated cardiac oxidative stress by activating the TLR9/AMPKa pathway. This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/AMPKa pathways in cardiomyocytes.

2.
Aging (Albany NY) ; 122020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32019904

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) is a serious malignant tumor. Long non-coding RNA NNT-AS1 (NNT-AS1) takes crucial roles in several tumors. So, we planned to research the roles and underlying mechanism of NNT-AS1 in CCA. RESULTS: NNT-AS1 overexpression was appeared in CCA tissues and cell lines. Proliferation was promoted by NNT-AS1 overexpression in CCLP1 and TFK1 cells. Besides, NNT-AS1 overexpression reduced E-cadherin level and raised levels of N-cadherin, vimentin, Snail and Slug. However, the opposite trend was occurred by NNT-AS1 knockdown. Further, NNT-AS1 overexpression promoted phosphatidylinositol 3 kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. MiR-203 was sponged by NNT-AS1 and miR-203 mimic reversed the above promoting effects of NNT-AS1. Additionally, insulin-like growth factor type 1 receptor (IGF1R) and zinc finger E-box binding homeobox 1 (ZEB1) were two potential targets of miR-203. CONCLUSION: NNT-AS1 promoted proliferation, EMT and PI3K/AKT and ERK1/2 pathways in CCLP1 and TFK1 cells through down-regulating miR-203. METHODS: CCLP1 and TFK1 cells were co-transfected with pcDNA-NNT-AS1 and miR-203 mimic. Bromodeoxyuridine (BrdU), flow cytometry, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were employed to detect roles and mechanism of NNT-AS1. Interaction between NNT-AS1 and miR-203 or miR-203 and target genes was examined through luciferase activity experiment.

3.
Lung Cancer ; 141: 82-88, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31982639

RESUMO

OBJECTIVES: We aimed to investigate the clinical efficacy of EGFR tyrosine kinase inhibitor (TKI, T) plus bevacizumab (an antiangiogenic therapy, A) in a real-world population and to provide insights into their mechanism of resistance. METHODS: This study included 256 NSCLC patients harboring EGFR sensitizing mutations (EGFR 19del and L858R) who underwent nextgeneration sequencing (NGS) with 168-gene panel prior to treatment between Jan 2015 to Aug 2018. Cohort A included 60 patients treated with A + T; while cohort B consisted of 120 patients treated with EGFR-TKI monotherapy with the patients identified using Propensity Score Matching (Ratio of 1:2). Clinical outcomes and potential resistance mechanism were evaluated. RESULTS: Baseline clinical characteristics were not significantly different between Cohort A and B. Compared with cohort B, cohort A had significantly better overall response rate (95% vs 74.2%, p = 0.001) and longer median progression-free survival (PFS, 16.5m vs.12.0 m, HR = 0.7, p = 0.001). Until Jan 2019, 31 and 103 patients in cohort A and B, respectively, were evaluated with progressive disease and underwent tissue re-biopsy and NGS profiling with 168-gene panel. In cohort B, T790M was the predominant acquired resistance mechanism, detected in 51.5% (53/103) of progressive tumors, followed by amplifications in EGFR (15.5%, 16/103) and MET (6.8%, 7/103). Contrastingly, cohort A had a significantly lower rate of T790 M mutation (35.5%, 11/31, p = 0.0003), followed by mutations in TP53 (29.0%, 9/31), RB1 (9.7%, 3/31), SMAD4 (3.2%, 1/31) and EGFR V834 L (3.2%, 1/31) and amplifications in EGFR (9.7%, 3/31), and MET(6.5%, 2/31). CONCLUSION: Treatment with first-line A + T significantly extends the time to progression and increases the response rate with acceptable safety profile. T790 M was the most common acquired resistance mechanism but it was less common in patients who received A + T.

4.
J Cell Physiol ; 235(3): 2149-2160, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31389030

RESUMO

miR-222 participates in many cardiovascular diseases, but its effect on cardiac remodeling induced by diabetes is unclear. This study evaluated the functional role of miR-222 in cardiac fibrosis in diabetic mice. Streptozotocin (STZ) was used to establish a type 1 diabetic mouse model. After 10 weeks of STZ injection, mice were intravenously injected with Ad-miR-222 to induce the overexpression of miR-222. miR-222 overexpression reduced cardiac fibrosis and improved cardiac function in diabetic mice. Mechanistically, miR-222 inhibited the endothelium to mesenchymal transition (EndMT) in diabetic mouse hearts. Mouse heart fibroblasts and endothelial cells were isolated and cultured with high glucose (HG). An miR-222 mimic did not affect HG-induced fibroblast activation and function but did suppress the HG-induced EndMT process. The antagonism of miR-222 by antagomir inhibited HG-induced EndMT. miR-222 regulated the promoter region of ß-catenin, thus negatively regulating the Wnt/ß-catenin pathway, which was confirmed by ß-catenin siRNA. Taken together, our results indicated that miR-222 inhibited cardiac fibrosis in diabetic mice via negatively regulating Wnt/ß-catenin-mediated EndMT.

5.
Environ Pollut ; : 113713, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31818622

RESUMO

Exposure to environmental metals has been reported to be associated with airway inflammation. Fractional exhaled nitric oxide (FeNO) is an important inflammatory biomarker of the airway. However, the associations between metal exposures and FeNO change and the underlying mechanisms remain unclear. To investigate the associations between urinary metals and FeNO, and the potential role of Club cell secretory protein (CC16), a lung epithelial biomarker, in these associations. We conducted a cross-sectional study from the Wuhan-Zhuhai cohort and measured eight urinary metals, plasma CC16 and FeNO among 3067 subjects by using inductively coupled plasma-mass spectrometry, enzyme-linked immunosorbent assay kit and Nano Coulomb Nitric Oxide Analyzer, respectively. Mixed linear models were used to quantify dose-relationships between urinary metals and FeNO, as well as urinary metals and plasma CC16. The potential role of plasma CC16 in the associations between urinary metals and FeNO was estimated using mediationanalyses. After adjusting for covariates, one percent increase in urinary vanadium, nickel or antimony was associated with a respective 6.60% (95% CI: 3.52%, 9.68%), 2.18% (0.45%, 3.91%), 4.87% (1.47%, 8.27%) increase in FeNO level. The adverse associations were much stronger among participants with low concentration of plasma CC16 than those with high CC16 level. Moreover, plasma CC16 decreased monotonically with increasing quartiles of urinary vanadium, nickel or antimony. Mediation analyses found that CC16 mediated the associations between urinary metals and FeNO by 5.64%, 39.06% and 25.18% for vanadium, nickel and antimony respectively. CC16 plays an important role in airway inflammation. General population with lower plasma CC16 concentration is more likely to suffer from airway inflammation when exposed to high levels of vanadium, nickel or antimony.

6.
Sci Rep ; 9(1): 19853, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882832

RESUMO

Landslide displacement time series can directly reflects landslide deformation and stability characteristics. Hence, forecasting of the non-linear and non-stationary displacement time series is necessary and significant for early warning of landslide failure. Traditionally, conventional machine learning methods are adopted as forecasting models, these forecasting models mainly determine the input and output variables experientially and does not address the non-stationary characteristics of displacement time series. However, it is difficult for these conventional machine learning methods to obtain appropriate input-output variables, to determine appropriate model parameters and to acquire satisfied prediction performance. To deal with these drawbacks, this study proposes the wavelet analysis (WA) to decompose the displacement time series into low- and high-frequency components to address the non-stationary characteristics; then proposes thee chaos theory to obtain appropriate input-output variables of forecasting models, and finally proposes Volterra filter model to construct the forecasting model. The GPS monitoring cumulative displacement time series, recorded on the Shuping and Baijiabao landslides, distance measuring equipment monitoring displacements on the Xintan landslide in Three Gorges Reservoir area of China, are used as test data of the proposed chaotic WA-Volterra model. The chaotic WA-support vector machine (SVM) model and single chaotic Volterra model without WA method, are used as comparisons. The results show that there are chaos characteristics in the GPS monitoring displacement time series, the non-stationary characteristics of landslide displacements are captured well by the WA method, and the model input-output variables are selected suitably using chaos theory. Furthermore, the chaotic WA-Volterra model has higher prediction accuracy than the chaotic WA-SVM and single chaotic Volterra models.

7.
Hear Res ; 384: 107827, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31683075

RESUMO

The association between shift work and hearing loss is unclear. We aimed to evaluate this association in a Chinese population independently and in combination with occupational noise. A total of 11,196 participants of the Dongfeng-Tongji cohort study were included. Shift work was self-reported and hearing loss was defined as a pure-tone mean of 25 dB or higher at 0.5, 1, 2, and 4 kHz in any ear. The Robust Poisson method were used to assess the relationship between shift work and hearing loss, and the prevalence ratios (PRs) were calculated. Compared to individuals who reported no shift work, the PRs of bilateral hearing loss were significantly higher for a shift work duration of fewer than 10 years in women, (PR = 1.024, 95% confidence interval [CI] = 1.002-1.053), but not in men (PR = 1.016, 95% confidence interval [CI] = 0.998-1.035). The association between short duration of shift work and bilateral hearing loss was just statistically significant in women when those with occupational noise exposure were excluded (PR = 1.067, 95%CI = 1.015-1.122). When shift work and occupational noise exposure were combined, the PRs for hearing loss were highest among individuals with the longest shift work (≥10 years) and longest noise exposure (≥20 years) durations, whether for bilateral (PR = 1.114, 95%CI = 1.068-1.162) or any ear (PR = 1.065, 95%CI = 1.034-1.096). A short duration of shift work may be a risk factor for hearing loss in women and could increase the prevalence of hearing loss when combined with occupational noise.

8.
Am J Transl Res ; 11(9): 5438-5456, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632521

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) is a biliary malignancy, which is notoriously difficult to diagnose and associated with poor survival. Accumulating evidence indicates that long non-coding RNA Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) is overexpressed in several tumors and plays a crucial role in the development of neoplasm. However, the expression pattern and functional role of NNT-AS1 in CCA remain largely unknown. METHODS: NNT-AS1 expression was assessed by RT-qPCR and In Situ Hybridization (ISH) assay. The clinical relevance of NNT-AS1 was analyzed using a CCA tissue microarray with follow-up data. The function role of NNT-AS1 and its underlying molecular mechanisms were evaluated using both in vitro/in vivo experiments and bioinformatics analysis. Luciferase reporter assay, western blot and RT-qPCR were conducted to identify the miRNA/target gene involved in the regulation of CCA progression. RESULTS: LncRNA NNT-AS1 was found highly expressed in CCA. Upregulated NNT-AS1 expression was tightly associated with clinical malignancies and predicted poor prognosis of CCA patients. Functional studies showed that NNT-AS1 knockdown inhibited cell proliferation, migration and invasion of CCA cells in vitro. Conversely, NNT-AS1 overexpression showed the opposite biological effects. In a tumor xenograft model, we confirmed that NNT-AS1 knockdown could significantly inhibit the growth of CCA, while NNT-AS1 overexpression promoted CCA development. Mechanistically, we demonstrated that NNT-AS1 might function as a ceRNA in regulating HMGA2 (high mobility group AT-hook 2) through competitively binding to miR-142-5p in CCA. Moreover, we showed that NNT-AS1 regulated epithelial-mesenchymal transition in CCA. CONCLUSION: In summary, these findings suggest the potential prognostic and therapeutic value of NNT-AS1/miR-142-5p/HMGA2 axis in CCA patients.

9.
Environ Pollut ; 255(Pt 2): 113341, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31610512

RESUMO

Cadmium (Cd) is a toxic heavy metal that is widely distributed in the environment. However, the mechanisms linking Cd exposure and type 2 diabetes risks are not completely elucidated. In this study, we aim to investigate the roles of C-reactive protein (CRP) on the association between urinary Cd and type 2 diabetes risk. We determined urinary Cd and plasma CRP concentrations among 3,140 adults from Wuhan-Zhuhai cohort. Dose-response relationships between urinary Cd, plasma CRP, and type 2 diabetes were explored using multivariate logistic regression and linear mixed regression models. Mediation analysis was performed to investigate the role of plasma CRP in the associations between urinary Cd and type 2 diabetes risk. With adjustment for potential confounders, the odds ratios (ORs) of type 2 diabetes showed an upward trend when urinary Cd concentration gradually increased (P trend <0.01). Significantly positive dose-response relationships were observed between urinary Cd and plasma CRP, as well as between plasma CRP and type 2 diabetes risk. Compared to those when both Cd and CRP levels were low, the adjusted ORs (95%CI) of type 2 diabetes was the highest [2.053(1.395-3.020)] in individuals with high levels of urinary Cd and plasma CRP. Mediation analysis estimated that plasma CRP mediated 4.01% of the association between urinary Cd and type 2 diabetes risk [mediating effect: OR (95%CI) = 1.019(1.002-1.057)]. Individuals with high levels of urinary Cd and plasma CRP had a much higher risk of type 2 diabetes. Plasma CRP may serve as a mediator in the association between urinary Cd and type 2 diabetes risk, providing clues for further study on the biological pathway for type 2 diabetes related to Cd exposure.


Assuntos
Proteína C-Reativa/metabolismo , Cádmio/urina , Diabetes Mellitus Tipo 2/metabolismo , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/metabolismo , Adulto , Cádmio/toxicidade , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances
10.
Sci Total Environ ; 684: 458-465, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31154218

RESUMO

Fine particulate matter (PM2.5) exposure has been associated with lung function decline, but impact of PM2.5 constituents especially for polycyclic aromatic hydrocarbons (PAHs) on lung function is unclear among community population. We enrolled 224 Chinese participants who participated in two study periods (2014-2015 and 2017-2018) of the Wuhan-Zhuhai cohort as a panel, and quantified the associations of personal PM2.5 and sixteen PM2.5-bound PAHs with lung function levels as well as lung function change in three years by linear mixed models. Diagnostic ratios were calculated to identify potential sources of PM2.5-bound PAHs in Wuhan and Zhuhai separately. In single-constituent models, we found that each one interquartile-range increase of naphthalene, acenaphthene, fluoranthene and pyrene were associated with 26.82, 60.99, 45.25 and 23.37 mL decline in FVC respectively; while fluoranthene and pyrene were associated with 27.43 and 15.49 mL decline in FEV1 respectively. Similar results were observed in consitituent-PM2.5 joint models and single-constituent residual models. Persistently long-term high levels of three HMW-PAHs (benzo[a]anthracene, dibenzo[a,h]anthracene, and benzo[ghi]perylene) were associated with 214.65, 226.13, and 265.00 mL decline in FVC decline in three years, compared with persistently low exposure level groups. The associations were different between Wuhan and Zhuhai. The results of diagnostic ratios suggested the differences in PAH emissions between two cities. Our findings provide evidence that both short- and long-term PM2.5-bound PAH exposures might affect lung function.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Material Particulado/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Adulto , Estudos Transversais , Relação Dose-Resposta a Droga , Feminino , Humanos , Estudos Longitudinais , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória
11.
Respir Med ; 152: 67-73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31128612

RESUMO

BACKGROUND: Central obesity and polycyclic aromatic hydrocarbons (PAHs) exposure were reported as independent risk factors for lung function decline. However, the interaction between central obesity and PAHs exposure on lung function is still unclear. OBJECTIVES: To evaluate the impact of central obesity, urinary polycyclic aromatic hydrocarbon metabolites (OH-PAHs) and their combined effects on lung function in general population. METHODS: Lung function and urinary OH-PAHs were measured for 3,749 participants from the Wuhan-Zhuhai cohort. Central obesity was evaluated by waist-to-hip ratio. Generalized linear regression was used to estimate combined effect of central obesity and OH-PAHs on lung function. RESULTS: Compared with participants without central obesity and with low urinary total OH-PAHs (∑OH-PAHs) level, those with central obesity and high urinary ∑OH-PAHs level had 59.4 mL and 61.0 mL reductions for forced vital capacity (FVC) and forced expiratory volume in 1s (FEV1), respectively (P < 0.05). The reductions were more evident in smokers and males. Additive interactions between central obesity and urinary ∑OH-PAHs on lung function were observed, especially on FEV1 (P < 0.05). Each 1-unit increase in log-transformed value of ∑OH-PAHs was associated with -34.4 ml (95% confidence interval [CI]: -66.9, -1.8) and -34.8 mL (-61.1, -8.5) changes in FVC and FEV1 among those without central obesity, while -21.4 ml (-49.9, 7.1) and -19.7 ml (-43.4, 4.0) changes among those with central obesity. CONCLUSION: Polycyclic aromatic hydrocarbons exposure has combined effect with central obesity on lung function parameters.

12.
Environ Toxicol Pharmacol ; 69: 120-128, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31026736

RESUMO

Few studies have compared the biological effects of PM2.5 from coal combustion, gasoline exhaust and urban ambient air, and the roles of polycyclic aromatic hydrocarbons (PAHs) and metals playing in the process remain unclear. In this study, PM2.5 samples from coal combustion, gasoline exhaust and urban ambient air were analyzed for 16 PAHs and 23 metals. Cytotoxic and inflammatory effects of different PM2.5 were evaluated on differentiated THP-1 and A549 cells, respectively. We found that the coal combustion PM2.5 samples induced stronger cytotoxic and inflammatory effects (p < 0.05). Pearson's correlation and principal component analysis showed that the PAHs containing four or more benzenoid rings and specific metals of cadmium, thallium, zinc and lead were positively related to the biological effects. Our results suggested that coal combustion PM2.5 might be a more serious health hazard. Specific PAHs and metals might be account for the PM2.5 induced biological effects.


Assuntos
Poluentes Atmosféricos/toxicidade , Carvão Mineral , Gasolina , Metais/toxicidade , Material Particulado/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Emissões de Veículos/toxicidade , Células A549 , Poluentes Atmosféricos/análise , Sobrevivência Celular/efeitos dos fármacos , Cidades , Humanos , Metais/análise , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Células THP-1 , Emissões de Veículos/análise
13.
Eur J Prev Cardiol ; 26(12): 1288-1297, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30966819

RESUMO

AIMS: This study aimed to evaluate the relationship between sleep duration, sleep quality and hyperlipidemia in middle-aged and older Chinese. METHODS: We included 20,712 individuals at baseline from September 2008 to June 2010, and they were followed-up until October 2013. Hyperlipidemia was defined according to the Chinese guidelines on the prevention and treatment of dyslipidemia in adults. Sleep duration was self-reported and sleep quality was evaluated with a questionnaire that was designed according to the Pittsburgh Sleep Quality Index. Logistic regression and Cox proportional hazard models were conducted to explore the associations. RESULTS: In the cross-sectional analyses, longer sleep duration (≥10 h) was significantly associated with higher prevalence of hyperlipidemia (odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.02-1.35) after adjusting for potential confounders. The ORs of hyperlipidemia were significantly elevated among participants with impaired sleep quality (OR = 1.14, 95% CI = 1.08-1.22) and poor sleep quality (OR = 1.20, 95% CI = 1.08-1.34) when compared to those with good sleep quality. In the longitudinal analyses, compared to participants with a sleep duration of 7-<8 h, those with a sleep duration of 9-<10 h (hazard ratio (HR) = 1.19, 95% CI = 1.04-1.35) and ≥10 h (HR = 1.27, 95% CI = 1.02-1.58) showed significantly higher risk of hyperlipidemia after adjusting for potential confounders. However, no statistically significant association was found between impaired or poor sleep quality and hyperlipidemia. CONCLUSIONS: Longer sleep duration was significantly associated with higher risk of hyperlipidemia. Impaired or poor sleep quality were associated with elevated prevalence of hyperlipidemia, but not with the incidence of hyperlipidemia.

14.
Life Sci ; 224: 12-22, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30872181

RESUMO

AIMS: MicroRNAs (miRNAs or miRs) are a large class of small noncoding RNAs. The present study aims to evaluate the effect of miR-451 on cardiac remodeling in diabetic cardiomyopathy. MAIN METHODS: Mice were injected with streptozotocin (STZ) to induce diabetes. Twelve weeks after final STZ injection, mice were subjected to myocardial injection of adenovirus (Ad)-shmiR-451 to knock down miR-451. Mouse heart endothelial cells (MHECs) were treated with a miR-451 antagomir to inhibit miR451 and were exposed to high glucose. KEY FINDINGS: Sixteen weeks after STZ injection, mice exhibited no significant cardiac hypertrophy but did exhibit serious cardiac fibrosis. MiR-451 knockdown attenuated cardiac fibrosis and improved cardiac function. Moreover, we found that miR-451 knockdown suppressed endothelial-to-mesenchymal transition (EndMT) in diabetic mouse hearts. Hyperglycemia-induced EndMT in MHECs was attenuated by the miR-451 antagomir. Activation of AMPKa1/mTOR was decreased in diabetic mouse heart tissue and hyperglycemia-stimulated MHECs, which was increased following miR-451 knockdown or inhibition. AMPKa1 siRNA abrogated the anti-EndMT effects of miR-451 knockdown in MHECs. SIGNIFICANCE: miR-451 participates in the pathology of diabetic cardiomyopathy via AMPKa1-regulated EndMT in endothelial cells.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Fibrose/terapia , Cardiopatias/terapia , MicroRNAs/antagonistas & inibidores , Substâncias Protetoras , RNA Interferente Pequeno/genética , Animais , Animais Recém-Nascidos , Fibrose/etiologia , Fibrose/genética , Cardiopatias/etiologia , Cardiopatias/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
15.
Thorac Cancer ; 10(5): 1252-1255, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788907

RESUMO

Drive gene mutation positive non-small cell lung cancer achieves reliable clinical responses to subsequent target therapy. However, most patients will inevitably develop disease progression with multiple treatment failure. Next generation sequencing can identify clear resistance mechanisms. We report a case of a late stage, non-smoking, male non-small cell lung cancer patient that developed dual mutations and our attempts to determine the novel resistance mechanism. After systematic chemotherapy, he was administered multiple target therapy according to different genotypes. Larger panel gene detection was adapted after the failure of different treatments to investigate the resistance mechanism. Re-biopsy and large panel NGS revealed an EGFR mutant lung adenocarcinoma with alternating changes in acquired resistance between EGFR and ALK. The total survival time was 73 months. The genotypes and treatments in this patient provide new insight of target therapy resistance mechanisms. Re-biopsy and large panel gene detection should be performed for each driver gene mutation to provide precision treatment strategies.

16.
Eur J Prev Cardiol ; : 2047487319830536, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30776917

RESUMO

BACKGROUND: Heavy metals were related to increased risk of atherosclerotic cardiovascular disease (ASCVD). However, potential mechanisms under such associations remain unclear. We aimed to investigate the mediating role of mean platelet volume in the associations between heavy metals exposure and 10-year ASCVD risk. METHOD: Urinary heavy metals and mean platelet volume were measured in 3081 adults from the Wuhan-Zhuhai cohort in China. The associations between urinary heavy metals, mean platelet volume and 10-year ASCVD risk were separately analyzed through generalized linear models and logistic regression models. Mediation analyses were conducted to assess the role of mean platelet volume in the associations between urinary heavy metals and 10-year ASCVD risk. RESULTS: After adjusting for potential confounders, 10-year ASCVD risk was positively associated with urinary iron (odds ratio (OR) = 1.142, 95% confidence interval (1.038-1.256)), copper (OR = 1.384 (1.197-1.601)), zinc (OR = 1.520 (1.296-1.783)), cadmium (OR = 1.153 (0.990, 1.342)) and antimony (OR = 1.452 (1.237-1.704)), and negatively related with urinary barium (OR = 0.905 (0.831-0.985)). Also, we found significant dose-response relationships between urinary iron, zinc, antimony and mean platelet volume, as well as between mean platelet volume and 10-year ASCVD risk (all pfor trends < 0.05). Furthermore, mediation analyses indicated that mean platelet volume mediated 17.55%, 6.15% and 7.38% of the associations between urinary iron, zinc, antimony and 10-year ASCVD risk, respectively (all pvalue < 0.05). CONCLUSIONS: Elevated concentrations of urinary iron, copper, zinc, cadmium and antimony were associated with increased risk of 10-year ASCVD. Mean platelet volume partially mediated the associations of urinary iron, zinc and antimony with 10-year ASCVD risk.

17.
Respir Res ; 20(1): 19, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691461

RESUMO

BACKGROUND: Soluble CD14 (sCD14) shedding from CD14 could regulate T lymphocyte activation and function, which has implicated in the pathogenesis of bronchial asthma. The level of sCD14 expression is obviously increased in asthmatic patients during acute asthma attacks. The objective of this study was to investigate the association between plasma sCD14 level and asthma severity in adults. METHODS: The plasma sCD14 level in asthma patients (n = 910) and healthy controls (n = 881) was quantified by commercially available enzyme-linked immunosorbent assay (ELISA) kits. The asthma cases were subdivided into intermittent asthma (n = 537), mild (n = 246), moderate (n = 96) and severe (n = 31) persistent asthma patients. Association between plasma sCD14 level and asthma severity, lung function parameters as well as asthma symptoms and signs in adults were performed using multivariate logistic regression models. RESULTS: We observed significant relationships of plasma sCD14 level with asthma severity, lung function parameters as well as asthma symptoms and signs in adults. After adjusting for multiple potential confounders, each one-unit increase in log sCD14 was significantly associated with 67, 82, 79 and 85% reduced ORs for intermittent asthma, mild, moderate and severe persistent asthma, respectively (all P < 0.0001). Compared with the participants of FEV1/FVC ≥75%, each one-unit increase in log sCD14 was significantly associated with a 37% decreased OR of FEV1/FVC < 75% (P < 0.0001). However, the adjusted odds ratios (ORs) of severe dyspnea, wheeze and cyanosis in asthma patients were 1.88, 1.46 and 2.20 for each one-unit increase in log sCD14, respectively. In addition, compared with health controls, the adjusted area under the curve (AUC) of sCD14 was 0.814 at a cut-off points of 0.53, and the sensitivity and specificity were 71.0 and 76.8% for predicting asthma in adults. And the adjusted AUC of sCD14 reached 0.786, 0.847, 0.887 and 0.917 in predicting intermittent asthma, mild, moderate and severe persistent asthma, respectively. CONCLUSIONS: Our results indicated that plasma sCD14 level is negatively associated with asthma severity, suggesting a protective role for sCD14 in the development of asthma in adults. And plasma sCD14 level might be a potential biomarker in prediction of asthma severity in adults.


Assuntos
Asma/sangue , Asma/epidemiologia , Receptores de Lipopolissacarídeos/sangue , Índice de Gravidade de Doença , Adulto , Asma/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
J Cell Physiol ; 234(8): 13680-13692, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30605239

RESUMO

Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality, worldwide. Long noncoding RNAs (lncRNAs) are involved in diverse biological processes, and their vital role in the regulation of cardiac hypertrophy is increasingly being discovered. Nevertheless, the biological roles of lncRNA X-inactive specific transcript (XIST) in cardiac hypertrophy are scarcely reported, and the current study was designed to determine whether cardiac hypertrophy can be regulated by XIST and to elucidate the related mechanism. The animals were randomized to receive either an adeno-associated virus expressing XIST or control plasmid via a single bolus-tail vein injection. Two weeks later, hypertrophy was established by transverse aortic constriction (TAC) surgery. In vitro, H9c2 cells were used to explore the potential molecular mechanism of XIST in the regulation of phenylephrine (PE)-induced cardiomyocyte hypertrophy. A luciferase reporter assay and RNA immunoprecipitation were performed to explore the relationships among XIST, microRNA (miR)-101, and toll-like receptor 2 (TLR2). In this study, we demonstrated that the expression of XIST was significantly upregulated in hypertrophic mouse hearts and PE-treated cardiomyocytes. Then, we observed that knockdown of XIST attenuated PE-induced cardiomyocyte hypertrophy. Conversely, overexpression of XIST aggravated TAC-induced cardiac hypertrophy. Finally, we demonstrated that miR-101 was a direct target of XIST, whereas TLR2 was a target of miR-101. Rescue assays further confirmed that XIST promoted the progression of cardiac hypertrophy through competitively binding with miR-101 to enhance the expression of TLR2. Collectively, these in vivo and in vitro findings identify XIST as a necessary regulator of cardiac hypertrophy due to its regulation of the miR-101/TLR2 axis, suggesting that XIST might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

19.
J Cell Mol Med ; 23(1): 328-339, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30467953

RESUMO

Multiple organs express testin (TES), including the heart. Nevertheless, current understanding of the influence of TES on cardiovascular diseases, especially on cardiac hypertrophy and its etiology, is insufficient. This study investigated the influence of TES on cardiac hypertrophy and its etiology. Murine models with excessive TES expression specific to the heart were constructed with an adeno-associated virus expression system. Cardiac hypertrophy was stimulated through aortic banding (AB). The severity of cardiac hypertrophy was evaluated through molecular, echocardiographic, pathological, and hemodynamic examination. The findings of our study revealed that TES expression was remarkably suppressed not only in failing human hearts but also in mouse hearts with cardiac hypertrophy. It was discovered that excessive TES expression driven by an adeno-associated viral vector noticeably inhibited hypertrophy triggered by angiotensin II (Ang II) in cultivated cardiomyocytes from newborn rats. It was also revealed that TES knockdown via AdshTES caused the reverse phenotype in cardiomyocytes. Furthermore, it was proved that excessive TES expression attenuated the ventricular dilation, cardiac hypertrophy, dysfunction, and fibrosis triggered by AB in mice. It was discovered that TES directly interacted with calcineurin and suppressed its downstream signalling pathway. Moreover, the inactivation of calcineurin with cyclosporin A greatly offset the exacerbated hypertrophic response triggered by AB in TES knockdown mice. Overall, the findings of our study suggest that TES serves as a crucial regulator of the hypertrophic reaction by hindering the calcineurin-dependent pathway in the heart.

20.
Chemosphere ; 215: 362-369, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30336313

RESUMO

Chromium exposure can induce altered lipoprotein metabolism in animals, but the health effects of chromium on dyslipidemia in humans have not been fully evaluated. In this study, we aimed to investigate the cross-sectional and longitudinal effects of urinary chromium on lipid levels and dyslipidemia risk among urban adults from two cities in China. A total of 3762 urban adults from the Wuhan-Zhuhai cohort were included in the initial investigation, and followed up three years later. Urinary chromium concentration was measured at baseline and repeated at follow-up. Associations of urinary chromium concentration with lipid levels and risk of dyslipidemia were analyzed by generalized linear and binary logistic regression models, respectively. We found significant relationships between increased urinary chromium concentration and both reduced triglyceride (TG) level and elevated high-density lipoprotein cholesterol (HDL-C) level at baseline and follow-up. In the cross-sectional analysis, each 1-unit increase in log-transformed urinary chromium was associated with a 0.25 mmol/L decrease in TG and a 0.05 mmol/L increase in HDL-C (P < 0.05); also, downward trends for odds ratios of hyperTG (TG level ≥ 1.7 mmol/L) and hypoHDL-C (HDL-C level < 1.0 mmol/L) were significantly associated with increasing quartiles of urinary chromium (P trend < 0.05). In the longitudinal analysis, each 1-unit increase in log-transformed urinary chromium concentration was associated with a 3% and 6% decrease in the risk of developing hyperTG and hypoHDL-C, respectively (P > 0.05). Our study indicated that significant dose-response relationships between urinary chromium concentration and lipid levels were observed at baseline and at follow-up.


Assuntos
Cromo/urina , Dislipidemias/urina , Adulto , China , HDL-Colesterol/análise , Estudos Transversais , Humanos , Metabolismo dos Lipídeos , Lipídeos/análise , Estudos Prospectivos , Triglicerídeos/análise , Saúde da População Urbana
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