Grape polyphenols attenuate inflammation and insulin resistance in human adipocytes and obese mice

Obesity is rapidly increasing worldwide among all age groups. Insulin resistance or type 2 diabetes is one of several debilitating health problems associated with obesity. An emerging feature of obesity and type 2 diabetes is their linkage with chronic, low-grade inflammation that begins in white adipose tissue (WAT) and eventually becomes systemic. One potential dietary strategy to reduce chronic inflammation is consumption of fruits and vegetables rich in polyphenols, including grape products, which possess anti-oxidant and anti-inflammatory properties. Notably, several clinical and animal studies have shown that supplementation with grape products like grape juice, grape powder or extracts, and red wine reduced oxidative damage and inflammation. However, the suppressive effects of grape powder on adipocyte-derived inflammation and insulin resistance remains uncertain. Additionally, the bioavailability of grape polyphenols and their ability to lower inflammation and insulin resistance in vitro and in a diet-induced obese animal model are unclear. Therefore, the specific aims of this research were to determine the extent to which 1) grape powder extract (GPE) and several of its polyphenols decrease tumor necrosis factor alpha (TNFa)-mediated inflammation and insulin resistance and their mechanisms of action in primary cultures of human adipocytes (Aim 1), and 2) grape powder polyphenols are absorbed and reduce markers of inflammation and insulin resistance in high fat-fed obese mice (Aim 2). In Aim 1, GPE and quercetin, an abundant polyphenol in GPE, attenuated TNFa-induced a) expression of inflammatory genes, b) activation of inflammatory mitogen-activated protein kinases (MAPKs) and transcription factors nuclear factor-kappa B (NF-kB) and activator protein-1 (AP-1), c) expression or abundance of two negative regulators of insulin sensitivity, and d) suppression of insulin-stimulated glucose uptake. Taken together, these data demonstrate that GPE and quercetin attenuate TNFa-mediated inflammation and insulin resistance in primary cultures of human adipocytes, possibly by suppressing the activation of inflammatory MAPKs and transcription factors that cause insulin resistance. In Aim 2, it was found that a) quercetin 3-O-glucoside was one of the most abundant polyphenols detected in the sera of mice gavaged with GPE, b) high fat-fed mice supplemented with quercetin-rich grape powder had improved glucose disposal rates acutely and reduced markers of inflammation in the sera and WAT chronically, and c) quercetin 3-O-glucoside reduced several markers of inflammation in primary cultures of human adipocytes. Collectively, these findings are expected to contribute critical insights for the development of dietary strategies using grape products for the control of obesity-related conditions including inflammation and insulin resistance or type 2 diabetes. However, clinical trials are needed to determine the extent to which these findings can be reproduced in humans

Expression of Wnt5a alternative promoters A and B during cancer progression and cellular differentiation

WNT5A is a secreted glycoprotein that plays an important role in cellular differentiation, cell homeostasis and development. It is also misregulated in numerous cancer cell types. The Wnt5a gene generates multiple transcripts from distinct promoters and alternative splicing, leading to different protein isoforms. Currently, little is known regarding the regulation of the Wnt5a alternative promoters. The goal of this study was to characterize the expression of Wnt5a alternative promoters A and B during differentiation and cellular transformation. TaqMan primer-probe sets, specific to promoter A and promoter B derived transcripts, were designed and characterized. The level of promoter A and B specific transcripts were determined in normal human osteoblasts and the osteosarcoma cell line, SaOS-2, as a model for cancer progression. The level of promoter A and B transcripts were nearly equal in osteoblasts cells. In contrast, there was a dramatic decrease in promoter B transcripts in osteosarcoma cells and an increase of 3.5 fold in promoter A transcripts, giving an A to B ratio of 2320 to 1. Wnt5a promoter A and promoter B luciferase reporter constructs were transfected into osteosarcoma cells. Promoter A and promoter B activities were found to be nearly equal, suggesting that the lower level of promoter B transcripts in osteosarcoma cells is not due to altered levels of transcription factors. Promoter A and promoter B specific transcripts were assayed in 3T3-L1 mouse fibroblasts, as a model for differentiation, in the following stages: exponential preadipocytes (EX PA), confluent preadipocytes (CON PA), two days after MDI treatment (D2 Post MDI) and in mature differentiated adipocytes (Diff AD). In EX PA and CON PA cells, both promoter A and promoter B transcripts increased followed by decreased transcript levels in D2 Post MDI cells. While promoter A transcripts slightly increased in Diff AD, promoter B transcript levels remained at a low level. Overall, these results suggest that Wnt5a promoter A and promoter B are differentially regulated

The fulfillment of a part of earth's furthest dream which is assigned to me

Painting is proverbially difficult to define and explain. The reason for this difficulty lies partly in the subject itself and partly in our attitude toward it. The production of a painting is a mysterious process; it is fulfilling a part of the Earth's furthest dream in a spiritual and unanticipated manner. The painter paints the dreams which wave before the half-shut eye, as the great singer sings our rhythmic silence. The one who has gone through the baptism of the sweat of agony and the tears of ecstasy, and is longing for an outlet of the spiritual pressure and a channel through which to relieve his overburdened mind, dips his brush into rare and rich colors and paints with the experiences of his life; then an artist is in existence. Experience as sculpturing dew softens the rock-like soul of man. Wisdom carves the mist into an image singing as an inspiration in an artist's heart

Feasibility of Tomotherapy-Based Image-Guided Radiotherapy for Locally Advanced Oropharyngeal Cancer

PURPOSE: The study aims to assess the feasibility of tomotherapy-based image-guided (IGRT) radiotherapy for locally advanced oropharyngeal cancer. A retrospective review of 33 patients undergoing concurrent chemoradiation for locally advanced oropharyngeal cancers was conducted. Radiotherapy planning, treatment toxicity and loco-regional control were assessed. RESULTS: At a median follow-up of 32 months (6-47 months), no patient developed loco-regional recurrence. Two patients (6%) developed distant metastases. Grade 3-4 acute toxicity was respectively 72% and 25% for mucositis and gastrointestinal toxicity. Two patients (6%) had long-term dependence on tube feedings. Dose-volume histogram demonstrated excellent target volume coverage and low radiation dose to the organs at risk for complications. CONCLUSIONS AND CLINICAL RELEVANCE: IGRT provides excellent loco-regional control but acute toxicity remains significant and needs to be addressed in future prospective trials. The feasibility of Tomotherapy to decrease radiation dose to the normal tissues merits further investigations

Feasibility of image-guided radiotherapy based on helical tomotherapy to reduce contralateral parotid dose in head and neck cancer

Background To evaluate the feasibility of image-guided radiotherapy based on helical Tomotherapy to spare the contralateral parotid gland in head and neck cancer patients with unilateral or no neck node metastases. Methods A retrospective review of 52 patients undergoing radiotherapy for head and neck cancers with image guidance based on daily megavoltage CT imaging with helical tomotherapy was performed. Results Mean contralateral parotid dose and the volume of the contralateral parotid receiving 40 Gy or more were compared between radiotherapy plans with significant constraint (SC) of less than 20 Gy on parotid dose (23 patients) and the conventional constraint (CC) of 26 Gy (29 patients). All patients had PTV coverage of at least 95% to the contralateral elective neck nodes. Mean contralateral parotid dose was, respectively, 14.1 Gy and 24.7 Gy for the SC and CC plans (p < 0.0001). The volume of contralateral parotid receiving 40 Gy or more was respectively 5.3% and 18.2% (p < 0.0001) Conclusion Tomotherapy for head and neck cancer minimized radiotherapy dose to the contralateral parotid gland in patients undergoing elective node irradiation without sacrificing target coverage

Parallel imaging: is GRAPPA a useful acquisition tool for MR imaging intended for volumetric brain analysis?

<p>Abstract</p> <p>Background</p> <p>The work presented here investigates parallel imaging applied to T1-weighted high resolution imaging for use in longitudinal volumetric clinical studies involving Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) patients. This was in an effort to shorten acquisition times to minimise the risk of motion artefacts caused by patient discomfort and disorientation. The principle question is, "Can parallel imaging be used to acquire images at 1.5 T of sufficient quality to allow volumetric analysis of patient brains?"</p> <p>Methods</p> <p>Optimisation studies were performed on a young healthy volunteer and the selected protocol (including the use of two different parallel imaging acceleration factors) was then tested on a cohort of 15 elderly volunteers including MCI and AD patients. In addition to automatic brain segmentation, hippocampus volumes were manually outlined and measured in all patients. The 15 patients were scanned on a second occasion approximately one week later using the same protocol and evaluated in the same manner to test repeatability of measurement using images acquired with the GRAPPA parallel imaging technique applied to the MPRAGE sequence.</p> <p>Results</p> <p>Intraclass correlation tests show that almost perfect agreement between repeated measurements of both segmented brain parenchyma fraction and regional measurement of hippocampi. The protocol is suitable for both global and regional volumetric measurement dementia patients.</p> <p>Conclusion</p> <p>In summary, these results indicate that parallel imaging can be used without detrimental effect to brain tissue segmentation and volumetric measurement and should be considered for both clinical and research studies where longitudinal measurements of brain tissue volumes are of interest.</p

Do real interest rates converge across Latin american countries?

In this study, we apply the Sequential Panel Selection Method (SPSM), pro- posed by Chortareas and Kapetanios (Journal of Banking and Finance 33:390–404, 2009), to investigate and assess the non-stationary properties of the real interest rate parity (RIRP) for fourteen Latin American countries. Utilizing the SPSM, we can classify the entire panel into a group of stationary series and a group of non-stationary series. We clearly identify how many and which series in the panel are stationary processes and provide robust evidence that clearly indicate RIRP holds true for ten countries. Our findings note that these countries’ real interest rate convergence is a mean reversion toward RIRP equilib- rium values in a non-linear way. Our results have important policy implications for these Latin American countries under study.info:eu-repo/semantics/publishedVersio

Sensory Transduction Channel Subunits, tax-4 and tax-2, Modify Presynaptic Molecular Architecture in C. elegans

During development, neural activity is important for forming proper connections in neural networks. The effect of activity on the gross morphology and synaptic strength of neurons has been well documented, but little is known about how activity affects different molecular components during development. Here, we examine the localization of four fluorescently-tagged presynaptic proteins, RAB-3, SNG-1/synaptogyrin, SYD-2/Liprin-α, and SAD-1/SAD kinase, in the C. elegans thermosensory neuron AFD. We show that tax-4 and tax-2, two genes that encode the cyclic nucleotide-gated channel necessary for sensory transduction in AFD, disrupt the localization of all four proteins. In wild-type animals, the synaptic vesicle (SV) markers RAB-3 and SNG-1 and the active zone markers SYD-2 and SAD-1 localize in a stereotyped, punctate pattern in the AFD axon. In tax-4 and tax-2 mutants, SV and SYD-2 puncta are more numerous and less intense. Interestingly, SAD-1 puncta are also less intense but do not increase in number. The change in puncta number can be rescued cell-autonomously in AFD. These results suggest that sensory transduction genes tax-4 and tax-2 are necessary for the proper assembly of presynapses