Squamocin modulates histone H3 phosphorylation levels and induces G1 phase arrest and apoptosis in cancer cells

<p>Abstract</p> <p>Background</p> <p>Histone modifications in tumorigenesis are increasingly recognized as important epigenetic factors leading to cancer. Increased phosphorylation levels of histone H3 as a result of aurora B and pMSK1 overexpression were observed in various tumors. We selected <it>aurora B </it>and <it>MSK1 </it>as representatives for testing various compounds and drugs, and found that squamocin, a bis-tetrahydrofuran annonaceous acetogenin, exerted a potent effect on histone H3 phosphorylation.</p> <p>Methods</p> <p>GBM8401, Huh-7, and SW620 cells were incubated with 15, 30, and 60 μM squamocin for 24 h. The expressions of mRNA and proteins were analyzed by qRT-PCR and Western blotting, respectively. The cell viability was determined by an MTT assay. Cell cycle distribution and apoptotic cells were analyzed by flow cytometry.</p> <p>Results</p> <p>Our results showed that squamocin inhibited the proliferation of GBM8401, Huh-7, and SW620 cells, arrested the cell cycle at the G₁phase, and activated both intrinsic and extrinsic pathways to apoptosis. In addition, we demonstrated that squamocin had the ability to modulate the phosphorylation levels of H3S10 (H3S10p) and H3S28 (H3S28p) in association with the downregulation of aurora B and pMSK1 expressions.</p> <p>Conclusions</p> <p>This study is the first to show that squamocin affects epigenetic alterations by modulating histone H3 phosphorylation at S10 and S28, providing a novel view of the antitumor mechanism of squamocin.</p

Oxidative Stress And Frailty: A Systematic Review And Best Evidence Synthesis

Objective: Oxidative stress (OS) is associated with accelerated aging. Previous studies have suggested a possible relationship between OS and frailty but this association remains unclear. We conducted a systematic review to investigate potential interactions between OS and frailty. Methods: A systematic literature search of original reports providing data on ‘OS and antioxidant’ parameters and frailty was carried out across major electronic databases from inception until May 2016. Cross-sectional/case control and longitudinal studies reporting data on the association between frailty and anti-oxidants-OS biomarkers were considered for inclusion. Results were summarized with a best-evidence based synthesis. Results: From 1,856 hits, 8 studies (cross-sectional/case control) were included (N = 6,349; mean age of 75 ± 12 years; 56.4% females). Overall, there were 588 (=9.3%) frail, 3,036 pre-frail (=47.8%), 40 (=0.6%) pre-frail/robust, and 2,685 (=42.3%) robust subjects. Six cross-sectional/case control studies demonstrated that frailty was associated with an increase in peripheral OS biomarkers including lipoprotein phospholipase A2 (studies = 1), isoprostanes (studies = 2), Malonaldehyde (studies = 2), 8-hydroxy-20-deoxyguanosine (studies = 2), derivate of reactive oxygen metabolites (studies = 2), oxidized Glutathione/Glutathione (studies = 1), 4-hydroxy-2,3-nonenal (studies = 1), and protein carbonylation levels (study = 1). In addition, preliminary evidence points to lower anti-oxidant parameters (vitamin C, E, α-tocopherol, biological anti-oxidant potential, total thiol levels) in frailty. Conclusion: Frailty and pre-frailty appear to be associated with higher OS and possibly lower anti-oxidant parameters. However, due to the cross sectional design, it is not possible to disentangle the directionality of the relationships observed. Thus, future high quality and in particular longitudinal research is required to confirm/refute these relationships and to further elucidate pathophysiological mechanisms

Studies toward a library of tetrahydrofurans: Click and MCR products of mono- and bis-tetrahydrofurans

Mono- and bis-tetrahydrofuran-based chemical libraries with diverse structural features have been prepared using the Sharpless azide-alkyne Click reaction and multi-component reactions (MCRs) such as Ugi and Biginelli reactions. Mono- and bis-tetrahydrofuran methyl azides, amines and ureas were key intermediates in these processes, and they were synthesized from the corresponding tetrahydrofuran methyl alcohols by mesylation followed by substitution with azide, reduction of the azide to the amine, and urea formation, as needed. Most mono- and tetrahydrofuran methyl alcohols were obtained by a Sharpless asymmetric dihydroxylation reaction. Alternatively, several mono-tetrahydrofurans were prepared by a cobalt(II) complex-catalyzed oxidative cyclization of bis-homoallylic alcohols, which were obtained by copper(I) iodide-catalyzed epoxide opening of 5,6-epoxyhex-1-ene with various alkyl and aryl Grignard reagents. These compounds are examples of an entirely new class of molecules in hitherto unknown chemical space, though their functions are yet to be determined presumably through random screening