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1.
Medicine (Baltimore) ; 98(52): e18435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876723

RESUMO

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) accounts for 10% to 15% of all primary hepatic carcinomas. However, there are no effective drug treatment strategies against ICC, and surgery is currently the only curative treatment. Here, we present a case of ICC successfully treated with anlotinib, a novel oral agent. PATIENT CONCERNS: The patient was a 66-year-old Han Chinese woman, and she was a retired worker. The patient had no history of hepatitis B infection or hypertension. Physical examination showed no abnormalities, and the patient showed no conscious discomfort. However, ultrasound revealed liver occupation. DIAGNOSIS: Liver ultrasound and enhanced computed tomography (CT) indicated liver cancer with intrahepatic metastasis. Serum carbohydrate antigen 199 and alpha fetoprotein levels were high at 4270 and 1561 ng/mL, respectively. Pathologic findings of CT-guided liver biopsy revealed an adenocarcinoma. Owing to further immunohistochemical staining and clinical results, a diagnosis of ICC was made. INTERVENTIONS: The patient had received 5 cycles of transhepatic arterial chemotherapy and embolization and 1 cycle of microwave ablation. Due to rapid tumor progression and loss of liver function, systemic chemotherapy was contraindicated. As second-line therapy, she received anlotinib, a novel tyrosine kinase inhibitor that inhibits tumor angiogenesis and proliferative signaling and has been used to treat refractory advanced non-small-cell lung cancer that shows progression despite treatment with ≥2 chemotherapy regimens. OUTCOMES: This patient showed a partial response after 2 cycles of treatment with anlotinib (12 mg daily, days 1-14 of a 21-day cycle). Drug-related side effects, such as hypertension and hand foot skin reaction, were observed. After 4 cycles of anlotinib, the efficacy appeared to be stable, and the patient showed a progression-free survival period of almost 4 months. However, the patient's condition worsened and she died of liver failure 6 months after treatment (overall survival, almost 6 months). CONCLUSION: Some cases of ICC may be responsive to the antiangiogenic drug, anlotinib, when combined with microwave ablation. Randomized clinical studies are required to further confirm the efficacy and safety of anlotinib in the clinical treatment of ICC.

2.
J Nutr ; 2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31875479

RESUMO

BACKGROUND: The protein kinase target of rapamycin (mTOR) in complex 1 (mTORC1) is activated by amino acids and in turn upregulates anabolic processes. Under nutrient-deficient conditions, e.g., amino acid insufficiency, mTORC1 activity is suppressed and autophagy is activated. Intralysosomal amino acids generated by autophagy reactivate mTORC1. However, sustained mTORC1 activation during periods of nutrient insufficiency would likely be detrimental to cellular homeostasis. Thus, mechanisms must exist to prevent amino acids released by autophagy from reactivating the kinase. OBJECTIVE: The objective of the present study was to test whether mTORC1 activity is inhibited during prolonged leucine deprivation through ATF4-dependent upregulation of the mTORC1 suppressors regulated in development and DNA damage response 1 (REDD1) and Sestrin2. METHODS: Mice (8 wk old; C57Bl/6 × 129SvEV) were food deprived (FD) overnight and one-half were refed the next morning. Mouse embryo fibroblasts (MEFs) deficient in ATF4, REDD1, and/or Sestrin2 were deprived of leucine for 0-16 h. mTORC1 activity and ATF4, REDD1, and Sestrin2 expression were assessed in liver and cell lysates. RESULTS: Refeeding FD mice resulted in activation of mTORC1 in association with suppressed expression of both REDD1 and Sestrin2 in the liver. In cells in culture, mTORC1 exhibited a triphasic response to leucine deprivation, with an initial suppression followed by a transient reactivation from 2 to 4 h and a subsequent resuppression after 8 h. Resuppression occurred concomitantly with upregulated expression of ATF4, REDD1, and Sestrin2. However, in cells lacking ATF4, neither REDD1 nor Sestrin2 expression was upregulated by leucine deprivation, and resuppression of mTORC1 was absent. Moreover, in cells lacking either REDD1 or Sestrin2, mTORC1 resuppression was attenuated, and in cells lacking both proteins resuppression was further blunted. CONCLUSIONS: The results suggest that leucine deprivation upregulates expression of both REDD1 and Sestrin2 in an ATF4-dependent manner, and that upregulated expression of both proteins is involved in resuppression of mTORC1 during prolonged leucine deprivation.

3.
Environ Pollut ; 258: 113589, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31841764

RESUMO

Studies have found that ambient particulate matter (PM) affects fasting blood glucose. However, the results are not consistent. We conducted a systematic review and meta-analysis to determine the relationship between PM with an aerodynamic diameter of 10 µm or less (PM10) and PM with an aerodynamic diameter of 2.5 µm or less (PM2.5) and fasting blood glucose. We searched PubMed, Web of Science, the Wanfang Database and the China National Knowledge Infrastructure up to April 1, 2019. A total of 24 papers were included in the review, and 17 studies with complete or convertible quantitative information were included in the meta-analysis. The studies were divided into groups by PM size fractions (PM10 and PM2.5) and length of exposure. Long-term exposures were based on annual average concentrations, and short-term exposures were those lasting less than 28 days. In the long-term exposure group, fasting blood glucose increased 0.10 mmol/L (95% CI: 0.02, 0.17) per 10 µg/m3 of increased PM10 and 0.23 mmol/L (95% CI: 0.01, 0.45) per 10 µg/m3 of increased PM2.5. In the short-term exposure group, fasting blood glucose increased 0.02 mmol/L (95% CI: -0.01, 0.04) per 10 µg/m3 of increased PM10 and 0.08 mmol/L (95% CI: 0.04, 0.11) per 10 µg/m3 of increased PM2.5. Further prospective studies are needed to explore the relationship between ambient PM exposure and fasting blood glucose.

4.
Chemosphere ; 241: 125081, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31622890

RESUMO

To take an insight into the long-term accumulation of chromium (Cr) and cadmium (Cd) in school-age children living near an MWI and to assess their early renal impairment, we conducted a cross-sectional study in 2015. A total of 116 children from the exposure area and 122 from the control area were recruited. We measured the urinary levels of Cr (U-Cr) and Cd (U-Cd) by inductively coupled plasma mass spectrometry (ICP-MS), and detected three classic renal tubule indicators, including N-acetyl-ß-d-glucosaminidase (NAG), ß2-microglobulin (BMG), and retinol binding protein (RBP). The U-Cd and U-Cr levels in children living near the MWI were 0.11 and 1.57 µg/g creatinine, respectively. Both the U-Cd and U-Cr levels in the exposure group were lower than those in the control group, although only U-Cd showed a statistical difference (p < 0.01). The U-NAG and U-RBP levels in the exposure group were also statistically lower than those in the control group (0.80 vs. 1.74 IU/g creatinine, 0.26 vs. 0.48 mg/g creatinine, respectively). The U-Cd level in this study was positively correlated with the U-NAG level (r = 0.26, p < 0.01), as the U-Cr level was also positively correlated with the levels of U-NAG, U-RBP, and U-BMG (r = 0.21, 0.33, 0.18, p < 0.01, respectively). This study indicates that children living close to this particular MWI may not suffer considerable long-term accumulation of Cd or Cr, nor early renal impairment.

5.
Hypertension ; 74(6): 1349-1356, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31630576

RESUMO

Central aortic blood pressure (BP) has been increasingly recognized as having a closer relationship with cardiovascular risks than peripheral BP. However, the effects of particulate matter pollution on central aortic BP have not been clearly demonstrated. In this study, we assessed the association between short-term ambient fine particulate matter (with an aerodynamic diameter ≤2.5 µm; PM2.5) exposure and central aortic BP in a Chinese community-based population. A total of 4715 visits were in our final analysis, including 2151 visits at the baseline and 2564 visits at the follow-up. Central aortic systolic BP (cSBP) was measured noninvasively using the method of radial artery tonometry with Omron HEM-9000AI machine. Data from air pollution monitoring stations were used to estimate daily PM2.5 exposure. Generalized additive mixed models with clinical and meteorologic covariates adjusted were used to examine the association between PM2.5 exposure and cSBP. The relationships between PM2.5 exposure and cSBP were nonlinear, and significant increments of cSBP were observed when the PM2.5 exposure concentration was above 100 µg/cm3. An interquartile range increase (80.25 µg/m3) in daily PM2.5 on the day of cSBP measurement (lag 0 day) was associated with 2.54 mm Hg (95% CI, 0.92-4.16) elevation in cSBP. The associations of PM2.5 with cSBP were not modified by age, sex, body mass index, medications, and comorbid diseases except for cardiovascular disease. Our findings demonstrated that short-term exposure to high concentration of ambient PM2.5 above 100 µg/cm3 was associated with significant increases in central aortic BP in a Chinese community-based population.

6.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470618

RESUMO

The aggregation morphology of anode materials plays a vital role in achieving high performance lithium-ion batteries. Herein, Co3O4 anode materials with different aggregation morphologies were successfully prepared by modulating the morphology of precursors with different cobalt sources by the mild coprecipitation method. The fabricated Co3O4 can be flower-like, spherical, irregular, and urchin-like. Detailed investigation on the electrochemical performance demonstrated that flower-like Co3O4 consisting of nanorods exhibited superior performance. The reversible capacity maintained 910.7 mAh·g-1 at 500 mA·g-1 and 717 mAh·g-1 at 1000 mA·g-1 after 500 cycles. The cyclic stability was greatly enhanced, with a capacity retention rate of 92.7% at 500 mA·g-1 and 78.27% at 1000 mA·g-1 after 500 cycles. Electrochemical performance in long-term storage and high temperature conditions was still excellent. The unique aggregation morphology of flower-like Co3O4 yielded a reduction of charge-transfer resistance and stabilization of electrode structure compared with other aggregation morphologies.

7.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470628

RESUMO

With the enhancement of people's environmental awareness, waterborne polyurethane (PU) paint-with its advantages of low release of volatile organic compounds (VOCs), low temperature flexibility, acid and alkali resistance, excellent solvent resistance and superior weather resistance-has made its application for wood furniture favored by the industry. However, due to its lower solid content and weak intermolecular force, the mechanical properties of waterborne PU paint are normally less than those of the traditional solvent-based polyurethane paint, which has become the key bottleneck restricting its wide applications. To this end, this study explores nanocellulose derived from biomass resources by the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) oxidation method to reinforce and thus improve the mechanical properties of waterborne PU paint. Two methods of adding nanocellulose to waterborne PU-chemical addition and physical blending-are explored. Results show that, compared to the physical blending method, the chemical grafting method at 0.1 wt% nanocellulose addition results in the maximum improvement of the comprehensive properties of the PU coating. With this method, the tensile strength, elongation at break, hardness and abrasion resistance of the waterborne PU paint increase by up to 58.7%, ~55%, 6.9% and 3.45%, respectively, compared to the control PU; while the glossiness and surface drying time were hardly affected. Such exploration provides an effective way for wide applications of water PU in the wood industry and nanocellulose in waterborne wood coating.

8.
Toxicol In Vitro ; 61: 104650, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520740

RESUMO

Chlorinated organic chemical 1,2-dichloroethane (1,2-DCE) is used widely in industrial production processes, and excessive exposure may lead to liver damage. The mechanisms underlying 1,2-DCE-induced hepatotoxicity are not fully understood. Numerous studies have demonstrated that long-non-coding RNAs (lncRNAs) play a pivotal role in the chemical-induced toxicity. To explore whether aberrant lncRNA expression is involved in hepatotoxicity mediated by 1,2-DCE exposure, we detected alterations of lncRNA expression profiling in a mouse model of 1,2-DCE-induced hepatotoxicity by microarray chip. Bioinformatic analysis indicated that a down-regulated lncRNA (lncRNA241) after 1,2-DCE exposure might be involved in 1,2-DCE-induced hepatotoxicity. We treated AML12 cells with 1,2-DCE and its metabolite 2-chloroacetic acid (2-CA) for 48 h, and the results revealed that it was 2-CA rather than primary form (1,2-DCE) that resulted in the decline of lncRNA241 expression in hepatocytes. In vitro intervention studies revealed that the repression of lncRNA241 expression after 2-CA exposure led to the down-regulation of anti-apoptosis-associated factor insulin growth factor-1 (Igf1) at mRNA and protein levels through modulation of their common target mmu-miR-451a, which promoted hepatic apoptosis. This study provides valuable insight into the role of lncRNAs in response to hepatocyte apoptosis induced by 1,2-DCE.

9.
Cell Death Dis ; 10(9): 661, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506427

RESUMO

Heterogeneity in chemotherapeutic response is directly associated with prognosis and disease recurrence in patients with ovarian cancer (OvCa). Despite the significant clinical need, a credible gene signature for predicting response to platinum-based chemotherapy and for guiding the selection of personalized chemotherapy regimens has not yet been identified. The present study used an integrated approach involving both OvCa tumors and cell lines to identify an individualized gene expression signature, denoted as IndividCRS, consisting of 16 robust chemotherapy-responsive genes for predicting intrinsic or acquired chemotherapy response in the meta-discovery dataset. The robust performance of this signature was subsequently validated in 25 independent tumor datasets comprising 2215 patients and one independent cell line dataset, across different technical platforms. The IndividCRS was significantly correlated with the response to platinum therapy and predicted the improved outcome. Moreover, the IndividCRS correlated with homologous recombination deficiency (HRD) and was also capable of discriminating HR-deficient tumors with or without platinum-sensitivity for guiding HRD-targeted clinical trials. Our results reveal the universality and simplicity of the IndividCRS as a promising individualized genomic tool to rapidly monitor response to chemotherapy and predict the outcome of patients with OvCa.

10.
Mol Carcinog ; 58(11): 2052-2064, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31397499

RESUMO

Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.

11.
Small ; : e1902464, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464072

RESUMO

Micro/nanomotors (MNMs) are miniaturized machines that can perform assigned tasks at the micro/nanoscale. Over the past decade, significant progress has been made in the design, preparation, and applications of MNMs that are powered by converting different sources of energy into mechanical force, to realize active movement and fulfill on-demand tasks. MNMs can be navigated to desired locations with precise controllability based on different guidance mechanisms. A considerable research effort has gone into demonstrating that MNMs possess the potential of biomedical cargo loading, transportation, and targeted release to achieve therapeutic functions. Herein, the recent advances of self-propelled MNMs for on-demand biomedical cargo transportation, including their self-propulsion mechanisms, guidance strategies, as well as proof-of-concept studies for biological applications are presented. In addition, some of the major challenges and possible opportunities of MNMs are identified for future biomedical applications in the hope that it may inspire future research.

12.
Am J Health Syst Pharm ; 76(13): 953-963, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31361885

RESUMO

PURPOSE: This study presents a medication-associated altered mental status (AMS) risk model for real-time implementation in inpatient electronic health record (EHR) systems. METHODS: We utilized a retrospective cohort of patients admitted to 2 large hospitals between January 2012 and October 2013. The study population included admitted patients aged ≥18 years with exposure to an AMS risk-inducing medication within the first 5 hospitalization days. AMS events were identified by a measurable mental status change documented in the EHR in conjunction with the administration of an atypical antipsychotic or haloperidol. AMS risk factors and AMS risk-inducing medications were identified from the literature, drug information databases, and expert opinion. We used multivariate logistic regression with a full and backward eliminated set of risk factors to predict AMS. The final model was validated with 100 bootstrap samples. RESULTS: During 194,156 at-risk days for 66,875 admissions, 262 medication-associated AMS events occurred (an event rate of 0.13%). The strongest predictors included a history of AMS (odds ratio [OR], 9.55; 95% confidence interval [CI], 5.64-16.17), alcohol withdrawal (OR, 3.34; 95% CI, 2.18-5.13), history of delirium or psychosis (OR, 3.25; 95% CI, 2.39-4.40), presence in the intensive care unit (OR, 2.53; 95% CI, 1.89-3.39), and hypernatremia (OR, 2.40; 95% CI, 1.61-3.56). With a C statistic of 0.85, among patients scoring in the 90th percentile, our model captured 159 AMS events (60.7%). CONCLUSION: The risk model was demonstrated to have good predictive ability, with all risk factors operationalized from discrete EHR fields. The real-time identification of higher-risk patients would allow pharmacists to prioritize surveillance, thus allowing early management of precipitating factors.

13.
Anticancer Res ; 39(7): 3651-3660, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262891

RESUMO

BACKGROUND/AIM: Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved. MATERIALS AND METHODS: PK03-mutant KrasG12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH-/- and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach. RESULTS: Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm3 vs. 519.3±60.6 mm3). In a separate experiment, sEH-/- mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant reduction in the weight and size of the pancreatic carcinoma compared to C57BL/6J control mice (weight: 0.26±.26 g and 0.39±.39 g vs. 0.69±0.11 g, respectively; size: 274.2±36.2 mm3 and 296.4±99.8 mm3 vs. 612.6±117.8 mm3, respectively). Moreover, compared to the pancreatic tumors in C57BL/6J control mice, the tumors in fat-1 transgenic mice treated with sEH inhibitor showed a significant less inflammatory cell infiltrate (62.6±9.2/HPF (high power field) vs. 8.0±1.2/HPF), tumor cell proliferation (48.5±1.7% vs. 16.5±1.6%), and angiogenesis (micro-vessel density (MVD): 35.0±1.0 vs. 11.1±0.5) immunohistochemically, as well as significantly increased caspase-3 labeled apoptosis (0.44±0.06% vs. 0.69±0.06%, respectively). Using western blot approach, significant inhibition of mutant Kras-activated signals including phosphorylated Serine/threonine kinases (cRAF), Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) were identified in pancreatic carcinoma of fat-1 transgenic mice treated with sEH inhibitor. Eicosanoic acid metabolic profiling of the serum specimens detected a significant increase of the ratios of epoxides to dihydroxy fatty acid (DiHDPE) for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and epoxides/dihydroxy octadecenoic acid (DiHOME) for arachidonic acid (ARA) and linoleic acid (LA), as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA in fat-1 transgenic mice treated with a sEH inhibitor. CONCLUSION: ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention.


Assuntos
Adenocarcinoma/terapia , Proteínas de Caenorhabditis elegans/genética , Suplementos Nutricionais , Compostos de Epóxi/farmacologia , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Ômega-3/farmacologia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Pancreáticas/patologia
14.
Sci Total Environ ; 689: 937-944, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280174

RESUMO

This study aimed to evaluate the body burdens of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and their associated health impacts toward school-age children living near a municipal waste incinerator (MWI). A total of 82 children from the exposure area and 49 from the control area were recruited. We measured blood PCDD/F levels, conducted comet assays, calculated the percentage of 5-methylcytosine (%5-mC) and 5-hydroxymethylcytosine (%5-hmC), performed flow cytometry, measured hormonal levels, and analyzed hematological parameters. We also examined 17 congeners of PCDD/Fs in environmental samples, namely, eggs, rice, water, soil, and PM2.5. The mean blood levels of ΣPCDD/Fs and TEQ-ΣPCDD/Fs were statistically higher in the exposure group than in the control group (3.40 vs. 2.77 pg/g wet weight and 0.40 vs. 0.28 pg WHO-TEQ/g wet weight, respectively; p < 0.05). By contrast, the %5-mC and %5-hmC levels were statistically lower in the exposure group than in the control group (1.15% vs. 4.66% and 0.22% vs. 0.30%, respectively; p < 0.01), whereas the mean % tail DNA was statistically higher in the exposure group than in the control group (10.10% vs. 8.28%, p < 0.01). The mean blood levels of ΣPCDD/Fs and TEQ-ΣPCDD/Fs were both negatively correlated with %5-mC (r = -0.245 and r = -0.217, respectively; p < 0.01) but not with %5-hmC and % tail DNA (p > 0.05). Furthermore, the mean ΣPCDD/F levels in eggs and soil obtained from the exposure area were statistically higher than those of the samples obtained from the control area (31.08 vs. 4.32 pg/g dry weight and 1026.04 vs. 674.97 pg/g dry weight, respectively). In conclusion, children living near the MWI may suffer genetic and epigenetic modifications, such as DNA damage or global DNA hypomethylation due to the MWI-emitted PCDD/Fs and other contaminants.


Assuntos
Dibenzofuranos Policlorados/efeitos adversos , Exposição Ambiental/efeitos adversos , Incineração , Dibenzodioxinas Policloradas/efeitos adversos , Criança , China , Estudos Transversais , Dibenzofuranos Policlorados/sangue , Monitoramento Ambiental , Feminino , Humanos , Masculino , Dibenzodioxinas Policloradas/sangue , Medição de Risco , Estudantes
15.
Front Pharmacol ; 10: 731, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293429

RESUMO

Polyunsaturated fatty acids (PUFAs) including epoxide-modified ω-3 and ω-6 fatty acids are made via oxidation to create highly polarized carbon-oxygen bonds crucial to their function as signaling molecules. A critical PUFA, arachidonic acid (ARA), is metabolized to a diverse set of lipids signaling molecules through cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 epoxygenase, or cytochrome P450 hydroxylase; however, the majority of ARA is metabolized into anti-inflammatory epoxides via cytochrome P450 enzymes. These short-lived epoxide lipids are rapidly metabolized or inactivated by the soluble epoxide hydrolase (sEH) into diol-containing products. sEH inhibition or knockout has been a practical approach to study the biology of the epoxide lipids, and has been shown to effectively treat inflammatory conditions in the preclinical models including gastrointestinal ulcers and colitis by shifting oxylipins to epoxide profiles, inhibiting inflammatory cell infiltration and activation, and enhancing epithelial cell defense via increased mucin production, thus providing further evidence for the role of sEH as a pro-inflammatory protein. Non-steroidal anti-inflammatory drugs (NSAIDs) with COX-inhibitor activity are among the most commonly used analgesics and have demonstrated applications in the management of cardiovascular disease and intriguingly cancer. Major side effects of NSAIDs however are gastrointestinal ulcers which frequently precludes their long-term application. In this review, we hope to bridge the gap between NSAID toxicity and sEH-mediated metabolic pathways to focus on the role of epoxy fatty acid metabolic pathway of PUFAs in NSAIDS-ulcer formation and healing as well as inflammation-related carcinogenesis. Specifically we address the potential application of sEH inhibition to enhance ulcer healing at the site of inflammation via their activity on altered lipid signaling, mitochondrial function, and diminished reactive oxygen species, and further discuss the significance of dual COX and sEH inhibitor in anti-inflammation and carcinogenesis.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31293986

RESUMO

Chemotherapy is one of the major treatment strategies for esophageal squamous cell carcinoma (ESCC). Unfortunately, most chemotherapeutic drugs have significant impacts on the intestinal microbes, resulting in side effects and reduced efficiency. Therefore, new strategies capable of overcoming these disadvantages of current chemotherapies are in urgent need. The natural product, Cepharanthine hydrochloride (CEH), is known for its anticancer and immunoregulatory properties. By sequencing the V4 region of 16S rDNA, we characterized the microbes of tumor-bearing mice treated with different chemotherapy strategies, including with CEH. We found that CEH improved the therapeutic effect of CDDP by manipulating the gut microbiota. Through metagenomic analyses of the microbes community, we identified a severe compositional and functional imbalance in the gut microbes community after CDDP treatment. However, CEH improved the effect of chemotherapy and ameliorated CDDP treatment-induced imbalance in the intestinal microbes. Mechanically, CEH activated TLR4 and MYD88 innate immune signaling, which is advantageous for the activation of the host's innate immunity to exert a balanced intestinal environment as well as to trigger a better chemotherapeutic response to esophageal cancer. In addition, TNFR death receptors were activated to induce apoptosis. In summary, our findings suggest that chemotherapy of CDDP combined with CEH increased the effect of chemotherapy and reduced the side effects on the microbes and intestinal mucosal immunity. We believe that these findings provide a theoretical basis for new clinical treatment strategies.

17.
Nanoscale ; 11(30): 14099-14112, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31214671

RESUMO

The advent of micro/nanomotors (MNMs) has shed light on the innovation of active biomedical systems or devices that might bring revolutionary solutions to traditional biomedical strategies. In spite of development beyond expectation over the last decade with a fair number of proof-of-concept demonstrations, the in vivo practical application of MNMs for clinical use is still in its infancy. The biocompatibility of MNMs is the first consideration before realizing practicality, taking into account the complicated interactions between the self-propelled MNMs and biological systems. Therefore, in this review, we focused on the biocompatibility of MNMs with regard to the fabrication materials and propulsion mechanisms by means of in-depth discussions on the advantages and limitations of MNMs for operating under physiological conditions. The future prospective and suggestions on the development of MNMs toward practical biomedical applications will also be proposed.

18.
BMJ Open Diabetes Res Care ; 7(1): e000653, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31245006

RESUMO

Objective: This study examined the effects of three doses of behavioral weight loss treatment, compared with a nutrition education control group, on changes in glycemic control in individuals with obesity and prediabetes. Research design and methods: The study included 287 adults (77% female, 81% White; mean (SD) age=54.1 (10.5) years, body mass index=36.3 (3.9) kg/m2, and hemoglobin A1c (HbA1c)=5.9 (0.2%)). Participants were randomized to one of three behavioral treatment doses (high=24 sessions, moderate=16 sessions, or low=8 sessions) or to an education group (control=8 sessions). Changes in HbA1c, fasting glucose, and body weight were assessed from baseline to 6 months. Results: Mean (99.2% credible interval (CI)) reductions in HbA1c were 0.11% (0.07% to 0.16%), 0.08% (0.03% to 0.13%), 0.03% (-0.01% to 0.07%), and 0.02% (-0.02% to 0.07%), for the high, moderate, low, and control conditions, respectively. Mean (CI) reductions in fasting blood glucose were 0.26 mmol/L (0.14 to 0.39), 0.09 mmol/L (0 to 0.19), 0.01 mmol/L (-0.07 to 0.09), and 0.04 mmol/L (-0.03 to 0.12) for the high, moderate, low, and control conditions, respectively. The high-dose treatment produced significantly greater reductions in HbA1c and fasting blood glucose than the low-dose and control conditions (posterior probabilities (pp)<0.001); no other significant between-group differences were observed. Mean (CI) reductions in body weight were 10.91 kg (9.30 to 12.64), 10.08 kg (8.38 to 11.72), 6.35 kg (5.19 to 7.69), and 3.82 kg (3.04 to 4.54) for the high, moderate, low, and control conditions, respectively. All between-group differences in 6-month weight change were significant (pps<0.001) except for the high-dose versus moderate-dose comparison. Conclusion: For adults with obesity and prediabetes a high dose of behavioral treatment involving 24 sessions over 6 months may be needed to optimize improvements in glycemic control. Trial registration number: NCT00912652.

19.
Nat Microbiol ; 4(8): 1282-1293, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31110362

RESUMO

Linear ubiquitin (Ub) chains regulate many cellular processes, including NF-κB immune signalling. Pathogenic bacteria have evolved to secrete effector proteins that harbour deubiquitinase activity into host cells to disrupt host ubiquitination signalling. All previously identified effector deubiquitinases hydrolyse isopeptide-linked polyubiquitin (polyUb). It has been a long-standing question whether bacterial pathogens have evolved an effector deubiquitinase to directly cleave linear Ub chains. In this study, we performed extensive screening of bacterial pathogens and found that Legionella pneumophila-the causative agent of human Legionnaire's disease-encodes an effector protein, RavD, which harbours deubiquitinase activity exquisitely specific for linear Ub chains. RavD hydrolyses linear Ub chains but not any type of isopeptide-linked polyUb. The crystal structure of RavD with linear diubiquitin reveals that RavD adopts a papain-like fold with a Cys-His-Ser catalytic triad. The Ub-binding surface and specific interacting residues in RavD determine its specificity for Met1 linkages. RavD prevents the accumulation of linear Ub chains on Legionella-containing vacuoles established by the pathogen in host cells to inhibit the NF-κB pathway during infection. This study identified a unique linear Ub chain-specific effector deubiquitinase and indicates its potential application as a tool to dissect linear polyUb-mediated signalling in mammalian cells.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31066059

RESUMO

PURPOSE: Bipolar disorder (BD) is frequently misdiagnosed, which can lead to negative outcomes. The 32-item Hypomania Checklist (HCL-32) is one of the most widely used self-reported screening instruments for hypomanic symptoms, which has several short versions. This systematic review examined the psychometric properties of HCL-32 short versions. DESIGN AND METHODS: Five international databases were systematically and independently searched by two researchers for studies that developed the HCL short versions. Basic demographic and clinical characteristics and the psychometric properties of the HCL short versions were recorded. FINDINGS: Eighteen studies were identified. The majority of the HCL short versions showed satisfactory to good psychometric properties. PRACTICE IMPLICATIONS: Validated HCL short versions with satisfactory psychometric properties may be helpful in screening for BD.

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