2-Aminophenoxazine-3-one and 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one cause cellular apoptosis by reducing higher intracellular pH in cancer cells

We examined intracellular pH (pHi) of ten cancer cell lines derived from different organs and two normal cell lines including human embryonic lung fibroblast cells (HEL) and human umbilical vein endothelial cells (HUVEC) in vitro, and found that pHi of most of these cancer cells was evidently higher (pH 7.5 to 7.7) than that of normal cells (7.32 and 7.44 for HEL and HUVEC, respectively) and that of primary leukemic cells and erythrocytes hitherto reported (≤7.2). Higher pHi in these cancer cells could be related to the Warburg effect in cancer cells with enhanced glycolytic metabolism. Since reversal of the Warburg effect may perturb intracellular homeostasis in cancer cells, we looked for compounds that cause extensive reduction of pHi, a major regulator of the glycolytic pathway and its associated metabolic pathway. We found that phenoxazine compounds, 2-aminophenoxazine-3-one (Phx-3) and 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one (Phx-1) caused a rapid and drastic dose-dependent decrease of pHi in ten different cancer cells within 30 min, though the extent of the decrease of pHi was significantly larger for Phx-3 (ΔpHi = 0.6 pH units or more for 100 µM Phx-3) than for Phx-1 (ΔpHi = 0.1 pH units or more for 100 µM Phx-1). This rapid and drastic decrease of pHi in a variety of cancer cells caused by Phx-3 and Phx-1 possibly perturbed their intracellular homeostasis, and extensively affected the subsequent cell death, because these phenoxazines exerted dose-dependent proapoptotic and cytotoxic effects on these cells during 72 h incubation, confirming a causal relationship between ΔpHi and cytotoxic effects due to Phx-3 and Phx-1. Phx-3 and Phx-1 also reduced pHi of normal cells including HEL and HUVEC, although they exerted less proapoptotic and cytotoxic effects on these cells than on cancer cells. Drugs such as Phx-3 and Phx-1 that reduce pHi and thereby induce cellular apoptosis might serve as benevolent anticancer drugs

Interaction of inflammatory cytokines and erythropoeitin in iron metabolism and erythropoiesis in anaemia of chronic disease

In chronic inflammatory conditions increased endogenous release of specific cytokines (TNFα, IL-1, IL-6, IFNγ and others) is presumed. It has been shown that those of monocyte lineage play a key role in cytokine expression and synthesis. This may be associated with changes in iron metabolism and impaired erythropoiesis and may lead to development of anaemia in patients with rheumatoid arthritis. Firstly, increased synthesis of acute phase proteins, like ferritin, during chronic inflammation is proposed as the way by which the toxic effect of iron and thereby the synthesis of free oxy-radicals causing the damage on the affected joints, may be reduced. This is associated with a shift of iron towards the mononuclear phagocyte system which may participate in the development of anaemia of chronic disease. Secondly, an inhibitory action of inflammatory cytokines (TNFα, IL-1), on proliferation and differentiation of erythroid progenitors as well as on synthesis of erythropoietin has been shown, thereby also contributing to anaemia. Finally, chronic inflammation causes multiple, complex disturbances in the delicate physiologic equilibrium of interaction between cytokines and cells (erythroid progenitors, cells of mononuclear phagocyte system and erythropoietin producing cells) leading to development of anaemia of chronic disease (Fig. 1)

Ultra-deep hubble space telescope imaging of the small magellanic cloud: The initial mass function of stars with M 72 1 M

We present a new measurement of the stellar initial mass function (IMF) based on ultra-deep, high-resolution photometry of >5000 stars in the outskirts of the Small Magellanic Cloud (SMC) galaxy. The Hubble Space Telescope (HST) Advanced Camera for Surveys observations reveal this rich, cospatial population behind the foreground globular cluster 47 Tuc, which we targeted for 121 HST orbits. The stellar main sequence of the SMC is measured in the F606W, F814W color-magnitude diagram down to 30th magnitude, and is cleanly separated from the foreground star cluster population using proper motions. We simulate the SMC population by extracting stellar masses (single and unresolved binaries) from specific IMFs and converting those masses to luminosities in our bandpasses. The corresponding photometry for these simulated stars is drawn directly from a rich cloud of 4 million artificial stars, thereby accounting for the real photometric scatter and completeness of the data. Over a continuous and well-populated mass range of M = 0.37-0.93 M(e.g., down to a 75% completeness limit at F606W = 28.7), we demonstrate that the IMF is well represented by a single power-law form with slope \u3b1 = -1.90 ( +0.15 0.10) (3\u3c3 error) (e.g., dN/dM M \u3b1). This is shallower than the Salpeter slope of \u3b1 = -2.35, which agrees with the observed stellar luminosity function at higher masses. Our results indicate that the IMF does not turn over to a more shallow power-law form within this mass range. We discuss implications of this result for the theory of star formation, the inferred masses of galaxies, and the (lack of a) variation of the IMF with metallicity. \ua9 2013. The American Astronomical Society. All rights reserved..Peer reviewed: YesNRC publication: Ye