Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose‐starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy. 相似文献
Gold nanoparticles (Au NPs) hold great promise in food, industrial and biomedical applications due to their unique physicochemical properties. However, influences of the gastrointestinal tract (GIT), a likely route for Au NPs administration, on the physicochemical properties of Au NPs has been rarely evaluated. Here, we investigated the influence of GIT fluids on the physicochemical properties of Au NPs (5, 50, and 100?nm) and their implications on intestinal epithelial permeability in vitro. Au NPs aggregated in fasted gastric fluids and generated hydroxyl radicals in the presence of H2O2. Cell studies showed that GIT fluids incubation of Au NPs affected the cellular uptake of Au NPs but did not induce cytotoxicity or disturb the intestinal epithelial permeability. 相似文献
Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells.
Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML.
Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease. 相似文献
BackgroundThe aim of this study was to estimate the prevalence of dental prosthetic treatment and to investigate the demographic, social, economic and medical factors associated with the use of fixed and removable dentures in a representative sample of adults living in France.MethodsThe data were obtained from the 2002–2003 Decennial Health Survey, a cross-sectional study of a representative sample of the population living in France, which included 29,679 adults. Information was collected by interview. The variables collected were fixed denture, removable denture, age, gender, number of children, area of residence, nationality, educational attainment, family social status, employment status, annual household income per capita, supplementary insurance, chronic disease, eyesight problems/glasses, hearing problems/hearing aids. Multinomial logistic regression models were used to study the relationship between prosthetic treatment and demographic, socioeconomic and medical characteristics unadjusted, adjusted for age and adjusted for all the characteristics.ResultsThe prevalence of prosthetic treatment was 34.6% (95% confidence interval (CI): [34.1; 35.2]) for fixed prosthetic dentures and 13.8% (95% CI: [13.4; 14.2]) for removable prosthetic dentures. We showed a gradient between educational attainment and removable dentures; the odds ratio adjusted for all the variables (aOR) associated with no or primary education compared to post-secondary education was 2.56; 95% CI: [2.09; 3.13]. When annual household income per capita was low, subjects were less likely to report fixed dentures (aOR = 0.68; 95% CI: [0.62; 0.75]) than those with high annual household income per capita. Individuals without insurance less often reported fixed dentures than those with private insurance. Those reporting chronic disease were less likely to report fixed dentures (aOR = 0.87; 95% CI: [0.79; 0.95]) but more likely to report removable dentures (aOR = 1.29; 95% CI: [1.17; 1.43]) than those without chronic disease.ConclusionThis study reveals social, economic and medical inequalities in fixed and removable prosthetic treatment among adults in France. 相似文献
ABSTRACT This project examined 55 picture books featuring transgender, gender expansive or genderqueer protagonists or narrators published between 2008 and 2018. The purpose of the study was to determine how this genre of children’s literature supports and challenges four gender assumptions: the gender binary, gender essentialism, sex/gender congruency and gender stability. Additionally, this critical analysis explored misgendering within this genre and themes of social rejection and acceptance. Protagonists and narrators were permitted a degree of gender nonconformity, however, the majority of picture books missed opportunities for a more complete exploration of gender possibilities. 相似文献