The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of ...epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.
Theoretical models predict that core-collapse supernovae (CCSNe) can be efficient dust producers (0.1-1.0 M...), potentially accounting for most of the dust production in the early Universe. ...Observational evidence for this dust production efficiency is however currently limited to only a few CCSN remnants (e.g. SN 1987A, Crab nebula). In this paper, we revisit the dust mass produced in Cassiopeia A (Cas A), a ~330-yr old O-rich Galactic supernova remnant (SNR) embedded in a dense interstellar foreground and background. We present the first spatially resolved analysis of Cas A based on Spitzer and Herschel infrared and submillimetre data at a common resolution of ~0.6 arcmin for this 5 arcmin diameter remnant following a careful removal of contaminating line emission and synchrotron radiation. We fit the dust continuum from 17 to 500 ...m with a four-component interstellar medium and supernova (SN) dust model. We find a concentration of cold dust in the unshocked ejecta of Cas A and derive a mass of 0.3-0.5 M... of silicate grains freshly produced in the SNR, with a lower limit of greater than or equal to 0.1-0.2 M... For a mixture of 50 per cent of silicate-type grains and 50 per cent of carbonaceous grains, we derive a total SN dust mass between 0.4 and 0.6 M... These dust mass estimates are higher than from most previous studies of Cas A and support the scenario of SN-dominated dust production at high redshifts. We furthermore derive an interstellar extinction map for the field around Cas A which towards Cas A gives average values of A sub( V) = 6-8 mag, up to a maximum of A sub( V) = 15 mag. (ProQuest: ... denotes formulae/symbols omitted.)
Abstract Dietary protocols that increase serum levels of ketones, such as calorie restriction and the ketogenic diet, offer robust protection against a multitude of acute and chronic neurological ...diseases. The underlying mechanisms, however, remain unclear. Previous studies have suggested that the ketogenic diet may reduce free radical levels in the brain. Thus, one possibility is that ketones may mediate neuroprotection through antioxidant activity. In the present study, we examined the effects of the ketones β-hydroxybutyrate and acetoacetate on acutely dissociated rat neocortical neurons subjected to glutamate excitotoxicity using cellular electrophysiological and single-cell fluorescence imaging techniques. Further, we explored the effects of ketones on acutely isolated mitochondria exposed to high levels of calcium. A combination of β-hydroxybutyrate and acetoacetate (1 mM each) decreased neuronal death and prevented changes in neuronal membrane properties induced by 10 μM glutamate. Ketones also significantly decreased mitochondrial production of reactive oxygen species and the associated excitotoxic changes by increasing NADH oxidation in the mitochondrial respiratory chain, but did not affect levels of the endogenous antioxidant glutathione. In conclusion, we demonstrate that ketones reduce glutamate-induced free radical formation by increasing the NAD+ /NADH ratio and enhancing mitochondrial respiration in neocortical neurons. This mechanism may, in part, contribute to the neuroprotective activity of ketones by restoring normal bioenergetic function in the face of oxidative stress.
Abstract
We present near-IR (NIR) and optical observations of the Type Ic supernova (SN Ic) SN 2020oi in the galaxy M100 and the broad-lined SN Ic SN 2020bvc in UGC 9379, using Gemini, Las Cumbres ...Observatory, Southern Astrophysical Telescope, and other ground-based telescopes. The NIR spectrum of SN 2020oi at day 63 since the explosion shows strong CO emissions and a rising
K
-band continuum, which is the first unambiguous dust detection from an SN Ic. Non-LTE CO modeling shows that CO is still optically thick and that the lower limit to the CO mass is 10
−3
M
⊙
. The dust temperature is 810 K, and the dust mass is ∼10
−5
M
⊙
. We explore the possibilities that the dust is freshly formed in the ejecta, heated dust in the preexisting circumstellar medium, and an infrared echo. The light curves of SN 2020oi are consistent with a STELLA model with canonical explosion energy, 0.07
M
⊙
Ni mass, and 0.7
M
⊙
ejecta mass. A model of high explosion energy of 10
52
erg, 0.4
M
⊙
Ni mass, and 6.5
M
⊙
ejecta mass with the circumstellar matter reproduces the double-peaked light curves of SN 2020bvc. We observe temporal changes of absorption features of the IR Ca
ii
triplet, S
i
at 1.043
μ
m, and Fe
ii
at 5169 Å. The blueshifted lines indicate high velocities, up to 60,000 km s
−1
for SN 2020bvc and 20,000 km s
−1
for SN 2020oi, and the expansion velocity rapidly declines before the optical maximum. We present modeled spectral signatures and diagnostics of CO and SiO molecular bands between 1.4 and 10
μ
m.
Foam cells are one of the major cellular components of atherosclerotic plaques, within which the trace of periodontal pathogens has also been identified in recent studies. In line with these ...findings, the correlation between periodontitis and atherosclerotic cardiovascular incidences has been repetitively supported by evidence from a number of experimental studies. However, the direct role of periodontal pathogens in altered cellular signaling underlying such cardiovascular events has not been clearly defined. To determine the role of periodontal pathogens in the pathogenesis of atherosclerosis, especially in the evolution of macrophages into foam cells, we monitored the pattern of lipid accumulation within macrophages in the presence of periodontal pathogens, followed by characterization of these lipids and investigation of major molecules involved in lipid homeostasis. The cells were stained with the lipophilic fluorescent dye BODIPY 493/503 and Oil Red O to characterize the lipid profile. The amounts of Oil Red O–positive droplets, representing neutral lipids, as well as fluorescent lipid aggregates were prominently increased in periodontal pathogen–infected macrophages. Subsequent analysis allowed us to locate the accumulated lipids in the endoplasmic reticulum. In addition, the levels of cholesteryl ester in periodontal pathogen–infected macrophages were increased, implying disrupted lipid homeostasis. Further investigations to delineate the key messengers and regulatory factors involved in the altered lipid homeostasis have revealed alterations in cholesterol efflux–related enzymes, such as ABCG1 and CYP46A1, as contributors to foam cell formation, and increased Ca2+ signaling and reactive oxygen species (ROS) production as key events underlying disrupted lipid homeostasis. Consistently, a treatment of periodontal pathogen–infected macrophages with ROS inhibitors and nifedipine attenuated the accumulation of lipid droplets, further confirming periodontal pathogen–induced alterations in Ca2+ and ROS signaling and the subsequent dysregulation of lipid homeostasis as key regulatory events underlying the evolution of macrophages into foam cells.
p130Cas regulates cancer progression by driving tyrosine receptor kinase signaling. Tight regulation of p130Cas expression is necessary for survival, apoptosis, and maintenance of cell motility in ...various cell types. Several studies revealed that transcriptional and post-translational control of p130Cas are important for maintenance of its expression and activity. To explore novel regulatory mechanisms of p130Cas expression, we studied the effect of microRNAs (miRs) on p130Cas expression in human breast cancer MCF7 cells. Here, we provide experimental evidence that miR-362-3p and miR-329 perform a tumor-suppressive function and their expression is downregulated in human breast cancer. miR-362-3p and miR-329 inhibited cellular proliferation, migration, and invasion, thereby suppressing tumor growth, by downregulating p130Cas. Ectopic expression of p130Cas attenuated the inhibitory effects of the two miRs on tumor progression. Relative expression levels of miR-362-3p/329 and p130Cas between normal and breast cancer correlated inversely; miR-362-3p/329 expression was decreased, whereas that of p130Cas increased in breast cancers. Furthermore, we showed that downregulation of miR-362-3p and miR-329 was caused by differential DNA methylation of miR genes. Enhanced DNA methylation (according to methylation-specific PCR) was responsible for downregulation of miR-362-3p and miR-329 in breast cancer. Taken together, these findings point to a novel role for miR-362-3p and miR-329 as tumor suppressors; the miR-362-3p/miR-329-p130Cas axis seemingly has a crucial role in breast cancer progression. Thus, modulation of miR-362-3p/miR-329 may be a novel therapeutic strategy against breast cancer.
A strong correlation between chronic periodontitis and systemic diseases (e.g., cardiovascular disease, metabolic disorders) has been suggested for several decades. However, the evidence supporting ...this correlation is restricted primarily to epidemiologic studies, with only a few experimental outcomes confirming such a correlation and providing information about the underlying molecular mechanisms. To reveal a correlation between periodontitis and systemic diseases as well as a relevant molecular pathway, we investigated the effects of Porphyromonas gingivalis and Fusobacterium nucleatum, which play roles in chronic periodontitis progression, on Raw264.7 and THP-1 macrophages. Infection with P. gingivalis or F. nucleatum significantly induced the expression of fatty acid binding protein 4 (FABP4), one of the most important adipokines that play a role in the progression of systemic diseases such as atherosclerosis and type 2 diabetes. Periodontal pathogen–induced FABP4 expression in macrophages promoted lipid uptake by these cells, as demonstrated by the diminished lipid accumulation in cells treated with an FABP4 inhibitor, BMS309403, or with knockdown of FABP4 expression. This periodontal pathogen–induced FABP4 expression was dependent on the JNK pathway, and JNK inhibition reduced lipid uptake by reducing FABP4 expression. Serum levels of antibodies against P. gingivalis correlated with serum FABP4 levels in humans, whereas no association occurred between F. nucleatum antibody titers and FABP4 levels. To our knowledge, this report is the first to experimentally demonstrate that periodontal pathogens stimulate lipid uptake in macrophages by modulating FABP4 expression. These findings strongly support the hypothesis that periodontitis may affect the progression of various systemic diseases.
Whether supernovae are major sources of dust in galaxies is a long-standing debate. We present infrared and submillimeter photometry and spectroscopy from the Herschel Space Observatory of the Crab ...Nebula between 51 and 670 mu m as part of the Mass Loss from Evolved StarS program. We compare the emission detected with Herschel with multiwavelength data including millimeter, radio, mid-infrared, and archive optical images. We carefully remove the synchrotron component using the Herschel and Planck fluxes measured in the same epoch. The contribution from line emission is removed using Herschel spectroscopy combined with Infrared Space Observatory archive data. Several forbidden lines of carbon, oxygen, and nitrogen are detected where multiple velocity components are resolved, deduced to be from the nitrogen-depleted, carbon-rich ejecta. No spectral lines are detected in the SPIRE wavebands; in the PACS bands, the line contribution is 5% and 10% at 70 and 100 mu m and negligible at 160 mu m. After subtracting the synchrotron and line emission, the remaining far-infrared continuum can be fit with two dust components. Assuming standard interstellar silicates, the mass of the cooler component is 0.24 super(+0.32) sub(-0.08) M sub(middot in circle) for T = 28.1 super(+5.5) sub(-3.2) K. Amorphous carbon grains require 0.11 + or - 0.01 M sub(middot in circle) of dust with T = 33.8 super(+2.3) sub(-1.8) K. A single temperature modified blackbody with 0.14 M sub(middot in circle) and 0.08 M sub(middot in circle) for silicate and carbon dust, respectively, provides an adequate fit to the far-infrared region of the spectral energy distribution but is a poor fit at 24-500 mu m. The Crab Nebula has condensed most of the relevant refractory elements into dust, suggesting the formation of dust in core-collapse supernova ejecta is efficient.
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