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1.
JAMA Pediatr ; 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33938946

RESUMO

Importance: Cardiorespiratory fitness is an important marker of childhood health and low fitness levels are a risk factor for disease later in life. Levels of children's fitness have declined in recent decades. Whether school-based physical activity interventions can increase fitness at the population level remains unclear. Objective: To evaluate the effect of an internet-based intervention on children's cardiorespiratory fitness across a large number of schools. Design, Setting, and Participants: In this cluster randomized clinical trial, 22 government-funded elementary schools (from 137 providing consent) including 1188 students stratified from grades 3 and 4 in New South Wales, Australia, were randomized. The other schools received the intervention but were not included in the analysis. Eleven schools received the internet-based intervention and 11 received the control intervention. Recruitment and baseline testing began in 2016 and ended in 2017. Research assistants, blinded to treatment allocation, completed follow-up outcome assessments at 12 and 24 months. Data were analyzed from July to August 2020. Interventions: The internet-based intervention included standardized online learning for teachers and minimal in-person support from a project mentor (9-10 months). Main Outcomes and Measures: Multistage 20-m shuttle run test for cardiorespiratory fitness. Results: Of 1219 participants (49% girls; mean [SD] age, 8.85 [0.71] years) from 22 schools, 1188 students provided baseline primary outcome data. At 12 months, the number of 20-m shuttle runs increased by 3.32 laps (95% CI, 2.44-4.20 laps) in the intervention schools and 2.11 laps (95% CI, 1.38-2.85 laps) in the control schools (adjusted difference = 1.20 laps; 95% CI, 0.17-2.24 laps). By 24 months, the adjusted difference was 2.22 laps (95% CI, 0.89-3.55 laps). The cost per student was AUD33 (USD26). Conclusions and Relevance: In this study, a school-based intervention improved children's cardiorespiratory fitness when delivered in a large number of schools. The low cost and sustained effect over 24 months of the intervention suggests that it may have potential to be scaled at the population level. Trial Registration: http://anzctr.org.au Identifier: ACTRN12616000731493.

2.
Radiother Oncol ; 159: 190-196, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33812913

RESUMO

BACKGROUND: To observe the long-term survival and late adverse events in a phase Ⅰ/Ⅱ trial (NCT01843049) of dose escalation for thoracic esophageal squamous cell carcinoma (ESCC) with simultaneous integrated boost (SIB) technique. METHODS: Patients with ESCC were treated with escalating radiation dose of four predefined levels. Dose of 62.5-64 Gy/25-32 fractions was delivered to the gross tumor volume (GTV), with (Level 3&4) or without (Level 1&2) a SIB up to 70 Gy for pre-treatment 50% SUVmax area of GTV. Patients also received 2 cycles of chemotherapy of cisplatin and fluorouracil concurrently and 2 more cycles after radiotherapy. RESULTS: Median follow-up duration was 17.2 (2.5-83.4) months for all 44 patients and 47.2 (3.9-83.4) months for 25 survivors. The 3-year overall survival and progression-free survival rates were 57.6% and 41.0%, respectively. One, one, four and twelve severe (grade≥3) esophageal late adverse events (SEAE) occurred in patients of Level 1/2/3/4 (n = 5/10/16/13), with median occurrence time of 6.5 months. In univariable and multivariable competing risk models, maximal dose of the esophagus (Dmax) was found to have significant impact on the incidence of SEAE, and the cutoff distinguishing patients who developed SEAE or not was 77 Gy. CONCLUSION: Boosting the gross tumor to 63 Gy while delivering 50.4 Gy to subclinical diseases in 28 fractions in locally advanced ESCC is well tolerated with promising long-term survival. Intenser dose regimen should be considered with caution before further toxicity assessment. Esophageal Dmax was significantly associated with severe late esophageal injury, while more findings of dose-volume predictors need larger-sample investigation.

3.
Sci Total Environ ; 781: 146730, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33798882

RESUMO

Previous studies demonstrated that microcystin-leucine-arginine (MC-LR) disrupted testosterone (T) synthesis, but the underlying mechanisms are not entirely elucidated. This study aims to explore the role of reactive oxygen species (ROS)-mediated GCN2/eIF2α activation on MC-LR-induced disruption of testicular T synthesis. Male mice were intraperitoneally injected with MC-LR (0 or 20 µg/kg) daily for 5 weeks. Serum T was decreased in MC-LR-exposed mice (0.626 ± 0.122 vs 24.565 ± 8.486 ng/ml, P < 0.01), so did testicular T (0.667 ± 0.15 vs 8.317 ± 1.387 ng/mg protein, P < 0.01). Steroidogenic proteins including StAR, CYP11A1 and CYP17A1 were downregulated in MC-LR-exposed mouse testes and TM3 cells. Mechanistically, p-GCN2 and p-eIF2α were elevated in MC-LR-exposed TM3 cells. GCN2iB attenuated MC-LR-induced GCN2 and eIF2α phosphorylation in TM3 cells. Moreover, GCN2iB attenuated MC-LR-induced downregulation of steroidogenic proteins in TM3 cells. Further analysis found that cellular ROS were elevated and HO-1 was upregulated in MC-LR-exposed TM3 cells. PBN rescued MC-LR-induced activation of GCN2/eIF2α signaling in TM3 cells. Additionally, pretreatment with PBN attenuated MC-LR induced downregulation of steroidogenic proteins and synthases in TM3 cells. These results suggest that ROS-mediated GCN2/eIF2α activation contributes partially to MC-LR-caused downregulation of steroidogenic proteins and synthases. The present study provides a new clue for understanding the mechanism of MC-LR-induced endocrine disruption.

4.
Environ Pollut ; 283: 117134, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33866216

RESUMO

1-Nitropyrene (1-NP) is one component of atmospheric fine particles. Previous report revealed that acute 1-NP exposure induced respiratory inflammation. This study aimed to investigate whether chronic 1-NP exposure induces pulmonary fibrosis. Male C57BL6/J mice were intratracheally instilled to 1-NP (20 µg/mouse/week) for 6 weeks. Diffuse interstitial inflammation, a-smooth muscle actin (a-SMA)-positive cells, a marker of epithelial-mesenchymal transition (EMT), and an extensive collagen deposition, measured by Masson staining, were observed in 1-NP-exposed mouse lungs. Pulmonary function showed that lung dynamic compliance (Cydn-min) was reduced in 1-NP-exposed mice. Conversely, inspiratory resistance (Ri) and expiratory resistance (Re) were elevated in 1-NP-exposed mice. Mechanistically, cell migration and invasion were accelerated in 1-NP-exposed pulmonary epithelial cells. In addition, E-cadherin, an epithelial marker, was downregulated, and vimentin, a-SMA and N-cadherin, three mesenchymal markers, were upregulated in 1-NP-exposed pulmonary epithelial cells. Although TGF-ß wasn't altered, phosphorylated Smad2/3 were enhanced in 1-NP-exposed pulmonary epithelial cells. Moreover, reactive oxygen species (ROS) were increased and endoplasmic reticulum (ER) stress was activated in 1-NP-exposed pulmonary epithelial cells. N-Acetylcysteine (NAC), an antioxidant, attenuated 1-NP-evoked excess ROS, ER stress and EMT in pulmonary epithelial cells. Similarly, pretreatment with NAC alleviated 1-NP-caused pulmonary EMT and lung fibrosis in mice. These results demonstrate that ROS-evoked ER stress contributes, at least partially, to 1-NP-induced EMT and pulmonary fibrosis.

5.
Chem Res Toxicol ; 34(4): 1101-1113, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33719395

RESUMO

Contamination with 1,2-unsaturated pyrrolizidine alkaloids (PAs) is a serious problem for certain phytomedicines, foods, and animal feeds. Several of these PAs are genotoxic and carcinogenic, primarily in the liver, upon cytochrome P450 (CYP)-catalyzed activation into reactive (pyrrolic and pyrrole-like) metabolites. Here we investigated the metabolism of selected PAs (echimidine, europine, lasiocarpine, lycopsamine, retrorsine, and senecionine) in rat hepatocytes in primary culture and in human CYP3A4-transfected HepG2 cells. The open-chained diesters echimidine and lasiocarpine and the cyclic diester senecionine were extensively metabolized in rat hepatocytes into a broad spectrum of products released into the medium. A large portion of unidentified, possibly irreversibly bound, products remained in the cells while detectable amounts of reactive and other metabolites were found in the incubation media. In HepG2-CYP3A4 cells, lasiocarpine was more extensively metabolized than echimidine and senecionine which also gave rise to the release of pyrrolic metabolites. In human cells, no pyrrolic metabolites were detected in retrorsine or lycopsamine incubations, while no such metabolites were detected from europine in both cell types. Other types of metabolic changes comprised modifications such as side chain demethylation or oxygenation reactions like the formation of N-oxides. The latter, considered as a detoxification step, was a major pathway with cyclic diesters, was less distinctive for echimidine and lycopsamine and almost negligible for lasiocarpine and europine. Our data are in agreement with previously published cyto- and genotoxicity findings and suggests that the metabolic pattern may contribute substantially to the specific toxic potency of a certain congener. In addition, marked differences were found for certain congeners between rat hepatocytes and transfected human HepG2 cells, whereby a high level of bioactivation was found for lasiocarpine, whereas a very low level of bioactivation was observed for monoesters, in particular in human cells.

6.
J Vis Exp ; (169)2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33779615

RESUMO

Gangliosides are glycosphingolipids that contain one or more sialic acid residues. They are found on all vertebrate cells and tissues but are especially abundant in the brain. Expressed primarily on the outer leaflet of the plasma membranes of cells, they modulate the activities of cell surface proteins via lateral association, act as receptors in cell-cell interactions and are targets for pathogens and toxins. Genetic dysregulation of ganglioside biosynthesis in humans results in severe congenital nervous system disorders. Because of their amphipathic nature, extraction, purification, and analysis of gangliosides require techniques that have been optimized by many investigators in the 80 years since their discovery. Here, we describe bench-level methods for the extraction, purification, and preliminary qualitative and quantitative analyses of major gangliosides from tissues and cells that can be completed in a few hours. We also describe methods for larger scale isolation and purification of major ganglioside species from brain. Together, these methods provide analytical and preparative scale access to this class of bioactive molecules.


Assuntos
Encéfalo/metabolismo , Membrana Celular/metabolismo , Gangliosídeos/isolamento & purificação , Gangliosídeos/metabolismo , Animais , Humanos
7.
Physiol Res ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33676385

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by vascular remodeling and chronic inflammation. Macrophages are the key orchestrators of inflammatory and repair responses, and have been demonstrated to be vital in the pathogenesis of PAH. However, specific phenotype of macrophage polarization (M1 & M2 macrophage) in the development of PAH and the underlying mechanisms how they work are still largely unclear. A rat model of monocrotaline (MCT) induced PAH was used. Hemodynamic analysis and histopathological experiments were conducted at day 3, 7, 14, 21 and 28, respectively. In PAH rat lung tissue, confocal microscopic images showed that CD68+NOS2+ M1-like macrophages were remarkably infiltrated on early stage, but dramatically decreased in mid-late stage. Meanwhile, CD68+CD206+ M2-like macrophages in lung tissue accumulated gradually since day 7 to day 28, and the relative ratio of M2/M1 macrophage increased over time. Results detected by western blot and immunohistochemistry were consistent. Further in vitro functional studies revealed the possible mechanism involved in this pathophysiological process. By using Transwell co-culture system, it was found that M1 macrophages induced endothelial cell apoptosis, while M2 macrophages significantly promoted proliferation of both endothelial cell and smooth muscle cell. These data preliminarily demonstrated a temporal dynamic change of macrophage M1/M2 polarization status in the development of experimental PAH. M1 macrophages participated in the initial stage of inflammation by accelerating apoptosis of endothelial cell, while M2 macrophages predominated in the reparative stage of inflammation and the followed stage of aberrant tissue remodeling.

8.
Sci Total Environ ; 777: 146006, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33677283

RESUMO

Cadmium (Cd), a noxious heavy metal, is widespread in the living environment. Gestational exposure to Cd at environmental dose has been shown to cause fetal growth restriction (FGR). However, the long-term effects and the mechanisms underlying environmental Cd exposure on glucose metabolism in offspring remain unclear. Here, we established a murine model to study the impacts of gestational exposure to environmental Cd on glucose metabolism at different life stages of offspring. Results demonstrated that the offspring mice developed hyperglycemia in puberty and impaired glucose tolerance in adulthood following maternal Cd exposure during gestation. Further mechanistic investigation showed that Cd exposure upregulated the expression of key proteins in hepatic gluconeogenesis, including p-CREB, PGC-1α and G6PC, in pubertal and adult offspring. In addition, we demonstrated that Cd exposure during pregnancy markedly elevated the level of oxidative stress-related proteins, including NOX2, NOX4 and HO-1, in the fetal liver. The effects of gestational exposure to N-acetylcysteine (NAC), a free-radical scavenging antioxidant, presented that NAC supplementation alleviated hepatic oxidative stress in fetuses, and thereby reversed hyperglycemia and glucose intolerance in mouse offspring. Collectively, our data suggested that gestational exposure to environmental Cd caused diabetes-like phenotypes via enhancing hepatic gluconeogenesis, which is associated with oxidative stress in fetal livers. This work provides new insights into the protective effects of antioxidants on fetal-originated diabetes triggered by environmental toxicants.

9.
J Nutr Biochem ; 91: 108601, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33548476

RESUMO

Vitamin D deficiency has been associated with adverse pregnant outcomes. Several studies investigated the effects of maternal vitamin D3 supplementation on fetal development with inconsistent results. The aim of this study was to investigate the effects of maternal supplementation with different doses of vitamin D3 on fetal development. Pregnant mice were administered with different doses of cholecalciferol (0, 2,000, 10,000, 40,000 IU/kg/day) by gavage throughout pregnancy. Fetal weight and crown-rump length were measured. Placental proliferation and mesenchymal characteristics were detected. HTR-8/SVneo cells were incubated in the absence or presence of calcitriol (500 nmol/L) to evaluate the effects of active vitamin D3 on migration and invasion of human trophoblast cells. Although a low dose of cholecalciferol was safe, fetal weight and crown-rump length were decreased in dams treated with high-dose cholecalciferol throughout pregnancy. Placental weight and labyrinth thickness were reduced in mice administered with high-dose cholecalciferol. An obvious calcification was observed in placentae of mice administered with high-dose cholecalciferol. Ki67-positive cells, a marker of placental proliferation, were reduced in mice administered with high-dose cholecalciferol. N-cadherin and vimentin, two mesenchymal markers, were decreased in cholecalciferol-treated mouse placentae and calcitriol-treated human trophoblast cells. MMP-2 and MMP-9, two matrix metalloproteinases, were downregulated in cholecalciferol-treated mouse placentae and calcitriol-treated human trophoblast cells. In addition, trophoblast migration and invasion were suppressed by calcitriol. Supplementation with high-dose cholecalciferol induces fetal growth restriction partially through inhibiting placental proliferation and trophoblast epithelial-mesenchymal transition.

10.
Environ Sci Pollut Res Int ; 28(17): 21696-21705, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33411269

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. This research is aimed at investigating the effect of pubertal DEHP exposure on testicular endoplasmic reticulum (ER) stress and germ cell apoptosis. Five-week-old male mice were orally administered with DEHP (0, 0.5, 50, or 500 mg/kg/day) for 35 days. Testis weight and sperm count were reduced in mice exposed to 500 mg/kg/day DEHP. The number of seminiferous tubules in stages VII-VIII, mature seminiferous tubules, was reduced and the number of seminiferous tubules in stages IX-XII, immature seminiferous tubules, was elevated in mice treated with 500 mg/kg/day DEHP. Numerous apoptotic germ cells were observed in mouse seminiferous tubules exposed to 50 and 500 mg/kg/day DEHP. Moreover, cleaved caspase-3 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. In addition, Bcl-2 was reduced and Bax/Bcl-2 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. Additional experiment showed that GRP78, an ER molecular chaperone, was downregulated in mouse testes exposed to 500 mg/kg/day DEHP. Testicular p-IRE-1α, p-JNK, and CHOP, three markers of ER stress, were upregulated in mice exposed to 500 mg/kg/day DEHP. These results suggest that pubertal exposure to high doses of DEHP induces germ cell apoptosis partially through initiating ER stress in testes.

11.
Eur J Health Econ ; 22(2): 341-350, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33438134

RESUMO

BACKGROUND: This study aims to derive country-specific EQ-5D-5L health status utility (HSU) from the MacNew Heart Disease Health-related Quality of Life questionnaire (MacNew) using both traditional regression analyses, as well as a machine learning technique. METHODS: Data were drawn from the Multi-Instrument Comparison (MIC) survey. The EQ-5D-5L was scored using 4 country-specific tariffs (United States, United Kingdom, Germany, and Canada). The traditional regression techniques, as well as a machine learning technique, deep neural network (DNN), were adopted to directly predict country-specific EQ-5D-5L HSUs (i.e. a direct mapping approach). An indirect response mapping was undertaken additionally. The optimal algorithm was identified based on three goodness-of-fit tests, namely, the mean absolute error (MAE), mean error (ME) and root mean square error (RMSE), with the first being the primary criteria. Internal validation was undertaken. RESULTS: Indirect response mapping and direct mapping (via betamix with MacNew items as the key predictors) were found to produce the optimal mapping algorithms with the lowest MAE when EQ-5D-5L were scored using three country-specific tariffs (United Kingdom, Canada, and Germany for the former and United Kingdom, United States, Canada and Germany for the latter approach). DNN approach generated the lowest MAE and RMSE when using the Germany-specific tariff. CONCLUSIONS: Among different approaches been explored, there is not a conclusive conclusion regarding the optimal method for developing mapping algorithms. A machine learning approach represents an alternative mapping approach that should be explored further. The reported algorithms from response mapping have the potential to be more widely used; however, the performance needs to be externally validated.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33440067

RESUMO

PTC596 is a novel, orally bioavailable, small-molecule tubulin-binding agent that reduces B-cell-specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open-label, multiple-ascending-dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration-time curve increased proportionally with body weight-adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels >2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half-life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half-life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596-related treatment-emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible. Stable disease as best overall response was observed among 7 patients, with 2 patients receiving the study drug up to 16 weeks. These results support the further development of PTC596 for the treatment of solid tumors.

13.
J Med Econ ; 24(1): 87-95, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406944

RESUMO

AIM: To assess the long-term cost-effectiveness of an atrial fibrillation disease management program (i.e. the SAFETY program) from the Australian healthcare system perspective. METHODS: A multistate Markov model was developed based on patient-level data from the SAFETY randomized controlled trial. Predicted long-term survival, dependent on hospital admission history, was estimated by extrapolating parametric survival models. Quality-adjusted life years (QALY) and life years (LY) were the primary and secondary outcome measures used to estimate the incremental cost-utility/effectiveness ratio (ICUR/ICER). Both deterministic and probabilistic sensitivity analyses (PSA) were undertaken. RESULTS: The SAFETY program was associated with both higher costs ($94,953 vs. $78,433) and benefits [QALY (3.99 vs 3.60); LY (5.86 vs 5.24)], with an ICUR of $42,513/QALY or ICER of $26,356/LY, compared to standard care. Due to the extended survival, the SAFETY was associated with a greater number of hospitalizations (14.85 vs 11.65) and higher costs for medications ($25,084 vs $22,402) and outpatient care ($12,904 vs $11,524). The cost per hospitalization for an average length of stay, analytical time horizon, and cost of medication are key determinants of ICUR. The PSA showed that the intervention has a 70.4% probability of being cost-effective at a threshold of $50,000/QALY. CONCLUSIONS: The SAFETY program has a high probability of being cost-effective for patients with atrial fibrillation. It is associated with uncertainty that further research could potentially eliminate; implementation with further evidence collection is recommended.

14.
J Hazard Mater ; 401: 123438, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-32763717

RESUMO

Cadmium (Cd), a well-known environmental pollutant, can lead to placental insufficiency and fetal growth restriction. However, the underlying mechanism is unknown. The purpose of our study is to explore the effect of Cd on placental angiogenesis and its mechanism using in vitro and in vivo models. Results found that gestational Cd exposure obviously decreased placental weight and impaired placental vascular development in mice. Correspondingly, Cd exposure evidently downregulated the expression of VEGF-A protein (a key indicator of angiogenesis) and progesterone receptor (PR) in placental trophoblasts. Further experiment showed that lentivirus PR overexpression reversed Cd-caused the reduction of VEGF-A level in human placental trophoblasts. In addition, Cd significantly reduced progesterone level, down-regulated the expression of key progesterone synthase (StAR, CYP11A1), and activated mitochondrial stress response and GCN-2/p-eIF2α signaling in placental trophoblasts. Additional experiment showed that GCN-2 siRNA pretreatment markedly alleviated Cd-activated mitochondrial stress response, restored Cd-downregulated the expression of CYP11A1, reversed Cd-reduced the level of progesterone and VEGF-A in human placental trophoblasts. Finally, our case-control study confirmed that impaired placental angiogenesis and reduced progesterone level occurred in all-cause small for gestational age placenta. Taken together, environmental exposure to Cd impairs fetal growth and placental angiogenesis via GCN-2-mediated mitochondrial stress.

15.
J Hazard Mater ; 406: 124768, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33310327

RESUMO

This study aimed to investigate whether genotoxic stress mediates arsenic (As)-induced decline in sperm quality. Mice drank ultrapure water containing NaAsO2 (15 mg/L) for 70 days. The mature seminiferous tubules and epididymal sperm count were reduced in As-exposed mice. Cell proliferation, determined by immunostaining with Ki67, was suppressed in As-exposed seminiferous tubules and GC-1 cells. PCNA, a proliferation marker, was reduced in As-exposed mouse testes. Cell growth index was decreased in As-exposed GC-1 cells. Flow analysis showed that As-exposed GC-1 cells were retarded at G2/M phase. CDK1 and cyclin B1 were reduced in As-exposed GC-1 cells and mouse testes. Additional experiment revealed that p-ATR, a marker of genotoxic stress, was elevated in As-exposed mouse testes and GC-1 cells. Accordingly, p-p53 and p21, two downstream molecules of ATR, were increased in As-exposed GC-1 cells. Excess reactive oxygen species (ROS), measured by immunofluorescence, and DNA-strand break, determined by Comet assay, were observed in As-exposed GC-1 cells. γH2AX, a marker of DNA-strand break, was elevated in As-exposed seminiferous tubules and GC-1 cells. NAC alleviated As-evoked DNA damage, genotoxic stress, cell proliferation inhibition and sperm count reduction. In conclusion, ROS-evoked genotoxic stress mediates As-induced germ cell proliferation inhibition and decline in sperm quality.

16.
Food Chem Toxicol ; 148: 111923, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33316355

RESUMO

In spite of its considerable value as a predictor of in vivo genotoxicity and even for carcinogenicity, false positive cases were reported for the Ames test, e.g., with a number of natural food constituents. Here we analyzed the effects of juice of Allium cepa, the common onion, a staple food and traditional remedy used in many civilizations, in the Ames fluctuation assay. We could find mild mutagenicity with an onion juice extract in Salmonella typhimurium strains TA98 and TA100, the latter being less sensitive towards the extract. Mutagenicity was not influenced markedly by the presence of rat liver S9 mix. Onion juice also exerted some toxicity to the bacteria in the same concentration range. Comparative studies with quercetin and rutin, major flavonoid glycosides in onions, revealed a mutagenic potency of quercetin with an EC50-value of 4 µM in TA98. The contents of quercetin and rutin in onion juice were determined as 0.71 ± 0.20, and 0.71 ± 0.21 mg/kg. Calculations of quercetin and rutin concentrations in mutagenic dilutions revealed that both compounds are highly unlikely to cause the mutagenic effects of onion juice and that other yet undefined constituents must be responsible for these effects.

17.
Environ Int ; 147: 106319, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33348103

RESUMO

Cadmium (Cd), an environmental toxicant, is positively associated with fetal growth restriction (FGR). However, the mechanism by which gestational exposure to Cd induces FGR remains unclear. This study designed in vitro and in vivo experiments to explore the role of placental mitophagy in Cd-impaired fetal growth. Based on our case-control study, we also investigated the association of placental mitophagy with reduced progesterone (P4) level and all-cause FGR. We firstly found environmental Cd exposure lowered the P4 content in maternal sera, placentae and amnioticfluids of mice. The level of three mitochondrial P4 synthases, including StAR, CYP11A1 and 3ß-HSD, was also reduced in Cd-treated placentae. Furthermore, Cd triggered mitophagy, as determined by the degradation of two mitochondrial proteins HSP60 and COX IV, and the accumulation of co-localizations of TOM20 with LC3B or Parkin in placental trophoblasts. Correspondingly, Cd elevated mitochondrial Parkin level in placental trophoblasts. Mdivi-1, a mitophagy inhibitor, obviously attenuated Cd-induced reduction of placental P4 and FGR in mice. Moreover, mdivi-1 and Parkin siRNA (siR) markedly reversed Cd-caused P4 synthesis inhibition in human placental trophoblasts. Interestedly, the PERK/ATF4 signaling was activated in Cd-stimulated placental trophoblasts. PERK siR inhibited mitochondrial proteins degradation in Cd-stimulated placental trophoblasts. In particularly, mitophagy activation and P4 synthesis suppression occurred in small-for-gestational-age placentae based on our case-control study. Environmental Cd exposure induced FGR via activating PERK-regulated mitophagy and inhibiting P4 synthesis in placentaltrophoblasts. Furthermore, placental mitophagy was related to the reduced progesterone level and all-cause fetal growth restriction based on our case-control study. As above, placental mitophagy maybe the common mechanism of environmental toxicants-impaired fetal growth.


Assuntos
Retardo do Crescimento Fetal , Trofoblastos , Animais , Cádmio/toxicidade , Estudos de Casos e Controles , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Camundongos , Mitofagia , Placenta , Gravidez
18.
Exp Eye Res ; 203: 108399, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33352197

RESUMO

Alkali burn to the cornea is one of the most intractable injuries to the eye due to the opacity resulting from neovascularization (NV) and fibrosis. Numerous studies have focused on studying the effect of drugs on alkali-induced corneal injury in mouse, but fewer on the involvement of alkali-induced DNA methylation and the PI3K/AKT/mTOR signaling pathway in the mechanism of alkali-induced corneal injury. Thus, the aim of this study was to determine the involvement of DNA methyltransferase 3 B-madiated DNA methylation and PI3K/AKT/mTOR signaling modulation in the mechanism of alkali-induced corneal injury in a mouse model. To this end, we used bisulfite sequencing polymerase chain reaction and Western blot analysis, to study the effects of 5-aza-2'-deoxycytidine and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, which inhibit methyltransferase and PI3K respectively, on DNA methylation and expression of downstream effectors of PI3K related to corneal NV, including TSC1 and mTOR genes. The results showed that, after an intraperitoneal injection of rapamycin (2 mg/kg/day) for seven days, the alkali-induced opacity and NV were remarkably decreased mainly by suppressing the infiltration of immune cells into injured corneas, angiogenesis, VEGF expression and myofibroblasts differentiation; as well as by promoting corneal cell proliferation and PI3K/AKT/mTOR signaling. More significantly, these findings showed that epigenetic regulatory mechanisms by DNA methylation played a key role in corneal NV, including in corneal alkali burn-induced methylation modification and rapamycin-induced DNA demethylation which involved the regulation of the PI3K/AKT/mTOR signaling pathway at the protein level. The precise findings of morphological improvement and regulatory mechanisms are helpful to guide the use of rapamycin in the treatment of corneal angiogenesis induced by alkaline-burn.


Assuntos
Queimaduras Químicas/prevenção & controle , Lesões da Córnea/prevenção & controle , Queimaduras Oculares/induzido quimicamente , Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Actinas/genética , Animais , Western Blotting , Queimaduras Químicas/genética , Queimaduras Químicas/patologia , Cromonas/farmacologia , Lesões da Córnea/genética , Lesões da Córnea/patologia , Metilação de DNA , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Hidróxido de Sódio/toxicidade , Fator A de Crescimento do Endotélio Vascular/genética
19.
Nanoscale Res Lett ; 15(1): 208, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33151365

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33151783

RESUMO

Objectives: To assess the cost-effectiveness of osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib, as first-line treatment for patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer in Australia from a healthcare system perspective. Methods: A partitioned survival model comprising three mutually exclusive health states with a five-year time horizon was developed. Model inputs were sourced from the pivotal trial (FLAURA) and published literature. Incremental cost-effectiveness ratios (ICERs), in terms of cost per quality-adjusted life-year (QALY) gained and cost per life-year (LY) gained, were calculated. Uncertainty of the results was assessed using deterministic and probabilistic sensitivity analyses. Results: Compared with standard EGFR-TKIs, osimertinib was associated with a higher incremental cost of A$118,502, and an incremental benefit of 0.274 QALYs and 0.313 LYs. The ICER was estimated to be A$432,197/QALY gained and A$378,157/LY gained. The base-case ICER was most sensitive to changes in cost of first-line osimertinib, time horizon, and choice of overall survival data (interim versus final analysis). Conclusions: At a willingness-to-pay threshold of A$50,000/QALY, first-line osimertinib is not cost-effective compared with standard EGFR-TKIs in Australia based on the current published price. To achieve acceptable cost-effectiveness, the cost of first-line osimertinib needs to be reduced by at least 68.4%.

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