Chrysophanic acid blocks proliferation of colon cancer cells by inhibiting EGFR/mTOR pathway

Inactivation of epidermal growth factor receptor (EGFR) is a prime method used in colon cancer therapy. Here it is shown that chrysophanic acid, a natural anthraquinone, has anticancer activity in EGFR-overexpressing SNU-C5 human colon cancer cells. Chrysophanic acid preferentially blocked proliferation in SNU-C5 cells but not in other cell lines (HT7, HT29, KM12C, SW480, HCT116 and SNU-C4) with low levels of EGFR expression. Chrysophanic acid treatment in SNU-C5 cells inhibited EGF-induced phosphorylation of EGFR and suppressed activation of downstream signaling molecules, such as AKT, extracellular signal-regulated kinase (ERK) and the mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K). Chrysophanic acid (80 and 120 μm) significantly blocked cell proliferation when combined with the mTOR inhibitor, rapamycin. These findings offer the first evidence of anticancer activity for chrysophanic acid via EGFR/mTOR mediated signaling transduction pathway.     

Effects of lead exposure on the expression of phospholipid hydroperoxidase glutathione peroxidase mRNA in the rat brain.

Oxidative damage associated with lead in the brain has been proposed as a possible mechanism of lead toxicity. Of the many antioxidant enzymes, phospholipid hydroperoxidase glutathione peroxidase (PHGPx) is known to protect cells from lipid peroxide-mediated damage by catalyzing lipid peroxide reduction. In this study, the effects of lead on the activity and expression of PHGPx mRNA were investigated in the brains of rats exposed to lead for 8 weeks. Male Sprague-Dawley rats (3 week old, n = 40) were randomly divided into four groups of 10 and treated with four different concentrations of lead in drinking water: a low dose (0.1% lead acetate), a medium dose (0.3% lead acetate), and a high dose (1.0% lead acetate), and a control group (0% lead acetate). We compared the four groups in terms of body and brain weight, lead concentrations in the brain and blood, and the activities of superoxide dismutase (SOD), gluthatione peroxidase (GPx), and PHGPx mRNA in the brain. Phospholipid hydroperoxidase glutathione peroxidase was found to have a dominant role in lead exposure. We also performed in situ hybridization of PHGPx mRNA in the brain to identity PHGPx mRNA active sites. We found that the level of PHGPx mRNA in brain increased in the medium- and low-dose groups, but decreased in the high-dose group versus the non-lead-treated control group. These results suggest that lead exposure increases the expression of PHGPx mRNA in the low- and medium-dose groups without inducing structural changes, and that the reduced expression of PHGPx mRNA in the high-dose group was associated with structural damage. An In situ hybridization study showed that PHGPx mRNA in the brain is expressed mainly in the white matter of the cerebral hemisphere and in the Purkinje cells of the cerebellar hemispheres; these sites are known to be the vulnerable to lead toxicity.     

Spatial gradient in value representation along the medial prefrontal cortex reflects individual differences in prosociality

Despite the importance of valuing another person’s welfare for prosocial behavior, currently we have only a limited understanding of how these values are represented in the brain and, more importantly, how they give rise to individual variability in prosociality. In the present study, participants underwent functional magnetic resonance imaging while performing a prosocial learning task in which they could choose to benefit themselves and/or another person. Choice behavior indicated that participants valued the welfare of another person, although less so than they valued their own welfare. Neural data revealed a spatial gradient in activity within the medial prefrontal cortex (MPFC), such that ventral parts predominantly represented self-regarding values and dorsal parts predominantly represented other-regarding values. Importantly, compared with selfish individuals, prosocial individuals showed a more gradual transition from self-regarding to other-regarding value signals in the MPFC and stronger MPFC–striatum coupling when they made choices for another person rather than for themselves. The present study provides evidence of neural markers reflecting individual differences in human prosociality.Ranging from small acts of kindness in daily life to self-sacrificing altruism under life-threatening situations, we often observe large individual differences in how humans value another person’s welfare. This differential valuation process seems to be the key to understanding various human prosocial behaviors, which are fundamental to the sustainability of human society (1). The underlying neural mechanisms and their relationship to individual differences in prosociality remain unclear, however.Perhaps the most powerful way of assessing how an outcome is valued is to use an instrumental learning paradigm that examines whether the occurrence of a response increases when it is followed by that outcome (2). The mechanisms underlying this type of learning have been described more formally with a computational model, known as the advantage learning model (3–5), which has been used successfully to reveal the neuroanatomical substrates of subjective valuation (3, 4, 6). Previous research has further refined the neurobiological model of reinforcement learning by emphasizing the specific roles played by the medial frontal cortex and the striatum; the medial frontal cortex computes the value of the chosen action, whereas the striatum processes reward prediction errors during reinforcement learning (4, 6–10).Unlike our current understanding of the valuation process for self-regarding choices (3, 6–12), it is much less clear whether learning also can be driven by other-regarding values, and whether this other-regarding valuation relies on the same mechanisms of reinforcement learning as those used for self. Moreover, despite the rapidly accumulating research on reward processing in social domains (13–19), the question remains of how neural representation of self-regarding vs. other-regarding values is related to individual differences in altruistic behavior.In this work, we designed a novel version of an instrumental learning task (i.e., a prosocial learning task) to assess behavioral and neural processes associated with self- and other-regarding valuation in a comparable, principled way. In the prosocial learning task, participants chose between two alternatives to achieve a higher probability of benefiting either themselves and/or another person by reducing the duration of exposure to unpleasantly loud noise. Thirty pairs of healthy right-handed female college students participated in the study. The scanned participant of each pair performed the prosocial learning task (Fig. 1). In each trial of the task, participants were presented with two options and had to choose one of them. In different conditions, the two options were represented by specific fractal images and associated with points only for the participant in the scanner (SELF condition), for both participants (BOTH condition), or only for the participant outside the scanner (OTHER condition). One of the two options always had a higher probability of yielding points than the other (70% vs. 30%). By trial and error, the participants in the scanner would learn about these probabilities and subsequently choose the option that they preferred. Participants were told that they would be exposed to unpleasant noise for 5 min after the task, and that the points earned in the task would be used to reduce the duration of the noise for themselves and/or the paired participant outside the scanner (see SI Appendix for details).Open in a separate windowFig. 1.Prosocial learning task and within-subject experimental conditions. Only rewarded trials are shown.We predicted that if participants valued others’ welfare, then the other-regarding outcome (i.e., points earned to reduce the duration of aversive noise for the other) would increase their performance above chance level, such that they would earn more points for the other participant than if they chose randomly. In line with the idea that avoidance of punishment is reinforcing and has been shown to activate brain regions similar to those involved in reward learning (3), the points earned in the task, which could be used later, just like money, were presumed to have appetitive motivational value. Therefore, regarding neural representation of the chosen value, we expected a spatial segregation within the medial prefrontal cortex (MPFC) in computing self- and other-regarding values, consistent with previous studies showing that the ventral and dorsal parts of the MPFC are involved in self- and other-regarding processes, respectively (19–25). More importantly, we hypothesized that the degree of spatial segregation would provide a neural index of the individual propensity to help others. Given that positive subjective valuation of others'' welfare can lead to prosocial decisions (17, 26–29), we expected to find that decreased segregation would be associated with greater prosociality. In addition, we examined whether and how corticostriatal communications contribute to individual differences in representing and updating self- and other-regarding values.     

The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression

Metabolic reprogramming is an important cancer hallmark. However, the mechanisms driving metabolic phenotypes of cancer cells are unclear. Here, we show that the interferon-inducible (IFN-inducible) protein viperin drove metabolic alteration in cancer cells. Viperin expression was observed in various types of cancer and was inversely correlated with the survival rates of patients with gastric, lung, breast, renal, pancreatic, or brain cancer. By generating viperin knockdown or stably expressing cancer cells, we showed that viperin, but not a mutant lacking its iron-sulfur cluster–binding motif, increased lipogenesis and glycolysis via inhibition of fatty acid β-oxidation in cancer cells. In the tumor microenvironment, deficiency of fatty acids and oxygen as well as production of IFNs upregulated viperin expression via the PI3K/AKT/mTOR/HIF-1α and JAK/STAT pathways. Moreover, viperin was primarily expressed in cancer stem-like cells (CSCs) and functioned to promote metabolic reprogramming and enhance CSC properties, thereby facilitating tumor growth in xenograft mouse models. Collectively, our data indicate that viperin-mediated metabolic alteration drives the metabolic phenotype and progression of cancer.     

Dynamic panel estimation and homogeneity testing under cross section dependence*

Summary. This paper deals with cross section dependence, homogeneity restrictions and small sample bias issues in dynamic panel regressions. To address the bias problem we develop a panel approach to median unbiased estimation that takes account of cross section dependence. The estimators given here considerably reduce the effects of bias and gain precision from estimating cross section error correlation. This paper also develops an asymptotic theory for tests of coefficient homogeneity under cross section dependence, and proposes a modified Hausman test to test for the presence of homogeneous unit roots. An orthogonalization procedure, based on iterated method of moments estimation, is developed to remove cross section dependence and permit the use of conventional and meta unit root tests with panel data. Some simulations investigating the finite sample performance of the estimation and test procedures are reported.     

Resonance frequency measurements in vivo and related surface properties of magnesium-incorporated, micropatterned and magnesium-incorporated TiUnite®, Osseotite®, SLA® and TiOblast® implants

Objective: To investigate implant stability using resonance frequency measurements of topographically changed and/or surface chemistry‐modified implants in rabbit bone. Material and methods: Six groups of microstructured, screw‐shaped titanium implants: two oxidized, cation‐incorporated experimental implants [Mg implants and MgMp implants with micropatterned thread flanges (80–150 μm wide and 60–70 μm deep)] and four commercially available clinical implants (TiUnite^®, Osseotite^®, SLA^®, and TiOblast^®) were installed in 10 rabbit tibia for 6 weeks. The surface properties of the implants were characterized in detail using several analytical techniques. Implant stability was measured using a resonance frequency analyzer (Osstell^?). Results: Surface characterization of the implants revealed microstructured, moderately rough implant surfaces varying 0.7–1.4 μm in S_a (mean height deviation), but with clear differences in surface chemistry. After 6 weeks, all implants showed statistically significantly higher increases in implant stability. When compared with one another, MgMp implants showed the most significant mean implant stability quotient (ISQ) value relative to the others (P≤0.016). In terms of increment (ΔISQ) in implant stability, MgMp implants showed a significantly greater value as compared with Osseotite^® (P≤0.005), TiOblast^® (P≤0.005), TiUnite^® (P≤0.005), SLA^® (P≤0.007), and Mg implants (P≤0.012). In addition, transducer direction dependence of resonance frequency analysis (RFA) measurements was observed such that the differences in the mean ISQ values between longitudinal and perpendicular measurements were significant at implant placement (P≤0.004) and after 6 weeks (P≤0). Conclusion: The present study found that implant surface properties influence RFA measurements of implant stability. Surface chemistry‐modified titanium implants showed higher mean ISQ values than did topographically changed implants. In particular, cation (magnesium)‐incorporated micropatterns in MgMp implants may play a primary role in ΔISQ.