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Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT?) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test (oGTT) was performed in five groups (n = 10/group) of rats: 1) lean strain-control 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg/kg · d olmesartan for 6 wk; OLETF ARB), 4) OLETF + 5% glucose water (HG) for 6 wk (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). The glucose response to the oGTT increased 58% in OLETF compared with lean-strain control, whereas glucose supplementation increased it an additional 26%. Blockade of angiotensin receptor reduced the oGTT response 19% in the ARB-treated groups and increased pancreatic insulin secretion 64 and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT? protein expression 20 and 27%, increased pancreatic glucagon-like peptide-1 (GLP-1) receptor protein expression 41 and 88%, respectively, and increased fasting plasma GLP-1 approximately 2.5-fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose-stimulated insulin secretion associated with decreased pancreatic AT? activation and increased GLP-1 signaling. 相似文献
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Pauwels R Beinsberger J Stamatakis H Tsiklakis K Walker A Bosmans H Bogaerts R Jacobs R Horner K;The SEDENTEXCT Project Consortium 《Oral surgery, oral medicine, oral pathology and oral radiology》2012,114(1):127-135
OBJECTIVE: The purpose was to evaluate the perceived spatial and contrast resolution for a wide range of cone-beam computed tomography (CBCT) devices. STUDY DESIGN: A customized polymethyl methacrylate (PMMA) phantom was developed. Inserts containing a line-pair and rod pattern were used. The phantom was scanned with 13 CBCT devices and 1 multislice CT (MSCT) device using a variety of scanning protocols. The images were presented to 4 observers for scoring. RESULTS: The observer scores showed excellent agreement. A wide range was seen in image quality between CBCT exposure protocols. Compared with the average CBCT scores, the MSCT protocols scored lower for the line-pair insert but higher for the rod insert. CONCLUSIONS: CBCT devices are generally suitable for the visualization of high-contrast structures. Certain exposure protocols can be used for depicting low-contrast structures or fine details. The user should be able to select appropriate exposure protocols according to varying diagnostic requirements. 相似文献
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Huang X Di Liberto M Jayabalan D Liang J Ely S Bretz J Shaffer AL Louie T Chen I Randolph S Hahn WC Staudt LM Niesvizky R Moore MA Chen-Kiang S 《Blood》2012,120(5):1095-1106
Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. 相似文献
67.
Hernaez R 《Gastroenterologia y hepatologia》2012,35(1):32-41
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Whereas insulin resistance and obesity are considered major risk factors for the development and progression of NAFLD, the genetic underpinnings are unclear. Before 2008, candidate gene studies based on prior knowledge of pathophysiology of fatty liver yielded conflicting results. In 2008, Romeo et al. published the first genome wide association study and reported the strongest genetic signal for the presence of fatty liver (PNPLA3, patatin-like phospholipase domain containing 3; rs738409). Since then, two additional genome wide scans were published and identified 9 additional genetic variants. Whereas these results shed light into the understanding of the genetics of NAFLD, most of associations have not been replicated in independent samples and, therefore, remain undetermined the significance of these findings. This review aims to summarize the understanding of genetic epidemiology of NAFLD and highlights the gaps in knowledge. 相似文献
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Otano I Suarez L Dotor J Gonzalez-Aparicio M Crettaz J Olagüe C Vales A Riezu JI Larrea E Borras F Benito A Hernandez-Alcoceba R Menne S Prieto J González-Aseguinolaza G 《Hepatology (Baltimore, Md.)》2012,56(2):474-483
Regulatory T cells (Treg) play a critical role in the modulation of immune responses to viral antigens in chronic viral hepatitis. Woodchucks (Marmota monax) infected with the woodchuck hepatitis virus (WHV) represent the best animal model for chronic hepatitis B virus (HBV) infection. Examination of intrahepatic and peripheral Treg in uninfected and WHV chronically infected woodchucks showed a significant increase of intrahepatic Treg numbers in chronically infected animals, whereas no differences were found in peripheral blood. In agreement with these data, higher expression levels of Forkhead box P3 (Foxp3), interleukin (IL)-10, transforming growth factor beta (TGF-β) were detected in the liver of chronic WHV carriers in comparison to uninfected animals. Furthermore, treatment of WHV-infected animals with an adenovirus encoding IL-12 failed to reduce viral load, a finding that was associated with lymphocyte unresponsiveness to IL-12 stimulation in vitro. We observed that TGF-β and Treg play a major role in the lack of lymphocyte response to IL-12 stimulation, as TGF-β inhibition and Treg depletion allowed recovery of T-cell responsiveness to this cytokine. Based on these results, woodchucks were treated with IL-12 in combination with a TGF-β inhibitory peptide or Treg depletion. However, no antiviral effect was achieved and, instead, an enhancement of the intrahepatic tolerogenic environment was observed. CONCLUSION: Our data show that TGF-β inhibition or Treg depletion had no added benefit over IL-12 therapy in chronic WHV infection. IL-12 immunostimulation induces a strong immunosuppressive reaction in the liver of chronic WHV carriers that counteracts the antiviral effect of the treatment. 相似文献
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Ruben T. Azevedo Emiliano Macaluso Alessio Avenanti Valerio Santangelo Valentina Cazzato Salvatore Maria Aglioti 《Human brain mapping》2013,34(12):3168-3181
Recent advances in social neuroscience research have unveiled the neurophysiological correlates of race and intergroup processing. However, little is known about the neural mechanisms underlying intergroup empathy. Combining event‐related fMRI with measurements of pupil dilation as an index of autonomic reactivity, we explored how race and group membership affect empathy‐related responses. White and Black subjects were presented with video clips depicting white, black, and unfamiliar violet‐skinned hands being either painfully penetrated by a syringe or being touched by a Q‐tip. Both hemodynamic activity within areas known to be involved in the processing of first and third‐person emotional experiences of pain, i.e., bilateral anterior insula, and autonomic reactivity were greater for the pain experienced by own‐race compared to that of other‐race and violet models. Interestingly, greater implicit racial bias predicted increased activity within the left anterior insula during the observation of own‐race pain relative to other‐race pain. Our findings highlight the close link between group‐based segregation and empathic processing. Moreover, they demonstrate the relative influence of culturally acquired implicit attitudes and perceived similarity/familiarity with the target in shaping emotional responses to others' physical pain. Hum Brain Mapp 34:3168–3181, 2013. © 2012 Wiley Periodicals, Inc. 相似文献