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

Degenerate Parallel Conducting Layer and Conductivity Type Conversion Observed from \u3ci\u3ep\u3c/i\u3e-Ge\u3csub\u3e1 - y\u3c/sub\u3eSn\u3csub\u3ey\u3c/sub\u3e (y = 0.06%) Grown on \u3ci\u3en\u3c/i\u3e-Si Substrate

Electrical properties of p-Ge1−ySny (y = 0.06%) grown on n-Si substrate were investigated through temperature-dependent Hall-effect measurements. It was found that there exists a degenerate parallel conducting layer in Ge1−ySny/Si and a second, deeper acceptor in addition to a shallow acceptor. This parallel conducting layer dominates the electrical properties of the Ge1−ySny layer below 50 K and also significantly affects those properties at higher temperatures. Additionally, a conductivity type conversion from p to n was observed around 370 K for this sample. A two-layer conducting model was used to extract the carrier concentration and mobility of the Ge1−ySny layer alone

Satellite remote sounding of mid-tropospheric CO_2

Human activity has increased the concentration of the earth's atmospheric carbon dioxide, which plays a direct role in contributing to global warming. Mid-tropospheric CO_2 retrieved by the Atmospheric Infrared Sounder shows a substantial spatiotemporal variability that is supported by in situ aircraft measurements. The distribution of middle tropospheric CO_2 is strongly influenced by surface sources and large-scale circulations such as the mid-latitude jet streams and by synoptic weather systems, most notably in the summer hemisphere. In addition, the effects of stratosphere-troposphere exchange are observed during a final stratospheric warming event. The results provide the means to understand the sources and sinks and the lifting of CO_2 from surface layers into the free troposphere and its subsequent transport around the globe. These processes are not adequately represented in three chemistry-transport models that have been used to study carbon budgets

Translation-Dependent Mechanisms Lead to PML Upregulation and Mediate Oncogenic K-RAS-Induced Cellular Senescence

Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the $PML-RAR\alpha$ oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo and in vitro. We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53. Under these circumstances, PML mRNA is selectively associated to polysomes. Importantly, we find that the PML 5′ untranslated mRNA region plays a key role in mediating PML protein upregulation and that its presence is essential for an efficient OIS response. These findings demonstrate that upregulation of PML translation plays a central role in oncogenic K-RAS-induced OIS. Thus, selective translation initiation plays a critical role in tumour suppression with important therapeutic implications for the treatment of solid tumours and APL

Population connectivity predicts vulnerability to white-nose syndrome in the Chilean myotis (Myotis chiloensis) - A genomics approach

Despite its peculiar distribution, the biology of the southernmost bat species in the world, the Chilean myotis (Myotis chiloensis), has garnered little attention so far. The species has a north-south distribution of c. 2800 km, mostly on the eastern side of the Andes mountain range. Use of extended torpor occurs in the southernmost portion of the range, putting the species at risk of bat white-nose syndrome, a fungal disease responsible for massive population declines in North American bats. Here, we examined how geographic distance and topology would be reflected in the population structure of M. chiloensis along the majority of its range using a double digestion RAD-seq method. We sampled 66 individuals across the species range and discovered pronounced isolation-by-distance. Furthermore, and surprisingly, we found higher degrees of heterozygosity in the southernmost populations compared to the north. A coalescence analysis revealed that our populations may still not have reached secondary contact after the Last Glacial Maximum. As for the potential spread of pathogens, such as the fungus causing WNS, connectivity among populations was noticeably low, especially between the southern hibernatory populations in the Magallanes and Tierra del Fuego, and more northerly populations. This suggests the probability of geographic spread of the disease from the north through bat-to-bat contact to susceptible populations is low. The study presents a rare case of defined population structure in a bat species and warrants further research on the underlying factors contributing to this. See the graphical abstract here.Peer reviewe

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

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

Accounting for aerosol scattering in the CLARS retrieval of column averaged CO_2 mixing ratios

The California Laboratory for Atmospheric Remote Sensing Fourier transform spectrometer (CLARS‐FTS) deployed at Mount Wilson, California, has been measuring column abundances of greenhouse gases in the Los Angeles (LA) basin in the near‐infrared spectral region since August 2011. CLARS‐FTS measures reflected sunlight and has high sensitivity to absorption and scattering in the boundary layer. In this study, we estimate the retrieval biases caused by aerosol scattering and present a fast and accurate approach to correct for the bias in the CLARS column averaged CO2 mixing ratio product, X_(CO2). The high spectral resolution of 0.06 cm^(−1) is exploited to reveal the physical mechanism for the bias. We employ a numerical radiative transfer model to simulate the impact of neglecting aerosol scattering on the CO_2 and O_2 slant column densities operationally retrieved from CLARS‐FTS measurements. These simulations show that the CLARS‐FTS operational retrieval algorithm likely underestimates CO_2 and O_2 abundances over the LA basin in scenes with moderate aerosol loading. The bias in the CO_2 and O_2 abundances due to neglecting aerosol scattering cannot be canceled by ratioing each other in the derivation of the operational product of X_(CO2). We propose a new method for approximately correcting the aerosol‐induced bias. Results for CLARS X_(CO2) are compared to direct‐Sun X_(CO2) retrievals from a nearby Total Carbon Column Observing Network (TCCON) station. The bias‐correction approach significantly improves the correlation between the X_(CO2) retrieved from CLARS and TCCON, demonstrating that this approach can increase the yield of useful data from CLARS‐FTS in the presence of moderate aerosol loading

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

Validation of Aura Microwave Limb Sounder OH measurements with Fourier Transform Ultra-Violet Spectrometer total OH column measurements at Table Mountain, California

The first seasonal and interannual validation of OH measurements from the Aura Microwave Limb Sounder (MLS) has been conducted using ground-based OH column measurements from the Fourier Transform Ultra-Violet Spectrometer (FTUVS) over the Jet Propulsion Laboratory's Table Mountain Facility (TMF) during 2004–2007. To compare with FTUVS total column measurements, MLS OH vertical profiles over TMF are integrated to obtain partial OH columns above 21.5 hPa, which covers nearly 90% of the total column. The tropospheric OH and the lower stratopheric OH not measured by MLS are estimated using GEOS (Goddard Earth Observing System)-Chem and a Harvard 2-D model implemented within GEOS-Chem, respectively. A number of field observations and calculations from a photochemical box model are compared to OH profiles from these models to estimate the variability in the lower atmospheric OH and thus the uncertainty in the combined total OH columns from MLS and models. In general, the combined total OH columns agree extremely well with TMF total OH columns, especially during seasons with high OH. In winter with low OH, the combined columns are often higher than TMF measurements. A slightly weaker seasonal variation is observed by MLS relative to TMF. OH columns from TMF and the combined total columns from MLS and models are highly correlated, resulting in a mean slope of 0.969 with a statistically insignificant intercept. This study therefore suggests that column abundances derived from MLS vertical profiles have been validated to within the mutual systematic uncertainties of the MLS and FTUVS measurements