Modulation of SIRT1-foxo1 signaling axis by resveratrol: Implications in skeletal muscle aging and insulin resistance

© 2015 S. Karger AG, Basel. Aging individuals and diabetic patients often exhibit concomitant reductions of skeletal muscle mass/strength and insulin sensitivity, suggesting an intimate link between muscle aging and insulin resistance. Foxo1, a member of the FOXO transcription factor family, is an important player in insulin signaling due to its inhibitory role in glucose uptake and utilization in skeletal muscle. Phosphorylation of Foxo1 is thought to mitigate the transactivation of pyruvate dehydrogenase lipoamide kinase 4 (PDK4), which is a negative regulator of the glycolytic enzyme pyruvate dehydrogenase (PDH). In contrast, how aging would regulate acetylation/deacetylation machineries and glucose utilization in skeletal muscle through the Foxo1/PDH axis remains largely undetermined. Accumulating body of evidence have shown that resveratrol, a natural polyphenol in grapes and red wine, activates the longevity-related protein sirtuin 1 (SIRT1) and augments insulin sensitivity in addition to its well-documented effects on mitochondrial energetics. The present review summarizes the role of Foxo1/SIRT1 in insulin signaling in skeletal muscle and proposes the insight that activation of SIRT1 deacetylase activity to deacetylate and suppress the Foxo1-induced transactivation of PDK4 may represent an anti-hyperglycemic mechanism of resveratrol in aging skeletal muscle.Link_to_subscribed_fulltex

SIRT1-dependent myoprotective effects of resveratrol on muscle injury induced by compression

© 2015 Sin, Yung, Yip, Chan, Wong, Tam and Siu. Our current understanding on the molecular mechanisms by which sustained compression induces skeletal muscle injury is very limited. This study aimed to test the hypothesis that activation of SIRT1 by the natural antioxidant resveratrol could deactivate apoptotic and catabolic signaling in skeletal muscle exposed to moderate compression. Two cycles of 6-h constant pressure at 100 mmHg was applied to the tibialis region of right, but not left hindlimbs of Sprague Dawley rats pre-treated with DMSO (vehicle control) or resveratrol with/without sirtinol. Skeletal muscle tissues lying underneath and spatially corresponding to the compressed sites were collected for analyses. Resveratrol prevented the compression-induced manifestations of pathohistological damages including elevations of the number of interstitial nuclei and area of interstitial space and ameliorated oxidative damages measured as 4-hydroxy-2-nonenal (4HNE) and nitrotyrosine in skeletal muscle. In parallel, resveratrol augmented the expression level and activity of SIRT1 and phosphorylation levels of Foxo3a and Akt while suppressed the increases in protein abundances of p53, Bax, MAFbx, and ubiquitin, enzymatic activities of caspase 3 and 20S proteasome, and apoptotic DNA fragmentation in the compressed muscle. These favorable myoprotective effects of resveratrol were diminished upon pharmacological blockade of SIRT1 by using sirtinol. These novel data support the hypothesis that the anti-apoptotic and anti-catabolic effects of resveratrol on compression injury in skeletal muscle required the action of SIRT1.Link_to_subscribed_fulltex

Gene network exploration of crosstalk between apoptosis and autophagy in chronic myelogenous leukemia

Copyright © 2015 Fengfeng Wang et al. Background. Gene expression levels change to adapt the stress, such as starvation, toxin, and radiation. The changes are signals transmitted through molecular interactions, eventually leading to two cellular fates, apoptosis and autophagy. Due to genetic variations, the signals may not be effectively transmitted to modulate apoptotic and autophagic responses. Such aberrant modulation may lead to carcinogenesis and drug resistance. The balance between apoptosis and autophagy becomes very crucial in coping with the stress. Though there have been evidences illustrating the apoptosis-autophagy interplay, the underlying mechanism and the participation of the regulators including transcription factors (TFs) and microRNAs (miRNAs) remain unclear. Results. Gene network is a graphical illustration for exploring the functional linkages and the potential coordinate regulations of genes. Microarray dataset for the study of chronic myeloid leukemia was obtained from Gene Expression Omnibus. The expression profiles of those genes related to apoptosis and autophagy, including MCL1, BCL2, ATG, beclin-1, BAX, BAK, E2F, cMYC, PI3K, AKT, BAD, and LC3, were extracted from the dataset to construct the gene networks. Conclusion. The network analysis of these genes explored the underlying mechanisms and the roles of TFs and miRNAs for the crosstalk between apoptosis and autophagy.Link_to_subscribed_fulltex

Constraining cosmology with machine learning and galaxy clustering: the CAMELS-SAM suite

As the next generation of large galaxy surveys come online, it is becoming increasingly important to develop and understand the machine learning tools that analyze big astronomical data. Neural networks are powerful and capable of probing deep patterns in data, but must be trained carefully on large and representative data sets. We developed and generated a new `hump' of the Cosmology and Astrophysics with MachinE Learning Simulations (CAMELS) project: CAMELS-SAM, encompassing one thousand dark-matter only simulations of (100 $h^{-1}$ cMpc)$^3$ with different cosmological parameters ($\Omega_m$ and $\sigma_8$) and run through the Santa Cruz semi-analytic model for galaxy formation over a broad range of astrophysical parameters. As a proof-of-concept for the power of this vast suite of simulated galaxies in a large volume and broad parameter space, we probe the power of simple clustering summary statistics to marginalize over astrophysics and constrain cosmology using neural networks. We use the two-point correlation function, count-in-cells, and the Void Probability Function, and probe non-linear and linear scales across $0.68<$ R $<27\ h^{-1}$ cMpc. Our cosmological constraints cluster around 3-8$\%$ error on $\Omega_{\text{M}}$ and $\sigma_8$, and we explore the effect of various galaxy selections, galaxy sampling, and choice of clustering statistics on these constraints. We additionally explore how these clustering statistics constrain and inform key stellar and galactic feedback parameters in the Santa Cruz SAM. CAMELS-SAM has been publicly released alongside the rest of CAMELS, and offers great potential to many applications of machine learning in astrophysics: https://camels-sam.readthedocs.io.Comment: 40 pages, 22 figures (11 made of subfigures

Implications of MicroRNAs in the treatment of gefitinib-resistant non-small cell lung cancer

2015-2016 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

S100A8 and S100A9 Are Associated with Doxorubicin-Induced Cardiotoxicity in the Heart of Diabetic Mice

© 2016 Pei, Tam, Sin, Wang, Yung, Chan, Wong, Ying, Lai and Siu. Cardiomyopathy is a clinical problem that occurs in the hearts of type 2 diabetic patients as well as cancer patients undergoing doxorubicin chemotherapy. The number of diabetic cancer patients is increasing but surprisingly the cardiac damaging effects of doxorubicin, a commonly used chemotherapeutic drug, on diabetic hearts have not been well-examined. As the signaling mechanisms of the doxorubicin-induced cardiomyopathy in type 2 diabetic heart are largely unknown, this study examined the molecular signaling pathways that are responsible for the doxorubicin-induced cardiotoxicity in type 2 diabetic hearts. Male 14- to 18-week-old db/db mice were used as the type 2 diabetic model, and age-matched non-diabetic db/+ mice served as controls. The db/+ non-diabetic and db/db diabetic mice were randomly assigned to the following groups: db/+CON, db/+DOX-5d, db/+DOX-7d, db/dbCON, db/dbDOX-5d, and db/dbDOX-7d. Mice assigned to doxorubicin (DOX) group were exposed to an intraperitoneal (i.p.) injection of DOX at a dose of 15 mg/kg to induce cardiomyopathy. Mice in control (CON) groups were i.p. injected with the same volume of saline instead of DOX. Mice were euthanized by overdose of ketamine and xylazine 5 or 7 days after the DOX injection. Microarray analysis was adopted to examine the changes of the whole transcriptional profile in response to doxorubicin exposure in diabetic hearts. Ventricular fractional shortening was examined as an indicator of cardiac function by transthoracic echocardiography. The presence of diabetic cardiomyopathy in db/db mice was evident by the reduction of fractional shortening. There was a further impairment of cardiac contractile function 7 days after the DOX administration in db/db diabetic mice. According to our microarray analysis, we identified a panel of regulatory genes associated with cardiac remodeling, inflammatory response, oxidative stress, and metabolism in the DOX-induced cardiac injury in diabetic heart. The microarray results of selected genes were confirmed by real time PCR. Notably, S100A8 and S100A9 were found to have a unique specific expression pattern that was coincident with the DOX-induced cardiomyopathy in diabetic hearts. Correspondingly, NF-κB expression in diabetic hearts was increased together with the elevation of S100A8/9 and activation of p38 MAPK signaling after DOX administration, which induced cardiac inflammation as demonstrated by the elevation of cardiac IL-6 level. These findings provide novel pre-clinical information for revealing the S100A8/A9-associated molecular signaling pathways that mediate the doxorubicin-induced cardiotoxicity in diabetic hearts.Link_to_subscribed_fulltex

Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data

OBJECTIVE: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. DESIGN: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. DATA SOURCES: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. RESULTS: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). CONCLUSIONS: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002780

Dephosphorylation of Nucleophosmin by PP1β Facilitates pRB Binding and Consequent E2F1-dependent DNA Repair

We report a new pathway through which PP1β signals to nucleophosmin (NPM) in response to DNA damage. UV induces dephosphorylation of NPM at multiple sites, leading to enhancement of complex formation between NPM and retinoblastoma tumor suppressor protein and the subsequent upregulation of E2F1. Consequently, such signaling pathway potentiates the cellular DNA repair capacity

CEERS: Spatially Resolved UV and mid-IR Star Formation in Galaxies at 0.2 < z < 2.5: The Picture from the Hubble and James Webb Space Telescopes

We present the mid-IR (MIR) morphologies for 64 star-forming galaxies at 0.210^{9}~M_\odot} using JWST MIRI observations from the Cosmic Evolution Early Release Science survey (CEERS). The MIRI bands span the MIR (7.7--21~$\mu$m), enabling us to measure the effective radii ($R_{\rm{eff}}$) and S\'{e}rsic indexes of these SFGs at rest-frame 6.2 and 7.7 $\mu$m, which contains strong emission from Polycyclic aromatic hydrocarbon (PAH) features, a well-established tracer of star formation in galaxies. We define a ``PAH-band'' as the MIRI bandpass that contains these features at the redshift of the galaxy. We then compare the galaxy morphologies in the PAH-bands to those in rest-frame Near-UV (NUV) using HST ACS/F435W or ACS/F606W and optical/near-IR using HST WFC3/F160W imaging from UVCANDELS and CANDELS, where the NUV-band and F160W trace the profile of (unobscured) massive stars and the stellar continuum, respectively. The $R_{\rm{eff}}$ of galaxies in the PAH-band are slightly smaller ($\sim$10\%) than those in F160W for galaxies with $\rm{M_*\gtrsim10^{9.5}~M_\odot}$ at $z\leq1.2$, but the PAH-band and F160W have a similar fractions of light within 1 kpc. In contrast, the $R_{\rm{eff}}$ of galaxies in the NUV-band are larger, with lower fractions of light within 1 kpc compared to F160W for galaxies at $z\leq1.2$. Using the MIRI data to estimate the $\rm{SFR_{\rm{IR}}}$ surface density, we find the correlation between the $\rm{SFR_{\rm{IR}}}$ surface density and stellar mass has a steeper slope than that of the $\rm{SFR_{\rm{UV}}}$ surface density and stellar mass, suggesting more massive galaxies having increasing amounts of obscured fraction of star formation in their inner regions. This paper demonstrates how the high-angular resolution data from JWST/MIRI can reveal new information about the morphology of obscured-star formation.Comment: 28 pages, 11 figures, Accepted by Ap

CEERS: 7.7 μ{\mu}m PAH Star Formation Rate Calibration with JWST MIRI

We test the relationship between UV-derived star formation rates (SFRs) and the 7.7 ${\mu}$m polycyclic aromatic hydrocarbon (PAH) luminosities from the integrated emission of galaxies at z ~ 0 - 2. We utilize multi-band photometry covering 0.2 - 160 ${\mu}$m from HST, CFHT, JWST, Spitzer, and Herschel for galaxies in the Cosmic Evolution Early Release Science (CEERS) Survey. We perform spectral energy distribution (SED) modeling of these data to measure dust-corrected far-UV (FUV) luminosities, $L_{FUV}$, and UV-derived SFRs. We then fit SED models to the JWST/MIRI 7.7 - 21 ${\mu}$m CEERS data to derive rest-frame 7.7 ${\mu}$m luminosities, $L_{770}$, using the average flux density in the rest-frame MIRI F770W bandpass. We observe a correlation between $L_{770}$ and $L_{FUV}$, where log $L_{770}$ is proportional to (1.27+/-0.04) log $L_{FUV}$. $L_{770}$ diverges from this relation for galaxies at lower metallicities, lower dust obscuration, and for galaxies dominated by evolved stellar populations. We derive a "single-wavelength" SFR calibration for $L_{770}$ which has a scatter from model estimated SFRs (${{\sigma}_{{\Delta}SFR}}$) of 0.24 dex. We derive a "multi-wavelength" calibration for the linear combination of the observed FUV luminosity (uncorrected for dust) and the rest-frame 7.7 ${\mu}$m luminosity, which has a scatter of ${{\sigma}_{{\Delta}SFR}}$ = 0.21 dex. The relatively small decrease in ${\sigma}$ suggests this is near the systematic accuracy of the total SFRs using either calibration. These results demonstrate that the rest-frame 7.7 ${\mu}$m emission constrained by JWST/MIRI is a tracer of the SFR for distant galaxies to this accuracy, provided the galaxies are dominated by star-formation with moderate-to-high levels of attenuation and metallicity.Comment: 20 pages, 11 figures, 2 tables, submitted to Ap