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[en] Highlights: • miR-15b-5p inhibits proliferation of OS cells. • miR-15b-5p reverse the Warburg effect in OS cells. • PDK4 is a direct target of miR-15b-5p. • PDK4 promotes the proliferation of OS cells and contributes to the Warburg effect in OS cells. • miR-15b-5p exerted anti-cancer effects on OS via inhibiting the expression of PDK4. Blocking aerobic glycolysis has been proposed as an attractive therapeutic strategy for impairing the proliferation of cancer cells. However, the underlying mechanisms are poorly understood. Here, we show that miR-15b-5p was downregulated in osteosarcoma (OS) and that lower expression of miR-15b-5p promoted proliferation and contributed to the Warburg effect in OS cells. Mechanistically, miR-15b-5p acted as a tumor suppressor in OS by directly targeting pyruvate dehydrogenase kinase-4 and inhibiting its expression. These results reveal a previously unknown function of miR-15b-5p in OS, which is associated with metabolic alterations that promote cancer progression. miR-15b-5p may play an essential role in the molecular therapy of patients with OS.
[en] Highlights: • Intracellular cholesterol positively regulates temozolomide-induced glioma apoptosis. • DR5-caspase-8 axis is essential for enhancement of glioma apoptosis by cholesterol. • HMG-CoA reductase inhibitors suppress temozolomide-induced glioma apoptosis. • Intracellular cholesterol loading overcomes temozolomide resistance of glioma cells. Development of resistance against temozolomide (TMZ) in glioblastoma (GBM) after continuous treatment with TMZ is one of the critical problems in clinical GBM therapy. Intracellular cholesterol regulates cancer cell biology, but whether intracellular cholesterol is involved in TMZ resistance of GBM cells remains unclear. The involvement of intracellular cholesterol in acquired resistance against TMZ in GBM cells was investigated. Intracellular cholesterol levels were measured in human U251 MG cells with acquired TMZ resistance (U251-R cells) and TMZ-sensitive control U251 MG cells (U251-Con cells), and found that the intracellular cholesterol level was significantly lower in U251-R cells than in U251-Con cells. In addition, treatment by intracellular cholesterol remover, methyl-beta cyclodextrin (MβCD), or intracellular cholesterol inducer, soluble cholesterol (Chol), regulated TMZ-induced U251-Con cell death in line with changes in intracellular cholesterol level. Involvement of death receptor 5 (DR5), a death receptor localized in the plasma membrane, was evaluated. TMZ without or with MβCD and/or Chol caused accumulation of DR5 into the plasma membrane lipid raft and formed a complex with caspase-8, an extrinsic caspase cascade inducer, reflected in the induction of cell death. In addition, treatment with caspase-8 inhibitor or knockdown of DR5 dramatically suppressed U251-Con cell death induced by combination treatment with TMZ, MβCD, and Chol. Combined treatment of Chol with TMZ reversed the TMZ resistance of U251-R cells and another GBM cell model with acquired TMZ resistance, whereas clinical antihypercholesterolemia agents at physiological concentrations suppressed TMZ-induced cell death of U251-Con cells. These findings suggest that intracellular cholesterol level affects TMZ treatment of GBM mediated via a DR5-caspase-8 mechanism.
[en] A radiochemical ligand binding assay for methotrexate is provided. A binder factor comprising a partially purified dihydrofolic acid reductase preparation is employed. The binder factor is conveniently prepared by homogenizing a factor containing animal organ such as liver, and extracting with isotonic saline and ammonium sulfate. A binder cofactor, NADPH2, is also employed in the binding reaction. The procedure contemplates both direct and sequential assay techniques, and it is not interfered with by vast excesses of many natural folate derivatives. 12 claims, 6 drawing figures
[en] Highlights: • Sodium benzoate induced developmental defects in zebrafish. • Sodium benzoate induced oxidative stress in zebrafish by upregulation of glutathione reductase (gsr). • Sodium benzoate induced anxiety-like behaviour in zebrafish. Sodium benzoate (SB) is a common food preservative. Its FDA described safety limit is 1000 ppm. Lately, increased use of SB has prompted investigations regarding its effects on biological systems. Data regarding toxicity of SB is divergent and controversial with studies reporting both harmful and beneficial effects. Therefore, we did a systematic dose dependent toxicity study of SB using zebrafish vertebrate animal model. We also investigated oxidative stress and anxiety-like behaviour in zebrafish larva treated with SB. Our results indicate that SB induced developmental (delayed hatching), morphological (pericardial edema, yolk sac edema and tail bending), biochemical (oxidative stress) and behavioural (anxiety-like behaviour) abnormalities in developing zebrafish larva. LC50 of SB induced toxicity was approximately 400 ppm after 48 h of SB exposure. Our study strongly supports its harmful effects on vertebrates at increasing doses. Thus, we suggest caution in the excessive use of this preservative in processed and convenience foods.
[en] Highlights: • The molecular mechanism of statin in diabetes to reduce the endothelial cell (EC) dysfunction and inflammation is proposed. • In high-glucose exposure, increased FOXO1 and ICAM1 leads to EC dysfunction and increased monocyte adhesion. • Atorvastatin facilitates ubiquitin-mediated degradation of FOXO1 and ICAM1 through Skp2 in EC exposed to high-glucose. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin has been reported to exert vasculo-protective action in diabetes. We investigated the vasculo-protective mechanism of atorvastatin by evaluating its effect on two major pathogenic molecules, FOXO1 and ICAM1, mediated by S-phase kinase-associated protein 2 (Skp2) in diabetic endothelial dysfunction.
[en] Highlights: • IDPc is phosphorylated at tyrosine residues during porcine sperm capacitation. • The tyrosine phosphorylated IDPc showed a significantly lowered enzymatic activity. • IDPc is mainly localized to the principal piece of the porcine sperm flagellum. • The decrease in IDPc activity is involved in the increased levels of ROS. • The decrease in IDPc activity induced the induction of the hyperactivated motility. In order to understand the molecular mechanisms involved in the sperm capacitation, we have identified the proteins tyrosine-phosphorylated during the capacitation especially in conjunction with the regulation of the levels of reactive oxygen species (ROS) in sperm. In the present study, the effects of the tyrosine phosphorylation of cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) on its catalytic activity and on the levels of ROS in sperm have been studied. The tyrosine phosphorylated IDPc showed a significantly lowered enzymatic activity. The immunocytochemical analyses using the highly specific antisera against IDPc revealed that IDPc was mainly localized to the principal piece of the porcine sperm flagellum. As IDPc is one of the major NADPH regenerating enzymes in porcine sperm, it is strongly suggested that the decrease in IDPc activity is involved in the increased levels of ROS, which results in the induction of hyperactivated flagellar movement and capacitation.
[en] Nitric oxide (NO) is an important gas signal that regulates many biological processes, and due to the high nitrogen recycling activity in the rhizosphere, NO is an important signaling molecule in this region. Thus, an understanding of the effect of NO on the rhizomicrobiome, especially on plant beneficial rhizobacteria, is important for the use of these bacteria in agriculture. In this study, the effect of exogenous NO on the beneficial rhizobacterium Bacillus amyloliquefaciens SQR9 was investigated. The results showed that low concentrations of NO increased the ability of the strain SQR9 to form biofilms, while high concentrations of NO inhibited the growth of this bacterium. The SQR9 gene yflM encodes nitric oxide synthase (NOS), which is used to synthesize NO, while the gene ykvO encodes a sepiapterin reductase that is used to synthesize tetrahydrobiopterin, the coenzyme of NOS. Isothermal titration calorimetry and high-performance liquid chromatography analyses demonstrated an interaction between YkvO and NADPH. SQR9 has two hmp genes, although only one was observed to be responsible for NO detoxification through oxidization. This study revealed the effect of NO on plant beneficial rhizobacterium and assessed the ability of this strain to adapt to exogenous NO, which will help to improve the application of this strain in agricultural production.