A near-IR ratiometric fluorescent probe for the precise tracking of senescence: a multidimensional sensing assay of biomarkers in cell senescence pathways.

Senescence is a complex physiological process that can be induced by a range of factors, and cellular damage caused by reactive oxygen species (ROS) is one of the major triggers. In order to learn and solve age-related diseases, tracking strategies through biomarkers, including senescence-associated ß-galactosidase (SA-ß-gal), with high sensitivity and accuracy, have been considered as a promising solution. However, endogenous ß-gal accumulation is not only associated with senescence but also with other physiological processes. Therefore, additional assays are needed to define cellular senescence further. In this work, a fancy fluorescent probe SA-HCy-1 for accurately monitoring senescence is developed, with SA-ß-gal and HClO as targets under high lysosomal pH conditions (pH > 6.0) specifically, on account of the role ß-gal commonly played as an ovarian cancer biomarker. Therefore, precise tracking of cellular senescence could be achieved in view of these three dimensions, with response in dual fluorescence channels providing a ratiometric sensing pattern. This elaborate strategy has been verified to be suitable for biological applications by skin photo-aging evaluation and cellular passage tracing, displaying a significantly improved sensitivity compared with the commercial X-gal kit measurement.

Synthesis and anticancer evaluation of novel 1H-benzo[d]imidazole derivatives of dehydroabietic acid as PI3Kα inhibitors.

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cancer treatment. In this study, a series of new 2-arylthio- and 2-arylamino-1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed, synthesized and characterized by 1H NMR, 13C NMR, IR and MS spectra analyses. In the in vitro anticancer assay, some title compounds showed significant inhibitory activities against four cancer cell lines (HCT-116, MCF-7, HeLa and HepG2). Among them, compound 9g exhibited the most potent activity with IC50 values of 0.18 ± 0.03, 0.43 ± 0.05, 0.71 ± 0.08 and 0.63 ± 0.09 µM against four cancer cell lines, and considerably lower cytotoxicity to human gastric mucosal cell line Ges-1 (IC50: 21.95 ± 0.73 µM). Besides, compound 9g displayed a certain selective activity to PI3Kα (IC50 = 0.012 ± 0.002 µM) over PI3Kß, γ and δ, and meanwhile, it can remarkably decrease the expression level of p-Akt (Ser473). In addition, compound 9g could increase intracellular reactive oxygen species level, decrease mitochondrial membrane potential, upregulate Bax and cleaved caspase-3/9 levels, downregulate Bcl-2 level and thus induce the apoptosis of HCT-116 cells in a dose-dependent manner. The results suggested that compound 9g could be considered as a promising PI3Kα inhibitor.

Dexamethasone-induced skeletal muscle atrophy was associated with upregulation of myostatin promoter activity.

Some recent studies showed that the glucocorticoid-induced muscle atrophy was associated with myostatin, a negative regulator of skeletal muscle. In this study, two experiments were performed to investigate the relationship between the glucocorticoid-induced ultrastructural changes in skeletal muscle and the myostatin gene expression, and to examine in vivo whether the glucocorticoid-induced upregulation of myostatin gene expression is associated with the myostatin promoter activity. In the first experiment, the Kun-Ming mice with similar body weights were treated with high-dose dexamethasone. The results showed that high-dose dexamethasone caused myofibrillar disorganization or degradation and mitochondrial swelling or vacuolization, which were accompanied with the upregulation of myostatin expression. In the second experiment, the mice were treated with the wild-type or GRE (glucocorticoid response elements)-mutant myostatin promoter vector and high-dose dexamethasone alone or together with RU486. The results showed that the mutation of GRE motif resulted in the obvious decrease of the myostatin promoter activity, the high-dose dexamethasone promoted significantly the activity of the wild-type myostatin promoter but did not affect the activity of the GRE-mutant myostatin promoter, and RU486 inhibited the effect of dexamethasone on the wild-type myostatin promoter activity. Taken together, these results suggested that the dexamethasone-induced changes in ultrastructure of skeletal muscle were associated with the upregulation of myostatin gene expression and the upregulation was partly attributed to the binding of glucocorticoid receptor to GRE motifs along myostatin promoter.