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Nonylphenol (NP) is a representative environmental endocrine-disrupting compound that can induce oxidative stress in organisms. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway acts an important role in preventing oxidative stress. The aim of this study was to investigate the influence of oxidative stress caused by NP on Keap1-Nrf2 pathway in rats. Rats were treated with NP (30, 90, 270 mg/kg) for different exposure time (7, 14 and 28 days). The levels of reactive oxygen species (ROS) in serum and glutathione S-transferase (GST), UDP-Glucuronosyl Transferase (UGT) in liver were detected by ELISA kits. Western blot was used to detect Keap1, Nrf2 protein expression in liver and cerebral cortex. KPT-330 ic50 The results showed that 28 days of NP exposure significantly increased ROS levels in NPH group. And 14 days exposure to NP significantly enhanced the levels of GST and UGT, while 28 days of exposure showed a suppressive effect. In liver, Keap1 levels was upregulated at 7, 14 and 28 days of NP exposure, while nuclear Nrf2 levels decreased at 7 and 28 days but increased at 14 days. In cerebral cortex, Keap1 and Nrf2 expression increased at 14 days but decreased at 28 days. Besides, with the prolongation of NP exposure time, the GST and UGT levels in NPM and NPH groups were increased firstly and then decreased, while Keap1 and Nrf2 protein levels were constantly decreased in liver and cerebral cortex. In conclusion, the lower dose and shorter exposure time of NP activated the Keap1-Nrf2 pathway that may reduce the damage of oxidative stress, but when further exposed to NP at higher dose and time, the pathway could be inhibited.Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents which has the survival rate of 20% in its advanced stages. Osteosarcomas are mostly resistance to our common treatments. DNA damage response (DDR) is a specialized multistep process containing abundant proteins which are necessary for the survival of any cell and organism. DDR machinery detects a diversity of DNA lesions and inhibits the cell cycle progression if these lesions are not repairable. DDR is involved in aging, age-related diseases, and cancer. In recent years, DDR inhibitors have gained the attention of researches due to their potentials in offering novel therapeutic targets and improving the response of many cancers to either chemo- or radio-therapy. In this regard, we tried to gather a great body of evidence about the role of DDR ingredients in osteosarcoma's initiation/progression, prognosis, and treatment.Despite the relevance of road crashes and their impact on social and health care costs, the effects of extreme temperatures on road crashes risk have been scarcely investigated, particularly for those occurring in occupational activities. A nationwide epidemiological study was carried out to estimate the risk of general indistinct and work-related road crashes related with extreme temperatures and to identify crash and occupation parameters mostly involved. Data about road crashes, resulting in death or injury, occurring during years 2013-2015 in Italy, were collected from the National Institute of Statistics, for general indistinct road crashes, and from the compensation claim applications registered by the national workers' compensation authority, for work-related ones. Time series of hourly temperature were derived from the results provided by the meteorological model WRF applied at a national domain with 5 km resolution. To consider the different spatial-temporal characteristics of the two road crashes araccident (urban vs out of town), presence of crossroads, as well as occupational factors like the use of a vehicle on duty were all found to produce higher risks of road crashes during extreme temperatures. Mitigation and prevention measures are needed to limit social and health care costs.Many researchers have developed predictive models of crashes based on the safety scores of commercial truck companies, but these studies have been based on aggregated data at the truck company level-evaluating the total crashes and violations per company over a period of time. This level of aggregation obscures critical information. Here, a new approach to organizing non-aggregated data is taken, and logistic regression and random forest models are applied to non-aggregated FMCSA roadside inspection, violation, and crash data at the specific vehicle level. Resampling methods are used to improve model performance where there are relatively few events of interest-crashes. These results point not to specific "unsafe" drivers, but rather, patterns of unsafe behaviors or conditions that predict roadway crashes. Working toward reducing these behaviors systematically could save lives on US highways.Gaucher disease type 3 (GD3) is a severely debilitating disorder characterized by multisystemic manifestations and neurodegeneration. Enzyme replacement therapy alleviates visceral signs and symptoms but has no effect on neurological features. Ambroxol has been suggested as an enzyme enhancement agent. Some studies have confirmed its effectiveness in preventing the progression of neurological manifestations of neuronopathic Gaucher disease. In this study, we report two GD3 siblings in whom ambroxol combined with enzyme replacement therapy was initiated at different stages of the disease. We demonstrate the enzyme enhancement effect of ambroxol on L444P/H225Q;D409H glucocerebrosidase activity through results of fibroblast studies and long-term clinical outcomes of the two patients. The sibling diagnosed at the age of four-and-a-half years with significant neurological involvement manifested relatively rapid improvement on ambroxol treatment, followed by stabilization of further course. The younger sibling, in whom the treatment was started at seven weeks, displayed attention deficit and low average cognitive functioning at the age of seven years, but did not manifest other neurological symptoms. The difference in neurological outcomes indicates that ambroxol delayed or even halted the evolution of neurological manifestations in the younger sibling. This observation suggests that early initiation of ambroxol treatment may arrest neurological involvement in some GD3 patients.
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