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(±)-Involucrasins A (1) and B (2), two pairs of flavanone enantiomers were isolated from Shuteria involucrata. Structurally, both 1 and 2 are rare representatives of 5-dehydroxy/5-demethoxy 2',3',4'-trisubstituted flavanones. Their structures were elucidated on the basis of comprehensive spectroscopic data analysis and comparison with the literature data. Involucrasin B (2) exhibited moderate anti-proliferative activity against Caco-2, MCF-7, MDA-MB-468, and HCT116 cell lines with IC50 values ranging from 7.9-22.7 μM. Involucrasin A (1) exhibited weak inhibitory activity against Caco-2 and MCF-7 cell lines with IC50 values of 25.8 and 26.5 μM, respectively.

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (3.75 μM) and 2-deoxy-D-glucose (1.25 mM) synergistically reduced cell viability, arrested cells in the G

(±)-Involucrasins A (

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (>3.75 μM) and 2-deoxy-D-glucose (>1.25 mM) synergistically reduced cell viability, arrested cells in the G(2)/M phase, and induced apoptosis. The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate, resulting in decreased production of ATP and lower steady-state ATP levels. Energy depletion markedly activated AMPK, inhibited mTOR and RAS signaling pathways, eventually inducing autophagy, the cellular pro-survival process under metabolic stress, whereas inhibition of autophagy by chloroquine (6.25 μM) enhanced the cytotoxic effect of the combination of lovastatin and 2-deoxy-D-glucose. These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells. Our findings suggest that concurrently targeting glycolysis, oxidative phosphorylation, and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.

Isocitrate dehydrogenase 1 (IDH1) mutant R132H, promoting the oncometabolite D-2-hydroxyglutarate (D2HG), is a driver mutation and an emerging therapeutic target in glioma. This study identified a novel mutant IDH1 inhibitor, WM17, by virtual screening and enzymatic confirmation. It could bind to and increase mutant IDH1 protein's thermostability in both endogenous heterozygous cells and exogenous overexpressed cells. Consequently, WM17 reversed the accumulation of D2HG and histone hypermethylation in IDH1 mutated cells. Finally, we concluded that WM17 significantly inhibited cell migration in IDH1 mutated glioma cells, although it has no apparent effect on cell proliferation. Further studies are guaranteed toward the development of WM17 as a therapeutic agent for IDH1 mutated glioma.

DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1α, IL-1β, IL-6, IL-8, TNF-α and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-α/IFN-γ-stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions.

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The medium carbon steel (C: 0.26%, mass percentage) was deoxidized by Ti alloys, and its features of inclusion and microstructure were systemically studied through the scanning electron microscope (SEM) and Energy Dispersive Spectrometer (EDS). The results show that the element of titanium in inclusions coexists with manganese, and no single-phase oxides of titanium are observed. Through the statistical analysis, it can be seen that the average size of Ti-contained inclusions is similar to the inclusions without the Ti, and the percentage of large inclusions (>5μm) is smaller in Ti-contained inclusions, which may reduce the harmful effect of inclusions. After etching in 3Vol% Nital solution, it’s found that the Ti-contained inclusions can act as nucleation sits for the intragranular acicular ferrite.

The division operation is not frequent relatively in traditional applications, but it is increasingly indispensable and important in many modern applications. In this paper, the implementation of modified signed-digit (MSD) floating-point division using Newton-Raphson method on the system of ternary optical computer (TOC) is studied. Since the addition of MSD floating-point is carry-free and the digit width of the system of TOC is large, it is easy to deal with the enough wide data and transform the division operation into multiplication and addition operations. And using data scan and truncation the problem of digits expansion is effectively solved in the range of error limit. The division gets the good results and the efficiency is high. The instance of MSD floating-point division shows that the method is feasible.