Sample records for forkhead box o-class
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Smuder, Ashley J; Sollanek, Kurt J; Min, Kisuk; Nelson, W Bradley; Powers, Scott K
2015-05-01
Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation-induced diaphragm weakness remains unknown. This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness. University research laboratory. Young adult female Sprague-Dawley rats. Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm. Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3. Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that targeting forkhead boxO transcription could be a key therapeutic target to combat ventilator-induced diaphragm dysfunction.
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The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.
Van Der Heide, Lars P; Hoekman, Marco F M; Smidt, Marten P
2004-01-01
FoxO (forkhead box O; forkhead members of the O class) are transcription factors that function under the control of insulin/insulin-like signalling. FoxO factors have been associated with a multitude of biological processes, including cell-cycle, cell death, DNA repair, metabolism and protection from oxidative stress. Central to the regulation of FoxO factors is a shuttling system, which confines FoxO factors to either the nucleus or the cytosol. Shuttling of FoxO requires protein phosphorylation within several domains, and association with 14-3-3 proteins and the nuclear transport machinery. Description of the FoxO-shuttling mechanism contributes to the understanding of FoxO function in relation to signalling and gene regulation. PMID:15005655
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Durrant, Jessica R.; Connell, Melanie L.; Folian, Brian J.; Donato, Anthony J.; Seals, Douglas R.
2011-01-01
We hypothesized that I kappa B kinase (IKK)-mediated nuclear factor kappa B and forkhead BoxO3a phosphorylation will be associated with age-related endothelial dysfunction. Endothelium-dependent dilation and aortic protein expression/phosphorylation were determined in young and old male B6D2F1 mice and old mice treated with the IKK inhibitor, salicylate. IKK activation was greater in old mice and was associated with greater nitrotyrosine and cytokines. Endothelium-dependent dilation, nitric oxide (NO), and endothelial NO synthase phosphorylation were lower in old mice. Endothelium-dependent dilation and NO bioavailability were restored by a superoxide dismutase mimetic. Nuclear factor kappa B and forkhead BoxO3a phosphorylation were greater in old and were associated with increased expression/activity of nicotinamide adenine dinucleotide phosphate oxidase and lower manganese superoxide dismutase expression. Salicylate lowered IKK phosphorylation and reversed age-associated changes in nitrotyrosine, endothelium-dependent dilation, NO bioavailability, endothelial NO synthase, nuclear factor kappa B and forkhead BoxO3a phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase, and manganese superoxide dismutase. Increased activation of IKK with advancing age stimulates nuclear factor kappa B and inactivates forkhead BoxO3a. This altered transcription factor activation contributes to a pro-inflammatory/pro-oxidative arterial phenotype that is characterized by increased cytokines and nicotinamide adenine dinucleotide phosphate oxidase and decreased manganese superoxide dismutase leading to oxidative stress-mediated endothelial dysfunction. PMID:21303813
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Role of Forkhead Box Class O proteins in cancer progression and metastasis.
Kim, Chang Geun; Lee, Hyemin; Gupta, Nehal; Ramachandran, Sharavan; Kaushik, Itishree; Srivastava, Sangeeta; Kim, Sung-Hoon; Srivastava, Sanjay K
2018-06-01
It is now widely accepted that several gene alterations including transcription factors are critically involved in cancer progression and metastasis. Forkhead Box Class O proteins (FoxOs) including FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX and FoxO6 transcription factors are known to play key roles in proliferation, apoptosis, metastasis, cell metabolism, aging and cancer biology through their phosphorylation, ubiquitination, acetylation and methylation. Though FoxOs are proved to be mainly regulated by upstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt signaling pathway, the role of FoxOs in cancer progression and metastasis still remains unclear so far. Thus, with previous experimental evidences, the present review discussed the role of FoxOs in association with metastasis related molecules including cannabinoid receptor 1 (CNR1), Cdc25A/Cdk2, Src, serum and glucocorticoid inducible kinases (SGKs), CXCR4, E-cadherin, annexin A8 (ANXA8), Zinc finger E-box-binding homeobox 2 (ZEB2), human epidermal growth factor receptor 2 (HER2) and mRNAs such as miR-182, miR-135b, miR-499-5p, miR-1274a, miR-150, miR-34b/c and miR-622, subsequently analyzed the molecular mechanism of some natural compounds targeting FoxOs and finally suggested future research directions in cancer progression and metastasis. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation
USDA-ARS?s Scientific Manuscript database
Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the '-amino group of lysi...
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Zhang, Jiayu; Wu, Liang; Chen, Jiawei; Lin, Sisi; Cai, Daqiu; Chen, Chengwei; Chen, Zhenguo
2018-05-01
Diabetic retinopathy is a neurological disease, which can lead to blindness in severe cases. The pathogenesis underlying diabetic retinopathy is unclear. The aim of this study was to explore the role of dysregulated microRNA 29a/b in the onset and progression of diabetic retinopathy. Diabetes mellitus was induced in rats using 60 mg/kg of streptozotocin. Glucose (5.5 and 25 mM) was used to stimulate rat retinal Müller cells. Real-time polymerase chain reaction and Western blot analyses were used to determine gene expression. A luciferase reporter assay was conducted to validate the relationship of microRNA 29a/b with glioma-associated oncogene homolog 1 and Forkhead box protein O4. The expression of microRNA 29a/b and glutamine synthetase decreased in both diabetes mellitus rats and rat retinal Müller cells stimulated with high glucose, whereas the expression of sonic hedgehog, glioma-associated oncogene homolog 1, glial fibrillary acidic protein, and vascular endothelial growth factor, as well as the content of glutamate, increased. Dysregulated microRNA 29a/b was directly regulated by the sonic hedgehog-glioma-associated oncogene homolog 1 signalling pathway, and microRNA 29a and microRNA 29b targeted Forkhead box protein O4 and regulated its expression. Downregulation of microRNA 29a/b, mediated by the sonic hedgehog-glioma-associated oncogene homolog 1 signalling pathway, exacerbated diabetic retinopathy by upregulating Forkhead box protein O4.
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Forkhead box transcription factors in embryonic heart development and congenital heart disease.
Zhu, Hong
2016-01-01
Embryonic heart development is a very complicated process regulated precisely by a network composed of many genes and signaling pathways in time and space. Forkhead box (Fox, FOX) proteins are a family of transcription factors characterized by the presence of an evolutionary conserved "forkhead"or "winged-helix" DNA-binding domain and able to organize temporal and spatial gene expression during development. They are involved in a wide variety of cellular processes, such as cell cycle progression, proliferation, differentiation, migration, metabolism and DNA damage response. An abundance of studies in model organisms and systems has established that Foxa2, Foxc1/c2, Foxh1 and Foxm1, Foxos and Foxps are important components of the signaling pathways that instruct cardiogenesis and embryonic heart development, playing paramount roles in heart development. The previous studies also have demonstrated that mutations in some of the forkhead box genes and the aberrant expression of forkhead box gene are heavily implicated in the congenital heart disease (CHD) of humans. This review primarily focuses on the current understanding of heart development regulated by forkhead box transcription factors and molecular genetic mechanisms by which forkhead box factors modulate heart development during embryogenesis and organogenesis. This review also summarizes human CHD related mutations in forkhead box genes as well as the abnormal expression of forkhead box gene, and discusses additional possible regulatory mechanisms of the forkhead box genes during embryonic heart development that warrant further investigation. Copyright © 2015 Elsevier Inc. All rights reserved.
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Gilley, Jonathan; Coffer, Paul J.; Ham, Jonathan
2003-01-01
Developing sympathetic neurons die by apoptosis when deprived of NGF. BIM, a BH3-only member of the BCL-2 family, is induced after NGF withdrawal in these cells and contributes to NGF withdrawal–induced death. Here, we have investigated the involvement of the Forkhead box, class O (FOXO) subfamily of Forkhead transcription factors in the regulation of BIM expression by NGF. We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation–induced death of sympathetic neurons. PMID:12913110
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Update: the role of FoxP3 in allergic disease.
Paik, Young; Dahl, Matthew; Fang, Deyu; Calhoun, Karen
2008-06-01
T-regulatory cells play a key role in allergic and asthmatic inflammatory airway diseases. This review discusses the importance of a critical gene associated with T-regulatory cells. Forkhead box P3 is a forkhead-winged helix transcription factor gene involved in immune function in allergy and asthma. Recently, many functions of forkhead box P3 and its influence on the immune system have been elucidated. T-regulatory cells that are CD4+CD25+ and express forkhead box P3, influence the development and expression of atopy and allergic response. The exact mechanisms are not yet delineated, but multiple recent studies provide greater understanding of the mechanism of forkhead box P3 and its influence on these T-regulatory cells. Greater understanding of the molecular and immunological mechanisms underlying the T-regulatory cells and forkhead box P3 will permit the development of targeted treatment modalities to influence disease processes such as allergic rhinitis and bronchial asthma.
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No significant impact of Foxf1 siRNA treatment in acute and chronic CCl4 liver injury.
Abshagen, Kerstin; Rotberg, Tobias; Genz, Berit; Vollmar, Brigitte
2017-08-01
Chronic liver injury of any etiology is the main trigger of fibrogenic responses and thought to be mediated by hepatic stellate cells. Herein, activating transcription factors like forkhead box f1 are described to stimulate pro-fibrogenic genes in hepatic stellate cells. By using a liver-specific siRNA delivery system (DBTC), we evaluated whether forkhead box f1 siRNA treatment exhibit beneficial effects in murine models of acute and chronic CCl 4 -induced liver injury. Systemic administration of DBTC-forkhead box f1 siRNA in mice was only sufficient to silence forkhead box f1 in acute CCl 4 model, but was not able to attenuate liver injury as measured by liver enzymes and necrotic liver cell area. Therapeutic treatment of mice with DBTC-forkhead box f1 siRNA upon chronic CCl 4 exposition failed to inhibit forkhead box f1 expression and hence lacked to diminish hepatic stellate cells activation or fibrosis development. As a conclusion, DBTC-forkhead box f1 siRNA reduced forkhead box f1 expression in a model of acute but not chronic toxic liver injury and showed no positive effects in either of these mice models. Impact statement As liver fibrosis is a worldwide health problem, antifibrotic therapeutic strategies are urgently needed. Therefore, further developments of new technologies including validation in different experimental models of liver disease are essential. Since activation of hepatic stellate cells is a key event upon liver injury, the activating transcription factor forkhead box f1 (Foxf1) represents a potential target gene. Previously, we evaluated Foxf1 silencing by a liver-specific siRNA delivery system (DBTC), exerting beneficial effects in cholestasis. The present study was designed to confirm the therapeutic potential of Foxf1 siRNA in models of acute and chronic CCl 4 -induced liver injury. DBTC-Foxf1 siRNA was only sufficient to silence Foxf1 in acute CCl 4 model and did not ameliorate liver injury or fibrogenesis. This underlines the significance of the experimental model used. Each model displays specific characteristics in the pathogenic nature, time course and severity of fibrosis and the optimal time point for starting a therapy.
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Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein*
Chen, Qing; Lu, Mingjian; Monks, Bobby R.; Birnbaum, Morris J.
2016-01-01
Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, whereas the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has been long established that insulin positively controls albumin gene expression. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin gene transcription. Albumin expression was decreased significantly in livers with insulin signaling disrupted by ablation of the insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, activation of Foxo1 in the liver is sufficient to suppress albumin expression. These results suggest that Foxo1 acts as a repressor of albumin expression. PMID:26668316
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Norambuena-Soto, Ignacio; Núñez-Soto, Constanza; Sanhueza-Olivares, Fernanda; Cancino-Arenas, Nicole; Mondaca-Ruff, David; Vivar, Raul; Díaz-Araya, Guillermo; Mellado, Rosemarie; Chiong, Mario
2017-05-23
Fibroblasts play several homeostatic roles, including electrical coupling, paracrine signaling and tissue repair after injury. Fibroblasts have low secretory activity. However, in response to injury, they differentiate to myofibroblasts. These cells have an increased extracellular matrix synthesis and secretion, including collagen fibers, providing stiffness to the tissue. In pathological conditions myofibroblasts became resistant to apoptosis, remaining in the tissue, causing excessive extracellular matrix secretion and deposition, which contributes to the progressive tissue remodeling. Therefore, increased myofibroblast content within damaged tissue is a characteristic hallmark of heart, lung, kidney and liver fibrosis. Recently, it was described that cardiac fibroblast to myofibroblast differentiation is triggered by the transforming growth factor β1 (TGF-β1) through a Smad-independent activation of Forkhead box O (FoxO). FoxO proteins are a transcription factor family that includes FoxO1, FoxO3, FoxO4 and FoxO6. In several cells types, they play an important role in cell cycle arrest, oxidative stress resistance, cell survival, energy metabolism, and cell death. Here, we review the role of FoxO family members on the regulation of cardiac fibroblast proliferation and differentiation.
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Kim, Dae Hyun; Lee, Bonggi; Kim, Min Jo; Park, Min Hi; An, Hye Jin; Lee, Eun Kyeong; Chung, Ki Wung; Park, June Whoun; Yu, Byung Pal; Choi, Jae Sue; Chung, Hae Young
2016-09-14
Betaine is a major water-soluble component of Lycium chinensis. Although there are reports about the protective effects of betaine on hepatic steatosis, the underlying mechanisms are unclear. We used db/db mice and HepG2 cells to examine the mechanism underlying betaine-mediated protection against hepatic steatosis. Here, we showed increased hepatic lipid accumulation in db/db mice, which is associated with increased activation of lipogenic transcription factors including forkhead box O1 (FoxO1) and peroxisome proliferator-activated receptor gamma (PPARγ), whereas betaine administration by oral gavage reversed these characteristics. We investigated whether betaine ameliorates hepatic steatosis by inhibiting FoxO1/PPARγ signaling in HepG2 cells. Although adenovirus-mediated FoxO1 overexpression notably increased mRNA expression levels of PPARγ and its target genes including FAS and ACC, betaine treatment reversed them. Furthermore, betaine inhibited FoxO1 binding to the PPARγ promoter and PPARγ transcriptional activity in HepG2 cells, which was previously shown to induce hepatic steatosis. We concluded that betaine ameliorates hepatic steatosis, at least in part, by inhibiting the FoxO1 binding to PPARγ and their downstream lipogenic signaling cascade.
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Oteiza, Alexandra; Mechti, Nadir
2011-01-01
Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway by the viral Tax oncoprotein plays a pivotal role in clonal expansion of human T-cell leukemia virus type 1 (HTLV-1)-infected cells. As the Forkhead box O (FoxO) tumor suppressors act as downstream effectors of PI3K/Akt, they represent good candidate targets whose dysregulation by Tax might be involved in HTLV-1-mediated activation and transformation of infected cells. In this report, we provide evidence showing that Tax induces a dose-dependent degradation of FoxO4 by the ubiquitin-proteasome pathway. Consistent with that, we demonstrate that Tax expression increases the interaction between FoxO4 and Mdm2 E3 ligase, leading to a strong FoxO4 polyubiquitination. These processes require the phosphorylation of FoxO4 by Akt, since a mutant of FoxO4 with mutations on its three Akt phosphorylation sites appears to be resistant to Tax-mediated degradation and ubiquitination. In addition, we show that Tax expression is associated with degradation and phosphorylation of endogenous FoxO4 in Jurkat T cells. Finally, we demonstrate that Tax represses FoxO4 transcriptional activity. Our study demonstrates that Tax can control FoxO4 protein stability and transcriptional activity and provides new insight into the subversion of cell signaling pathways during HTLV-1 infection. PMID:21525355
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Kim, Maengjo; Hunter, Roger W; Garcia-Menendez, Lorena; Gong, Guohua; Yang, Yu-Ying; Kolwicz, Stephen C; Xu, Jason; Sakamoto, Kei; Wang, Wang; Tian, Rong
2014-03-14
AMP-activated protein kinase is a master regulator of cell metabolism and an attractive drug target for cancer and metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMP-activated protein kinase (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular preexcitation, and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the use of AMP-activated protein kinase as a drug target. We sought to identify the pro-growth-signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage. In a mouse model of N488I mutation of the Prkag2 gene (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate-stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular preexcitation but did not affect the excessive cardiac growth in R2M mice. The progrowth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mammalian target of rapamycin and inactivation of forkhead box O transcription factor-signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mammalian target of rapamycin activity by rapamycin or restoration of forkhead box O transcription factor activity by overexpressing forkhead box O transcription factor 1 rescued the abnormal cardiac growth. Our study reveals a novel mechanism for Prkag2 cardiomyopathy, independent of glycogen storage. The role of γ2-AMP-activated protein kinase in cell growth also has broad implications in cardiac development, growth, and regeneration.
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The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver
DOE Office of Scientific and Technical Information (OSTI.GOV)
Oiso, Hiroshi; Furukawa, Noboru, E-mail: n-furu@gpo.kumamoto-u.ac.jp; Suefuji, Mihoshi
2011-01-07
Research highlights: {yields} A novel class I HDAC inhibitor decreased hepatic PEPCK mRNA and gluconeogenesis. {yields} Inhibition of HDAC decreased PEPCK by reducing HNF4{alpha} expression and FoxO1 activity. {yields} siRNA knockdown of HDAC1 in HepG2 cells reduced the expression of PEPCK and HNF4{alpha}. {yields} Inhibition of class I HDAC improves glucose homeostasis in HFD mice. -- Abstract: Hepatic gluconeogenesis is crucial for glucose homeostasis. Although sirtuin 1 (Sirt1) is implicated in the regulation of gluconeogenesis in the liver, the effects of other histone deacetylases (HDAC) on gluconeogenesis are unclear. The aim of this study was to identify the role ofmore » class I HDACs in hepatic gluconeogenesis. In HepG2 cells and the liver of mice, the expressions of phosphoenol pyruvate carboxykinase (PEPCK) and hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) were significantly decreased by treatment with a newly designed class I HDAC inhibitor, Ky-2. SiRNA knockdown of HDAC1 expression, but not of HDAC2 or HDAC3, in HepG2 cells decreased PEPCK and HNF4{alpha} expression. In HepG2 cells, insulin-stimulated phosphorylation of Akt and forkhead box O 1 (FoxO1) was increased by Ky-2. Pyruvate tolerance tests in Ky-2-treated high-fat-diet (HFD)-fed mice showed a marked reduction in blood glucose compared with vehicle-treated HFD mice. These data suggest that class I HDACs increase HNF4{alpha} protein expression and the transcriptional activity of FoxO1, followed by the induction of PEPCK mRNA expression and gluconeogenesis in liver.« less
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Wang, Bo; Zhang, XueBin; Wang, Wei; Zhu, ZhiZhong; Tang, Fan; Wang, Dong; Liu, Xi; Zhuang, Hao; Yan, XiaoLing
2018-01-01
Forkhead box K2 (FOXK2) is a member of the forkhead box family of transcription factors. Recently, researchers discovered that overexpression of FOXK2 inhibits the proliferation and metastasis of breast cancer, non-small cell lung cancer, and colorectal cancer, and is related to the clinical prognosis. However, in hepatocellular carcinoma, FOXK2 results in the opposite phenotypes. Currently, the contribution of FOXK2 to glioma pathogenesis is not clear. We evaluated the expression of FOXK2 in 151 glioma patients using immunohistochemistry assays. The associations among the expression of FOXK2, clinicopathological parameters, and the prognosis of glioma patients were statistically analyzed. We downregulated and upregulated the level of FOXK2 in glioma cells by transfections with small interfering RNA and plasmids. Then, we investigated the effects on tumor cell behavior in vitro by Cell Counting Kit-8 assays, colony-formation assay, transwell assay, and the epithelial-to-mesenchymal transition (EMT) biomarker levels. The clinical data showed that expression of FOXK2 gradually decreased with increasing World Health Organization (WHO) grades and a low level of FOXK2 indicates a poor prognosis. FOXK2 expression is negatively correlated with Ki67 expression and the WHO degree but is not correlated with other clinicopathological parameters, including sex, age, Karnofsky Performance Status, tumor diameter, O -6-methylguanine-DNA methyltransferase, and glutathione S -transferase pi. FOXK2 knockdown enhances glioma cell proliferation, migration, invasion, and EMT process, and, in contrast, FOXK2 overexpression inhibits glioma cell proliferation, migration, invasion, and the EMT process. Expression of FOXK2 gradually decreases with increasing WHO grades. FOXK2 inhibits tumor proliferation, migration, and invasion. FOXK2 is a critical mediator of the EMT process.
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Agamia, N F; Abdallah, D M; Sorour, O; Mourad, B; Younan, D N
2016-06-01
Acne vulgaris is a multifactorial disorder of the pilosebaceous units. Several studies have reported that insulin-like growth factor (IGF)-1, forkhead box transcription factor (Fox)O1 and mammalian target of rapamycin (mTOR) interactions may be the key to understanding the links between genetic and environmental factors in acne vulgaris. To evaluate the immunohistochemical detection of mTOR and FoxO1 in the skin, and the serum level of IGF-1 in patients with acne vulgaris. This study was carried out on 60 participants, including 40 patients with acne and 20 controls. A diet questionnaire was administered to the patients and controls. Serum levels of IGF-1 were measured using enzyme-linked immunosorbent assay, and skin biopsies were taken from lesions on the backs of the patients and controls. FoxO1 and mTOR expression was detected using immunohistochemistry. A significantly higher serum IGF-1 level was found in the patients with acne than in the controls. The cytoplasmic expression of FoxO1 was found to be significantly greater in the acne group, whereas in the control subjects this expression was likely to be nuclear. Both the cytoplasmic expression and the nuclear expression of mTOR were significantly more intense in the patients with acne than in the controls. Excess consumption of a high-glycaemic-load diet was significantly associated with higher serum levels of IGF-1 and cytoplasmic expression of FoxO1 and mTOR. These results suggest that FoxO1, mTOR, serum IGF-1 and a high-glycaemic-load diet may play a role in acne pathogenesis. © 2016 British Association of Dermatologists.
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Postnikoff, Spike D. L.; Malo, Mackenzie E.; Wong, Berchman; Harkness, Troy A. A.
2012-01-01
Forkhead box O (FOXO) transcription factors have a conserved function in regulating metazoan lifespan. A key function in this process involves the regulation of the cell cycle and stress responses including free radical scavenging. We employed yeast chronological and replicative lifespan assays, as well as oxidative stress assays, to explore the potential evolutionary conservation of function between the FOXOs and the yeast forkhead box transcription factors FKH1 and FKH2. We report that the deletion of both FKH genes impedes normal lifespan and stress resistance, particularly in stationary phase cells, which are non-responsive to caloric restriction. Conversely, increased expression of the FKHs leads to extended lifespan and improved stress response. Here we show the Anaphase-Promoting Complex (APC) genetically interacts with the Fkh pathway, likely working in a linear pathway under normal conditions, as fkh1Δ fkh2Δ post-mitotic survival is epistatic to that observed in apc5CA mutants. However, under stress conditions, post-mitotic survival is dramatically impaired in apc5CA fkh1Δ fkh2Δ, while increased expression of either FKH rescues APC mutant growth defects. This study establishes the FKHs role as evolutionarily conserved regulators of lifespan in yeast and identifies the APC as a novel component of this mechanism under certain conditions, likely through combined regulation of stress response, genomic stability, and cell cycle regulation. PMID:22438832
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Wang, Yu-Chen; Ma, Hong-Di; Yin, Xue-Ying; Wang, Yin-Hu; Liu, Qing-Zhi; Yang, Jing-Bo; Shi, Qing-Hua; Sun, Baolin; Gershwin, M Eric; Lian, Zhe-Xiong
2016-12-01
The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2). Here, we found that macrophages formed sporadic aggregates in the liver during infection. Within those aggregates, macrophages co-localized with T cells and were indispensable for their infiltration. In addition, we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor O1 (FoxO1) conditional knockout Lys Cre/+ FoxO1 fl/fl mice following S. aureus infection and report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1. Indeed, for effective FoxO1 activity, stimulation of TLR2 is essential. However, following S. aureus challenge, there was a decrease in macrophage FoxO1, with increased phosphorylation of FoxO1 because of TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway. Following infection in Lys Cre/+ FoxO1 fl/fl mice, mice became more susceptible to S. aureus with reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses. FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S. aureus and enhanced M2 polarization in macrophages. In contrast, overexpression of FoxO1 in macrophages increased pro-inflammatory mediators and functional surface molecule expression. In conclusion, macrophage FoxO1 is critical to promote M1 polarization and maintain a competent T cell immune response against S. aureus infection in the liver. FoxO1 regulates macrophage M1-M2 polarization downstream of TLR2 dynamically through phosphorylation.
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Regulatory T Cell and Forkhead Box Protein 3 as Modulators of Immune Homeostasis
Pereira, Leonn Mendes Soares; Gomes, Samara Tatielle Monteiro; Ishak, Ricardo; Vallinoto, Antonio Carlos Rosário
2017-01-01
The transcription factor forkhead box protein 3 (FOXP3) is an essential molecular marker of regulatory T cell (Treg) development in different microenvironments. Tregs are cells specialized in the suppression of inadequate immune responses and the maintenance of homeostatic tolerance. Studies have addressed and elucidated the role played by FOXP3 and Treg in countless autoimmune and infectious diseases as well as in more specific cases, such as cancer. Within this context, the present article reviews aspects of the immunoregulatory profile of FOXP3 and Treg in the management of immune homeostasis, including issues relating to pathology as well as immune tolerance. PMID:28603524
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Aquatide Activation of SIRT1 Reduces Cellular Senescence through a SIRT1-FOXO1-Autophagy Axis.
Lim, Chae Jin; Lee, Yong-Moon; Kang, Seung Goo; Lim, Hyung W; Shin, Kyong-Oh; Jeong, Se Kyoo; Huh, Yang Hoon; Choi, Suin; Kor, Myungho; Seo, Ho Seong; Park, Byeong Deog; Park, Keedon; Ahn, Jeong Keun; Uchida, Yoshikazu; Park, Kyungho
2017-09-01
Ultraviolet (UV) irradiation is a relevant environment factor to induce cellular senescence and photoaging. Both autophagy- and silent information regulator T1 (SIRT1)-dependent pathways are critical cellular processes of not only maintaining normal cellular functions, but also protecting cellular senescence in skin exposed to UV irradiation. In the present studies, we investigated whether modulation of autophagy induction using a novel synthetic SIRT1 activator, heptasodium hexacarboxymethyl dipeptide-12 (named as Aquatide), suppresses the UVB irradiation-induced skin aging. Treatment with Aquatide directly activates SIRT1 and stimulates autophagy induction in cultured human dermal fibroblasts. Next, we found that Aquatide-mediated activation of SIRT1 increases autophagy induction via deacetylation of forkhead box class O (FOXO) 1. Finally, UVB irradiation-induced cellular senescence measured by SA-β-gal staining was significantly decreased in cells treated with Aquatide in parallel to occurring SIRT1 activation-dependent autophagy. Together, Aquatide modulates autophagy through SIRT1 activation, contributing to suppression of skin aging caused by UV irradiation.
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Jia, Pengbo; Wei, Guangbing; Zhou, Cancan; Gao, Qi; Wu, Yunhua; Sun, Xuejun; Li, Xuqi
2018-01-01
MicroRNAs are involved in hepatocellular carcinoma metastasis, a principal cause of hepatocellular carcinoma-related death in patients worldwide. MiR-212 is a microRNA that has been identified in several types of cancers and is postulated to influence cell signaling and subsequent malignant pathogenesis. Despite emerging reports suggesting that miR-212 plays a significant role in the onset, progression, and migration of these types of malignant tumors, its involvement in the development of hepatocellular carcinoma has not been fully elucidated. Quantitative reverse transcription polymerase chain reaction, wound healing, transwell migration and invasion assays, Western blotting, and xenograft tumor growth models were performed to test the expression levels and functions of miR-212 in hepatocellular carcinoma. Luciferase reporter assay, quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry were used to identify and verify the target of miR-212. In this study, we identify significant repression of miR-212 in hepatocellular carcinoma and demonstrate that overexpression of miR-212 inhibits the migration of hepatocellular carcinoma cells in vitro and in vivo. Furthermore, we identify forkhead box M1, whose expression is inversely related to that of miR-212, as a direct target of miR-212. Additionally, reexpression of forkhead box M1 rescues the miR-212-mediated inhibition of cell migration. We observed that inhibition of miR-212 activates forkhead box M1 but inhibits the Wnt/β-catenin pathway by suppressing Wnt, LEF-1, c-Myc, and nuclear β-catenin. Finally, in vivo studies confirmed the inhibitory effect of miR-212 on hepatocellular carcinoma growth. Our present findings indicate that miR-212 is a potential prognostic biomarker of hepatocellular carcinoma and that the miR-212/forkhead box M1 regulatory axis may represent a new therapeutic objective for hepatocellular carcinoma treatment.
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Guo, Honghui; Xia, Min; Zou, Tangbin; Ling, Wenhua; Zhong, Ruimin; Zhang, Weiguo
2012-04-01
Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. Here, we hypothesized that cyanidin 3-glucoside (C3G), a typical anthocyanin reported to possess potent anti-inflammatory properties, would ameliorate obesity-associated inflammation and metabolic disorders, such as insulin resistance and hepatic steatosis in mouse models of diabesity. Male C57BL/6J obese mice fed a high-fat diet for 12 weeks and genetically diabetic db/db mice at an age of 6 weeks received dietary C3G supplementation (0.2%) for 5 weeks. We found that dietary C3G lowered fasting glucose levels and markedly improved the insulin sensitivity in both high-fat diet fed and db/db mice as compared with unsupplemented controls. White adipose tissue messenger RNA levels and serum concentrations of inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1) were reduced by C3G, as did macrophage infiltration in adipose tissue. Concomitantly, hepatic triglyceride content and steatosis were alleviated by C3G. Moreover, C3G treatment decreased c-Jun N-terminal kinase activation and promoted phosphorylation and nuclear exclusion of forkhead box O1 after refeeding. These findings clearly indicate that C3G has significant potency in antidiabetic effects by modulating the c-Jun N-terminal kinase/forkhead box O1 signaling pathway and the related inflammatory adipocytokines. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.
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Yang, Yi; Li, Wang; Liu, Yang; Sun, Yuning; Li, Yan; Yao, Qing; Li, Jianning; Zhang, Qian; Gao, Yujing; Gao, Ling; Zhao, Jiajun
2014-11-01
Understanding the mechanism by which alpha-lipoic acid supplementation has a protective effect upon nonalcoholic fatty liver disease in vivo and in vitro may lead to targets for preventing hepatic steatosis. Male C57BL/6J mice were fed a normal diet, high-fat diet or high-fat diet supplemented with alpha-lipoic acid for 24 weeks. HepG2 cells were incubated with normal medium, palmitate or alpha-lipoic acid. The lipid-lowering effects were measured. The protein expression and distribution were analyzed by Western blot, immunoprecipitation and immunofluorescence, respectively. We found that alpha-lipoic acid enhanced sirtuin 1 deacetylase activity through liver kinase B1 and stimulated AMP-activated protein kinase. By activating the sirtuin 1/liver kinase B1/AMP-activated protein kinase pathway, the translocation of sterol regulatory element-binding protein-1 into the nucleus and forkhead box O1 into the cytoplasm was prevented. Alpha-lipoic acid increased adipose triacylglycerol lipase expression and decreased fatty acid synthase abundance. In in vivo and in vitro studies, alpha-lipoic acid also increased nuclear NF-E2-related factor 2 levels and downstream target amounts via the sirtuin 1 pathway. Alpha-lipoic acid eventually reduced intrahepatic and serum triglyceride content. The protective effects of alpha-lipoic acid on hepatic steatosis appear to be associated with the transcription factors sterol regulatory element-binding protein-1, forkhead box O1 and NF-E2-related factor 2. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress.
Manolopoulos, K N; Klotz, L-O; Korsten, P; Bornstein, S R; Barthel, A
2010-11-01
Oxidative stress is an important determinant not only in the pathogenesis of Alzheimer's disease (AD), but also in insulin resistance (InsRes) and diabetic complications. Forkhead box class O (FoxO) transcription factors are involved in both insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and InsRes. For example, the expression of intra- and extracellular antioxidant enzymes, such as manganese-superoxide dismutase and selenoprotein P, is regulated by FoxO proteins, as is the expression of important hepatic enzymes of gluconeogenesis. Here, we review the molecular mechanisms involved in the pathogenesis of AD and InsRes and discuss the function of FoxO proteins in these processes. Both InsRes and oxidative stress may promote the transcriptional activity of FoxO proteins, resulting in hyperglycaemia and a further increased production of reactive oxygen species (ROS). The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of β-amyloid plaques and τ protein phosphorylation. Wnt inhibition may also result in a sustained activation of FoxO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, InsRes and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. In view of their central function in this model, FoxO proteins may provide a potential molecular target for the treatment of both InsRes and AD.
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The Emerging Roles of Forkhead Box (FOX) Proteins in Osteosarcoma
Zhang, Wentao; Duan, Ning; Song, Tao; Li, Zhong; Zhang, Caiguo; Chen, Xun
2017-01-01
Osteosarcoma is the most common bone cancer primarily occurring in children and young adults. Over the past few years, the deregulation of a superfamily transcription factors, known as forkhead box (FOX) proteins, has been demonstrated to contribute to the pathogenesis of osteosarcoma. Molecular mechanism studies have demonstrated that FOX family proteins participate in a variety of signaling pathways and that their expression can be regulated by multiple factors. The dysfunction of FOX genes can alter osteosarcoma cell differentiation, metastasis and progression. In this review, we summarized the evidence that FOX genes play direct or indirect roles in the development and progression of osteosarcoma, and evaluated the emerging role of FOX proteins as targets for therapeutic intervention. PMID:28775781
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Ido, Yasuo
2016-07-01
Recent research in nutritional control of aging suggests that cytosolic increases in the reduced form of nicotinamide adenine dinucleotide and decreasing nicotinamide adenine dinucleotide metabolism plays a central role in controlling the longevity gene products sirtuin 1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). High nutrition conditions, such as the diabetic milieu, increase the ratio of reduced to oxidized forms of cytosolic nicotinamide adenine dinucleotide through cascades including the polyol pathway. This redox change is associated with insulin resistance and the development of diabetic complications, and might be counteracted by insulin C-peptide. My research and others' suggest that the SIRT1-liver kinase B1-AMPK cascade creates positive feedback through nicotinamide adenine dinucleotide synthesis to help cells cope with metabolic stress. SIRT1 and AMPK can upregulate liver kinase B1 and FOXO3, key factors that help residential stem cells cope with oxidative stress. FOXO3 directly changes epigenetics around transcription start sites, maintaining the health of stem cells. 'Diabetic memory' is likely a result of epigenetic changes caused by high nutritional conditions, which disturb the quiescent state of residential stem cells and impair tissue repair. This could be prevented by restoring SIRT1-AMPK positive feedback through activating FOXO3. © 2016 The Author. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.
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Molecular changes in obese and depressive patients are similar to neurodegenerative disorders
Habibi, Laleh; Tafakhori, Abbas; Hadiani, Rasoul; Maserat-Mashhadi, Maryam; Kafrash, Zeinab; Torabi, Shahla; Azhdarzadeh, Mohammad; Akrami, Seyed Mohammad; Mahmoudi, Morteza; Dinarvand, Rasoul
2017-01-01
Background: Neurodegenerative disorders (NDs) are categorized as multifactorial conditions with different molecular and environmental causes. Disturbance of important signaling pathways, such as energy metabolism and inflammation induced by environmental agents, is involved in the pathophysiology of NDs. It has been proposed that changes in the lifestyle and nutrition (metabolism) during mid-life could trigger and accumulate cellular and molecular damages resulting in NDs during aging. Methods: In order to test the hypothesis, we investigated the expression level of two energy metabolism-related [forkhead box O1 (FOXO1) and forkhead box O3 (FOXO3A)] and two pro-inflammatory cytokines [interleukin 1β (IL-1β) and IL-6] genes, using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Furthermore, changes in the ionic concentration of three essential heavy metals [iron (Fe), copper (Cu), and zinc (Zn)] by atomic absorption spectroscopy in patients with NDs, depression, obesity, and diabetes type II, were evaluated and compared with the results of normal individuals. Results: More than half of the participants in obesity, depression, and ND groups had significant up-regulation of FOXO1 and FOXO3A, down-regulation of IL-1β and IL-6, and higher levels of Fe and Cu in their blood. This pattern of gene expression was not repeated in diabetic patients. Conclusion: It could be concluded that individuals affected with different levels of obesity and depression have increased the risk of developing NDs later in life, probably through changes in energy metabolism, inflammatory pathways, and ionic concentrations. PMID:29736225
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Molecular changes in obese and depressive patients are similar to neurodegenerative disorders.
Habibi, Laleh; Tafakhori, Abbas; Hadiani, Rasoul; Maserat-Mashhadi, Maryam; Kafrash, Zeinab; Torabi, Shahla; Azhdarzadeh, Mohammad; Akrami, Seyed Mohammad; Mahmoudi, Morteza; Dinarvand, Rasoul
2017-10-07
Background: Neurodegenerative disorders (NDs) are categorized as multifactorial conditions with different molecular and environmental causes. Disturbance of important signaling pathways, such as energy metabolism and inflammation induced by environmental agents, is involved in the pathophysiology of NDs. It has been proposed that changes in the lifestyle and nutrition (metabolism) during mid-life could trigger and accumulate cellular and molecular damages resulting in NDs during aging. Methods: In order to test the hypothesis, we investigated the expression level of two energy metabolism-related [forkhead box O1 (FOXO1) and forkhead box O3 (FOXO3A)] and two pro-inflammatory cytokines [interleukin 1β (IL-1β) and IL-6] genes, using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Furthermore, changes in the ionic concentration of three essential heavy metals [iron (Fe), copper (Cu), and zinc (Zn)] by atomic absorption spectroscopy in patients with NDs, depression, obesity, and diabetes type II, were evaluated and compared with the results of normal individuals. Results: More than half of the participants in obesity, depression, and ND groups had significant up-regulation of FOXO1 and FOXO3A, down-regulation of IL-1β and IL-6, and higher levels of Fe and Cu in their blood. This pattern of gene expression was not repeated in diabetic patients. Conclusion: It could be concluded that individuals affected with different levels of obesity and depression have increased the risk of developing NDs later in life, probably through changes in energy metabolism, inflammatory pathways, and ionic concentrations.
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Kinoshita, Asako; Locher, Lena; Tienken, Reka; Meyer, Ulrich; Dänicke, Sven; Rehage, Jürgen; Huber, Korinna
2016-01-01
Forkhead box protein O1 (FoxO1) is a transcription factor which promotes hepatic glucose production (HGP) by up-regulating the transcription of gluconeogenic enzymes in monogastric species. The activity of FoxO1 is inhibited by insulin-induced phosphorylation. The aims of the present study were to find associations between FoxO1 expression and variables associated with HGP as affected by feeding regimen in dairy cows during the transition period. Twenty one healthy German Holstein cows were allocated to four groups (LC-CON, HC-CON, LC-NA with 5 cows/group and HC-NA with 6 cows/group, respectively). Cows received 0 (LC-CON and HC-CON) or 24 (LC-NA and HC-NA) g/d nicotinic acid with high (HC) or low (LC) concentrate proportion from -42 days (-41.8 + 4.8; mean + standard deviation) relative to expected calving date (d-42) to d24. Liver biopsy was taken at d-42, 1, 21, and 100. The total protein expression of FoxO1 (tFoxO1) and the extent of phosphorylation of FoxO1 at serine 256 (pFoxO1) were analysed semiquantitatively by Western Blotting. The expression of hepatic mRNA of FoxO1 and seven genes associated with HGP was measured by real-time RT-PCR. Mixed model and Pearson's correlation were used for statistical evaluation with the level of significance at P<0.05. No dietary effect was observed either on feed intake, energy balance, or on the concentration of blood metabolites. Neither time nor diet affected the expression of FoxO1 total protein and mRNA. A NA × concentrate interaction was found in pFoxO1. However, no corresponding dietary effect was found in the mRNA expression of investigated genes. Different patterns of correlations between FoxO1-related variables and investigated indicators for HGP were found at d21 and 100. The results indicated that the regulation of HGP did not take place on the levels of mRNA and protein expression and the phosphorylation of FoxO1 in dairy cows in early lactation.
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Kinoshita, Asako; Locher, Lena; Tienken, Reka; Meyer, Ulrich; Dänicke, Sven; Rehage, Jürgen; Huber, Korinna
2016-01-01
Forkhead box protein O1 (FoxO1) is a transcription factor which promotes hepatic glucose production (HGP) by up-regulating the transcription of gluconeogenic enzymes in monogastric species. The activity of FoxO1 is inhibited by insulin-induced phosphorylation. The aims of the present study were to find associations between FoxO1 expression and variables associated with HGP as affected by feeding regimen in dairy cows during the transition period. Twenty one healthy German Holstein cows were allocated to four groups (LC-CON, HC-CON, LC-NA with 5 cows/group and HC-NA with 6 cows/group, respectively). Cows received 0 (LC-CON and HC-CON) or 24 (LC-NA and HC-NA) g/d nicotinic acid with high (HC) or low (LC) concentrate proportion from -42 days (-41.8 + 4.8; mean + standard deviation) relative to expected calving date (d-42) to d24. Liver biopsy was taken at d-42, 1, 21, and 100. The total protein expression of FoxO1 (tFoxO1) and the extent of phosphorylation of FoxO1 at serine 256 (pFoxO1) were analysed semiquantitatively by Western Blotting. The expression of hepatic mRNA of FoxO1 and seven genes associated with HGP was measured by real-time RT-PCR. Mixed model and Pearson’s correlation were used for statistical evaluation with the level of significance at P<0.05. No dietary effect was observed either on feed intake, energy balance, or on the concentration of blood metabolites. Neither time nor diet affected the expression of FoxO1 total protein and mRNA. A NA × concentrate interaction was found in pFoxO1. However, no corresponding dietary effect was found in the mRNA expression of investigated genes. Different patterns of correlations between FoxO1-related variables and investigated indicators for HGP were found at d21 and 100. The results indicated that the regulation of HGP did not take place on the levels of mRNA and protein expression and the phosphorylation of FoxO1 in dairy cows in early lactation. PMID:26800252
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2011-01-01
Oral isotretinoin (13-cis retinoic acid) is the most effective drug in the treatment of acne and restores all major pathogenetic factors of acne vulgaris. isotretinoin is regarded as a prodrug which after isomerizisation to all-trans-retinoic acid (ATRA) induces apoptosis in cells cultured from human sebaceous glands, meibomian glands, neuroblastoma cells, hypothalamic cells, hippocampus cells, Dalton's lymphoma ascites cells, B16F-10 melanoma cells, and neuronal crest cells and others. By means of translational research this paper provides substantial indirect evidence for isotretinoin's mode of action by upregulation of forkhead box class O (FoxO) transcription factors. FoxOs play a pivotal role in the regulation of androgen receptor transactivation, insulin/insulin like growth factor-1 (IGF-1)-signaling, peroxisome proliferator-activated receptor-γ (PPArγ)- and liver X receptor-α (LXrα)-mediated lipogenesis, β-catenin signaling, cell proliferation, apoptosis, reactive oxygene homeostasis, innate and acquired immunity, stem cell homeostasis, as well as anti-cancer effects. An accumulating body of evidence suggests that the therapeutic, adverse, teratogenic and chemopreventive effecs of isotretinoin are all mediated by upregulation of FoxO-mediated gene transcription. These FoxO-driven transcriptional changes of the second response of retinoic acid receptor (RAR)-mediated signaling counterbalance gene expression of acne due to increased growth factor signaling with downregulated nuclear FoxO proteins. The proposed isotretinoin→ATRA→RAR→FoxO interaction offers intriguing new insights into the mode of isotretinoin action and explains most therapeutic, adverse and teratogenic effects of isotretinoin in the treatment of acne by a common mode of FoxO-mediated transcriptional regulation. PMID:22110774
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Targeting forkhead box transcription factors FOXM1 and FOXO in leukemia (Review).
Zhu, Hong
2014-10-01
Deregulation of forkhead box (FOX) proteins has been found in many genetic diseases and malignancies including leukemia. Leukemia is a common neoplastic disease of the blood or bone marrow characterized by the presence of immature leukocytes and is one of the leading causes of death due to cancer. Forkhead transcription factors, FOXM1 and FOXO family members (FOXOs), are important mediators in leukemia development. Aberrant expression of FOXM1 and FOXOs results in leukemogenesis. Usually the expression of FOXM1 is upregulated, whereas the expression of FOXOs is downregulated due to phosphorylation, nuclear exclusion and degradation in leukemia. On the one hand, FOXOs are bona fide tumor suppressors, on the other hand, active FOXOs maintain leukemia stem cells and stimulate drug resistance genes, contributing to leukemogenesis. FOXM1 and FOXOs have been proven to be potential targets for the development of leukemia therapeutics. They are also valuable diagnostic and prognostic markers in leukemia for clinical applications. This review summarizes the present knowledge concerning the molecular mechanisms by which FOXM1 and FOXOs modulate leukemogenesis and leukemia development, the clinical relevance of these FOX proteins in leukemia and related areas that warrant further investigation.
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Kim, Arang; Lee, Wooje; Yun, Jung-Mi
2017-10-01
Chronic hyperglycemia induces oxidative stress via accumulation of reactive oxygen species (ROS) and contributes to diabetic complications. Hyperglycemia induces mitochondrial superoxide anion production through the increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This study aimed to determine whether fisetin and luteolin treatments suppress the oxidative stress by modulating the expression of sirtuins (SIRTs) and forkhead box O3a (FOXO3a) under hyperglycemic conditions in human monocytes. Human monocytic cells (THP-1) were cultured under osmotic control (14.5 mmol/L mannitol), normoglycemic (NG, 5.5 mmol/L glucose), or hyperglycemic (HG, 20 mmol/L glucose) conditions, in the absence or presence of fisetin and luteolin for 48 h. To determine the effect of fisetin and luteolin treatments on high glucose-induced oxidative stress, western blotting and intracellular staining were performed. Hyperglycemic conditions increased the ROS production, as compared to normoglycemic condition. However, fisetin and luteolin treatments inhibited ROS production under hyperglycemia. To obtain further insight into ROS production in hyperglycemic conditions, evaluation of p47phox expression revealed that fisetin and luteolin treatments inhibited p47phox expression under hyperglycemic conditions. Conversely, the expression levels of SIRT1, SIRT3, SIRT6, and FOXO3a were decreased under high glucose conditions compared to normal glucose conditions, but exposure to fisetin and luteolin induced the expression of SIRT1, SIRT3, SIRT6, and FOXO3a. The above findings suggest that fisetin and luteolin inhibited high glucose-induced ROS production in monocytes through the activation of SIRTs and FOXO3a. The results of our study supports current researches that state fisetin and luteolin as potential agents for the development of novel strategies for diabetes.
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Kim, Arang; Lee, Wooje
2017-01-01
BACKGROUND/OBJECTIVE Chronic hyperglycemia induces oxidative stress via accumulation of reactive oxygen species (ROS) and contributes to diabetic complications. Hyperglycemia induces mitochondrial superoxide anion production through the increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This study aimed to determine whether fisetin and luteolin treatments suppress the oxidative stress by modulating the expression of sirtuins (SIRTs) and forkhead box O3a (FOXO3a) under hyperglycemic conditions in human monocytes. MATERIALS/METHODS Human monocytic cells (THP-1) were cultured under osmotic control (14.5 mmol/L mannitol), normoglycemic (NG, 5.5 mmol/L glucose), or hyperglycemic (HG, 20 mmol/L glucose) conditions, in the absence or presence of fisetin and luteolin for 48 h. To determine the effect of fisetin and luteolin treatments on high glucose-induced oxidative stress, western blotting and intracellular staining were performed. RESULTS Hyperglycemic conditions increased the ROS production, as compared to normoglycemic condition. However, fisetin and luteolin treatments inhibited ROS production under hyperglycemia. To obtain further insight into ROS production in hyperglycemic conditions, evaluation of p47phox expression revealed that fisetin and luteolin treatments inhibited p47phox expression under hyperglycemic conditions. Conversely, the expression levels of SIRT1, SIRT3, SIRT6, and FOXO3a were decreased under high glucose conditions compared to normal glucose conditions, but exposure to fisetin and luteolin induced the expression of SIRT1, SIRT3, SIRT6, and FOXO3a. The above findings suggest that fisetin and luteolin inhibited high glucose-induced ROS production in monocytes through the activation of SIRTs and FOXO3a. CONCLUSIONS The results of our study supports current researches that state fisetin and luteolin as potential agents for the development of novel strategies for diabetes. PMID:28989580
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Lokireddy, Sudarsanareddy; McFarlane, Craig; Ge, Xiaojia; Zhang, Huoming; Sze, Siu Kwan; Sharma, Mridula
2011-01-01
Ubiquitination-mediated proteolysis is a hallmark of skeletal muscle wasting manifested in response to negative growth factors, including myostatin. Thus, the characterization of signaling mechanisms that induce the ubiquitination of intracellular and sarcomeric proteins during skeletal muscle wasting is of great importance. We have recently characterized myostatin as a potent negative regulator of myogenesis and further demonstrated that elevated levels of myostatin in circulation results in the up-regulation of the muscle-specific E3 ligases, Atrogin-1 and muscle ring finger protein 1 (MuRF1). However, the exact signaling mechanisms by which myostatin regulates the expression of Atrogin-1 and MuRF1, as well as the proteins targeted for degradation in response to excess myostatin, remain to be elucidated. In this report, we have demonstrated that myostatin signals through Smad3 (mothers against decapentaplegic homolog 3) to activate forkhead box O1 and Atrogin-1 expression, which further promotes the ubiquitination and subsequent proteasome-mediated degradation of critical sarcomeric proteins. Smad3 signaling was dispensable for myostatin-dependent overexpression of MuRF1. Although down-regulation of Atrogin-1 expression rescued approximately 80% of sarcomeric protein loss induced by myostatin, only about 20% rescue was seen when MuRF1 was silenced, implicating that Atrogin-1 is the predominant E3 ligase through which myostatin manifests skeletal muscle wasting. Furthermore, we have highlighted that Atrogin-1 not only associates with myosin heavy and light chain, but it also ubiquitinates these sarcomeric proteins. Based on presented data we propose a model whereby myostatin induces skeletal muscle wasting through targeting sarcomeric proteins via Smad3-mediated up-regulation of Atrogin-1 and forkhead box O1. PMID:21964591
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Zhu, Jie; Wang, Peng; Yu, Zhimin; Lai, Wei; Cao, Yi; Huang, Pinbo; Xu, Qiaodong; Yu, Menglei; Xu, Junyao; Huang, Zitong; Zeng, Bing
2016-01-01
Diabetes mellitus is frequently accompanied by chronic complications like delayed wound healing, which is consider to be attributed to the accumulation of advanced glycosylation end product (AGE). However, the impacts of AGE on epidermal stem cells (ESCs) are largely unknown. This study aims to address the influence and mechanism of AGE on ESCs. ESCs isolated from rats were cultured in AGE-modified bovine serum albumin and transfected with small interfering RNA to knock down AGE-specific receptor (AGER). Expression of stem cell markers integrin β1 (ITGB1) and keratin 19 (KRT19), cell viability, apoptosis and reactive oxygen species (ROS) were examined. Wnt pathway-related factors Wnt family member 1 (WNT1), WNT3A, β-catenin, v-myc avian myelocytomatosis viral oncogene homolog (MYC), cyclin D1 (CCND1) and matrix metallopeptidase 7 (MMP7) were quantified. The interaction between forkhead box O1 (FOXO1) and β-catenin was assessed by co-immunoprecipitation. Results indicated that AGE down-regulated ITGB1 and KRT19 expression, suppressed ESC viability and promoted apoptosis, and ROS level ( P < 0.01), implying decreased capacities of ESCs. AGE also promoted AGER and FOXO1, while AGER knockdown had the opposite effects. Moreover, AGER knockdown elevated the level of WNT1, WNT3A, MYC, CCND1 and MMP7 that were suppressed by AGE ( P < 0.01). Immunoprecipitation analysis showed that FOXO1 could compete with lymphoid enhancer binding factor 1 to interact with β-catenin, which might help to elucidate the mechanism of AGE repressing ESCs. This study helps to understand the mechanism of accumulated AGE in affecting ESC capacities, and provides potential therapeutic targets to meliorate diabetic wound healing.
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Nerurkar, Pratibha V; Nishioka, Adrienne; Eck, Philip O; Johns, Lisa M; Volper, Esther; Nerurkar, Vivek R
2012-07-01
Renewed interest in alternative medicine among diabetic individuals prompted us to investigate anti-diabetic effects of Morinda citrifolia (noni) in high-fat diet (HFD)-fed mice. Type 2 diabetes is associated with increased glucose production due to the inability of insulin to suppress hepatic gluconeogenesis and promote glycolysis. Insulin inhibits gluconeogenesis by modulating transcription factors such as forkhead box O (FoxO1). Based on microarray analysis data, we tested the hypothesis that fermented noni fruit juice (fNJ) improves glucose metabolism via FoxO1 phosphorylation. C57BL/6 male mice were fed a HFD and fNJ for 12 weeks. Body weights and food intake were monitored daily. FoxO1 expression was analysed by real-time PCR and Western blotting. Specificity of fNJ-associated FoxO1 regulation of gluconeogenesis was confirmed by small interfering RNA (siRNA) studies using human hepatoma cells, HepG2. Supplementation with fNJ inhibited weight gain and improved glucose and insulin tolerance and fasting glucose in HFD-fed mice. Hypoglycaemic properties of fNJ were associated with the inhibition of hepatic FoxO1 mRNA expression, with a concomitant increase in FoxO1 phosphorylation and nuclear expulsion of the proteins. Gluconeogenic genes, phosphoenolpyruvate C kinase (PEPCK) and glucose-6-phosphatase (G6P), were significantly inhibited in mice fed a HFD+fNJ. HepG2 cells demonstrated more than 80 % inhibition of PEPCK and G6P mRNA expression in cells treated with FoxO1 siRNA and fNJ. These data suggest that fNJ improves glucose metabolism via FoxO1 regulation in HFD-fed mice.
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Nerurkar, Pratibha V.; Nishioka, Adrienne; Eck, Philip O.; Nerurkar, Vivek R.
2016-01-01
Renewed interest in alternative medicine among diabetic individuals prompted us to investigate anti-diabetic effects of Morinda citrifolia (noni) in high-fat diet (HFD)-fed mice. Type 2 diabetes is associated with increased glucose production due to the inability of insulin to suppress hepatic gluconeogenesis and promote glycolysis. Insulin inhibits gluconeogenesis by modulating transcription factors such as forkhead box O (FoxO1). Based on microarray analysis data, we tested the hypothesis that fermented noni fruit juice (fNJ) improves glucose metabolism via FoxO1 phosphorylation. C57BL/6 male mice were fed a HFD and fNJ for 12 weeks. Body weights and food intake were monitored daily. FoxO1 expression was analysed by real-time PCR and Western blotting. Specificity of fNJ-associated FoxO1 regulation of gluconeogenesis was confirmed by small interfering RNA (siRNA) studies using human hepatoma cells, HepG2. Supplementation with fNJ inhibited weight gain and improved glucose and insulin tolerance and fasting glucose in HFD-fed mice. Hypoglycaemic properties of fNJ were associated with the inhibition of hepatic FoxO1 mRNA expression, with a concomitant increase in FoxO1 phosphorylation and nuclear expulsion of the proteins. Gluconeogenic genes, phosphoenolpyruvate C kinase (PEPCK) and glucose-6-phosphatase (G6P), were significantly inhibited in mice fed a HFD + fNJ. HepG2 cells demonstrated more than 80% inhibition of PEPCK and G6P mRNA expression in cells treated with FoxO1 siRNA and fNJ. These data suggest that fNJ improves glucose metabolism via FoxO1 regulation in HFD-fed mice. PMID:22011624
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Macleod, Kay F.
2010-01-01
Exposure to pro-oxidants and defects in the repair of oxidative base damage are associated with disease and ageing and also contribute to the development of anaemia, bone marrow failure and haematopoietic malignancies. This Review assesses emerging data indicative of a specific role for the RB tumour suppressor pathway in the response of the haematopoietic system to oxidative stress. This is mediated through signalling pathways that involve DNA damage sensors, forkhead box O (Foxo) transcription factors and p38 mitogen-activated protein kinases and has downstream consequences for cell cycle progression, antioxidant capacity, mitochondrial mass and cellular metabolism. PMID:18800074
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Kim, Il-Man; Ramakrishna, Sneha; Gusarova, Galina A; Yoder, Helena M; Costa, Robert H; Kalinichenko, Vladimir V
2005-06-10
Transgenic and gene knock-out studies demonstrated that the mouse Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) is essential for hepatocyte entry into mitosis during liver development, regeneration, and liver cancer. Targeted deletion of Foxm1 gene in mice produces an embryonic lethal phenotype due to severe abnormalities in the development of liver and heart. In this study, we show for the first time that Foxm1(-/-) lungs exhibit severe hypertrophy of arteriolar smooth muscle cells and defects in the formation of peripheral pulmonary capillaries as evidenced by significant reduction in platelet endothelial cell adhesion molecule 1 staining of the distal lung. Consistent with these findings, significant reduction in proliferation of the embryonic Foxm1(-/-) lung mesenchyme was found, yet proliferation levels were normal in the Foxm1-deficient epithelial cells. Severe abnormalities of the lung vasculature in Foxm1(-/-) embryos were associated with diminished expression of the transforming growth factor beta receptor II, a disintegrin and metalloprotease domain 17 (ADAM-17), vascular endothelial growth factor receptors, Polo-like kinase 1, Aurora B kinase, laminin alpha4 (Lama4), and the Forkhead Box f1 transcription factor. Cotransfection studies demonstrated that Foxm1 stimulates transcription of the Lama4 promoter, and this stimulation requires the Foxm1 binding sites located between -1174 and -1145 bp of the mouse Lama4 promoter. In summary, development of mouse lungs depends on the Foxm1 transcription factor, which regulates expression of genes essential for mesenchyme proliferation, extracellular matrix remodeling, and vasculogenesis.
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FoxO is a critical regulator of stem cell maintenance in immortal Hydra.
Boehm, Anna-Marei; Khalturin, Konstantin; Anton-Erxleben, Friederike; Hemmrich, Georg; Klostermeier, Ulrich C; Lopez-Quintero, Javier A; Oberg, Hans-Heinrich; Puchert, Malte; Rosenstiel, Philip; Wittlieb, Jörg; Bosch, Thomas C G
2012-11-27
Hydra's unlimited life span has long attracted attention from natural scientists. The reason for that phenomenon is the indefinite self-renewal capacity of its stem cells. The underlying molecular mechanisms have yet to be explored. Here, by comparing the transcriptomes of Hydra's stem cells followed by functional analysis using transgenic polyps, we identified the transcription factor forkhead box O (FoxO) as one of the critical drivers of this continuous self-renewal. foxO overexpression increased interstitial stem cell and progenitor cell proliferation and activated stem cell genes in terminally differentiated somatic cells. foxO down-regulation led to an increase in the number of terminally differentiated cells, resulting in a drastically reduced population growth rate. In addition, it caused down-regulation of stem cell genes and antimicrobial peptide (AMP) expression. These findings contribute to a molecular understanding of Hydra's immortality, indicate an evolutionarily conserved role of FoxO in controlling longevity from Hydra to humans, and have implications for understanding cellular aging.
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Intracellular distribution of a speech/language disorder associated FOXP2 mutant
DOE Office of Scientific and Technical Information (OSTI.GOV)
Mizutani, Akifumi; Department of Pediatrics, Jichi Medical University, Yakushiji 3311-1, Shimotsukeshi, Tochigi 329-0498; Matsuzaki, Ayumi
Although a mutation (R553H) in the forkhead box (FOX)P2 gene is associated with speech/language disorder, little is known about the function of FOXP2 or its relevance to this disorder. In the present study, we identify the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. A truncated version of FOXP2 lacking the leu-zip, Zn{sup 2+} finger, and forkhead domains that was observed in another patient with speech abnormalities demonstrated an aggregated cytoplasmic localization. Furthermore, FOXP2 (R553H) mainly exhibited a cytoplasmic localizationmore » despite retaining interactions with nuclear transport proteins (importin {alpha} and {beta}). Interestingly, wild type FOXP2 promoted the transport of FOXP2 (R553H) into the nucleus. Mutant and wild type FOXP2 heterodimers in the nucleus or FOXP2 R553H in the cytoplasm may underlie the pathogenesis of the autosomal dominant speech/language disorder.« less
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Park, Hyun Jung; Costa, Robert H.; Lau, Lester F.; Tyner, Angela L.; Raychaudhuri, Pradip
2008-01-01
The forkhead box M1 (FoxM1) transcription factor is overexpressed in many cancers, and in mouse models it is required for tumor progression. FoxM1 activates expression of the cell cycle genes required for both S and M phase progression. Here we demonstrate that FoxM1 is degraded in late mitosis and early G1 phase by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. FoxM1 interacts with the APC/C complex and its adaptor, Cdh1. Expression of Cdh1 stimulated degradation of the FoxM1 protein, and depletion of Cdh1 resulted in stabilization of the FoxM1 protein in late mitosis and in early G1 phase of the cell cycle. Cdh1 has been implicated in regulating S phase entry. We show that codepletion of FoxM1 inhibits early S phase entry observed in Cdh1-depleted cells. The N-terminal region of FoxM1 contains both destruction box (D box) and KEN box sequences that are required for targeting by Cdh1. Mutation of either the D box sequence or the KEN box sequence stabilized FoxM1 and blocked Cdh1-induced proteolysis. Cells expressing a nondegradable form of FoxM1 entered S phase rapidly following release from M phase arrest. Together, our observations show that FoxM1 is one of the targets of Cdh1 in late M or early G1 phase and that its proteolysis is important for regulated entry into S phase. PMID:18573889
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Park, Hyun Jung; Costa, Robert H; Lau, Lester F; Tyner, Angela L; Raychaudhuri, Pradip
2008-09-01
The forkhead box M1 (FoxM1) transcription factor is overexpressed in many cancers, and in mouse models it is required for tumor progression. FoxM1 activates expression of the cell cycle genes required for both S and M phase progression. Here we demonstrate that FoxM1 is degraded in late mitosis and early G(1) phase by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. FoxM1 interacts with the APC/C complex and its adaptor, Cdh1. Expression of Cdh1 stimulated degradation of the FoxM1 protein, and depletion of Cdh1 resulted in stabilization of the FoxM1 protein in late mitosis and in early G(1) phase of the cell cycle. Cdh1 has been implicated in regulating S phase entry. We show that codepletion of FoxM1 inhibits early S phase entry observed in Cdh1-depleted cells. The N-terminal region of FoxM1 contains both destruction box (D box) and KEN box sequences that are required for targeting by Cdh1. Mutation of either the D box sequence or the KEN box sequence stabilized FoxM1 and blocked Cdh1-induced proteolysis. Cells expressing a nondegradable form of FoxM1 entered S phase rapidly following release from M phase arrest. Together, our observations show that FoxM1 is one of the targets of Cdh1 in late M or early G(1) phase and that its proteolysis is important for regulated entry into S phase.
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FOXO family in regulating cancer and metabolism.
Ma, Jian; Matkar, Smita; He, Xin; Hua, Xianxin
2018-06-01
FOXO proteins are a sub-group of a superfamily of forkhead box (FOX)-containing transcription factors (TFs). FOXOs play an important role in regulating a plethora of biological activities ranging from development, cell signaling, and tumorigenesis to cell metabolism. Here we mainly focus on reviewing the role of FOXOs in regulating tumor and metabolism. Moreover, how crosstalk among various pathways influences the function of FOXOs will be reviewed. Further, the paradoxical role for FOXOs in controlling the fate of cancer and especially resistance/sensitivity of cancer to the class of drugs that target PI3K/AKT will also be reviewed. Finally, how FOXOs regulate crosstalk between common cancer pathways and cell metabolism pathways, and how these crosstalks affect the fate of the cancer will be discussed. Copyright © 2018. Published by Elsevier Ltd.
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Wang, F J; Jin, L; Guo, Y Q; Liu, R; He, M N; Li, M Z; Li, X W
2014-11-27
Muscle growth and development is associated with remarkable changes in protein-coding and microRNA (miRNA) gene expression. To determine the expression patterns of genes and miRNAs related to muscle growth and development, we measured the expression levels of 25 protein-coding and 16 miRNA genes in skeletal and cardiac muscles throughout 5 developmental stages by quantitative reverse transcription-polymerase chain reaction. The Short Time-Series Expression Miner (STEM) software clustering results showed that growth-related genes were downregulated at all developmental stages in both the psoas major and longissimus dorsi muscles, indicating their involvement in early developmental stages. Furthermore, genes related to muscle atrophy, such as forkhead box 1 and muscle ring finger, showed unregulated expression with increasing age, suggesting a decrease in protein synthesis during the later stages of skeletal muscle development. We found that development of the cardiac muscle was a complex process in which growth-related genes were highly expressed during embryonic development, but they did not show uniform postnatal expression patterns. Moreover, the expression level of miR-499, which enhances the expression of the β-myosin heavy chain, was significantly different in the psoas major and longissimus dorsi muscles, suggesting the involvement of miR-499 in the determination of skeletal muscle fiber types. We also performed correlation analyses of messenger RNA and miRNA expression. We found negative relationships between miR-486 and forkhead box 1, and miR-133a and serum response factor at all developmental stages, suggesting that forkhead box 1 and serum response factor are potential targets of miR-486 and miR-133a, respectively.
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The cunning little vixen: Foxo and the cycle of life and death.
Hedrick, Stephen M
2009-10-01
A screen for increased longevity in Caenorhabditis elegans has identified a transcription factor that programs cells for resistance to oxidative stress, DNA repair and cell cycle control. The mammalian orthologs of this factor are referred to as 'Foxo' for 'Forkhead box', with the second 'o' in the name denoting a subfamily of four members related by sequence. This family of factors is regulated by growth factors, oxidative stress or nutrient deprivation. Thus, it might readily control the inflammatory conflagration associated with infection-driven lymphocyte proliferation. Surprisingly, the first insights into Foxo-mediated immune regulation have instead revealed direct control of highly specialized genes of the adaptive immune system.
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Overexpression of androgen receptor and forkhead-box A1 protein in apocrine breast carcinoma.
Sasahara, Manami; Matsui, Akira; Ichimura, Yoshiko; Hirakata, Yuuko; Murata, Yuuya; Marui, Eiji
2014-03-01
Apocrine breast carcinoma often lacks estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type-2 (HER2) expression. Accordingly, development of a new treatment strategy is important for this type of cancer. The growth stimulus through the androgen receptor (AR) can be a candidate for targeted treatment. Therefore, we examined the factors related to AR transcription. We immunohistochemically evaluated 54 apocrine cancer lesions for ER, PgR, AR, HER2, Ki-67, forkhead-box protein A1 (FOXA1), and prostate-specific antigen (PSA) expression. ER, PgR, and HER2 were expressed at a low level, thus 44 out of 54 (81.4%) cases were of triple-negative breast cancer. AR, PSA and FOXA1 were expressed in 100% (54/54), 48% (26/54) and 93% (50/54) of cases, respectively. Most of apocrine breast carcinomas were immunohistochemically-positive for AR and FOXA1. Anti-androgenic therapies can potentially serve as a cancer-targeting therapy for apocrine breast carcinoma.
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Kluth, O; Mirhashemi, F; Scherneck, S; Kaiser, D; Kluge, R; Neschen, S; Joost, H-G; Schürmann, A
2011-03-01
Carbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days. Mice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days. Dietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins. The dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells.
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Zhao, Zhiming; Li, Chenggang; Xi, Hao; Gao, Yuanxing; Xu, Dabin
2015-10-01
Previous population investigations have suggested that the application of curcumin may be associated with decreased incidence and improved prognosis in certain types of cancer. Forkhead box O1 (FOXO1) has been implicated in the regulation of several biological processes, including stress resistance, metabolism, DNA repair, cell cycle and apoptosis. The aims of the present study were to investigate the effects and molecular mechanisms of curcumin on the induction of anti‑proliferation, cell cycle arrest and apoptosis, by FOXO1, in pancreatic cancer cells. The MTT assay and ELISA‑Brdu assay were used to assess cell proliferation. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were used to detect the expression of PCNA, Ki‑67, B‑cell lymphoma‑2 (Bcl‑2), B‑cell‑associated X protein (Bax), cyclin D1, p21, p27 and FOXO1. Cell apoptosis was detected using a Cell Death ELISA detection kit. A Caspase‑3/9 Fluorescent Assay kit was used to detect caspase activity. The findings revealed that curcumin significantly decreased cell proliferation, which was associated with increased expression of the p21/CIP1 and p27/KIP1 cyclin‑dependent kinase inhibitors, and inhibited expression of cyclin D1. In addition, curcumin induced apoptosis by decreasing the Bcl‑2/Bax protein ratio and increasing caspase‑9/3 activation in the pancreatic cancer cells. Using siRNA against FOXO1, and Akt inhibitor and activator, the present study confirmed that curcumin induced the expression of FOXO1 by inhibition of phosphoinositide 3‑kinase/Akt signaling, leading to cell cycle arrest and apoptosis. In conclusion, these findings offer support for a mechanism that may underlie the anti‑neoplastic effects of curcumin and justify further investigation to examine the potential roles for activators of FOXO1 in the prevention and treatment of pancreatic cancer.
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Jedlička, Pavel; Ernst, Ulrich R; Votavová, Alena; Hanus, Robert; Valterová, Irena
2016-01-01
Understanding the social evolution leading to insect eusociality requires, among other, a detailed insight into endocrine regulatory mechanisms that have been co-opted from solitary ancestors to play new roles in the complex life histories of eusocial species. Bumblebees represent well-suited models of a relatively primitive social organization standing on the mid-way to highly advanced eusociality and their queens undergo both, a solitary and a social phase, separated by winter diapause. In the present paper, we characterize the gene expression levels of major endocrine regulatory pathways across tissues, sexes, and life-stages of the buff-tailed bumblebee, Bombus terrestris , with special emphasis on critical stages of the queen's transition from solitary to social life. We focused on fundamental genes of three pathways: (1) Forkhead box protein O and insulin/insulin-like signaling, (2) Juvenile hormone (JH) signaling, and (3) Adipokinetic hormone signaling. Virgin queens were distinguished by higher expression of forkhead box protein O and downregulated insulin-like peptides and JH signaling, indicated by low expression of methyl farnesoate epoxidase ( MFE ) and transcription factor Krüppel homolog 1 ( Kr-h1 ). Diapausing queens showed the expected downregulation of JH signaling in terms of low MFE and vitellogenin ( Vg ) expressions, but an unexpectedly high expression of Kr-h1 . By contrast, reproducing queens revealed an upregulation of MFE and Vg together with insulin signaling. Surprisingly, the insulin growth factor 1 (IGF-1) turned out to be a queen-specific hormone. Workers exhibited an expression pattern of MFE and Vg similar to that of reproducing queens. Males were characterized by high Kr-h1 expression and low Vg level. The tissue comparison unveiled an unexpected resemblance between the fat body and hypopharyngeal glands across all investigated genes, sexes, and life stages.
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Fetterman, Christina D; Rannala, Bruce; Walter, Michael A
2008-09-24
Members of the forkhead gene family act as transcription regulators in biological processes including development and metabolism. The evolution of forkhead genes has not been widely examined and selection pressures at the molecular level influencing subfamily evolution and differentiation have not been explored. Here, in silico methods were used to examine selection pressures acting on the coding sequence of five multi-species FOX protein subfamily clusters; FoxA, FoxD, FoxI, FoxO and FoxP. Application of site models, which estimate overall selection pressures on individual codons throughout the phylogeny, showed that the amino acid changes observed were either neutral or under negative selection. Branch-site models, which allow estimated selection pressures along specified lineages to vary as compared to the remaining phylogeny, identified positive selection along branches leading to the FoxA3 and Protostomia clades in the FoxA cluster and the branch leading to the FoxO3 clade in the FoxO cluster. Residues that may differentiate paralogs were identified in the FoxA and FoxO clusters and residues that differentiate orthologs were identified in the FoxA cluster. Neutral amino acid changes were identified in the forkhead domain of the FoxA, FoxD and FoxP clusters while positive selection was identified in the forkhead domain of the Protostomia lineage of the FoxA cluster. A series of residues under strong negative selection adjacent to the N- and C-termini of the forkhead domain were identified in all clusters analyzed suggesting a new method for refinement of domain boundaries. Extrapolation of domains among cluster members in conjunction with selection pressure information allowed prediction of residue function in the FoxA, FoxO and FoxP clusters and exclusion of known domain function in residues of the FoxA and FoxI clusters. Consideration of selection pressures observed in conjunction with known functional information allowed prediction of residue function and refinement of domain boundaries. Identification of residues that differentiate orthologs and paralogs provided insight into the development and functional consequences of paralogs and forkhead subfamily composition differences among species. Overall we found that after gene duplication of forkhead family members, rapid differentiation and subsequent fixation of amino acid changes through negative selection has occurred.
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FOXO1, TGF-β Regulation and Wound Healing
Hameedaldeen, Alhassan; Liu, Jian; Batres, Angelika; Graves, Gabrielle S.; Graves, Dana T.
2014-01-01
Re-epithelialization is a complex process that involves migration and proliferation of keratinocytes, in addition to the production of cytokines and growth factors that affect other cells. The induction of transcription factors during these processes is crucial for successful wound healing. The transcription factor forkhead boxO-1 (FOXO1) has recently been found to be an important regulator of wound healing. In particular, FOXO1 has significant effects through regulation of transforming growth factor-beta (TGF-β) expression and protecting keratinocytes from oxidative stress. In the absence of FOXO1, there is increased oxidative damage, reduced TGF-β1 expression, reduced migration and proliferation of keratinocytes and increased keratinocytes apoptosis leading to impaired re-epithelialization of wounds. PMID:25226535
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SIRT1 may play a crucial role in overload-induced hypertrophy of skeletal muscle.
Koltai, Erika; Bori, Zoltán; Chabert, Clovis; Dubouchaud, Hervé; Naito, Hisashi; Machida, Shuichi; Davies, Kelvin Ja; Murlasits, Zsolt; Fry, Andrew C; Boldogh, Istvan; Radak, Zsolt
2017-06-01
Silent mating type information regulation 2 homologue 1 (SIRT1) activity and content increased significantly in overload-induced hypertrophy. SIRT1-mediated signalling through Akt, the endothelial nitric oxide synthase mediated pathway, regulates anabolic process in the hypertrophy of skeletal muscle. The regulation of catabolic signalling via forkhead box O 1 and protein ubiquitination is SIRT1 dependent. Overload-induced changes in microRNA levels regulate SIRT1 and insulin-like growth factor 1 signalling. Significant skeletal muscle mass guarantees functional wellbeing and is important for high level performance in many sports. Although the molecular mechanism for skeletal muscle hypertrophy has been well studied, it still is not completely understood. In the present study, we used a functional overload model to induce plantaris muscle hypertrophy by surgically removing the soleus and gastrocnemius muscles in rats. Two weeks of muscle ablation resulted in a 40% increase in muscle mass, which was associated with a significant increase in silent mating type information regulation 2 homologue 1 (SIRT1) content and activity (P < 0.001). SIRT1-regulated Akt, endothelial nitric oxide synthase and GLUT4 levels were also induced in hypertrophied muscles, and SIRT1 levels correlated with muscle mass, paired box protein 7 (Pax7), proliferating cell nuclear antigen (PCNA) and nicotinamide phosphoribosyltransferase (Nampt) levels. Alternatively, decreased forkhead box O 1 (FOXO1) and increased K48 polyubiquitination also suggest that SIRT1 could be involved in the catabolic process of hypertrophy. Furthermore, increased levels of K63 and muscle RING finger 2 (MuRF2) protein could also be important enhancers of muscle mass. We report here that the levels of miR1 and miR133a decrease in hypertrophy and negatively correlate with muscle mass, SIRT1 and Nampt levels. Our results reveal a strong correlation between SIRT1 levels and activity, SIRT1-regulated pathways and overload-induced hypertrophy. These findings, along with the well-known regulatory roles that SIRT1 plays in modulating both anabolic and catabolic pathways, allow us to propose the hypothesis that SIRT1 may actually play a crucial causal role in overload-induced hypertrophy of skeletal muscle. This hypothesis will now require rigorous direct and functional testing. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.
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SIRT1 may play a crucial role in overload‐induced hypertrophy of skeletal muscle
Koltai, Erika; Bori, Zoltán; Chabert, Clovis; Dubouchaud, Hervé; Naito, Hisashi; Machida, Shuichi; Davies, Kelvin JA; Murlasits, Zsolt; Fry, Andrew C; Boldogh, Istvan
2017-01-01
Key points Silent mating type information regulation 2 homologue 1 (SIRT1) activity and content increased significantly in overload‐induced hypertrophy.SIRT1‐mediated signalling through Akt, the endothelial nitric oxide synthase mediated pathway, regulates anabolic process in the hypertrophy of skeletal muscle.The regulation of catabolic signalling via forkhead box O 1 and protein ubiquitination is SIRT1 dependent.Overload‐induced changes in microRNA levels regulate SIRT1 and insulin‐like growth factor 1 signalling. Abstract Significant skeletal muscle mass guarantees functional wellbeing and is important for high level performance in many sports. Although the molecular mechanism for skeletal muscle hypertrophy has been well studied, it still is not completely understood. In the present study, we used a functional overload model to induce plantaris muscle hypertrophy by surgically removing the soleus and gastrocnemius muscles in rats. Two weeks of muscle ablation resulted in a 40% increase in muscle mass, which was associated with a significant increase in silent mating type information regulation 2 homologue 1 (SIRT1) content and activity (P < 0.001). SIRT1‐regulated Akt, endothelial nitric oxide synthase and GLUT4 levels were also induced in hypertrophied muscles, and SIRT1 levels correlated with muscle mass, paired box protein 7 (Pax7), proliferating cell nuclear antigen (PCNA) and nicotinamide phosphoribosyltransferase (Nampt) levels. Alternatively, decreased forkhead box O 1 (FOXO1) and increased K48 polyubiquitination also suggest that SIRT1 could be involved in the catabolic process of hypertrophy. Furthermore, increased levels of K63 and muscle RING finger 2 (MuRF2) protein could also be important enhancers of muscle mass. We report here that the levels of miR1 and miR133a decrease in hypertrophy and negatively correlate with muscle mass, SIRT1 and Nampt levels. Our results reveal a strong correlation between SIRT1 levels and activity, SIRT1‐regulated pathways and overload‐induced hypertrophy. These findings, along with the well‐known regulatory roles that SIRT1 plays in modulating both anabolic and catabolic pathways, allow us to propose the hypothesis that SIRT1 may actually play a crucial causal role in overload‐induced hypertrophy of skeletal muscle. This hypothesis will now require rigorous direct and functional testing. PMID:28251652
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Kang, Seol-Hee; Lee, Hae-Ahm; Kim, Mina; Lee, Eunjo; Sohn, Uy Dong; Kim, Inkyeom
2017-06-01
Cushing's syndrome is caused by overproduction of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal grand to make cortisol. Skeletal muscle wasting occurs in pathophysiological response to Cushing's syndrome. The forkhead box (FOX) protein family has been implicated as a key regulator of muscle loss under conditions such as diabetes and sepsis. However, the mechanistic role of the FOXO family in ACTH-induced muscle atrophy is not understood. We hypothesized that FOXO3a plays a role in muscle atrophy through expression of the E3 ubiquitin ligases, muscle RING finger protein-1 (MuRF-1), and atrogin-1 in Cushing's syndrome. For establishment of a Cushing's syndrome animal model, Sprague-Dawley rats were implanted with osmotic minipumps containing ACTH (40 ng·kg -1 ·day -1 ). ACTH infusion significantly reduced muscle weight. In ACTH-infused rats, MuRF-1, atrogin-1, and FOXO3a were upregulated and the FOXO3a promoter was targeted by the glucocorticoid receptor (GR). Transcriptional activity and expression of FOXO3a were significantly decreased by the GR antagonist RU486. Treatment with RU486 reduced MuRF-1 and atrogin-1 expression in accordance with reduced enrichment of FOXO3a and Pol II on the promoters. Knockdown of FOXO3a prevented dexamethasone-induced MuRF-1 and atrogin-1 expression. These results indicate that FOXO3a plays a role in muscle atrophy through expression of MuRF-1 and atrogin-1 in Cushing's syndrome. Copyright © 2017 the American Physiological Society.
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Bong, Jin Jong; Jeong, Jin Young; Rajasekar, Panchamoorthy; Cho, Young Moo; Kwon, Eung Gi; Kim, Hyeong Cheol; Paek, Bong Hyun; Baik, Myunggi
2012-07-01
The objective of this study was to compare expression of genes associated with lipid deposition and removal between bulls and steers in the longissimus dorsi muscle (LM) tissue of Korean cattle. Castration increased the expression of lipid uptake lipoprotein lipase, fatty acid translocase, and fatty acid transport protein 1 in LM. Castration increased lipogenic gene expression of both acetyl-CoA carboxylase and fatty acid synthase. In contrast, castration downregulated lipolytic gene expression of both adipose triglyceride lipase (ATGL) and monoglyceride lipase. Steers showed higher expression levels of insulin signaling phospho-v-akt murine thymoma viral oncogene homolog 1 than bulls but lower protein levels of nuclear Forkhead box O 1 (FoxO1) than bulls, suggesting that increased insulin signaling following castration decreases nuclear FoxO1 levels, leading to downregulation of ATGL gene expression. These findings suggest that castration contributes to increases in lipid uptake and lipogenesis and a decrease in lipolysis, resulting in improved marbling. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Dynamic Regulation of FoxA1 by Steroid Receptors | Center for Cancer Research
The estrogen receptor (ER) is a key regulator in breast cancer initiation and progression. A widely discussed model proposes that forkhead box protein A1 (FoxA1) acts as a pioneer factor in cancer by binding and penetrating closed chromatin to allow access by transcription factors (TFs), including ER.
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Tanabe, Yuko; Fujita, Eriko; Momoi, Takashi
2011-07-08
FOXP2 is a forkhead box-containing transcription factor with several recognizable sequence motifs. However, little is known about the FOXP2-associated proteins except for C-terminal binding protein (CtBP). In the present study, we attempted to isolate the FOXP2-associated protein with a yeast two-hybrid system using the C-terminal region, including the forkhead domain, as a bait probe, and identified protection of telomeres 1 (POT1) as a FOXP2-associated protein. Immunoprecipitation assay confirmed the association with FOXP2 and POT1. POT1 alone localized in the cytoplasm but co-localized with FOXP2 and the forkhead domain of FOXP2 in nuclei. However, both FOXP2 with mutated nuclear localization signals and (R553H) mutated forkhead, which is associated with speech-language disorder, prevented the nuclear translocation of POT1. These results suggest that FOXP2 is a binding partner for the nuclear translocation of POT1. As loss of POT1 function induces the cell arrest, the impaired nuclear translocation of POT1 in the developing neuronal cells may be associated with the pathogenesis of speech-language disorder with FOXP2(R553H) mutation. Copyright © 2011 Elsevier Inc. All rights reserved.
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Foucher, Isabelle; Volovitch, Michel; Frain, Monique; Kim, J Julie; Souberbielle, Jean-Claude; Gan, Lixia; Unterman, Terry G; Prochiantz, Alain; Trembleau, Alain
2002-09-01
Transgenic mice expressing the homeobox gene Hoxa5 under the control of Hoxb2 regulatory elements present a growth arrest during weeks two and three of postnatal development, resulting in proportionate dwarfism. These mice present a liver phenotype illustrated by a 12-fold increase in liver insulin-like growth factor binding protein 1 (IGFBP1) mRNA and a 50% decrease in liver insulin-like growth factor 1 (IGF1) mRNA correlated with a 50% decrease in circulating IGF1. We show that the Hoxa5 transgene is expressed in the liver of these mice, leading to an overexpression of total (endogenous plus transgene) Hoxa5 mRNA in this tissue. We have used several cell lines to investigate a possible physiological interaction of Hoxa5 with the main regulator of IGFBP1 promoter activity, the Forkhead box transcription factor FKHR. In HepG2 cells, Hoxa5 has little effect by itself but inhibits the FKHR-dependent activation of the IGFBP1 promoter. In HuF cells, Hoxa5 cooperates with FKHR to dramatically enhance IGFBP1 promoter activity. This context-dependent physiological interaction probably corresponds to the existence of a direct interaction between Hoxa5 and FKHR and FoxA2/HNF3beta, as demonstrated by pull-down experiments achieved either in vitro or after cellular co-expression. In conclusion, we propose that the impaired growth observed in this transgenic line relates to a liver phenotype best explained by a direct interaction between Hoxa5 and liver-specific Forkhead box transcription factors, in particular FKHR but also Foxa2/HNF3beta. Because Hoxa5 and homeogenes of the same paralog group are normally expressed in the liver, the present results raise the possibility that homeoproteins, in addition to their established role during early development, regulate systemic physiological functions.
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Janikashvili, Nona; Trad, Malika; Gautheron, Alexandrine; Samson, Maxime; Lamarthée, Baptiste; Bonnefoy, Francis; Lemaire-Ewing, Stéphanie; Ciudad, Marion; Rekhviashvili, Khatuna; Seaphanh, Famky; Gaugler, Béatrice; Perruche, Sylvain; Bateman, Andrew; Martin, Laurent; Audia, Sylvain; Saas, Philippe; Larmonier, Nicolas; Bonnotte, Bernard
2015-06-01
Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells. We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders. HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo. The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc(-/-) [NSG] mice). CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo. The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3-positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice. Ex vivo-generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3-positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Majumdar, Sreeparna; Farris, Corrie L.; Kabat, Brock E.; Jung, Deborah O.; Ellsworth, Buffy S.
2012-01-01
Congenital pituitary hormone deficiencies have been reported in approximately one in 4,000 live births, however studies reporting mutations in some widely studied transcription factors account for only a fraction of congenital hormone deficiencies in humans. Anterior pituitary hormones are required for development and function of several glands including gonads, adrenals, and thyroid. In order to identify additional factors that contribute to human congenital hormone deficiencies, we are investigating the forkhead transcription factor, FOXO1, which has been implicated in development of several organs including ovary, testis, and brain. We find that FOXO1 is present in the nuclei of non-dividing pituitary cells during embryonic development, consistent with a role in limiting proliferation and/or promoting differentiation. FOXO1 is present in a subset of differentiated cells at e18.5 and in adult with highest level of expression in somatotrope cells. We detected FOXO1 in p27Kip1-positive cells at e14.5. In the absence of p27Kip1 the number of pituitary cells containing FOXO1 is significantly increased at e14.5 suggesting that a feedback loop regulates the interplay between FOXO1 and p27Kip1. PMID:23251696
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Zimmer, J; Takahashi, T; Hofmann, A D; Puri, Prem
2016-12-01
High mortality and morbidity in infants born with congenital diaphragmatic hernia (CDH) are attributed to pulmonary hypoplasia and pulmonary hypertension (PH). Forkhead box (Fox) transcription factors are known to be crucial for cell proliferation and homeostasis. FoxF1 is essential for lung morphogenesis, vascular development, and endothelial proliferation. Mutations in FoxF1 and also the Fox family member FoxC2 have been identified in neonates with PH. In human and experimental models of arterial PH, the Fox protein FoxO1 was found to be downregulated. We hypothesized that Fox expression is altered in the lungs of the nitrofen-induced CDH rat model and investigated the expression of FoxF1, FoxC2, and FoxO1. Following ethical approval (Rec 913b), time-pregnant Sprague-Dawley rats received nitrofen or vehicle on gestational day (D9). Fetuses were sacrificed on D21, inspected for CDH and divided into CDH (n = 11) and control group (n = 11). Gene expression of FoxF1, FoxC2, and FoxO1 was evaluated with qRT-PCR. Detected alterations of mRNA levels were subsequently assessed on the protein level by performing western blot analysis and laser scanning confocal microscopy. The relative mRNA level of FoxF1 was significantly downregulated in CDH lungs compared to controls (FoxF1 CDH 1.047 ± 0.108, FoxF1 Ctrl 1.419 ± 0.01, p = 0.014). Relative mRNA levels of FoxC2 and FoxO1 were not found to be altered between the experimental groups (FoxC2 CDH 30.74 ± 8.925, FoxC2 Ctrl 27.408 ± 7.487, p = 0.776; FoxO1 CDH 0.011 ± 0.002, FoxO1 Ctrl 0.011 ± 0.001, p = 0.809). On the protein level, western blotting demonstrated a reduced pulmonary protein expression of FoxF1 in CDH lungs. Confocal microscopy showed a markedly diminished expression of FoxF1 in the pulmonary vasculature of CDH lungs compared to controls. Our study demonstrates a strikingly reduced expression of FoxF1 in the pulmonary vasculature of nitrofen-induced CDH. Altered FoxF1 gene expression during embryogenesis may participate in vascular maldevelopment resulting in PH in this animal model.
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Pedersen, Kim Brint; Chodavarapu, Harshita
2017-01-01
Angiotensin-converting enzyme 2 (ACE2) has protective effects on a wide range of morbidities associated with elevated angiotensin-II signaling. Most tissues, including pancreatic islets, express ACE2 mainly from the proximal promoter region. We previously found that hepatocyte nuclear factors 1α and 1β stimulate ACE2 expression from three highly conserved hepatocyte nuclear factor 1 binding motifs in the proximal promoter region. We hypothesized that other highly conserved motifs would also affect ACE2 expression. By systematic mutation of conserved elements, we identified five regions affecting ACE2 expression, of which two regions bound transcriptional activators. One of these is a functional FOXA binding motif. We further identified the main protein binding the FOXA motif in 832/13 insulinoma cells as well as in mouse pancreatic islets as FOXA2. PMID:29082356
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Zhang, Yanni; Zhao, Hui; Zhang, Lichuan
2018-06-01
Circular RNAs (circRNAs) are a class of endo-genous noncoding RNAs that have been demonstrated to be potential regulators in the development and progression of various types of human cancer. However, little is known about their roles in cancer initiation and progression, particular in non‑small cell lung cancer (NSCLC). In the present study, the expression level of circRNA‑forkhead box O3 class (FOXO3) in NSCLC specimens was determined and its functional role was investigated in NSCLC cells. By performing Taq‑man based RT‑qPCR, it was identified that circRNA‑FOXO3 was downregulated in NSCLC tissues and cell lines. Receiver operating curve analysis indicated that circRNA‑FOXO3 had a relatively higher diagnostic accuracy. The functional relevance was further examined by biological assays. circRNA‑FOXO3 significantly promoted the ability of cell proliferation, migration and invasion of NSCLC cells. The linear isomer of circRNA‑FOXO3, FOXO3 gene, was identified as a downstream target. RNA immunoprecipitation indicated that circRNA‑FOXO3 sequestering miR‑155, which further promoted linear FOXO3 expression. In addition, gain and loss functional assays indicated that circRNA‑FOXO3 served an anti‑oncogenic role through sequestering miR‑155 and enhancing FOXO3 expression. These results suggest that circRNA‑FOXO3 is a tumor‑suppressor in NSCLC and may serve as a promising therapeutic target. Therefore, restoration of circRNA‑FOXO3 expression could be a future approach to develop a novel treatment strategy.
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Zhou, Hong-Jing; Zeng, Chen-Ye; Yang, Ting-Ting; Long, Fang-Yi; Kuang, Xi; Du, Jun-Rong
2018-05-01
Oxidative stress caused by aging aggravates neuropathological changes and cognitive deficits. Klotho, an anti-aging protein, shows an anti-oxidative effect. The aims of the present study were to determine the potential therapeutic effect of klotho in aging-related neuropathological changes and memory impairments in senescence-accelerated mouse prone-8 (SAMP8) mice, and identify the potential mechanism of these neuroprotective effects. A lentivirus was used to deliver and sustain the expression of klotho. The lentiviral vectors were injected into the bilateral lateral ventricles of 7-month-old SAMP8 mice or age-matched SAMR1 mice. Three months later, the Y-maze alternation task and passive avoidance task were used to assess the memory deficits of the mice. In situ hybridization, immunohistochemistry, immunofluorescence, Nissl staining, quantitative real-time PCR and Western blot assays were applied in the following research. Our results showed that 3 months after injection of the lentiviral vectors encoding the full-length klotho gene, the expression of klotho in the brain was significantly increased in 10-month-old SAMP8 mice. This treatment reduced memory deficits, neuronal loss, synaptic damage and 4-HNE levels but increased mitochondrial manganese-superoxide dismutase (Mn-SOD) and catalase (CAT) expression. Moreover, the up-regulation of klotho expression decreased Akt and Forkhead box class O1 (FoxO1) phosphorylation. The present study provides a novel approach for klotho gene therapy and demonstrates that direct up-regulation of klotho in the brain might improve aging-related memory impairments and decrease oxidative stress. The underlying mechanism of this effect likely involves the inhibition of the Akt/FoxO1 pathway. Copyright © 2018 Elsevier Inc. All rights reserved.
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A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP‐2
Li, Yujie; Song, Yongfeng; Zhao, Meng; Guo, Yanjing; Yu, Chunxiao; Chen, Wenbin; Shao, Shanshan; Xu, Chao; Zhou, Xinli; Zhao, Lifang; Zhang, Zhenhai; Bo, Tao; Xia, Yu; Proud, Christopher G.; Wang, Xuemin; Wang, Li; Zhao, Jiajun
2017-01-01
Cholesterol synthesis is regulated by the transcription factor sterol regulatory element binding protein 2 (SREBP‐2) and its target gene 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR), which is the rate‐limiting enzyme in cholesterol synthesis. Cyclic adenosine monophosphate–responsive element (CRE) binding protein–regulated transcription coactivator (CRTC) 2 is the master regulator of glucose metabolism. However, the effect of CRTC2 on cholesterol and its potential molecular mechanism remain unclear. Here, we demonstrated that CRTC2 expression and liver cholesterol content were increased in patients with high serum cholesterol levels who underwent resection of liver hemangiomas, as well as in mice fed a 4% cholesterol diet. Mice with adenovirus‐mediated CRTC2 overexpression also showed elevated lipid levels in both serum and liver tissues. Intriguingly, hepatic de novo cholesterol synthesis was markedly increased under these conditions. In contrast, CRTC2 ablation in mice fed a 4% cholesterol diet (18 weeks) showed decreased lipid levels in serum and liver tissues compared with those in littermate wild‐type mice. The expression of lipogenic genes (SREBP‐2 and HMGCR) was consistent with hepatic CRTC2 levels. In vivo imaging showed enhanced adenovirus‐mediated HMGCR‐luciferase activity in adenovirus‐mediated CRTC2 mouse livers; however, the activity was attenuated after mutation of CRE or sterol regulatory element sequences in the HMGCR reporter construct. The effect of CRTC2 on HMGCR in mouse livers was alleviated upon SREBP‐2 knockdown. CRTC2 modulated SREBP‐2 transcription by CRE binding protein, which recognizes the half‐site CRE sequence in the SREBP‐2 promoter. CRTC2 reduced the nuclear protein expression of forkhead box O1 and subsequently increased SREBP‐2 transcription by binding insulin response element 1, rather than insulin response element 2, in the SREBP‐2 promoter. Conclusion: CRTC2 regulates the transcription of SREBP‐2 by interfering with the recognition of insulin response element 1 in the SREBP‐2 promoter by forkhead box O1, thus inducing SREBP‐2/HMGCR signaling and subsequently facilitating hepatic cholesterol synthesis. (Hepatology 2017;66:481–497). PMID:28395113
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Thorn, Stephanie R.; Brown, Laura D.; Rozance, Paul J.; Hay, William W.; Friedman, Jacob E.
2013-01-01
Intrauterine growth restriction (IUGR) increases the risk for metabolic disease and diabetes, although the developmental origins of this remain unclear. We measured glucose metabolism during basal and insulin clamp periods in a fetal sheep model of placental insufficiency and IUGR. Compared with control fetuses (CON), fetuses with IUGR had increased basal glucose production rates and hepatic PEPCK and glucose-6-phosphatase expression, which were not suppressed by insulin. In contrast, insulin significantly increased peripheral glucose utilization rates in CON and IUGR fetuses. Insulin robustly activated AKT, GSK3β, and forkhead box class O (FOXO)1 in CON and IUGR fetal livers. IUGR livers, however, had increased basal FOXO1 phosphorylation, nuclear FOXO1 expression, and Jun NH2-terminal kinase activation during hyperinsulinemia. Expression of peroxisome proliferator–activated receptor γ coactivator 1α and hepatocyte nuclear factor-4α were increased in IUGR livers during basal and insulin periods. Cortisol and norepinephrine concentrations were positively correlated with glucose production rates. Isolated IUGR hepatocytes maintained increased glucose production in culture. In summary, fetal sheep with IUGR have increased hepatic glucose production, which is not suppressed by insulin despite insulin sensitivity for peripheral glucose utilization. These data are consistent with a novel mechanism involving persistent transcriptional activation in the liver that seems to be unique in the fetus with IUGR. PMID:22933111
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Novel mutation in forkhead box G1 (FOXG1) gene in an Indian patient with Rett syndrome.
Das, Dhanjit Kumar; Jadhav, Vaishali; Ghattargi, Vikas C; Udani, Vrajesh
2014-03-15
Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by the progressive loss of intellectual functioning, fine and gross motor skills and communicative abilities, deceleration of head growth, and the development of stereotypic hand movements, occurring after a period of normal development. The classic form of RTT involves mutation in MECP2 while the involvement of CDKL5 and FOXG1 genes has been identified in atypical RTT phenotype. FOXG1 gene encodes for a fork-head box protein G1, a transcription factor acting primarily as transcriptional repressor through DNA binding in the embryonic telencephalon as well as a number of other neurodevelopmental processes. In this report we have described the molecular analysis of FOXG1 gene in Indian patients with Rett syndrome. FOXG1 gene mutation analysis was done in a cohort of 34 MECP2/CDKL5 mutation negative RTT patients. We have identified a novel mutation (p. D263VfsX190) in FOXG1 gene in a patient with congenital variant of Rett syndrome. This mutation resulted into a frameshift, thereby causing an alteration in the reading frames of the entire coding sequence downstream of the mutation. The start position of the frameshift (Asp263) and amino acid towards the carboxyl terminal end of the protein was found to be well conserved across species using multiple sequence alignment. Since the mutation is located at forkhead binding domain, the resultant mutation disrupts the secondary structure of the protein making it non-functional. This is the first report from India showing mutation in FOXG1 gene in Rett syndrome. Copyright © 2014 Elsevier B.V. All rights reserved.
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Huang, Carol
2013-03-01
Abstract β-Cell mass increases during pregnancy in adaptation to the insulin resistance of pregnancy. This increase is accompanied by an increase in β-cell proliferation, a process that requires intact prolactin receptor (Prlr) signalling. Previously, it was found that during pregnancy, heterozygous prolactin receptor-null (Prlr(+/-)) mice had lower number of β-cells, lower serum insulin and higher blood glucose levels than wild-type (Prlr(+/+)) mice. An unexpected observation was that the glucose homeostasis of the experimental mouse depends on the genotype of her mother, such that within the Prlr(+/+) group, the Prlr(+/+) offspring derived from Prlr(+/+) mothers (Prlr(+/+(+/+))) had higher β-cell mass and lower blood glucose than those derived from Prlr(+/-) mothers (Prlr(+/+(+/-))). Pathways that are known to regulate β-cell proliferation during pregnancy include insulin receptor substrate-2, Akt, menin, the serotonin synthetic enzyme tryptophan hydroxylase-1, Forkhead box M1 and Forkhead box D3. The aim of the present study was to determine whether dysregulation in these signalling molecules in the islets could explain the maternal effect on the phenotype of the offspring. It was found that the pregnancy-induced increases in insulin receptor substrate-2 and Akt expression in the islets were attenuated in the Prlr(+/+(+/-)) mice in comparison to the Prlr(+/+(+/+)) mice. The expression of Forkhead box D3, which plays a permissive role for β-cell proliferation during pregnancy, was also lower in the Prlr(+/+(+/-)) mice. In contrast, the pregnancy-induced increases in phospho-Jak2, tryptophan hydroxylase-1 and FoxM1, as well as the pregnancy-associated reduction in menin expression, were comparable between the two groups. There was also no difference in expression levels of genes that regulate insulin synthesis and secretion (i.e. glucose transporter 2, glucokinase and pancreatic and duodenal homeobox-1) between these two groups. Taken together, these results suggest that the in utero environment of the Prlr(+/-) mother confers long-term changes in the pancreatic islets of her offspring such that when the offspring themselves became pregnant, they cannot adapt to the increased insulin demands of their own pregnancy.
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Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers
2016-10-01
AWARD NUMBER: W81XWH-15-1-0566 TITLE : Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers PRINCIPAL INVESTIGATOR: Dipanjan...RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2016 2. REPORT TYPE Annual 3. DATES COVERED 30 Sep 2015 - 29 Sep 2016 4. TITLE AND...amplification, Homologous Recombination, Platinum analogues, MicroRNAs, Heat shock protein 90 inhibitors, Forkhead box protein M1, Retinoblastoma 16
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Shimoda, Yuki; Ubukata, Yasunari; Handa, Tadashi; Yokobori, Takehiko; Watanabe, Takayoshi; Gantumur, Dolgormaa; Hagiwara, Kei; Yamanaka, Takahiro; Tsukagoshi, Mariko; Igarashi, Takamichi; Watanabe, Akira; Kubo, Norio; Araki, Kenichiro; Harimoto, Norifumi; Katayama, Ayaka; Hikino, Toshiaki; Sano, Takaaki; Ogata, Kyoichi; Kuwano, Hiroyuki; Shirabe, Ken; Oyama, Tetsunari
2018-05-25
Hepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC. The expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma. A high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis. The high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.
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The controversial role of forkhead box F2 (FOXF2) transcription factor in breast cancer.
Lo, Pang-Kuo
2017-01-01
Deregulating the subcellular localization, functions and expression of Forkhead box (FOX) transcription factors that are critically involved in embryonic development and multiple biological processes is known to result in the development and progression of diseases, in particular cancer. Human FOXF transcription factors, including FOXF1 and FOXF2, are a subfamily of the FOX gene family. The recent findings from ours and others have linked FOXF2 to breast cancer development and progression. Our studies have shown that FOXF2 acts as a tumor-suppressive inhibitor of DNA replication in luminal and HER2-positive breast cancers and as an oncogenic activator of the epithelial-mesenchymal transition (EMT) in triple-negative/basal-like breast cancers (TN/BLBC), suggesting that FOXF2 plays a dual role in breast cancer. However, studies from Feng's research group have pointed out an opposite role of FOXF2 in TN/BLBC, which acts as an inhibitor of the EMT and as a promoter of cell proliferation in TN/BLBC. These discrepancies between our and Feng's studies have caused controversy in the role of FOXF2 in breast cancer. This article reviews both studies and discusses what causes might have led to these inconsistencies as well as what future experiments are needed to solve this debate.
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Rao, Wenwang; Du, Xiangdong; Zhang, Yingyang; Yu, Qiong; Hui, Li; Yu, Yaqin; Kou, Changgui; Yin, Guangzhong; Zhu, Xiaomin; Man, Lijuan; Soares, Jair C; Zhang, Xiang Yang
2017-07-01
The forkhead-box P2 (FOXP2) gene polymorphism has been reported to be involved in the susceptibility to schizophrenia; however, few studies have investigated the association between FOXP2 gene polymorphism and clinical symptoms in schizophrenia. This study investigated whether the FOXP2 gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese population. The FOXP2 rs10447760 polymorphism was genotyped in 1069 schizophrenia inpatients and 410 healthy controls using a case-control design. The patients' psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the genotype and allele distributions between the patient and control groups. Interestingly, we found significant differences in PANSS total, positive symptom, and general psychopathology scores between genotypic subgroups in patients, with the higher score in patients with CC genotype than those with CT genotype (all p < 0.05). After adjusting demographic and clinical variables, the difference still remained significant for the PANSS positive symptom score and general psychopathology (both p < 0.05). Our findings suggest that the FOXP2 rs10447760 polymorphism may not contribute to the development of schizophrenia, but may contribute to the clinical symptoms of schizophrenia among Han Chinese.
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Shute, Robert J.; Kreiling, Jodi L.
2016-01-01
The purpose of this study was to determine mitochondrial biogenesis-related mRNA expression, binding of transcription factors to the peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) promoter, and subcellular location of PGC-1α protein in human skeletal muscle following exercise in a hot environment compared with a room temperature environment. Recreationally trained males (n = 11) completed two trials in a temperature- and humidity-controlled environmental chamber. Each trial consisted of cycling in either a hot (H) or room temperature (C) environment (33 and 20°C, respectively) for 1 h at 60% of maximum wattage (Wmax) followed by 3 h of supine recovery at room temperature. Muscle biopsies were taken from the vastus lateralis pre-, post-, and 3 h postexercise. PGC-1α mRNA increased post (P = 0.039)- and 3 h postexercise in C (P = 0.002). PGC-1α, estrogen-related receptor-α (ERRα), and nuclear respiratory factor 1 (NRF-1) mRNA was all lower in H than C post (P = 0.038, P < 0.001, and P = 0.030, respectively)- and 3 h postexercise (P = 0.035, P = 0.007, and P < 0.001, respectively). Binding of cAMP response element-binding protein (CREB) (P = 0.005), myocyte enhancer factor 2 (MEF2) (P = 0.047), and FoxO forkhead box class-O1 (FoxO1) (P = 0.010) to the promoter region of the PGC-1α gene was lower in H than C. Nuclear PGC-1α protein increased postexercise in both H and C (P = 0.029) but was not different between trials (P = 0.602). These data indicate that acute exercise in a hot environment blunts expression of mitochondrial biogenesis-related mRNA, due to decreased binding of CREB, MEF2, and FoxO1 to the PGC-1α promoter. PMID:27445305
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FOXO Transcriptional Factors and Long-Term Living
Rashid, Rehana; Muneer, Saiqa; Hasan, Syed Muhammad Farid
2017-01-01
Several pathologies such as neurodegeneration and cancer are associated with aging, which is affected by many genetic and environmental factors. Healthy aging conceives human longevity, possibly due to carrying the defensive genes. For instance, FOXO (forkhead box O) genes determine human longevity. FOXO transcription factors are involved in the regulation of longevity phenomenon via insulin and insulin-like growth factor signaling. Only one FOXO gene (FOXO DAF-16) exists in invertebrates, while four FOXO genes, that is, FOXO1, FOXO3, FOXO4, and FOXO6 are found in mammals. These four transcription factors are involved in the multiple cellular pathways, which regulate growth, stress resistance, metabolism, cellular differentiation, and apoptosis in mammals. However, the accurate mode of longevity by FOXO factors is unclear until now. This article describes briefly the existing knowledge that is related to the role of FOXO factors in human longevity. PMID:28894507
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Hypothalamic KLF4 mediates leptin's effects on food intake via AgRP
Imbernon, Monica; Sanchez-Rebordelo, Estrella; Gallego, Rosalia; Gandara, Marina; Lear, Pamela; Lopez, Miguel; Dieguez, Carlos; Nogueiras, Ruben
2014-01-01
Krüppel-like factor 4 (KLF4) is a zinc-finger-type transcription factor expressed in a range of tissues that plays multiple functions. We report that hypothalamic KLF4 represents a new transcription factor specifically modulating agouti-related protein (AgRP) expression in vivo. Hypothalamic KLF4 colocalizes with AgRP neurons and is modulated by nutritional status and leptin. Over-expression of KLF4 in the hypothalamic arcuate nucleus (ARC) induces food intake and increases body weight through the specific stimulation of AgRP, as well as blunting leptin sensitivity in lean rats independent of forkhead box protein 01 (FoxO1). Down-regulation of KLF4 in the ARC inhibits fasting-induced food intake in both lean and diet-induced obese (DIO) rats. Silencing KLF4, however, does not, on its own, enhance peripheral leptin sensitivity in DIO rats. PMID:24944903
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Hypothalamic KLF4 mediates leptin's effects on food intake via AgRP.
Imbernon, Monica; Sanchez-Rebordelo, Estrella; Gallego, Rosalia; Gandara, Marina; Lear, Pamela; Lopez, Miguel; Dieguez, Carlos; Nogueiras, Ruben
2014-07-01
Krüppel-like factor 4 (KLF4) is a zinc-finger-type transcription factor expressed in a range of tissues that plays multiple functions. We report that hypothalamic KLF4 represents a new transcription factor specifically modulating agouti-related protein (AgRP) expression in vivo. Hypothalamic KLF4 colocalizes with AgRP neurons and is modulated by nutritional status and leptin. Over-expression of KLF4 in the hypothalamic arcuate nucleus (ARC) induces food intake and increases body weight through the specific stimulation of AgRP, as well as blunting leptin sensitivity in lean rats independent of forkhead box protein 01 (FoxO1). Down-regulation of KLF4 in the ARC inhibits fasting-induced food intake in both lean and diet-induced obese (DIO) rats. Silencing KLF4, however, does not, on its own, enhance peripheral leptin sensitivity in DIO rats.
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Fu, G; Peng, C
2011-09-15
Nodal, a member of the transforming growth factor-β superfamily, has been recently shown to suppress cell proliferation and to stimulate the expression of cyclin G2 (CCNG2) in human epithelial ovarian cancer cells. However, the precise mechanisms underlying these events are not fully understood. In this study, we investigated the transcriptional regulation of CCNG2 by the Nodal signaling pathway. In ovarian cancer cells, overexpression of Nodal or its receptors, activin receptor-like kinase 7 (ALK7) or ALK4, resulted in an increase in the CCNG2 promoter activity. Several putative Forkhead box class O (FoxO)3a-binding sites are present in the human CCNG2 promoter and overexpression of FoxO3a enhanced the CCNG2 promoter activity. The functional FoxO3a-binding element (FBE) was mapped to a proximal region located between -398 and -380 bp (FBE1) through deletion and mutation analyses, as well as chromatin immunoprecipitation (IP) assay. Interestingly, mutation of the FBE1 not only abolished the effect of FoxO3a, but also blocked Nodal-induced CCNG2 transcription. Nodal stimulated FoxO3a mRNA and protein expression through the canonical Smad pathway and suppressed FoxO3a inactivation by inhibiting AKT activity. Silencing of FoxO3a using small interfering RNA significantly reduced the effect of Nodal on the CCNG2 promoter activity. On the other hand, overexpression of Smad2 and Smad3 enhanced the FoxO3a-induced CCNG2 promoter activity whereas knockdown of Smad4 blocked the activity of FoxO3a. Furthermore, IP assays revealed that FoxO3a formed complexes with Smad proteins and that Nodal enhanced the binding of FoxO3a to the CCNG2 promoter. Finally, silencing of FoxO3a reversed the inhibitory effect of Nodal on cell proliferation. Taken together, these findings demonstrated that Nodal signaling promotes CCNG2 transcription by upregulating FoxO3a expression, inhibiting FoxO3a phosphorylation and enhancing its synergistic interaction with Smads. These results also suggest that FoxO3a is an important mediator of Nodal signaling in ovarian cancer cells.
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FoxM1 Promotes Glioma Cells Progression by Up-Regulating Anxa1 Expression
Cheng, Shi-Xiang; Tu, Yue; Zhang, Sai
2013-01-01
Forkhead box M1 (FoxM1) is a member of the forkhead transcription factor family and is overexpression in malignant gliomas. However, the molecular mechanisms by which FoxM1lead to glioma carcinogenesis and progression are still not well known. In the present study, we show that Anxa1 was overexpression in gliomas and predicted the poor outcome. Furthermore, Anxa1 closely related to the FoxM1 expression and was a direct transcriptional target of FoxM1. Overexpression of FoxM1 up-regulated Anxa1 expression, whereas suppression of FoxM1 expression down-regulated Anxa1 expression in glioma cells. Finally, FoxM1 enhanced the proliferation, migration, and angiogenesis in Anxa1-dependent manner both in vitro and in vivo. Our findings provide both clinical and mechanistic evidences that FoxM1 contributes to glioma development by directly up-regulating Anxa1 expression. PMID:23991102
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Niu, Yucun; Na, Lixin; Feng, Rennan; Gong, Liya; Zhao, Yue; Li, Qiang; Li, Ying; Sun, Changhao
2013-12-01
It is known that phytochemicals have many potential health benefits in humans. The aim of this study was to investigate the effects of long-term consumption of the phytochemical, epigallocatechin gallate (EGCG), on body growth, disease protection, and lifespan in healthy rats. 68 male weaning Wistar rats were randomly divided into the control and EGCG groups. Variables influencing lifespan such as blood pressure, serum glucose and lipids, inflammation, and oxidative stress were dynamically determined from weaning to death. The median lifespan of controls was 92.5 weeks. EGCG increased median lifespan to 105.0 weeks and delayed death by approximately 8-12 weeks. Blood pressure and serum glucose and lipids significantly increased with age in both groups compared with the levels at 0 week. However, there were no differences in these variables between the two groups during the whole lifespan. Inflammation and oxidative stress significantly increased with age in both groups compared with 0 week and were significantly lower in serum and liver and kidney tissues in the EGCG group. Damage to liver and kidney function was significantly alleviated in the EGCG group. In addition, EGCG decreased the mRNA and protein expressions of transcription factor NF-κB and increased the upstream protein expressions of silent mating type information regulation two homolog one (SIRT1) and forkhead box class O 3a (FOXO3a). In conclusion, EGCG extends lifespan in healthy rats by reducing liver and kidney damage and improving age-associated inflammation and oxidative stress through the inhibition of NF-κB signaling by activating the longevity factors FoxO3a and SIRT1. © 2013 the Anatomical Society and John Wiley & Sons Ltd.
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The genetics of early telencephalon patterning: some assembly required
Hébert, Jean M.; Fishell, Gord
2009-01-01
The immense range of human behaviours is rooted in the complex neural networks of the cerebrum. The creation of these networks depends on the precise integration of specific neuronal subtypes that are born in different regions of the telencephalon. Here, using the mouse as a model system, we review how these proliferative zones are established. Moreover, we discuss how these regions can be traced back in development to the function of a few key genes, including those that encode fibroblast growth factors (FGFs), sonic hedgehog (SHH), bone morphogenetic proteins (BMPs), forkhead box G1 (FoxG1), paired box 6 (PAX6) and LIM homeobox protein 2 (LHX2), that pattern the early telencephalon. PMID:19143049
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Jo, Dong-Gyu; Park, Daeui; Chung, Hae Young
2014-01-01
During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for the latter mechanism is grounded in the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examplesof such pathways include those involving the transcription factors nuclear factor erythroid 2-related factor 2, nuclear factor-κB, hypoxia-inducible factor 1α, peroxisome proliferator-activated receptor γ, and forkhead box subgroup O, as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against tissue injury and disease. Because neurons are particularly sensitive to potentially noxious phytochemicals, we focus on the nervous system but also include findings from other cell types in which actions of phytochemicals on specific signal transduction pathways have been more thoroughly studied. PMID:24958636
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Tanabe, Yuko; Fujiwara, Yuji; Matsuzaki, Ayumi; Fujita, Eriko; Kasahara, Tadashi; Yuasa, Shigeki; Momoi, Takashi
2012-07-01
FOXP2, a forkhead box-containing transcription factor, forms homo- or hetero-dimers with FOXP family members and localizes to the nucleus, while FOXP2(R553H), which contains a mutation related to speech/language disorders, features reduced DNA binding activity and both cytoplasmic and nuclear localization. In addition to being a loss-of-function mutation, it is possible that FOXP2(R553H) also may act as a gain-of-function mutation to inhibit the functions of FOXP2 isoforms including FOXP2Ex10+ lacking forkhead domain. Foxp2(R552H) knock-in mouse pups exhibit impaired ultrasonic vocalization and poor dendritic development in Purkinje cells. However, expressions of Foxp2 isoforms in the developing Purkinje are unclear. The appearance of 'apical cytoplasmic swelling' (mitochondria-rich regions that are the source of budding processes) correlates with dendritic development of Purkinje cells. In the present study, we focused on Foxp2 isoforms localizing to the apical cytoplasmic swelling and identified two isoforms lacking forkhead domain: Foxp2Ex12+ and Foxp2Ex15. They partly localized to the membrane fraction that includes mitochondria. Foxp2Ex12+ mainly localized to the apical cytoplasmic swelling in early developing Purkinje cells at the stellate stage (P2-P4). Mitochondrial localization of Foxp2Ex12+ in Purkinje cells was confirmed by immune-electron microscopic analysis. Foxp2Ex12+ may play a role in dendritic development in Purkinje cells. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
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Reed, Sarah A.; Sandesara, Pooja B.; Senf, Sarah M.; Judge, Andrew R.
2012-01-01
Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth.—Reed, S. A., Sandesara, P. B., Senf, S. F., Judge, A. R. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. PMID:22102632
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Transcription Factor FoxO1 Is Essential for Enamel Biomineralization
Poché, Ross A.; Sharma, Ramaswamy; Garcia, Monica D.; Wada, Aya M.; Nolte, Mark J.; Udan, Ryan S.; Paik, Ji-Hye; DePinho, Ronald A.; Bartlett, John D.; Dickinson, Mary E.
2012-01-01
The Transforming growth factor β (Tgf-β) pathway, by signaling via the activation of Smad transcription factors, induces the expression of many diverse downstream target genes thereby regulating a vast array of cellular events essential for proper development and homeostasis. In order for a specific cell type to properly interpret the Tgf-β signal and elicit a specific cellular response, cell-specific transcriptional co-factors often cooperate with the Smads to activate a discrete set of genes in the appropriate temporal and spatial manner. Here, via a conditional knockout approach, we show that mice mutant for Forkhead Box O transcription factor FoxO1 exhibit an enamel hypomaturation defect which phenocopies that of the Smad3 mutant mice. Furthermore, we determined that both the FoxO1 and Smad3 mutant teeth exhibit changes in the expression of similar cohort of genes encoding enamel matrix proteins required for proper enamel development. These data raise the possibility that FoxO1 and Smad3 act in concert to regulate a common repertoire of genes necessary for complete enamel maturation. This study is the first to define an essential role for the FoxO family of transcription factors in tooth development and provides a new molecular entry point which will allow researchers to delineate novel genetic pathways regulating the process of biomineralization which may also have significance for studies of human tooth diseases such as amelogenesis imperfecta. PMID:22291941
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FoxO inhibits juvenile hormone biosynthesis and vitellogenin production in the German cockroach.
Süren-Castillo, Songül; Abrisqueta, Marc; Maestro, José L
2012-07-01
The transcription factor Forkhead-box O (FoxO) is the main transcriptional effector of the Insulin Receptor/Phosphatidylinositol 3-kinase (InR/PI3K) pathway. In a situation of nutrient restriction, the pathway is inactive and FoxO translocates to the nucleus to exert its transcriptional action. In starved females of the cockroach Blattella germanica, the reproductive processes, and in particular the synthesis of juvenile hormone in the corpora allata and that of vitellogenin in the fat body, are arrested. In the present report we examine the possible role of FoxO in the transduction of the nutritional signals to these reproductive events. We first cloned FoxO cDNA from B. germanica (BgFoxO), and showed that its expression is not nutritionally regulated. BgFoxO knockdown using systemic RNAi in vivo in starved females elicited an increase of juvenile hormone biosynthesis, although without modifying mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase-1, HMG-CoA synthase-2, HMG-CoA reductase or methyl farnesoate epoxidase (CYP15A1) in corpora allata. In addition, BgFoxO RNAi treatment produced a remarkable increase of vitellogenin mRNA levels in fat body and of vitellogenin protein in the haemolymph. Our results indicate that BgFoxO plays an inhibitory role on juvenile hormone biosynthesis and vitellogenin production in a situation of nutrient shortage. Copyright © 2012 Elsevier Ltd. All rights reserved.
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FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus
Maiese, Kenneth
2015-01-01
Mammalian forkhead transcription factors of the O class (FoxO) are exciting targets under consideration for the development of new clinical entities to treat metabolic disorders and diabetes mellitus (DM). DM, a disorder that currently affects greater than 350 million individuals globally, can become a devastating disease that leads to cellular injury through oxidative stress pathways and affects multiple systems of the body. FoxO proteins can regulate insulin signaling, gluconeogenesis, insulin resistance, immune cell migration, and cell senescence. FoxO proteins also control cell fate through oxidative stress and pathways of autophagy and apoptosis that either lead to tissue regeneration or cell demise. Furthermore, FoxO signaling can be dependent upon signal transduction pathways that include silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), Wnt, and Wnt1 inducible signaling pathway protein 1 (WISP1). Cellular metabolic pathways driven by FoxO proteins are complex, can lead to variable clinical outcomes, and require in-depth analysis of the epigenetic and post-translation protein modifications that drive FoxO protein activation and degradation. PMID:26256004
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75 FR 20774 - Establishment of Class E Airspace; Fort A.P. Hill, VA
Federal Register 2010, 2011, 2012, 2013, 2014
2010-04-21
...-0739; Airspace Docket No. 09-AEA-14] Establishment of Class E Airspace; Fort A.P. Hill, VA AGENCY... December 7, 2009 that establishes Class E airspace at Fort A.P. Hill, VA. DATES: Effective Date: 0901 UTC... Service Center, Federal Aviation Administration, P.O. Box 20636, Atlanta, Georgia 30320; telephone (404...
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Yang, Y; Isaac, C; Wang, C; Dragon, F; Pogacic, V; Meier, U T
2000-02-01
Small nucleolar ribonucleoprotein particles (snoRNPs) mainly catalyze the modification of rRNA. The two major classes of snoRNPs, box H/ACA and box C/D, function in the pseudouridylation and 2'-O-methylation, respectively, of specific nucleotides. The emerging view based on studies in yeast is that each class of snoRNPs is composed of a unique set of proteins. Here we present a characterization of mammalian snoRNPs. We show that the previously characterized NAP57 is specific for box H/ACA snoRNPs, whereas the newly identified NAP65, the rat homologue of yeast Nop5/58p, is a component of the box C/D class. Using coimmunoprecipitation experiments, we show that the nucleolar and coiled-body protein Nopp140 interacts with both classes of snoRNPs. This interaction is corroborated in vivo by the exclusive depletion of snoRNP proteins from nucleoli in cells transfected with a dominant negative Nopp140 construct. Interestingly, RNA polymerase I transcription is arrested in nucleoli depleted of snoRNPs, raising the possibility of a feedback mechanism between rRNA modification and transcription. Moreover, the Nopp140-snoRNP interaction appears to be conserved in yeast, because depletion of Srp40p, the yeast Nopp140 homologue, in a conditional lethal strain induces the loss of box H/ACA small nucleolar RNAs. We propose that Nopp140 functions as a chaperone of snoRNPs in yeast and vertebrate cells.
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Yang, Yunfeng; Isaac, Cynthia; Wang, Chen; Dragon, François; Pogac̆ić, Vanda; Meier, U. Thomas
2000-01-01
Small nucleolar ribonucleoprotein particles (snoRNPs) mainly catalyze the modification of rRNA. The two major classes of snoRNPs, box H/ACA and box C/D, function in the pseudouridylation and 2′-O-methylation, respectively, of specific nucleotides. The emerging view based on studies in yeast is that each class of snoRNPs is composed of a unique set of proteins. Here we present a characterization of mammalian snoRNPs. We show that the previously characterized NAP57 is specific for box H/ACA snoRNPs, whereas the newly identified NAP65, the rat homologue of yeast Nop5/58p, is a component of the box C/D class. Using coimmunoprecipitation experiments, we show that the nucleolar and coiled-body protein Nopp140 interacts with both classes of snoRNPs. This interaction is corroborated in vivo by the exclusive depletion of snoRNP proteins from nucleoli in cells transfected with a dominant negative Nopp140 construct. Interestingly, RNA polymerase I transcription is arrested in nucleoli depleted of snoRNPs, raising the possibility of a feedback mechanism between rRNA modification and transcription. Moreover, the Nopp140-snoRNP interaction appears to be conserved in yeast, because depletion of Srp40p, the yeast Nopp140 homologue, in a conditional lethal strain induces the loss of box H/ACA small nucleolar RNAs. We propose that Nopp140 functions as a chaperone of snoRNPs in yeast and vertebrate cells. PMID:10679015
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Tanabe, Yuko; Fujita, Eriko; Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498
Highlights: {yields} We isolated protection of telomeres 1 (POT1) as a FOXP2-associated protein by a yeast two-hybrid. {yields} FOXP2 associated and co-localized with POT1 in the nuclei. {yields} FOXP2(R553H) also co-localized with POT1 in both the cytoplasm and nuclei. {yields} FOXP2(R553H) partially prevented the nuclear translocation of POT1. {yields} FOXP2(R553H) mutation may be associated with the pathogenesis of speech-language disorder. -- Abstract: FOXP2 is a forkhead box-containing transcription factor with several recognizable sequence motifs. However, little is known about the FOXP2-associated proteins except for C-terminal binding protein (CtBP). In the present study, we attempted to isolate the FOXP2-associated protein withmore » a yeast two-hybrid system using the C-terminal region, including the forkhead domain, as a bait probe, and identified protection of telomeres 1 (POT1) as a FOXP2-associated protein. Immunoprecipitation assay confirmed the association with FOXP2 and POT1. POT1 alone localized in the cytoplasm but co-localized with FOXP2 and the forkhead domain of FOXP2 in nuclei. However, both FOXP2 with mutated nuclear localization signals and (R553H) mutated forkhead, which is associated with speech-language disorder, prevented the nuclear translocation of POT1. These results suggest that FOXP2 is a binding partner for the nuclear translocation of POT1. As loss of POT1 function induces the cell arrest, the impaired nuclear translocation of POT1 in the developing neuronal cells may be associated with the pathogenesis of speech-language disorder with FOXP2(R553H) mutation.« less
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Calabuig-Navarro, Virtu; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Liu, Yun-Zi; Sadlek, Kelsey; Coudriet, Gina M; Piganelli, Jon D; Jiang, Chun-Lei; Miller, Rita; Lowe, Mark; Harashima, Hideyoshi; Dong, H Henry
2015-06-19
Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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Calabuig-Navarro, Virtu; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Liu, Yun-Zi; Sadlek, Kelsey; Coudriet, Gina M.; Piganelli, Jon D.; Jiang, Chun-Lei; Miller, Rita; Lowe, Mark; Harashima, Hideyoshi; Dong, H. Henry
2015-01-01
Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice. PMID:25944898
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PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake.
Iskandar, Kristy; Cao, Yongheng; Hayashi, Yoshitake; Nakata, Masanori; Takano, Eisuke; Yada, Toshihiko; Zhang, Changliang; Ogawa, Wataru; Oki, Miyo; Chua, Streamson; Itoh, Hiroshi; Noda, Tetsuo; Kasuga, Masato; Nakae, Jun
2010-04-01
Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI(3)K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI(3)K-dependent manner. However, the interrelationship between PI(3)K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice (POMCPdk1(-/-)) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (Delta256)FoxO1 in POMC neurons (CNFoxO1(POMC) or Delta256FoxO1(POMC)). POMCPdk1(-/-) mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1(POMC) mice exhibited mild obesity and hyperphagia compared with POMCPdk1(-/-) mice. Although expression of the CNFoxO1 made POMCPdk1(-/-) mice more obese due to excessive suppression of Pomc gene, overexpression of Delta256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1(-/-) mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.
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Does Resveratrol Improve Insulin Signalling in HepG2 Cells?
Norouzzadeh, Marjan; Amiri, Fatemehsadat; Saboor-Yaraghi, Ali Akbar; Shemirani, Farnoosh; Kalikias, Yas; Sharifi, Loghman; Seyyedsalehi, Monireh Sadat; Mahmoudi, Maryam
2017-04-01
Diabetes mellitus is a common metabolic disorder with high global prevalence. It is characterized by a decrease in insulin secretion or a decrease in insulin sensitivity or both. The aim of the present study was to investigate the effects of resveratrol treatment on the expression of the genes involved in insulin signalling cascade, such as Forkhead box protein O1 (FoxO1), 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and mammalian target of rapamycin (mTOR). HepG2 cells were cultured in serum-free medium with high concentrations of glucose and insulin and then were treated with resveratrol (5, 10 and 20 µM) for 24 and 48 hours. Complementary deoxyribonucleic acids (cDNAs) were synthesized followed by RNA extraction. Real-time quantitative reverse transcription polymerase chain reaction was used to analyze the expression of FoxO1, PDPK1 and mTOR. Resveratrol increased the expression of PDPK1, mTOR and FoxO1. No significant difference was seen among differing dosages of resveratrol, but treatments for 48 hours exerted the greatest effectiveness. Our results were consistent with other studies showing the beneficial effects of resveratrol on diabetes. However, considering the effects of resveratrol in increasing FoxO1 and gluconeogenic gene expression, long-term usage of resveratrol should be investigated in greater depth in future studies. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
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Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism.
Kauwe, Grant; Tsurudome, Kazuya; Penney, Jay; Mori, Megumi; Gray, Lindsay; Calderon, Mario R; Elazouzzi, Fatima; Chicoine, Nicole; Sonenberg, Nahum; Haghighi, A Pejmun
2016-12-21
While beneficial effects of fasting on organismal function and health are well appreciated, we know little about the molecular details of how fasting influences synaptic function and plasticity. Our genetic and electrophysiological experiments demonstrate that acute fasting blocks retrograde synaptic enhancement that is normally triggered as a result of reduction in postsynaptic receptor function at the Drosophila larval neuromuscular junction (NMJ). This negative regulation critically depends on transcriptional enhancement of eukaryotic initiation factor 4E binding protein (4E-BP) under the control of the transcription factor Forkhead box O (Foxo). Furthermore, our findings indicate that postsynaptic 4E-BP exerts a constitutive negative input, which is counteracted by a positive regulatory input from the Target of Rapamycin (TOR). This combinatorial retrograde signaling plays a key role in regulating synaptic strength. Our results provide a mechanistic insight into how cellular stress and nutritional scarcity could acutely influence synaptic homeostasis and functional stability in neural circuits. Copyright © 2016 Elsevier Inc. All rights reserved.
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FOXO1 expression in keratinocytes promotes connective tissue healing
Zhang, Chenying; Lim, Jason; Liu, Jian; Ponugoti, Bhaskar; Alsadun, Sarah; Tian, Chen; Vafa, Rameen; Graves, Dana T.
2017-01-01
Wound healing is complex and highly orchestrated. It is well appreciated that leukocytes, particularly macrophages, are essential for inducing the formation of new connective tissue, which requires the generation of signals that stimulate mesenchymal stem cells (MSC), myofibroblasts and fibroblasts. A key role for keratinocytes in this complex process has yet to be established. To this end, we investigated possible involvement of keratinocytes in connective tissue healing. By lineage-specific deletion of the forkhead box-O 1 (FOXO1) transcription factor, we demonstrate for the first time that keratinocytes regulate proliferation of fibroblasts and MSCs, formation of myofibroblasts and production of collagen matrix in wound healing. This stimulation is mediated by a FOXO1 induced TGFβ1/CTGF axis. The results provide direct evidence that epithelial cells play a key role in stimulating connective tissue healing through a FOXO1-dependent mechanism. Thus, FOXO1 and keratinocytes may be an important therapeutic target where healing is deficient or compromised by a fibrotic outcome. PMID:28220813
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Constantin-Teodosiu, Dumitru; Constantin, Despina; Stephens, Francis; Laithwaite, David; Greenhaff, Paul L
2012-05-01
High-fat feeding inhibits pyruvate dehydrogenase complex (PDC)-controlled carbohydrate (CHO) oxidation, which contributes to muscle insulin resistance. We aimed to reveal molecular changes underpinning this process in resting and exercising humans. We also tested whether pharmacological activation of PDC overrides these diet-induced changes. Healthy males consumed a control diet (CD) and on two further occasions an isocaloric high-fat diet (HFD). After each diet, subjects cycled for 60 min after intravenous infusion with saline (CD and HFD) or dichloroacetate (HFD+DCA). Quadriceps muscle biopsies obtained before and after 10 and 60 min of exercise were used to estimate CHO use, PDC activation, and mRNAs associated with insulin, fat, and CHO signaling. Compared with CD, HFD increased resting pyruvate dehydrogenase kinase 2 (PDK2), PDK4, forkhead box class O transcription factor 1 (FOXO1), and peroxisome proliferator-activated receptor transcription factor α (PPARα) mRNA and reduced PDC activation. Exercise increased PDC activation and whole-body CHO use in HFD, but to a lower extent than in CD. Meanwhile PDK4 and FOXO1, but not PPARα or PDK2, mRNA remained elevated. HFD+DCA activated PDC throughout and restored whole-body CHO use during exercise. FOXO1 appears to play a role in HFD-mediated muscle PDK4 upregulation and inhibition of PDC and CHO oxidation in humans. Also, pharmacological activation of PDC restores HFD-mediated inhibition of CHO oxidation during exercise.
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Sun, Liang; Hu, Caiyou; Zheng, Chenguang; Qian, Yu; Liang, Qinghua; Lv, Zeping; Huang, Zezhi; Qi, KeYan; Gong, Huan; Zhang, Zheng; Huang, Jin; Zhou, Qin; Yang, Ze
2015-01-01
Forkhead box class O (FOXO) transcription factors play a crucial role in longevity across species. Several polymorphisms in FOXO3 were previously reported to be associated with human longevity. However, only one Chinese replication study has been performed so far. To verify the role of FOXO3 in southern Chinese in the Red River Basin, a community-based case-control study was conducted, and seven polymorphisms were genotyped in 1336 participants, followed by a meta-analysis of eight case-control studies that included 5327 longevity cases and 4608 controls. In our case-control study, we found rs2802288*A and rs2802292*G were beneficial to longevity after Bonferroni correction (pallele = 0.005, OR = 1.266; pallele = 0.026, OR = 1.207). In addition, in the longevity group, carriers with rs2802288*A and rs2802292*G presented reduced HbA1c (p = 0.001), and homozygotes of rs2802292*GG presented improved HOMA–IR (p = 0.014). The meta-analysis further revealed the overall contribution of rs2802288*A and rs2802292*G to longevity. However, our stratified analysis revealed that rs2802292*G might act more strongly in Asians than Europeans, for enhancement of longevity. In conclusion, our study provides convincing evidence for a significant association between the rs2802288*A and rs2802292*G gene variants in FOXO3 and human longevity, and adds the Southern Chinese in the Red River Basin to the growing number of human replication populations. PMID:25913413
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Yan, Dongjing; Liao, Xiaoping; Wang, Xianshou; Fu, Yunxin; Cai, Wangwei
2016-01-01
Recent studies suggested that forkhead box class O3 (FOXO3) functions as a key regulator for the insulin/insulin-like growth factor-1signaling pathway that influence aging and longevity. This study aimed to comprehensively elucidate the association of common genetic variants in FOXO3 with human longevity in a Chinese population. Eighteen single-nucleotide polymorphisms (SNPs) in FOXO3 were successfully genotyped in 616 unrelated long-lived individuals and 846 younger controls. No nominally significant effects were found. However, when stratifying by gender, four SNPs (rs10499051, rs7762395, rs4946933 and rs3800230) previously reported to be associated with longevity and one novel SNP (rs4945815) showed significant association with male longevity (P-values: 0.007–0.032), but all SNPs were not associated with female longevity. Correspondingly, males carrying the G-G-T-G haplotype of rs10499051, rs7762395, rs4945815 and rs3800230 tended to have longer lifespan than those carrying the most common haplotype A-G-C-T (odds ratio = 2.36, 95% confidence interval = 1.20–4.63, P = 0.013). However, none of the associated SNPs and haplotype remained significant after Bonferroni correction. In conclusion, our findings revealed that the FOXO3 variants we tested in our population of Chinese men and women were associated with longevity in men only. None of these associations passed Bonferroni correction. Bonferroni correction is very stringent for association studies. We therefore believe the effects of these nominally significant variants on human longevity will be confirmed by future studies. PMID:27936216
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Sun, Liang; Hu, Caiyou; Zheng, Chenguang; Qian, Yu; Liang, Qinghua; Lv, Zeping; Huang, Zezhi; Qi, KeYan; Gong, Huan; Zhang, Zheng; Huang, Jin; Zhou, Qin; Yang, Ze
2015-04-27
Forkhead box class O (FOXO) transcription factors play a crucial role in longevity across species. Several polymorphisms in FOXO3 were previously reported to be associated with human longevity. However, only one Chinese replication study has been performed so far. To verify the role of FOXO3 in southern Chinese in the Red River Basin, a community-based case-control study was conducted, and seven polymorphisms were genotyped in 1336 participants, followed by a meta-analysis of eight case-control studies that included 5327 longevity cases and 4608 controls. In our case-control study, we found rs2802288*A and rs2802292*G were beneficial to longevity after Bonferroni correction (pallele = 0.005, OR = 1.266; pallele = 0.026, OR = 1.207). In addition, in the longevity group, carriers with rs2802288*A and rs2802292*G presented reduced HbA1c (p = 0.001), and homozygotes of rs2802292*GG presented improved HOMA-IR (p = 0.014). The meta-analysis further revealed the overall contribution of rs2802288*A and rs2802292*G to longevity. However, our stratified analysis revealed that rs2802292*G might act more strongly in Asians than Europeans, for enhancement of longevity. In conclusion, our study provides convincing evidence for a significant association between the rs2802288*A and rs2802292*G gene variants in FOXO3 and human longevity, and adds the Southern Chinese in the Red River Basin to the growing number of human replication populations.
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Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke
Yin, Junxiang; Han, Pengcheng; Tang, Zhiwei; Liu, Qingwei; Shi, Jiong
2015-01-01
Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD+/NADH ratio. In this study, we investigated whether mitochondrial NAD+-dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD+-dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway. PMID:26058697
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Hsiao, Chun-Jen; Hsu, Chih-Hsiang; Lin, Ching-Lung; Wu, Chung-Hsin; Jen, Philip Hung-Sun
2016-08-17
Although echolocating bats and other mammals share the basic design of laryngeal apparatus for sound production and auditory system for sound reception, they have a specialized laryngeal mechanism for ultrasonic sound emissions as well as a highly developed auditory system for processing species-specific sounds. Because the sounds used by bats for echolocation and rodents for communication are quite different, there must be differences in the central nervous system devoted to producing and processing species-specific sounds between them. The present study examines the difference in the relative size of several brain structures and expression of auditory-related and vocal-related proteins in the central nervous system of echolocation bats and rodents. Here, we report that bats using constant frequency-frequency-modulated sounds (CF-FM bats) and FM bats for echolocation have a larger volume of midbrain nuclei (inferior and superior colliculi) and cerebellum relative to the size of the brain than rodents (mice and rats). However, the former have a smaller volume of the cerebrum and olfactory bulb, but greater expression of otoferlin and forkhead box protein P2 than the latter. Although the size of both midbrain colliculi is comparable in both CF-FM and FM bats, CF-FM bats have a larger cerebrum and greater expression of otoferlin and forkhead box protein P2 than FM bats. These differences in brain structure and protein expression are discussed in relation to their biologically relevant sounds and foraging behavior.
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Yamamura, Nobuhisa; Fugo, Kazunori; Kishimoto, Takashi
2017-09-01
Alpha-fetoprotein (AFP)-producing adenocarcinoma is a high-malignant variant of adenocarcinoma with a hepatic or fetal-intestinal phenotype. The number of cases of AFP-producing adenocarcinomas is increasing, but the molecular mechanism underlying the aberrant production of AFP is unclear. Here we sought to assess the role of Forkhead box A (FoxA)2, which is a pioneer transcription factor in the differentiation of hepatoblasts. FoxA2 expression was investigated in five cases of AFP-producing gastric adenocarcinomas by immunohistochemistry, and all cases showed FoxA2 expression. Chromatin immunoprecipitation revealed the DNA binding of FoxA2 on the regulatory element of AFP gene in AFP-producing adenocarcinoma cells. The inhibition of FoxA2 expression with siRNA reduced the mRNA expression of liver-specific proteins, including AFP, albumin, and transferrin. The inhibition of FoxA2 also reduced the expressions of liver-enriched nuclear factors, i.e., hepatocyte nuclear factor (HNF) 4α and HNF6, although the expressions of HNF1α and HNF1β were not affected. The same effect as FoxA2 knockdown in AFP producing adenocarcinoma cells was also observed in hepatocellular carcinoma cells. Our results suggest that FoxA2 plays a key role in the expression of hepatic phenotype of AFP-producing adenocarcinomas. Copyright © 2017 Elsevier GmbH. All rights reserved.
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Tzang, Bor-Show; Liu, Chung-Hsien; Hsu, Kuo-Ching; Chen, Yi-Hsing; Huang, Chih-Yang; Hsu, Tsai-Ching
2017-09-01
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by a dysregulation of the immune system, which causes inflammation responses, excessive oxidative stress and a reduction in the number of cluster of differentiation (CD)4+CD25+forkhead box P3 (FoxP3)+ T cells. Supplementation with certain Lactobacillus strains has been suggested to be beneficial in the comprehensive treatment of SLE. However, little is known about the effect and mechanism of certain Lactobacillus strains on SLE. To investigate the effects of Lactobacillus on SLE, NZB/W F1 mice were orally gavaged with Lactobacillus paracasei GMNL-32 (GMNL-32), Lactobacillus reuteri GMNL-89 (GMNL-89) and L. reuteri GMNL-263 (GMNL-263). Supplementation with GMNL-32, GMNL-89 and GMNL-263 significantly increased antioxidant activity, reduced IL-6 and TNF-α levels and significantly decreased the toll-like receptors/myeloid differentiation primary response gene 88 signalling in NZB/W F1 mice. Notably, supplementation with GMNL-263, but not GMNL-32 and GMNL-89, in NZB/W F1 mice significantly increased the differentiation of CD4+CD25+FoxP3+ T cells. These findings reveal beneficial effects of GMNL-32, GMNL-89 and GMNL-263 on NZB/W F1 mice and suggest that these specific Lactobacillus strains can be used as part of a comprehensive treatment of SLE patients.
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Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1.
Bai, Xiao-Zhi; He, Ting; Gao, Jian-Xin; Liu, Yang; Liu, Jia-Qi; Han, Shi-Chao; Li, Yan; Shi, Ji-Hong; Han, Jun-Tao; Tao, Ke; Xie, Song-Tao; Wang, Hong-Tao; Hu, Da-Hai
2016-09-07
Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling.
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FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver
Kim, Dae Hyun; Perdomo, German; Zhang, Ting; Slusher, Sandra; Lee, Sojin; Phillips, Brett E.; Fan, Yong; Giannoukakis, Nick; Gramignoli, Roberto; Strom, Stephen; Ringquist, Steven; Dong, H. Henry
2011-01-01
OBJECTIVE Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism. RESEARCH DESIGN AND METHODS We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver. RESULTS FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice. CONCLUSIONS Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes. PMID:21940782
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Hinds, Terry D; Peck, Bailey; Shek, Evan; Stroup, Steven; Hinson, Jennifer; Arthur, Susan; Marino, Joseph S
2016-02-11
Unlike the glucocorticoid receptor α (GRα), GR β (GRβ) has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GRα as the mediator of glucocorticoid-induced skeletal muscle loss. Because GRβ causes glucocorticoid resistance, targeting GRβ may be beneficial in impairing muscle loss as a result of GRα activity. The purpose of this study was to determine how the overexpression of GRβ affects myotube formation and dexamethasone (Dex) responsiveness. We measured GR isoform expression in C₂C12 muscle cells in response to Dex and insulin, and through four days of myotube formation. Next, lentiviral-mediated overexpression of GRβ in C₂C12 was performed, and these cells were characterized for cell fusion and myotube formation, as well as sensitivity to Dex via the expression of ubiquitin ligases. GRβ overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GRβ overexpressing myotubes had an increased fusion index. Myotubes overexpressing GRβ had lower forkhead box O3 (Foxo3a) mRNA levels and a blunted muscle atrophy F-box/Atrogen-1 (MAFbx) and muscle ring finger 1 (MuRF1) response to Dex. We showed that GRβ may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GRβ levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids.
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A Key Evolutionary Mutation Enhances DNA Binding of the FOXP2 Forkhead Domain.
Morris, Gavin; Fanucchi, Sylvia
2016-04-05
Forkhead box (FOX) transcription factors share a conserved forkhead DNA binding domain (FHD) and are key role players in the development of many eukaryotic species. Their involvement in various congenital disorders and cancers makes them clinically relevant targets for novel therapeutic strategies. Among them, the FOXP subfamily of multidomain transcriptional repressors is unique in its ability to form DNA binding homo and heterodimers. The truncated FOXP2 FHD, in the absence of the leucine zipper, exists in equilibrium between monomeric and domain-swapped dimeric states in vitro. As a consequence, determining the DNA binding properties of the FOXP2 FHD becomes inherently difficult. In this work, two FOXP2 FHD hinge loop mutants have been generated to successfully prevent both the formation (A539P) and the dissociation (F541C) of the homodimers. This allows for the separation of the two species for downstream DNA binding studies. Comparison of DNA binding of the different species using electrophoretic mobility shift assay, fluorescence anisotropy and isothermal titration calorimetry indicates that the wild-type FOXP2 FHD binds DNA as a monomer. However, comparison of the DNA-binding energetics of the monomer and wild-type FHD, reveals that there is a difference in the mechanism of binding between the two species. We conclude that the naturally occurring reverse mutation (P539A) seen in the FOXP subfamily increases DNA binding affinity and may increase the potential for nonspecific binding compared to other FOX family members.
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First-principles theory of cation- and intercalation-ordering in Li_xCoO_2
NASA Astrophysics Data System (ADS)
Wolverton, C.; Zunger, Alex
1998-03-01
Using a combination of first-principles total energies, a cluster expansion technique, and Monte Carlo simulations, we present a first-principles theory which can predict both cation- and intercalation-ordering patterns at both zero and finite temperatures, and can provide first-principles predictions of battery voltages of Li_xCoO_2/Li cells. The classes of ordering problems that we study are the following: (i) The LiMO2 oxides (M=3d metal) form a series of structures based on an octahedrally-coordinated network with anions (O) on one fcc sublattice and cations (Li and M) on the other, leading to Li/Co ordering in LiCoO2 (x=1). We find the ground state is the CuPt or (111)-layered cation arrangment, in agreement with the observed structure. (ii) In battery applications, Li is (de)intercalated from the compound, creating a vacancy (denoted Box) that can be positioned in different lattice locations; Thus, Box/Co ordering in BoxCoO2 (x=0) is also of interest. We find the ground state for BoxCoO2 is also a (111)-layered structure, although a different stacking sequence (AAA) of close-packed layers is preferred. (iii) The vacancies left behind by Li extraction can form ordered vacancy compounds in partially de-lithiated Li_xCoO_2, leading to a Box/Li ordering problem (0<=x<=1). Our calculations agree with the observed voltage profiles in these systems, and predict the existence of new intercalation-ordered compounds. Supported by BES/OER/DMS under contract DE-AC36-83CH10093.
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Halperin, Julia; Devi, Sangeeta Y.; Elizur, Shai; Stocco, Carlos; Shehu, Aurora; Rebourcet, Diane; Unterman, Terry G.; Leslie, Nancy D.; Le, Jamie; Binart, Nadine; Gibori, Geula
2008-01-01
Prolactin (PRL) is a hormone with over 300 biological activities. Although the signaling pathway downstream of the long form of its receptor (RL) has been well characterized, little is known about PRL actions upon activation of the short form (RS). Here, we show that mice expressing only RS exhibit an ovarian phenotype of accelerated follicular recruitment followed by massive follicular death leading to premature ovarian failure. Consequently, RS-expressing ovaries of young adults are depleted of functional follicles and formed mostly by interstitium. We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death. Coexpression of RL with RS prevents PRL inhibition of Galt, and the ovarian defect is no longer seen in RS transgenic mice that coexpress RL, suggesting that RL prevents RS-induced ovarian impairment. In summary, we show that PRL signals through RS and causes, in the absence of RL, a severe ovarian pathology by repressing the expression of FOXO3 and that of its target gene Galt. We also provide evidence of a link between the premature ovarian failure seen in mice expressing RS and in mice with FOXO3 gene deletion as well as in human with Galt mutation. PMID:17975019
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Manley, Sharon; Ni, Hong-Min; Williams, Jessica A.; Kong, Bo; DiTacchio, Luciano; Guo, Grace; Ding, Wen-Xing
2014-01-01
Alcoholic liver disease encompasses a wide spectrum of pathogenesis including steatosis, fibrosis, cirrhosis, and alcoholic steatohepatitis. Autophagy is a lysosomal degradation process that degrades cellular proteins and damaged/excess organelles, and serves as a protective mechanism in response to various stresses. Acute alcohol treatment induces autophagy via FoxO3a-mediated autophagy gene expression and protects against alcohol-induced steatosis and liver injury in mice. Farnesoid X Receptor (FXR) is a nuclear receptor that regulates cellular bile acid homeostasis. In the present study, wild type and FXR knockout (KO) mice were treated with acute ethanol for 16 h. We found that ethanol treated-FXR KO mice had exacerbated hepatotoxicity and steatosis compared to wild type mice. Furthermore, we found that ethanol treatment had decreased expression of various essential autophagy genes and several other FoxO3 target genes in FXR KO mice compared with wild type mice. Mechanistically, we did not find a direct interaction between FXR and FoxO3. Ethanol-treated FXR KO mice had increased Akt activation, increased phosphorylation of FoxO3 resulting in decreased FoxO3a nuclear retention and DNA binding. Furthermore, ethanol treatment induced hepatic mitochondrial spheroid formation in FXR KO mice but not in wild type mice, which may serve as a compensatory alternative pathway to remove ethanol-induced damaged mitochondria in FXR KO mice. These results suggest that lack of FXR impaired FoxO3a-mediated autophagy and in turn exacerbated alcohol-induced liver injury. PMID:25460735
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Newton, Fay G.; zur Lage, Petra I.; Karak, Somdatta; Moore, Daniel J.; Göpfert, Martin C.; Jarman, Andrew P.
2012-01-01
Summary Cilia have evolved hugely diverse structures and functions to participate in a wide variety of developmental and physiological processes. Ciliary specialization requires differences in gene expression, but few transcription factors are known to regulate this, and their molecular function is unclear. Here, we show that the Drosophila Forkhead box (Fox) gene, fd3F, is required for specialization of the mechanosensory cilium of chordotonal (Ch) neurons. fd3F regulates genes for Ch-specific axonemal dyneins and TRPV ion channels, which are required for sensory transduction, and retrograde transport genes, which are required to differentiate their distinct motile and sensory ciliary zones. fd3F is reminiscent of vertebrate Foxj1, a motile cilia regulator, but fd3F regulates motility genes as part of a broader sensory regulation program. Fd3F cooperates with the pan-ciliary transcription factor, Rfx, to regulate its targets directly. This illuminates pathways involved in ciliary specialization and the molecular mechanism of transcription factors that regulate them. PMID:22698283
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Zeng, Zhiwen; Wang, Haitao; Shang, Fu; Zhou, Lihua; Little, Peter J; Quirion, Remi; Zheng, Wenhua
2016-03-01
Lithium is currently used in the treatment of mental illness. We have previously reported that lithium stimulated the protein kinase B/Forkhead box O1 (Akt/FoxO1) pathway in rats. However, little information is available regarding its neuroprotective role of this pathway and underlying mechanisms. PC12 cells treated with serum deprivation were used as a toxicity model to study the protective effect of lithium and its underlying mechanisms. Cell viability was determined by methyl thiazolyl tetrazolium assay and Hoechst staining. FoxO1 subcellular location and its overexpression were used to study the underlying mechanisms. Various pathway inhibitors were used to investigate the possible pathways, while the phosphorylation of Akt and FoxO1 was analyzed by Western blot. Lithium pretreatment dose-dependently reduced PC12 cell apoptosis induced by serum starvation. The protective effect of lithium was abolished by LY294002, a PI3K-specific inhibitor, and Akt inhibitor Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MEK kinase) inhibitor U0126 had no effect. Lithium induced the phosphorylation of Akt and FoxO1 in a time- and concentration-dependent manner. Lithium-induced phosphorylation of Akt and FoxO1 is mediated by the PI3K/Akt pathway. Serum deprivation caused nuclear translocation of FoxO1 while application of lithium reversed the effect of serum deprivation. Moreover, overexpression of FoxO1 enhanced cell apoptosis induced by serum withdrawal. Finally, lithium was found to reduce the exogenous and endogenous FoxO1 protein levels in PC12 cells in a concentration-dependent fashion. The protective effect of lithium against serum starvation cell death is mediated by the PI3K/Akt/FoxO1 pathway.
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Dai, Bingbing; Gong, Aihua; Jing, Zhitao; Aldape, Kenneth D.; Kang, Shin-Hyuk; Sawaya, Raymond; Huang, Suyun
2013-01-01
The forkhead box M1 (FoxM1) is a key transcription factor regulating multiple aspects of cell biology. Prior studies have shown that FoxM1 is overexpressed in a variety of human tumors, including brain tumor, and plays a critical role in cancer development and progression. In this study we found that FoxM1 was up-regulated by heat shock factor 1 (HSF1) under heat shock stress condition in multiple cell lines. Knockdown of HSF1 with HSF1 siRNA or inhibition of HSF1 with a HSF1 inhibitor abrogated heat shock-induced expression of FoxM1. Genetic deletion of HSF1 in mouse embryo fibroblast cells also abolished heat shock stress-induced FoxM1 expression. Moreover, we showed that HSF1 directly bound to FoxM1 promoter and increased FoxM1 promoter activity. Furthermore, we demonstrated that FoxM1 was required for the G2-M phase progression through regulating Cdc2, Cdc20, and Cdc25B under a mild heat shock stress but enhanced cell survival under lethal heat shock stress condition. Finally, in human glioblastoma specimens, FoxM1 overexpression correlated with elevated HSF1 expression. Our results indicate that FoxM1 is regulated by HSF1 and is critical for HSF1-mediated heat shock response. We demonstrated a novel mechanism of stress resistance controlled by HSF1 and a new HSF-FoxM1 connection that mediates cellular thermotolerance. PMID:23192351
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Hussaini, H M; Parachuru, V P B; Seymour, G J; Rich, A M
2017-04-01
The function of forkhead box-P3 (FoxP3) regulatory T cells (Treg) and toll-like receptor (TLR)2 protein in the oral cancer microenvironment is not fully understood, but evidence from other malignancies suggests it is likely they are involved with tumour development and progression. The aim of this study was to investigate the distribution of FoxP3 + cells, TLR2 + cells and double-labelled FoxP3 + TLR2 + immune cells in oral squamous cell carcinoma (OSCC), using immunohistochemistry (IHC) and immunofluorescence (IF). 25 archival cases of OSCC were immunostained with anti-FoxP3 and anti-TLR2 antibodies. Inflamed hyperplastic oral mucosal tissues were used as controls. The proportion of single-labelled, double-labelled and negative cells was determined. A higher frequency of double-labelled FoxP3 + TLR2 + Tregs was observed within the immune cells of OSCC compared to inflamed controls using IHC (p<0.05). Cell-to-cell contact between single-stained TLR2 + cells and FoxP3 + cells was noted. Double IF studies validated demonstration of co-expression of FoxP3 + /TLR2 + immune cells in OSCC. The presence of FoxP3 + TLR2 + cells within the OSCC microenvironment may represent a dendritic cell-dependent pathway capable of inhibiting Treg suppressive activity, potentially enhancing the anti-tumour response. Modulation of TLR2-Treg interactions should be further explored to determine if they have a role in the therapeutic management of OSCC. Copyright © 2017 Elsevier GmbH. All rights reserved.
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Ribasés, Marta; Sánchez-Mora, Cristina; Ramos-Quiroga, Josep Antoni; Bosch, Rosa; Gómez, Núria; Nogueira, Mariana; Corrales, Montse; Palomar, Gloria; Jacob, Christian P; Gross-Lesch, Silke; Kreiker, Susanne; Reif, Andreas; Lesch, Klaus Peter; Cormand, Bru; Casas, Miquel; Bayés, Mónica
2012-08-01
Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder manifesting as symptoms of inattention, hyperactivity, and/or impulsivity. Learning disabilities co-occur with ADHD in 20-30% of cases and this high co-occurrence raises the possibility of a common etiological background. Forkhead box P2 (FOXP2) encodes a transcription factor involved in speech and language impairment and in the control of the corticobasal ganglia circuits known to be relevant in ADHD, suggesting a possible role of FOXP2 in ADHD. Our aim was to carry out an association study between FOXP2 and adulthood ADHD. We carried out a case-control association study in 643 adult ADHD patients and 619 controls from Germany and in 361 adult ADHD patients and 442 controls from Spain with 12 tagging single nucleotide polymorphisms covering the FOXP2 gene. The single-marker and multiple-marker analyses showed an association between FOXP2 and combined ADHD in the German cohort [rs12533005: P=0.0033; odds ratio=1.30 (1.09-1.56); rs12533005/rs1229761: P=4.1e-04; odds ratio=1.38 (1.15-1.66)]. These positive results, however, were not confirmed in the Spanish sample. Although these preliminary findings provide a tentative evidence for the contribution of FOXP2 to ADHD and suggest common genetic factors for this psychiatric disorder and learning disabilities, they should be interpreted with caution. Further studies in larger samples are needed to clarify the role of this transcription factor in ADHD.
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Liu, Xia; Ji, Baoju; Sun, Mengyi; Wu, Weijiang; Huang, Lili; Sun, Aihua; Zong, Yangyong; Xia, Sheng; Shi, Liyun; Qian, Hui; Xu, Wenrong; Shao, Qixiang
2015-07-01
Regulatory T cells (T(regs)) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T(reg) development and function. Here, we generated a cell-permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)-γ expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD-mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL-17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORγt). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T(regs). These results suggest that PTD-mFoxP3 may be a candidate for RA therapy. © 2015 British Society for Immunology.
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Zeng, Zhiwen; Wang, Xue; Bhardwaj, Sanjeev K; Zhou, Xuanhe; Little, Peter J; Quirion, Remi; Srivastava, Lalit K; Zheng, Wenhua
2017-07-01
Schizophrenia is one of the most severe psychiatric disorders. Increasing evidence implicates that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics are neuroprotective and successful in slowing the progressive morphological brain changes. As an antipsychotic agent, clozapine has superior and unique effects, but the intracellular signaling pathways that mediate clozapine action remain to be elucidated. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is crucial for neuronal survival. However, little information is available regarding this pathway with clozapine. In the present study, we investigated the protective effect of clozapine on the PC12 cells against corticosterone toxicity. Our results showed that corticosterone decreases the phosphorylation of Akt and FoxO3a, leading to the nuclear localization of FoxO3a and the apoptosis of PC12 cells, while clozapine concentration dependently protected PC12 cells against corticosterone insult. Pathway inhibitors studies displayed that the protective effect of clozapine was reversed by LY294002 and wortmannin, two PI3K inhibitors, or Akt inhibitor VIII although several other inhibitors had no effect. The shRNA knockdown results displayed that downregulated Akt1 or FoxO3a attenuated the protective effect of clozapine. Western blot analyses revealed that clozapine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a and the nuclear translocation of FoxO3a evoked by corticosterone. Together, our data indicates that clozapine protects PC12 cells against corticosterone-induced cell death by modulating activity of the PI3K/Akt/FoxO3a pathway.
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Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss.
Maiese, Kenneth
2017-01-01
With almost 47 million individuals worldwide suffering from some aspect of dementia, it is clear that cognitive loss impacts a significant proportion of the global population. Unfortunately, definitive treatments to resolve or prevent the onset of cognitive loss are limited. In most cases such care is currently non-existent prompting the need for novel treatment strategies. Mammalian forkhead transcription factors of the O class (FoxO) are one such avenue of investigation that offer an exciting potential to bring new treatments forward for disorders that involve cognitive loss. Here we examine the background, structure, expression, and function of FoxO transcription factors and their role in cognitive loss, programmed cell death in the nervous system with apoptosis and autophagy, and areas to target FoxOs for dementia and specific disorders such as Alzheimer's disease. FoxO proteins work in concert with a number of other cell survival pathways that involve growth factors, such as erythropoietin and neurotrophins, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), Wnt signaling, and cancer-related pathways. FoxO transcription factors oversee proinflammatory pathways, affect nervous system amyloid (Aβ) production and toxicity, lead to mitochondrial dysfunction, foster neuronal apoptotic cell death, and accelerate the progression of degenerative disease. However, under some scenarios such as those involving autophagy, FoxOs also can offer protection in the nervous system and reduce toxic intracellular protein accumulations and potentially limit Aβ toxicity. Given the ability of FoxOs to not only promote apoptotic cell death in the nervous system, but also through the induction of autophagy offer protection against degenerative disease that can lead to dementia, a fine balance in the activity of FoxOs may be required to target cognitive loss in individuals. Future work should yield exciting new prospects for FoxO proteins as new targets to treat the onset and progression of cognitive loss and dementia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Lebovitz, Harold E
2013-06-01
During the last 50 years, three major classes of autoimmune polyglandular syndromes (APSs) have been defined, and their characteristics and heritability have been delineated. Simultaneously, studies of the immunologic bases of these syndromes provided fundamental information in understanding immune regulation. Genetic analyses of patients and their families with APS type 1 (autoimmune polyendocrinopathy candidiasis, ectodermal dystrophy) identified the autoimmune regulator (AIRE) gene, which drives the expression of peripheral tissue-specific antigens in thymic cells and is critical in the development of self-tolerance. Mutations in this gene cause APS type 1. In contrast, studies in APS type 2 have been instrumental in understanding the role of human leukocyte antigen type II and related molecules in the pathogenesis of polygenetic autoimmune diseases such as type 1A diabetes. Immune dysfunction polyendocrinopathy, enteropathy, X-linked syndrome, which is caused by mutations in the forkhead box P3 gene, has been a model for studying regulatory T cell biology. The APSs epitomize the synergies that the merger of clinical and basic science can achieve. This is the environment that George Eisenbarth was able to create at the Barbara Davis Center for Diabetes.
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Lin, Chih-Li; Huang, Wen-Nung; Li, Hsin-Hua; Huang, Chien-Ning; Hsieh, Sam; Lai, Copper; Lu, Fung-Jou
2015-10-05
Amyloid β (Aβ) peptides are identified in cause of neurodegenerative diseases such as Alzheimer's disease (AD). Previous evidence suggests Aβ-induced neurotoxicity is linked to the stimulation of reactive oxygen species (ROS) production. The accumulation of Aβ-induced ROS leads to increased mitochondrial dysfunction and triggers apoptotic cell death. This suggests antioxidant therapies may be beneficial for preventing ROS-related diseases such as AD. Recently, hydrogen-rich water (HRW) has been proven effective in treating oxidative stress-induced disorders because of its ROS-scavenging abilities. However, the precise molecular mechanisms whereby HRW prevents neuronal death are still unclear. In the present study, we evaluated the putative pathways by which HRW protects against Aβ-induced cytotoxicity. Our results indicated that HRW directly counteracts oxidative damage by neutralizing excessive ROS, leading to the alleviation of Aβ-induced cell death. In addition, HRW also stimulated AMP-activated protein kinase (AMPK) in a sirtuin 1 (Sirt1)-dependent pathway, which upregulates forkhead box protein O3a (FoxO3a) downstream antioxidant response and diminishes Aβ-induced mitochondrial potential loss and oxidative stress. Taken together, our findings suggest that HRW may have potential therapeutic value to inhibit Aβ-induced neurotoxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney.
Sasaki, Motohiro; Sasako, Takayoshi; Kubota, Naoto; Sakurai, Yoshitaka; Takamoto, Iseki; Kubota, Tetsuya; Inagi, Reiko; Seki, George; Goto, Moritaka; Ueki, Kohjiro; Nangaku, Masaomi; Jomori, Takahito; Kadowaki, Takashi
2017-09-01
Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs. © 2017 by the American Diabetes Association.
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Autophagy protects chondrocytes from glucocorticoids-induced apoptosis via ROS/Akt/FOXO3 signaling.
Shen, C; Cai, G-Q; Peng, J-P; Chen, X-D
2015-12-01
Glucocorticoids (GCs) have been widely used in the management of osteoarthritis (OA) and rheumatoid arthritis (RA). Nevertheless, there has been some concern about their ability of increasing reactive oxygen species (ROS) in the cartilage. Forkhead-box class O (FOXO) transcription factors have been proved to have a protective role in chondrocytes through regulation of autophagy and defending oxidative stress. The objective of this study was to investigate the role of FOXO3 in Dex-induce up-regulation of ROS. Healthy cartilages debris from six patients were used for chondrocytes culture. After the treatment of dexamethasone (Dex), the ROS levels, autophagic flux, the expression of FOXO3 in chondrocytes were measured. RNA interference technique was also used to determine the role of FOXO3 in Dex-induced autophagy. The metabolism of the extra-cellular matrix was also investigated. Dex increased intracellular ROS level, the expression of Akt, FOXO3 as well as autophagy flux in human chondrocytes. The expression of aggrecanases also increased after the treatment of Dex. Catalase, the ROS scavenger, suppressed Dex-induced up-regulation of autophagy flux and expression of aggrecanases and Akt. MK-2206 and LY294002, the PI3K/Akt inhibitors, repressed Dex-induced up-regulation of FOXO3. Silencing FOXO3 resulted in down-regulation of Dex-induced autophagy. Moreover, knockdown of FOXO3 increased Dex-induced apoptosis as well as ROS levels in chondrocytes. In addition, up-regulation of autophagy by Rapamycin resulted in decreasing ROS level in chondrocytes. Dex could advance the degenerative process in cartilage. Autophagy was induced in response to Dex-induced up-regulation of ROS via ROS/Akt/FOXO3 signal pathway. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice.
Egawa, Tatsuro; Goto, Ayumi; Ohno, Yoshitaka; Yokoyama, Shingo; Ikuta, Akihiro; Suzuki, Miho; Sugiura, Takao; Ohira, Yoshinobu; Yoshioka, Toshitada; Hayashi, Tatsuya; Goto, Katsumasa
2015-10-01
AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT (n = 24) and AMPK-DN (n = 24) mice were randomly divided into two groups: an untreated preexperimental control group (n = 12 in each group) and an unloading (n = 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ∼30% in WT mice by hindlimb unloading and by ∼20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of κBα, microRNA (miR)-1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system. Copyright © 2015 the American Physiological Society.
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Chi, Hsiang-Cheng; Chen, Shen-Liang; Cheng, Yi-Hung; Lin, Tzu-Kang; Tsai, Chung-Ying; Tsai, Ming-Ming; Lin, Yang-Hsiang; Huang, Ya-Hui; Lin, Kwang-Huei
2016-01-01
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells. PMID:27490929
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Ursolic acid improves domoic acid-induced cognitive deficits in mice
DOE Office of Scientific and Technical Information (OSTI.GOV)
Wu, Dong-mei; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, Jiangsu Province; Lu, Jun, E-mail: lu-jun75@163.com
Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitivemore » deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.« less
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Regulation of FOXO1-mediated transcription and cell proliferation by PARP-1
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sakamaki, Jun-ichi; Daitoku, Hiroaki; Yoshimochi, Kenji
2009-05-08
Forkhead box O (FOXO) transcription factors play an important role in a wide range of biological processes, including cell cycle control, apoptosis, detoxification of reactive oxygen species, and gluconeogenesis through regulation of gene expression. In this study, we demonstrated that PARP-1 functions as a negative regulator of FOXO1. We showed that PARP-1 directly binds to and poly(ADP-ribosyl)ates FOXO1 protein. PARP-1 represses FOXO1-mediated expression of cell cycle inhibitor p27{sup Kip1} gene. Notably, poly(ADP-ribosyl)ation activity was not required for the repressive effect of PARP-1 on FOXO1 function. Furthermore, knockdown of PARP-1 led to a decrease in cell proliferation in a manner dependentmore » on FOXO1 function. Chromatin immunoprecipitation experiments confirmed that PARP-1 is recruited to the p27{sup Kip1} gene promoter through a binding to FOXO1. These results suggest that PARP-1 acts as a corepressor for FOXO1, which could play an important role in proper cell proliferation by regulating p27{sup Kip1} gene expression.« less
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FOXO1 promotes wound healing through the up-regulation of TGF-β1 and prevention of oxidative stress
Ponugoti, Bhaskar; Xu, Fanxing; Zhang, Chenying; Tian, Chen; Pacios, Sandra
2013-01-01
Keratinocyte mobilization is a critical aspect of wound re-epithelialization, but the mechanisms that control its precise regulation remain poorly understood. We set out to test the hypothesis that forkhead box O1 (FOXO1) has a negative effect on healing because of its capacity to inhibit proliferation and promote apoptosis. Contrary to expectations, FOXO1 is required for keratinocyte transition to a wound-healing phenotype that involves increased migration and up-regulation of transforming growth factor β1 (TGF-β1) and its downstream targets, integrin-α3 and -β6 and MMP-3 and -9. Furthermore, we show that FOXO1 functions in keratinocytes to reduce oxidative stress, which is necessary to maintain cell migration and prevent cell death in a TGF-β1–independent manner. Thus, our studies identify a novel function for FOXO1 in coordinating the response of keratinocytes to wounding through up-regulation of TGF-β1 and other factors needed for keratinocyte migration and protection against oxidative stress, which together promote migration and decrease apoptosis. PMID:24145170
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Mifuji-Moroka, Rumi; Hara, Nagisa; Miyachi, Hirohide; Sugimoto, Ryosuke; Tanaka, Hideaki; Fujita, Naoki; Gabazza, Esteban C.; Takei, Yoshiyuki
2013-01-01
Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver. PMID:23936183
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Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1
Bai, Xiao-Zhi; He, Ting; Gao, Jian-Xin; Liu, Yang; Liu, Jia-Qi; Han, Shi-Chao; Li, Yan; Shi, Ji-Hong; Han, Jun-Tao; Tao, Ke; Xie, Song-Tao; Wang, Hong-Tao; Hu, Da-Hai
2016-01-01
Acute kidney injury (AKI) is a common complication after severe burns. Melatonin has been reported to protect against multiple organ injuries by increasing the expression of SIRT1, a silent information regulator that regulates stress responses, inflammation, cellular senescence and apoptosis. This study aimed to investigate the protective effects of melatonin on renal tissues of burned rats and the role of SIRT1 involving the effects. Rat severely burned model was established, with or without the administration of melatonin and SIRT1 inhibitor. The renal function and histological manifestations were determined to evaluate the severity of kidney injury. The levels of acetylated-p53 (Ac-p53), acetylated-p65 (Ac-p65), NF-κB, acetylated-forkhead box O1 (Ac-FoxO1), Bcl-2 and Bax were analyzed to study the underlying mechanisms. Our results suggested that severe burns could induce acute kidney injury, which could be partially reversed by melatonin. Melatonin attenuated oxidative stress, inflammation and apoptosis accompanied by the increased expression of SIRT1. The protective effects of melatonin were abrogated by the inhibition of SIRT1. In conclusion, we demonstrate that melatonin improves severe burn-induced AKI via the activation of SIRT1 signaling. PMID:27599451
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Fox transcription factors: from development to disease.
Golson, Maria L; Kaestner, Klaus H
2016-12-15
Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development. © 2016. Published by The Company of Biologists Ltd.
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Chen, Baolin; Wu, Qiang; Xiong, Zhaojun; Ma, Yuedong; Yu, Sha; Chen, Dandan; Huang, Shengwen; Dong, Yugang
2016-09-01
Control of cardiac muscle mass is thought to be determined by a dynamic balance of protein synthesis and degradation. Recent studies have demonstrated that atrophy-related forkhead box O 3a (FOXO3a)/muscle atrophy F-box (MAFbx) signaling pathway plays a central role in the modulation of proteolysis and exert inhibitory effect on cardiomyocyte hypertrophy. In this study, we tested the hypothesis that adenosine monophosphate-activated protein kinase (AMPK) activation attenuates cardiomyocyte hypertrophy by regulating FOXO3a/MAFbx signaling pathway and its downstream protein degradation. The results showed that activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated cardiomyocyte hypertrophy induced by angiotensin II (Ang II). The antihypertrophic effects of AICAR were blunted by AMPK inhibitor Compound C. In addition, AMPK dramatically increased the activity of transcription factor FOXO3a, up-regulated the expression of its downstream ubiquitin ligase MAFbx, and enhanced cardiomyocyte proteolysis. Meanwhile, the effects of AMPK on protein degradation and cardiomyocyte hypertrophy were blocked after MAFbx was silenced by transfection of cardiomyocytes with MAFbx-siRNA. These results indicate that AMPK plays an important role in the inhibition of cardiomyocyte hypertrophy by activating protein degradation via FOXO3a/MAFbx signaling pathway. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Hinds, Terry D.; Peck, Bailey; Shek, Evan; Stroup, Steven; Hinson, Jennifer; Arthur, Susan; Marino, Joseph S.
2016-01-01
Unlike the glucocorticoid receptor α (GRα), GR β (GRβ) has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GRα as the mediator of glucocorticoid-induced skeletal muscle loss. Because GRβ causes glucocorticoid resistance, targeting GRβ may be beneficial in impairing muscle loss as a result of GRα activity. The purpose of this study was to determine how the overexpression of GRβ affects myotube formation and dexamethasone (Dex) responsiveness. We measured GR isoform expression in C2C12 muscle cells in response to Dex and insulin, and through four days of myotube formation. Next, lentiviral-mediated overexpression of GRβ in C2C12 was performed, and these cells were characterized for cell fusion and myotube formation, as well as sensitivity to Dex via the expression of ubiquitin ligases. GRβ overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GRβ overexpressing myotubes had an increased fusion index. Myotubes overexpressing GRβ had lower forkhead box O3 (Foxo3a) mRNA levels and a blunted muscle atrophy F-box/Atrogen-1 (MAFbx) and muscle ring finger 1 (MuRF1) response to Dex. We showed that GRβ may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GRβ levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids. PMID:26875982
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Vidal, Rene L.; Figueroa, Alicia; Court, Felipe A.; Thielen, Peter; Molina, Claudia; Wirth, Craig; Caballero, Benjamin; Kiffin, Roberta; Segura-Aguilar, Juan; Cuervo, Ana Maria; Glimcher, Laurie H.; Hetz, Claudio
2012-01-01
Mutations leading to expansion of a poly-glutamine track in Huntingtin (Htt) cause Huntington's disease (HD). Signs of endoplasmic reticulum (ER) stress have been recently reported in animal models of HD, associated with the activation of the unfolded protein response (UPR). Here we have investigated the functional contribution of ER stress to HD by targeting the expression of two main UPR transcription factors, XBP1 and ATF4 (activating transcription factor 4), in full-length mutant Huntingtin (mHtt) transgenic mice. XBP1-deficient mice were more resistant to developing disease features, associated with improved neuronal survival and motor performance, and a drastic decrease in mHtt levels. The protective effects of XBP1 deficiency were associated with enhanced macroautophagy in both cellular and animal models of HD. In contrast, ATF4 deficiency did not alter mHtt levels. Although, XBP1 mRNA splicing was observed in the striatum of HD transgenic brains, no changes in the levels of classical ER stress markers were detected in symptomatic animals. At the mechanistic level, we observed that XBP1 deficiency led to augmented expression of Forkhead box O1 (FoxO1), a key transcription factor regulating autophagy in neurons. In agreement with this finding, ectopic expression of FoxO1 enhanced autophagy and mHtt clearance in vitro. Our results provide strong evidence supporting an involvement of XBP1 in HD pathogenesis probably due to an ER stress-independent mechanism involving the control of FoxO1 and autophagy levels. PMID:22337954
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Li, Fanni; Dong, Xiwen; Lin, Peng; Jiang, Jianli
2018-01-01
The maintenance of ordinal cell cycle phases is a critical biological process in cancer genesis, which is a crucial target for anti-cancer drugs. As an important natural isoquinoline alkaloid from Chinese herbal medicine, Berberine (BBR) has been reported to possess anti-cancer potentiality to induce cell cycle arrest in hepatocellular carcinoma cells (HCC). However, the underlying mechanism remains to be elucidated. In our present study, G0/G1 phase cell cycle arrest was observed in berberine-treated Huh-7 and HepG2 cells. Mechanically, we observed that BBR could deactivate the Akt pathway, which consequently suppressed the S-phase kinase-associated protein 2 (Skp2) expression and enhanced the expression and translocation of Forkhead box O3a (FoxO3a) into nucleus. The translocated FoxO3a on one hand could directly promote the transcription of cyclin-dependent kinase inhibitors (CDKIs) p21Cip1 and p27Kip1, on the other hand, it could repress Skp2 expression, both of which lead to up-regulation of p21Cip1 and p27Kip1, causing G0/G1 phase cell cycle arrest in HCC. In conclusion, BBR promotes the expression of CDKIs p21Cip1 and p27Kip1 via regulating the Akt/FoxO3a/Skp2 axis and further induces HCC G0/G1 phase cell cycle arrest. This research uncovered a new mechanism of an anti-cancer effect of BBR. PMID:29360760
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Li, Yirong; Ligr, Martin; McCarron, James P; Daniels, Garrett; Zhang, David; Zhao, Xin; Ye, Fei; Wang, Jinhua; Liu, Xiaomei; Osman, Iman; Mencher, Simon K; Lepor, Hebert; Wang, Long G; Ferrari, Anna; Lee, Peng
2011-07-01
The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC. The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts. Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC(50) between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha. Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone-refractory PC with minimal side effects.
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Li, Yirong; Ligr, Martin; McCarron, James P; Daniels, Garrett; Zhang, David; Zhao, Xin; Ye, Fei; Wang, Jinhua; Liu, Xiaomei; Osman, Iman; Mencher, Simon K; Lepor, Hebert; Wang, Long G; Lee, Peng
2011-01-01
Purpose The development of new effective therapeutic agents with minimal side effects for prostate cancer treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine – Qing Dai (Indigo Naturalis), has been used to treat leukemia for decades. However, the anti-cancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in prostate cancer. Experimental Design Human prostate cancer cell lines were treated with or without Natura-alpha followed by cell growth and invasion assays measured. The anti-tumor effects of Natura-alpha were examined in nude mice tumor xenograft models, as well as in a patient with advanced hormone refractory metastatic prostate cancer. Signal network proteins targeted by Natura-alpha were analyzed using Proteomic Pathway Array Analysis (PPAA) on xenografts. Results Natura-alpha inhibited the growth of both androgen-dependent (LNCaP), and androgen-independent (LNCaP-AI, PC-3, and DU145) prostate cancer cells with IC50 between 4 to 10 Μm, also inhibits invasion of androgen-independent prostate cancer cells. Its anti-tumor effects were further evident in vivo tumor reduction in androgen-dependent and -independent nude mice tumor xenograft models as well as reduced tumor volume in the patient with hormone refractory metastatic prostate cancer. PPAA revealed that anti-proliferative and anti-invasive activities of Natura-alpha on prostate cancer might primarily be through its down-regulation of Forkhead box M1 (FOXM1) protein. Forced over-expression of FOXM1 largely reversed the inhibition by Natura-alpha. Conclusion Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone sensitive and hormone refractory prostate cancer with minimal side effects. PMID:21606178
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Schiavo, G; Bertolini, F; Utzeri, V J; Ribani, A; Geraci, C; Santoro, L; Óvilo, C; Fernández, A I; Gallo, M; Fontanesi, L
2018-04-19
Casertana is an endangered autochthonous pig breed (raised in south-central Italy) that is considered to be the descendant of the influential Neapolitan pig population that was used to improve British breeds in the 19th century. Casertana pigs are characterized by a typical, almost complete, hairless phenotype, even though a few Casertana pigs are normal haired. In this work, using Illumina PorcineSNP60 BeadChip data, we carried out a genome-wide association study and an F ST analysis with this breed by comparing animals showing the classical hairless phenotype (n = 81) versus pigs classified as haired (n = 15). Combining the results obtained with the two approaches, we identified two significant regions: one on porcine chromosome (SSC) 7 and one on SSC15. The SSC7 region contains the forkhead box N3 (FOXN3) gene, the most plausible candidate gene of this region, considering that mutations in another gene of the same family (forkhead box N1; Foxn1 or FOXN1) are responsible for the nude locus in rodents and alopecia in humans. Another potential candidate gene, rho guanine nucleotide exchange factor 10 (ARHGEF10), is located in the SSC15 region. FOXN3 and ARHGEF10 have been detected as differentially expressed in androgenetic and senescent alopecia respectively. This study on an autochthonous pig breed contributes to shed some light on novel genes potentially involved in hair development and growth and demonstrates that local animal breeds can be valuable genetic resources for disclosing genetic factors affecting unique traits, taking advantage of phenotype variability segregating in small populations. © 2018 Stichting International Foundation for Animal Genetics.
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Sacchi, Sandro; Marinaro, Federica; Xella, Susanna; Marsella, Tiziana; Tagliasacchi, Daniela; La Marca, Antonio
2017-09-01
Anti-Müllerian hormone (AMH) and forkhead box L2 (FOXL2) are two pivotal genes expressed in human granulosa cells (hGCs) where both genes share similar inhibitory functions on activation and follicular growth in order to preserve the ovarian follicle reserve. Furthermore, AMH and FOXL2 contribute to inhibit steroidogenesis, decreasing or preventing the activation of gonadotrophin-dependent aromatase CYP19A1 cytochrome P450 family 19 subfamily A member 1 (CYP19A1). The purpose of this study is to evaluate the role of AMH in regulating the expression of FOXL2. Primary cultures of hGCs were treated with increasing concentrations of recombinant human AMH (rhAMH; range 10-100 ng/ml) for 3 h. Negative controls were performed using corresponding amounts of AMH vehicle. Total RNA or proteins were purified and quantified by spectrophotometry. FOXL2 and CYP19A1 gene expression, normalized by reference gene ribosomal protein S7 (RpS7), was evaluated by RT-qPCR. Each reaction was repeated in triplicate. Statistical analysis was performed. Extracted proteins were analyzed by immunoblot using anti-FOXL2 and anti-β-actin as primary antibodies. rhAMH treatments tested did not modulate the basal expression of aromatase CYP19A1 gene. rhAMH (50 ng/ml) was able to increase FOXL2 gene expression and its intracellular content. This study demonstrated the existence of an AMH-FOXL2 relationship in hGCs. AMH is capable of increasing both gene and protein expression of FOXL2. Because FOXL2 induces AMH transcription, these ovarian factors could be finely regulated by a positive feedback loop mechanism to preserve the ovarian follicle reserve.
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Kristensen, B; Hegedüs, L; Madsen, H O; Smith, T J; Nielsen, C H
2015-04-01
T helper type 17 (Th17) cells play a pathogenic role in autoimmune disease, while interleukin (IL)-10-producing Th10 cells serve a protective role. The balance between the two subsets is regulated by the local cytokine milieu and by the relative expression of intact forkhead box protein 3 (FoxP3) compared to FoxP3Δ2, missing exon 2. Th17 and Th10 cell differentiation has usually been studied using polyclonal stimuli, and little is known about the ability of physiologically relevant self-antigens to induce Th17 or Th10 cell differentiation in autoimmune thyroid disease. We subjected mononuclear cells from healthy donors and patients with Hashimoto's thyroiditis (HT) or Graves' disease (GD) to polyclonal stimulation, or stimulation with human thyroglobulin (TG), human thyroid peroxidase (TPO), or Esherichia coli lipopolysaccharide (LPS). TPO and LPS induced increased differentiation of naive CD4(+) CD45RA(+) CD45R0(-) T cells from HT patients into Th17 cells. Th10 cell proportions were decreased in HT after polyclonal stimulation, but were comparable to those of healthy donors after antigen-specific stimulation. Taken together, our data show that an increased Th17 : Th10 ratio was found in HT patients after stimulation with thyroid-specific self-antigens. We also observed an elevated baseline production of IL-6 and transforming growth factor (TGF)-β1 and of mRNA encoding FoxP3Δ2 rather than intact FoxP3. This may contribute to the skewing towards Th17 cell responses in HT. © 2014 British Society for Immunology.
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Syed, Aleena; Garcia, Marco A; Lyu, Shu-Chen; Bucayu, Robert; Kohli, Arunima; Ishida, Satoru; Berglund, Jelena P; Tsai, Mindy; Maecker, Holden; O'Riordan, Gerri; Galli, Stephen J; Nadeau, Kari C
2014-02-01
The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance. Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy. In a phase 1 single-site study, we studied participants (n = 23) undergoing peanut OIT and compared them with age-matched allergic control subjects (n = 20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n = 7), whereas those who had an allergic reaction were categorized as nontolerant (NT; n = 13). Antibody and basophil activation measurements did not statistically differentiate between NT versus IT participants. However, T-cell function and demethylation of forkhead box protein 3 (FOXP3) CpG sites in antigen-induced regulatory T cells were significantly different between IT versus NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months), only 3 participants remained classified as IT participants, and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced regulatory T cells. In summary, modifications at the DNA level of antigen-induced T-cell subsets might be predictive of a state of operationally defined clinical immune tolerance during peanut OIT. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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Bottema, R W B; Kerkhof, M; Reijmerink, N E; Koppelman, G H; Thijs, C; Stelma, F F; Smit, H A; Brunekreef, B; van Schayck, C P; Postma, D S
2010-07-01
The Forkhead Box P3 (FOXP3) gene, located on the X-chromosome, encodes a transcription factor that directs T cells toward a regulatory phenotype. Regulatory T cells may suppress development of atopy. We evaluated whether single-nucleotide polymorphisms (SNPs) of FOXP3 are associated with atopy development in childhood. Seven SNPs in FOXP3 were genotyped in 3062 children (51% boys) participating in the Allergenic study, which consists of three Dutch birth cohorts (PIAMA, PREVASC and KOALA). Association of FOXP3 SNPs with total serum IgE and sensitisation (presence of specific serum IgE to egg, milk, and indoor, i.e. house-dust mite, cat, and/or dog allergens) was investigated at ages 1, 2, 4, and 8. Analysis of variance and logistic regression were performed, stratified for gender. Our most consistent finding was observed for sensitisation to egg and indoor allergens. In girls, five FOXP3 SNPs (rs5906761, rs2294021, rs2294019, rs6609857 and rs3761548) were significantly associated with sensitisation to egg at ages 1 and 2 and with sensitisation to indoor allergens at age 2 (P < 0.05), but not at 4 and 8, a finding that was observed across the three cohorts. Rs5906761 and rs2294021 were associated with remission of sensitisation to food allergens in boys, as tested in the PIAMA cohort. This is the first study showing across three cohorts that X-chromosomal FOXP3 genotypes may contribute to development of sensitisation against egg and indoor allergens in girls in early childhood. In addition, an association with remission of sensitisation to food allergens existed in boys only.
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Expression of forkhead box transcription factor genes Foxp1 and Foxp2 during jaw development.
Cesario, Jeffry M; Almaidhan, Asma A; Jeong, Juhee
2016-03-01
Development of the face is regulated by a large number of genes that are expressed in temporally and spatially specific patterns. While significant progress has been made on characterizing the genes that operate in the oral region of the face, those regulating development of the aboral (lateral) region remain largely unknown. Recently, we discovered that transcription factors LIM homeobox (LHX) 6 and LHX8, which are key regulators of oral development, repressed the expression of the genes encoding forkhead box transcription factors, Foxp1 and Foxp2, in the oral region. To gain insights into the potential role of the Foxp genes in region-specific development of the face, we examined their expression patterns in the first pharyngeal arch (primordium for the jaw) of mouse embryos at a high spatial and temporal resolution. Foxp1 and Foxp2 were preferentially expressed in the aboral and posterior parts of the first pharyngeal arch, including the developing temporomandibular joint. Through double immunofluorescence and double fluorescent RNA in situ hybridization, we found that Foxp1 was expressed in the progenitor cells for the muscle, bone, and connective tissue. Foxp2 was expressed in subsets of bone and connective tissue progenitors but not in the myoblasts. Neither gene was expressed in the dental mesenchyme nor in the oral half of the palatal shelf undergoing extensive growth and morphogenesis. Together, we demonstrated for the first time that Foxp1 and Foxp2 are expressed during craniofacial development. Our data suggest that the Foxp genes may regulate development of the aboral and posterior regions of the jaw. Copyright © 2016 Elsevier B.V. All rights reserved.
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Zhang, Mingting; Xu, Qingli; Yan, Shufen; Li, Zhigang; Yan, Wei; Jia, Xiaojing
2016-05-01
MicroRNAs (miRNAs) play a pivotal role in cancer progression and development, representing novel therapeutic tools for cancer therapy. Forkhead box Q1 (FOXQ1) functions as an oncogene in various cancer types. However, the functional significance of FOXQ1 in cervical cancer remains unknown. In this study, we investigated the biological function of FOXQ1 in cervical cancer and tested whether or not FOXQ1 can be targeted and regulated by specific miRNAs. We found that FOXQ1 was highly expressed in cervical cancer cell lines. Knockdown of FOXQ1 by small interfering RNA (siRNA) significantly suppressed the proliferation and epithelial-mesenchymal transition (EMT) of cervical cancer cells. FOXQ1 was predicted as a target gene of microRNA-506 (miR-506), and this prediction was validated by dual-luciferase reporter assay. Quantitative real-time PCR and western blot analyses demonstrated that mRNA and protein expression was negatively regulated by miR-506. The expression of miR-506 was downregulated in cervical cancer tissues, and miR-506 expression was inversely correlated with FOXQ1 expression in cervical cancer. The overexpression of miR-506 dramatically suppressed the proliferation and EMT of cervical cancer cells that mimicked the suppression of FOXO1 siRNA. Furthermore, the restoration of FOXQ1 expression significantly reversed the inhibitory effect of miR-506. Overall, our study demonstrated that miR-506 inhibited the proliferation and EMT of cervical cancer cells by targeting FOXQ1 and provided evidence that the miR-506/FOXQ1 axis plays an important role in the pathogenesis of cervical cancer, representing potential molecular targets for the development of anticancer agents for cervical cancer treatment.
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SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner
Bollinger, Lance M.; Witczak, Carol A.; Houmard, Joseph A.
2014-01-01
Muscle-specific RING finger-1 (MuRF-1), a ubiquitin ligase and key regulator of proteasome-dependent protein degradation, is highly expressed during skeletal muscle atrophy. The transcription factor forkhead box O3 (FoxO3) induces MuRF-1 expression, but the direct role of other major atrophy-related transcription factors, such as SMAD3, is largely unknown. The goal of this study was to determine whether SMAD3 individually regulates, or with FoxO3 coordinately regulates, MuRF-1 expression. In cultured myotubes or human embryonic kidney cells, MuRF-1 mRNA content and promoter activity were increased by FoxO3 but not by SMAD3 overexpression. However, FoxO3 and SMAD3 coexpression synergistically increased MuRF-1 mRNA and promoter activity. Mutation of the SMAD-binding element (SBE) in the proximal MuRF-1 promoter or overexpression of a SMAD3 DNA-binding mutant attenuated FoxO3-dependent MuRF-1 promoter activation, showing that SMAD binding to DNA is required for optimal activation of FoxO3-induced transcription of MuRF-1. Using chromatin immunoprecipitation, SMAD3 DNA binding increased FoxO3 abundance and SBE mutation reduced FoxO3 abundance on the MuRF-1 promoter. Furthermore, SMAD3 overexpression dose-dependently increased FoxO3 protein content, and coexpression of FoxO3 and SMAD3 synergistically increased FoxO-dependent gene transcription [assessed with a FoxO response element (FRE)-driven reporter]. Collectively, these results show that SMAD3 regulates transcription of MuRF-1 by increasing FoxO3 binding at a conserved FRE-SBE motif within the proximal promoter region, and by increasing FoxO3 protein content and transcriptional activity. These data are the first to indicate that two major transcription factors regulating protein degradation, FoxO3 and SMAD3, converge to coordinately and directly regulate transcription of MuRF-1. PMID:24920680
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NASA Astrophysics Data System (ADS)
Aung, Khin Moh Moh; Lim, Michelle Gek Liang; Hong, Shuzhen; Cheung, Edwin; Su, Xiaodi
Forkhead box protein 1 (FoxA1) is a member of the forkhead family of winged-helix transcription factors. It plays crucial roles in the development and differentiation of multiple organs and in the regulation of estrogen-stimulated genes. In this study, in order to determine the regions of FoxA1 necessary for efficient Deoxyribonucleic Acid (DNA) binding, we cloned, expressed and purified a series of FoxA1 constructs that contain either the DNA Binding Domain (DBD), the Transcription Activation Domain (TAD), or both. We determined the DNA binding behavior of these constructs using traditional electrophoretic mobility shift assay (EMSA) and a recently developed gold nanoparticles (AuNPs)-based fast screening method. We conclude that just the DBD region alone is not sufficient for protein-DNA binding activity. Amino acids flanking the upstream of the DBD region are required for maximal DNA binding activity. Through this study, we have also further validated the AuNPs assay for its generality and expanded the existing protocol for comparing the DNA binding behavior of multiple proteins of different charge properties and molecular weights.
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Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.
Melnik, Bodo C
2015-01-01
Acne vulgaris, an epidemic inflammatory skin disease of adolescence, is closely related to Western diet. Three major food classes that promote acne are: 1) hyperglycemic carbohydrates, 2) milk and dairy products, 3) saturated fats including trans-fats and deficient ω-3 polyunsaturated fatty acids (PUFAs). Diet-induced insulin/insulin-like growth factor (IGF-1)-signaling is superimposed on elevated IGF-1 levels during puberty, thereby unmasking the impact of aberrant nutrigenomics on sebaceous gland homeostasis. Western diet provides abundant branched-chain amino acids (BCAAs), glutamine, and palmitic acid. Insulin and IGF-1 suppress the activity of the metabolic transcription factor forkhead box O1 (FoxO1). Insulin, IGF-1, BCAAs, glutamine, and palmitate activate the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the key regulator of anabolism and lipogenesis. FoxO1 is a negative coregulator of androgen receptor, peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α, and sterol response element binding protein-1c (SREBP-1c), crucial transcription factors of sebaceous lipogenesis. mTORC1 stimulates the expression of PPARγ and SREBP-1c, promoting sebum production. SREBP-1c upregulates stearoyl-CoA- and Δ6-desaturase, enhancing the proportion of monounsaturated fatty acids in sebum triglycerides. Diet-mediated aberrations in sebum quantity (hyperseborrhea) and composition (dysseborrhea) promote Propionibacterium acnes overgrowth and biofilm formation with overexpression of the virulence factor triglyceride lipase increasing follicular levels of free palmitate and oleate. Free palmitate functions as a "danger signal," stimulating toll-like receptor-2-mediated inflammasome activation with interleukin-1β release, Th17 differentiation, and interleukin-17-mediated keratinocyte proliferation. Oleate stimulates P. acnes adhesion, keratinocyte proliferation, and comedogenesis via interleukin-1α release. Thus, diet-induced metabolomic alterations promote the visible sebofollicular inflammasomopathy acne vulgaris. Nutrition therapy of acne has to increase FoxO1 and to attenuate mTORC1/SREBP-1c signaling. Patients should balance total calorie uptake and restrict refined carbohydrates, milk, dairy protein supplements, saturated fats, and trans-fats. A paleolithic-like diet enriched in vegetables and fish is recommended. Plant-derived mTORC1 inhibitors and ω-3-PUFAs are promising dietary supplements supporting nutrition therapy of acne vulgaris.
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Linking diet to acne metabolomics, inflammation, and comedogenesis: an update
Melnik, Bodo C
2015-01-01
Acne vulgaris, an epidemic inflammatory skin disease of adolescence, is closely related to Western diet. Three major food classes that promote acne are: 1) hyperglycemic carbohydrates, 2) milk and dairy products, 3) saturated fats including trans-fats and deficient ω-3 polyunsaturated fatty acids (PUFAs). Diet-induced insulin/insulin-like growth factor (IGF-1)-signaling is superimposed on elevated IGF-1 levels during puberty, thereby unmasking the impact of aberrant nutrigenomics on sebaceous gland homeostasis. Western diet provides abundant branched-chain amino acids (BCAAs), glutamine, and palmitic acid. Insulin and IGF-1 suppress the activity of the metabolic transcription factor forkhead box O1 (FoxO1). Insulin, IGF-1, BCAAs, glutamine, and palmitate activate the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the key regulator of anabolism and lipogenesis. FoxO1 is a negative coregulator of androgen receptor, peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α, and sterol response element binding protein-1c (SREBP-1c), crucial transcription factors of sebaceous lipogenesis. mTORC1 stimulates the expression of PPARγ and SREBP-1c, promoting sebum production. SREBP-1c upregulates stearoyl-CoA- and Δ6-desaturase, enhancing the proportion of monounsaturated fatty acids in sebum triglycerides. Diet-mediated aberrations in sebum quantity (hyperseborrhea) and composition (dysseborrhea) promote Propionibacterium acnes overgrowth and biofilm formation with overexpression of the virulence factor triglyceride lipase increasing follicular levels of free palmitate and oleate. Free palmitate functions as a “danger signal,” stimulating toll-like receptor-2-mediated inflammasome activation with interleukin-1β release, Th17 differentiation, and interleukin-17-mediated keratinocyte proliferation. Oleate stimulates P. acnes adhesion, keratinocyte proliferation, and comedogenesis via interleukin-1α release. Thus, diet-induced metabolomic alterations promote the visible sebofollicular inflammasomopathy acne vulgaris. Nutrition therapy of acne has to increase FoxO1 and to attenuate mTORC1/SREBP-1c signaling. Patients should balance total calorie uptake and restrict refined carbohydrates, milk, dairy protein supplements, saturated fats, and trans-fats. A paleolithic-like diet enriched in vegetables and fish is recommended. Plant-derived mTORC1 inhibitors and ω-3-PUFAs are promising dietary supplements supporting nutrition therapy of acne vulgaris. PMID:26203267
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Cyr, Nicole E; Steger, Jennifer S; Toorie, Anika M; Yang, Jonathan Z; Stuart, Ronald; Nillni, Eduardo A
2015-03-01
In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of hypothalamic Sirt1 in body weight and energy balance regulation is debated. The first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague-Dawley rats. Central inhibition of Sirt1 decreased body weight and food intake as a result of a forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin (POMC) and decrease in the orexigenic Agouti-related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which in turn increased phosphorylated FoxO1 via improved insulin/phosphorylated AKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the α-melanocyte-stimulating hormone (α-MSH) maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product α-MSH released into the paraventricular nucleus. Increased in α-MSH led to augmented TRH levels and circulating T3 levels (triiodothyronine, thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic-pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics.
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Cyr, Nicole E; Steger, Jennifer S; Toorie, Anika M; Yang, Jonathan Z; Stuart, Ronald; Nillni, Eduardo A
2014-07-01
In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of Sirt1 in the brain, particularly the hypothalamus, in body weight and energy balance regulation is debated. Among the first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague Dawley rats. In that study, central inhibition of Sirt1 decreased body weight and food intake as a result of a Forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin (POMC) and decrease in the orexigenic Agouti-related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which, in turn, increased phosphorylated FoxO1 via improved insulin/pAKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the α-MSH maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product α-MSH released into the paraventricular nucleus. Increased in α-MSH led to augmented TRH levels and circulating T3 levels (thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic-pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics.
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Kappel, Ben Arpad; Stöhr, Robert; De Angelis, Lorenzo; Mavilio, Maria; Menghini, Rossella; Federici, Massimo
2016-06-01
Forkhead box protein O1 (FoxO1) plays a key role in energy homeostasis, stress response and autophagy and is dysregulated in diabetes and ischemia. We investigated cardiac FoxO1 expression and posttranstranslational modifications after myocardial infarction (MI) and further tested if active posttranstranslational modulation of FoxO1 can alter cardiac remodeling in postischemic heart failure. Non-diabetic and diabetic C57BL/6 mice were subjected to MI by ligation of left anterior descending artery. In selected experiments we combined this model with intramyocardial injection of adenovirus expressing different isoforms of FoxO1. We used Millar catheter, histology, Western blot and metabolomics for further analyses. We show that after MI total cardiac FoxO1 is downregulated and partly recovers after 7 days. This downregulation is accompanied by fundamental posttranslational modifications of FoxO1, particularly acetylation. Adenovirus experiments revealed smaller infarction size and improved heart function in mice expressing a constitutively deacetylated variant of FoxO1 compared to a wild type variant of FoxO1 in both non-diabetic (MI size: -13.4 ± 3.5%; LVDP: +29.1 ± 9.4 mmHg; p < 0.05) and diabetic mice (MI size: -17.6 ± 3.7%; LVDP: +10.9 ± 3.6 mmHg; p < 0.05). Metabolomics analyses showed alterations in metabolites connected to muscle breakdown, collagen/elastin and energy metabolism between the two groups. First, our results demonstrate that myocardial ischemia is associated with downregulation and posttranslational modification of cardiac FoxO1. Second, we show in a mouse model of postischemic heart failure that posttranslational modulation of FoxO1 alters heart function involving collagen and protein metabolism. Therefore, posttranslational modifications of FoxO1 could be an option to target remodeling processes in postischemic heart failure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
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2010-01-01
using linker -mediated PCR as described previously (25). Amplified DNA was labeled and hybridized in triplicate by NimbleGen Systems, Inc., to their human...leading edge analysis (37) of these gene sets identified TGFb–induced SMAD3 direct target genes (Supplementary Table S5) as enriched in SOX4 target...3.06E11 PAX5 Paired box 2.07E10 WHN Forkhead 2.94E10 SMAD3 SMAD 1.82E09 SMAD4 SMAD 3.33E09 MYC MYC 6.25E09 NFKAPPAB NF-nB 2.95E08 LEF1/TCF1 LEF
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Type I neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice
Arai, Takatomo; Ono, Yumika; Arimura, Yujiro; Sayama, Keimon; Suzuki, Tomohiro; Shinjo, Satoko; Kanai, Mai; Abe, Shin-ichi; Semba, Kentaro; Goda, Nobuhito
2017-01-01
Neuregulin1 is an epidermal growth factor (EGF)-like domain-containing protein that has multiple isoforms and functions as a local mediator in the control of various cellular functions. Here we show that type I isoform of neuregulin1 with an α-type EGF-like domain (Nrg1α) is the major isoform in mouse liver and regulates hepatic glucose production. Forced expression of Nrg1α in mouse liver enhanced systemic glucose disposal and decreased hepatic glucose production with reduced fasting blood glucose levels. Nuclear forkhead box protein O1 (FoxO1) and its downstream targets, PEPCK and G6Pase, were suppressed in liver and isolated hepatocytes by Nrg1α overexpression. In contrast, silencing of Nrg1α enhanced glucose production with increased PEPCK and G6Pase expressions in cAMP/dexamethasone-stimulated hepatocytes. Mechanistically, the recombinant α-type EGF-like domain of NRG1α (rNRG1α) stimulated the ERBB3 signalling pathway in hepatocytes, resulting in decreased nuclear FoxO1 accumulation via activation of both the AKT and ERK pathways. In addition, acute treatment with rNRG1α also suppressed elevation of blood glucose levels after both glucose and pyruvate challenge. Although a liver-specific deletion of Nrg1 gene in mice showed little effect on systemic glucose metabolism, these results suggest that NRG1α have a novel regulatory function in hepatic gluconeogenesis by regulating the ERBB3-AKT/ERK-FoxO1 cascade. PMID:28218289
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Yu, Seok-Yeong; Lee, Jin-Ha; Cho, MyoungLae; Lee, Jong Seok; Hong, Hee-Do; Lee, Young-Chul; Kim, Young-Chan; Cho, Chang-Won; Kim, Kyung-Tack; Lee, Ok-Hwan
2016-01-01
Korean red ginseng (KRG), a highly valuable medicinal herb in oriental societies, has biological activity similar to that of Panax ginseng. Recently, it has been discovered that the biological activities of red ginseng can vary according to heating and steaming processes under different conditions that change the principal components of KRG and result in changes in biological activity. This study evaluated and compared the effects of high temperature- and high pressure-treated red ginseng (HRG) and commercial red ginseng (RG) on β-oxidation in C2C12 myotubes. HRG enhanced the phosphorylation levels of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), but RG did not affect the phosphorylation of AMPK in C2C12 myotubes. HRG also promoted the nuclear translocation of forkhead box protein O1 (FoxO1), and the translocation exerted an increase in the protein expression of adipose triglyceride lipase (ATGL). As a consequence, HRG increased the mRNA expression level of carnitine palmitoyltransferase 1 (CPT-1) compared to the control. Taken together, our results indicated that HRG promotes the lipolysis of triglycerides and mitochondrial β-oxidation of fatty acids in C2C12 myotubes, suggesting that alterations to the principal components by high temperature and pressure may positively influence the nutraceutical functions of HRG.
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Yu, Lushan; Wang, Zhangting; Huang, Minmin; Li, Yingying; Zeng, Kui; Lei, Jinxiu; Hu, Haihong; Chen, Baian; Lu, Jing; Xie, Wen; Zeng, Su
2016-09-01
The constitutive androstane receptor (CAR) is a key sensor in xenobiotic detoxification and endobiotic metabolism. Increasing evidence suggests that CAR also plays a role in energy metabolism by suppressing the hepatic gluconeogenesis and lipogenesis. In this study, we investigated the effects of two evodia alkaloids, rutaecarpine (Rut) and evodiamine (Evo), on gluconeogenesis and lipogenesis through their activation of the human CAR (hCAR). We found that both Rut and Evo exhibited anti-lipogenic and anti-gluconeogenic effects in the hyperlipidemic HepG2 cells. Both compounds can potently activate hCAR, and treatment of cells with hCAR antagonists reversed the anti-lipogenic and anti-gluconeogenic effects of Rut and Evo. The anti-gluconeogenic effect of Rut and Evo was due to the CAR-mediated inhibition of the recruitment of forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4α (HNF4α) onto the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene promoters. In vivo, we showed that treatment of mice with Rut improved glucose tolerance in a CAR-dependent manner. Our results suggest that the evodia alkaloids Rut and Evo may have a therapeutic potential for the treatment of hyperglycemia and type 2 diabetes. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. Copyright © 2015 Elsevier B.V. All rights reserved.
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The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System*
Zeldich, Ella; Chen, Ci-Di; Colvin, Teresa A.; Bove-Fenderson, Erin A.; Liang, Jennifer; Tucker Zhou, Tracey B.; Harris, David A.; Abraham, Carmela R.
2014-01-01
Generation of reactive oxygen species (ROS), leading to oxidative damage and neuronal cell death, plays an important role in the pathogenesis of neurodegenerative disorders, including Alzheimer disease. The present study aimed to examine the mechanism by which the anti-aging protein Klotho exerts neuroprotective effects against neuronal damage associated with neurodegeneration and oxidative stress. Pretreatment of rat primary hippocampal neurons and mouse hippocampal neuronal cell line HT22 with recombinant Klotho protected these cells from glutamate and oligomeric amyloid β (oAβ)-induced cytotoxicity. In addition, primary hippocampal neurons obtained from Klotho-overexpressing mouse embryos were more resistant to both cytotoxic insults, glutamate and oAβ, compared with neurons from wild-type littermates. An antioxidative stress array analysis of neurons treated with Klotho revealed that Klotho significantly enhances the expression of the thioredoxin/peroxiredoxin (Trx/Prx) system with the greatest effect on the induction of Prx-2, an antioxidant enzyme, whose increase was confirmed at the mRNA and protein levels. Klotho-induced phosphorylation of the PI3K/Akt pathway, a pathway important in apoptosis and longevity, was associated with sustained inhibitory phosphorylation of the transcription factor forkhead box O3a (FoxO3a) and was essential for the induction of Prx-2. Down-regulation of Prx-2 expression using a lentivirus harboring shRNA almost completely abolished the ability of Klotho to rescue neurons from glutamate-induced death and significantly, but not completely, inhibited cell death mediated by oAβ, suggesting that Prx-2 is a key modulator of neuroprotection. Thus, our results demonstrate, for the first time, the neuroprotective role of Klotho and reveal a novel mechanism underlying this effect. PMID:25037225
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Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway
Gupta, Sanjay
2014-01-01
Forkhead box O (FoxO) transcription factors play an important role as tumor suppressor in several human malignancies. Disruption of FoxO activity due to loss of phosphatase and tensin homolog and activation of phosphatidylinositol-3 kinase (PI3K)/Akt are frequently observed in prostate cancer. Apigenin, a naturally occurring plant flavone, exhibits antiproliferative and anticarcinogenic activities through mechanisms, which are not fully defined. In the present study, we show that apigenin suppressed prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice through the PI3K/Akt/FoxO-signaling pathway. Apigenin-treated TRAMP mice (20 and 50 μg/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate as well as completely abolished distant organ metastasis. Apigenin treatment resulted in significant decrease in the weight of genitourinary apparatus (P < 0.0001), dorsolateral (P < 0.0001) and ventral prostate (P < 0.028), compared with the control group. Apigenin-treated mice showed reduced phosphorylation of Akt (Ser473) and FoxO3a (Ser253), which correlated with its increased nuclear retention and decreased binding of FoxO3a with 14-3-3. These events lead to reduced proliferation as assessed by Ki-67 and cyclin D1, along with upregulation of FoxO-responsive proteins BIM and p27/Kip1. Complementing in vivo results, similar observations were noted in human prostate cancer LNCaP and PC-3 cells after apigenin treatment. Furthermore, binding of FoxO3a with p27/Kip1 was markedly increased after 10 and 20 μM apigenin treatment resulting in G0/G1-phase cell cycle arrest, which was consistent with the effects elicited by PI3K/Akt inhibitor, LY294002. These results provide convincing evidence that apigenin effectively suppressed prostate cancer progression, at least in part, by targeting the PI3K/Akt/FoxO-signaling pathway. PMID:24067903
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miR-182 attenuates atrophy-related gene expression by targeting FoxO3 in skeletal muscle
Rahnert, Jill A.; Zheng, Bin; Woodworth-Hobbs, Myra E.; Franch, Harold A.; Russ Price, S.
2014-01-01
Skeletal muscle atrophy occurs in response to a variety of conditions including chronic kidney disease, diabetes, cancer, and elevated glucocorticoids. MicroRNAs (miR) may play a role in the wasting process. Activation of the forkhead box O3 (FoxO3) transcription factor causes skeletal muscle atrophy in patients, animals, and cultured cells by increasing the expression of components of the ubiquitin-proteasome and autophagy-lysosome proteolytic systems. To identify microRNAs that potentially modulate the atrophy process, an in silico target analysis was performed and miR-182 was predicted to target FoxO3 mRNA. Using a combination of immunoblot analysis, quantitative real-time RT-PCR, and FoxO3 3′-UTR luciferase reporter genes, miR-182 was confirmed to regulate FoxO3 expression in C2C12 myotubes. Transfection of miR-182 into muscle cells decreased FoxO3 mRNA 30% and FoxO3 protein 67% (P < 0.05) and also prevented a glucocorticoid-induced upregulation of multiple FoxO3 gene targets including MAFbx/atrogin-1, autophagy-related protein 12 (ATG12), cathepsin L, and microtubule-associated protein light chain 3 (LC3). Treatment of C2C12 myotubes with dexamethasone (Dex) (1 μM, 6 h) to induce muscle atrophy decreased miR-182 expression by 63% (P < 0.05). Similarly, miR-182 was decreased 44% (P < 0.05) in the gastrocnemius muscle of rats injected with streptozotocin to induce diabetes compared with controls. Finally, miR-182 was present in exosomes isolated from the media of C2C12 myotubes and Dex increased its abundance. These data identify miR-182 as an important regulator of FoxO3 expression that participates in the control of atrophy-inducing genes during catabolic diseases. PMID:24871856
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Li, Lei; Lyu, Dan
2017-06-01
Objective To purify the recombinant protein specific to conserved region of forkhead box O3 (FOXO3) and prepare mouse anti-human FOXO3 polyclonal antibody. Methods The DNA fragment (aa290-472) encoding conserved domain of FOXO3 was amplified by PCR, and subsequently cloned into pET28a vector. Following transformation into E.coli BL21, the soluble fusion protein His-FOXO3 was induced by IPTG and purified by Ni-NTA affinity chromatography. The purified protein was used to immunize BALB/c mice to generate polyclonal antibody. The characteristics of the polyclonal antibody were assessed by ELISA, Western blotting and immunoprecipitation assays. Results We successfully prepared the expression vector pET28a-FOXO3 (aa290-472) and expressed the purified fusion protein in a soluble form. By immunizing mice with the fusion protein, we obtained anti-human FOXO3 polyclonal antibody. ELISA and Western blotting showed that the mouse antibody could recognize specifically the endogenous FOXO3 protein. Conclusion The polyclonal antibody against conserved domain of FOXO3 can identify the endogenous FOXO3 protein. It can be used to analyze the endogenous FOXO3 expression level.
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Ma, Jiexian; Wu, Kefei; Bai, Weiya; Cui, Xiaoxian; Chen, Yan; Xie, Youhua; Xie, Yanhui
2017-06-01
At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways. The two drugs synergistically inhibit the same pathways, but through different sites. Cereblon was found expressed in most of the MCL tissues (91.3% positivity). Moreover, cereblon expression is positively correlated with LD regimen sensitivity: long-term lenalidomide exposure downregulates cereblon and induces multi-drug resistance against lenalidomide, dexamethasone, cytarabine, cisplatin, and methotrexate in vitro. Removal of lenalidomide resensitizes lenalidomide-resistant MCL cells to lenalidomide and dexamethasone. Our work suggests that rotating the LD regimen with other regimens would improve MCL maintenance therapy. Copyright © 2017. Published by Elsevier B.V.
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Jung, T.W.; Lee, K.T.; Lee, M.W.; Ka, K.H.
2012-01-01
Endoplasmic reticulum (ER) stress has been implicated in the pathology of type 2 diabetes mellitus (T2DM). Although SIRT1 has a therapeutic effect on T2DM, the mechanisms by which SIRT1 ameliorates insulin resistance (IR) remain unclear. In this study, we investigated the impact of SIRT1 on palmitate-induced ER stress in HepG2 cells and its underlying signal pathway. Treatment with resveratrol, a SIRT1 activator significantly inhibited palmitate-induced ER stress, leading to the protection against palmitate-induced ER stress and insulin resistance. Resveratrol and SIRT1 overexpression induced the expression of oxygen-regulated protein (ORP) 150 in HepG2 cells. Forkhead box O1 (FOXO1) was involved in the regulation of ORP150 expression because suppression of FOXO1 inhibited the induction of ORP150 by SIRT1. Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress.
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Panossian, Alexander; Wikman, Georg
2010-01-01
Adaptogens were initially defined as substances that enhance the “state of non-specific resistance” in stress, a physiological condition that is linked with various disorders of the neuroendocrine-immune system. Studies on animals and isolated neuronal cells have revealed that adaptogens exhibit neuroprotective, anti-fatigue, antidepressive, anxiolytic, nootropic and CNS stimulating activity. In addition, a number of clinical trials demonstrate that adaptogens exert an anti-fatigue effect that increases mental work capacity against a background of stress and fatigue, particularly in tolerance to mental exhaustion and enhanced attention. Indeed, recent pharmacological studies of a number of adaptogens have provided a rationale for these effects also at the molecular level. It was discovered that the stress—protective activity of adaptogens was associated with regulation of homeostasis via several mechanisms of action, which was linked with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of stress response, such as molecular chaperons (e.g., HSP70), stress-activated c-Jun N-terminal protein kinase 1 (JNK1), Forkhead box O (FOXO) transcription factor DAF-16, cortisol and nitric oxide. PMID:27713248
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Kim, Jonggun; Park, Min Young; Kim, Yoo; Yoon, Kyong Sup; Clark, John Marshall; Park, Yeonhwa; Whang, Kwang-Youn
2017-12-01
Most countries have banned the use of 4,4'-dichlorodiphenyltrichloroethane (DDT). However, owing to its extremely high lipophilic characteristics, DDT and its metabolite 4,4'-dichlorodiphenyldichloroethylene (DDE) are ubiquitous in the environment and in many types of food. The positive correlation between exposure to insecticides, including DDT and DDE, and weight gain, resulting in impaired energy metabolism in offspring following perinatal DDT and DDE exposure, was previously reported. Therefore the influence of DDT and DDE on myogenesis using C2C12 myoblasts was investigated in this study. DDT and DDE decreased myotube formation dose- and time-dependently. Among myogenic regulatory factors, DDT and DDE mainly decreased MyoD1 and Myf5 expression. DDT and DDE treatment also altered Myostatin expression, phosphorylation of protein kinase B, p70 ribosomal protein S6 kinase, forkhead box O protein 3 and mammalian target of rapamycin, resulting in attenuation of myotube formation. These results may have significant implications for understanding the effects of developmental exposure of DDT and DDE on myogenesis and development of obesity and type 2 diabetes later in life. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.
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Genome-wide identification and characterization of Fox genes in the silkworm, Bombyx mori.
Song, JiangBo; Li, ZhiQuan; Tong, XiaoLing; Chen, Cong; Chen, Min; Meng, Gang; Chen, Peng; Li, ChunLin; Xin, YaQun; Gai, TingTing; Dai, FangYin; Lu, Cheng
2015-09-01
The forkhead box (Fox) transcription factor family has a characteristic of forkhead domain, a winged DNA-binding domain. The Fox genes have been classified into 23 subfamilies, designated FoxA to FoxS, of which the FoxR and FoxS subfamilies are specific to vertebrates. In this review, using whole-genome scanning, we identified 17 distinct Fox genes distributed on 13 chromosomes of the silkworm, Bombyx mori. A phylogenetic tree showed that the silkworm Fox genes could be classified into 13 subfamilies. The FoxK subfamily is specifically absent from the silkworm, although it is present in other lepidopteran insects, including Danaus plexippus and Heliconius melpomene. Microarray data revealed that the Fox genes have distinct expression patterns in the tissues on day 3 of the 5th instar larva. A Gene Ontology analysis suggested that the Fox genes have roles in cellular components, molecular functions, and biological processes, except in pore complex biogenesis. An analysis of the selective pressure on the proteins indicated that most of the amino acid sites in the Fox proteins are undergoing strong purifying selection. Here, we summarize the general characteristics of the Fox genes in the silkworm, which should support further functional studies of the silkworm Fox proteins.
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Nerurkar, Pratibha V; Johns, Lisa M; Buesa, Lance M; Kipyakwai, Gideon; Volper, Esther; Sato, Ryuei; Shah, Pranjal; Feher, Domonkos; Williams, Philip G; Nerurkar, Vivek R
2011-06-03
The rising epidemic of obesity is associated with cognitive decline and is considered as one of the major risk factors for neurodegenerative diseases. Neuroinflammation is a critical component in the progression of several neurological and neurodegenerative diseases. Increased metabolic flux to the brain during overnutrition and obesity can orchestrate stress response, blood-brain barrier (BBB) disruption, recruitment of inflammatory immune cells from peripheral blood and microglial cells activation leading to neuroinflammation. The lack of an effective treatment for obesity-associated brain dysfunction may have far-reaching public health ramifications, urgently necessitating the identification of appropriate preventive and therapeutic strategies. The objective of our study was to investigate the neuroprotective effects of Momordica charantia (bitter melon) on high-fat diet (HFD)-associated BBB disruption, stress and neuroinflammatory cytokines. C57BL/6 female mice were fed HFD with and without bitter melon (BM) for 16 weeks. BBB disruption was analyzed using Evans blue dye. Phosphate-buffered saline (PBS) perfused brains were analyzed for neuroinflammatory markers such as interleukin-22 (IL-22), IL-17R, IL-16, NF-κB1, and glial cells activation markers such as Iba1, CD11b, GFAP and S100β. Additionally, antioxidant enzymes, ER-stress proteins, and stress-resistant transcription factors, sirtuin 1 (Sirt1) and forkhead box class O transcription factor (FoxO) were analyzed using microarray, quantitative real-time RT-PCR, western immunoblotting and enzymatic assays. Systemic inflammation was analyzed using cytokine antibody array. BM ameliorated HFD-associated changes in BBB permeability as evident by reduced leakage of Evans blue dye. HFD-induced glial cells activation and expression of neuroinflammatory markers such as NF-κB1, IL-16, IL-22 as well as IL-17R were normalized in the brains of mice supplemented with BM. Similarly, HFD-induced brain oxidative stress was significantly reduced by BM supplementation with a concomitant reduction in FoxO, normalization of Sirt1 protein expression and up-regulation of Sirt3 mRNA expression. Furthermore, plasma antioxidant enzymes and pro-inflammatory cytokines were also normalized in mice fed HFD with BM as compared to HFD-fed mice. Functional foods such as BM offer a unique therapeutic strategy to improve obesity-associated peripheral inflammation and neuroinflammation.
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Miralem, Tihomir; Lerner-Marmarosh, Nicole; Gibbs, Peter E. M.; Jenkins, Jermaine L.; Heimiller, Chelsea; Maines, Mahin D.
2016-01-01
Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1–3) are downstream of IRK and are activated by phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylating T308 before S473 autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present in hBVR. Phosphorylation of glycogen synthase kinase 3 (GSK3) isoforms α/β by Akts inhibits their activity; nonphosphorylated GSK3β inhibits activation of various genes. We examined the role of hBVR in PDK1/Akt1/GSK3 signaling and Akt1 in hBVR phosphorylation. hBVR activates phosphorylation of Akt1 at S473 independent of hBVR’s kinase competency. hBVR and Akt1 coimmunoprecipitated, and in-cell Förster resonance energy transfer (FRET) and glutathione S-transferase pulldown analyses identified Akt1 pleckstrin homology domain as the interactive domain. hBVR activates phosphorylation of Akt1 at S473 independent of hBVR’s kinase competency. Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S230 in hBVR 225RNRYLSF sequence as the Akt1 target. Underlined amino acids are the essential residues of the signaling motifs. In cells, hBVR-activated Akt1 increased both GSK3α/β and forkhead box of the O class transcription class 3 (FoxO3) phosphorylation and inhibited total GSK3 activity; depletion of hBVR released inhibition and stimulated glucose uptake. Immunoprecipitation analysis showed that PDK1 and hBVR interact through hBVR’s PDK1 binding 161RFGFPAFS motif and formation of the PDK1/hBVR/Akt1 complex. sihBVR blocked complex formation. Findings identify hBVR as a previously unknown coactivator of Akt1 and as a key mediator of Akt1/GSK3 pathway, as well as define a key role for hBVR in Akt1 activation by PDK1.—Miralem, T., Lerner-Marmarosh, N., Gibbs, P. E. M., Jenkins, J. L., Heimiller, C., Maines, M. D. Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation. PMID:27166089
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Miralem, Tihomir; Lerner-Marmarosh, Nicole; Gibbs, Peter E M; Jenkins, Jermaine L; Heimiller, Chelsea; Maines, Mahin D
2016-08-01
Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1-3) are downstream of IRK and are activated by phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylating T(308) before S(473) autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present in hBVR. Phosphorylation of glycogen synthase kinase 3 (GSK3) isoforms α/β by Akts inhibits their activity; nonphosphorylated GSK3β inhibits activation of various genes. We examined the role of hBVR in PDK1/Akt1/GSK3 signaling and Akt1 in hBVR phosphorylation. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. hBVR and Akt1 coimmunoprecipitated, and in-cell Förster resonance energy transfer (FRET) and glutathione S-transferase pulldown analyses identified Akt1 pleckstrin homology domain as the interactive domain. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target. Underlined amino acids are the essential residues of the signaling motifs. In cells, hBVR-activated Akt1 increased both GSK3α/β and forkhead box of the O class transcription class 3 (FoxO3) phosphorylation and inhibited total GSK3 activity; depletion of hBVR released inhibition and stimulated glucose uptake. Immunoprecipitation analysis showed that PDK1 and hBVR interact through hBVR's PDK1 binding (161)RFGFPAFS motif and formation of the PDK1/hBVR/Akt1 complex. sihBVR blocked complex formation. Findings identify hBVR as a previously unknown coactivator of Akt1 and as a key mediator of Akt1/GSK3 pathway, as well as define a key role for hBVR in Akt1 activation by PDK1.-Miralem, T., Lerner-Marmarosh, N., Gibbs, P. E. M., Jenkins, J. L., Heimiller, C., Maines, M. D. Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation. © FASEB.
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76 FR 56099 - Amendment of Class E Airspace; Orangeburg, SC
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-12
... Group, Eastern Service Center, Federal Aviation Administration, P.O. Box 20636, Atlanta, Georgia 30320... the airspace descriptor from ``ASO GA E5 Orangeburg, SC [Amended]'' to ``ASO SC E5 Orangeburg, SC... Airport, SC, remove ``lat. 33[deg]27[min]39[sec] N., long. 80[deg]51[min]32[sec] W.'' and insert ``lat. 33...
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Li, Hongliang; Xu, Mingjiang; Lee, Jiyeon; He, Chaoyong; Xie, Zhonglin
2012-11-15
Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementation-prevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD(+) levels, which decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) and forkhead box O1 (FoxO1). The deacetylation of PGC1α may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1α and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity.
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Li, Hongliang; Xu, Mingjiang; Lee, Jiyeon; He, Chaoyong
2012-01-01
Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementation-prevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD+ levels, which decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) and forkhead box O1 (FoxO1). The deacetylation of PGC1α may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1α and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity. PMID:22967499
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Hu, Zilong; Hu, Shidong; Wu, Youjun; Li, Songyan; He, Changzheng; Xing, Xiaowei; Wang, Yufeng; Du, Xiaohui
2018-04-01
Although adoptive cell therapy (ACT) has demonstrated effective and remarkable clinical responses in several studies, this approach does not lead to objective clinical responses in all cases. The function of ACT is often compromised by various tumor escape mechanisms, including the accumulation of immunoregulatory cells. As a result of peritoneal metastasis in the terminal stage, malignant ascites fluid lacks effectiveness and is a poor prognostic factor for gastric cancer. The present study assessed T-cell subsets in lymphocytes derived from malignant ascites, and investigated the effects of arsenic trioxide (As 2 O 3 ) on regulatory T cells (Tregs) and ascites-derived tumor-infiltrating lymphocytes (TILs) in vitro . In this study, lymphocytes were separated from malignant ascites and T-cell subsets were detected via flow cytometry. Forkhead box P3 (FoxP3) expression was assessed by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. In addition, cytokines, including interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and interferon-γ (IFN-γ), were measured by enzyme-linked immunosorbent assay (ELISA). Abundant Tregs were observed in ascites lymphocytes, which and exhibited a significantly increased frequency compared with that in the peripheral blood of patients. Furthermore, As 2 O 3 treatment significantly reduced Treg numbers and Foxp3 mRNA levels in vitro (P<0.05). IFN-γ levels in the supernatant of ascites-derived TILs were increased by As 2 O 3 , whereas IL-10 and TGF-β levels were significantly reduced (P<0.05). As 2 O 3 may induce selective depletion and inhibit immunosuppressive function of Tregs, and may enhance the cytotoxic activity of ascites-derived TILs.
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Nunn, Alistair VW; Bell, Jimmy; Barter, Philip
2007-01-01
The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle. PMID:17531095
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Lou, Kexin; Chen, Ning; Li, Zhihong; Zhang, Bei; Wang, Xiuli; Chen, Ye; Xu, Haining; Wang, Dongwei; Wang, Hao
2017-01-02
Abnormal expression of microRNA (miR)-142-5p has been reported in hepatocellular carcinoma (HCC). However, little information is available regarding the functional role of miR-142-5p in HCC. We aimed to explore the effects of miR-142-5p aberrant expression on HCC cell growth and cell apoptosis, as well as the underlying mechanism. Human HCC cell lines HepG2 and SMMC-7721 cells were transfected with miR-142-5p mimic, inhibitor, or a corresponding negative control. Cell viability, cell cycle distribution, and cell apoptosis were then analyzed. In addition, protein expression of Forkhead box, class O (FOXO) 1 and 3, a Bcl-2-interacting mediator of cell death (Bim), procaspase 3, and activated caspase 3 was measured. After transfection with miR-142-5p inhibitor, FOXO1 and FOXO3 were overexpressed, and then the cell viability and cell apoptosis were determined again. The relative cell viability in both HepG2 and SMMC-7721 cells was significantly reduced by miR-142-5p overexpression (p < 0.05). miR-142-5p overexpression displayed a significant blockage at the G1/S transition and significantly increased the percentages of G0/G1 phase. Moreover, the results showed that miR-142-5p overexpression significantly induced cell apoptosis and statistically elevated the protein expression levels of FOXO1, FOXO3, Bim, procaspase 3, and activated caspase 3. However, the cells transfected with miR-142-5p inhibitor showed contrary results. Additionally, the effects of miR-142-5p inhibitor on cell viability and apoptosis were reversed by overexpression of FOXO. In conclusion, our results suggest that miR-142-5p overexpression shows an important protective role in HCC by inhibiting cell growth and inducing apoptosis. These effects might be by regulating FOXO expression in HCC cells.
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Fenelon, Jane C; Shaw, Geoffrey; Frankenberg, Stephen R; Murphy, Bruce D; Renfree, Marilyn B
2017-04-01
Embryonic diapause is a period of developmental arrest which requires coordination of a molecular cross-talk between the endometrium and blastocyst to ensure a successful reactivation, but the exact mechanisms are undefined. The objectives of this study were to screen the tammar blastocyst for potential diapause control factors and to investigate the potential for members of the epidermal growth factor (EGF) family to coordinate reactivation. A select number of factors were also examined in the mink to determine whether their expression patterns were conserved across diapause species. The full-length sequences of the tammar genes of interest were first cloned to establish their level of sequence conservation with other mammals. The uterine expression of EGF family members EGF and heparin-binding EGF (HBEGF) and their receptors (EGFR and erb-b2 receptor tyrosine kinase 4 (ERBB4)) was determined by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Both HBEGF and EGF were significantly upregulated at reactivation compared to diapause. In the blastocyst, the expression of the potential diapause factors Forkhead box class O family members (FOXO1, FOXO3, and FOXO4), tumor protein 53 (TP53), cyclin-dependent kinase inhibitor 1A (CDKN1A), and the EGF family were examined by RT-PCR and immunofluorescence. Nuclear (and hence active) FOXO expression was confirmed for the first time in a mammalian diapause blastocyst in both the tammar and the mink-CDKN1A was also expressed, but TP53 is not involved and EGFR was not detected in the blastocyst. These results indicate that the EGF family, FOXOs, and CDKN1A are promising candidates for the molecular control of embryonic diapause in mammals. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Jiang, Guosong; Huang, Chao; Li, Jingxia; Huang, Haishan; Wang, Jingjing; Li, Yawei; Xie, Fei; Jin, Honglei; Zhu, Junlan; Huang, Chuanshu
2018-03-08
There are few approved drugs available for the treatment of muscle-invasive bladder cancer (MIBC). Recently, we have demonstrated that isorhapontigenin (ISO), a new derivative isolated from the Chinese herb Gnetum cleistostachyum, effectively induces cell-cycle arrest at the G0/G1 phase and inhibits anchorage-independent cell growth through the miR-137/Sp1/cyclin D1 axis in human MIBC cells. Herein, we found that treatment of bladder cancer (BC) cells with ISO resulted in a significant upregulation of p27, which was also observed in ISO-treated mouse BCs that were induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Importantly, knockdown of p27 caused a decline in the ISO-induced G0-G1 growth arrest and reversed ISO suppression of anchorage-independent growth in BC cells. Mechanistic studies revealed that ISO promoted p27 expression at mRNA transcription level through increasing direct binding of forkhead box class O1 (FOXO1) to its promoter, while knockdown of FOXO1 attenuated ISO inhibition of BC cell growth. On the other hand, ISO upregulated the 3'-untranslated region (3'-UTR) activity of p27, which was accompanied by a reduction of miR-182 expression. In line with these observations, ectopic expression of miR-182 significantly blocked p27 3'-UTR activity, whereas mutation of the miR-182-binding site at p27 mRNA 3'-UTR effectively reversed this inhibition. Accordingly, ectopic expression of miR-182 also attenuated ISO upregulation of p27 expression and impaired ISO inhibition of BC cell growth. Our results not only provide novel insight into understanding of the underlying mechanism related to regulation of MIBC cell growth but also identify new roles and mechanisms underlying ISO inhibition of BC cell growth.
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Jiang, Guosong; Wu, Amy D; Huang, Chao; Gu, Jiayan; Zhang, Liping; Huang, Haishan; Liao, Xin; Li, Jingxia; Zhang, Dongyun; Zeng, Xingruo; Jin, Honglei; Huang, Haojie; Huang, Chuanshu
2016-07-01
Although our most recent studies have identified Isorhapontigenin (ISO), a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, for its inhibition of human bladder cancer growth, nothing is known whether ISO possesses an inhibitory effect on bladder cancer invasion. Thus, we addressed this important question in current study and discovered that ISO treatment could inhibit mouse-invasive bladder cancer development following bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) exposure in vivo We also found that ISO suppressed human bladder cancer cell invasion accompanied by upregulation of the forkhead box class O 1 (FOXO1) mRNA transcription in vitro Accordingly, FOXO1 was profoundly downregulated in human bladder cancer tissues and was negatively correlated with bladder cancer invasion. Forced expression of FOXO1 specifically suppressed high-grade human bladder cancer cell invasion, whereas knockdown of FOXO1 promoted noninvasive bladder cancer cells becoming invasive bladder cancer cells. Moreover, knockout of FOXO1 significantly increased bladder cancer cell invasion and abolished the ISO inhibition of invasion in human bladder cancer cells. Further studies showed that the inhibition of Signal transducer and activator of transcription 1 (STAT1) phosphorylation at Tyr701 was crucial for ISO upregulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector, which was also supported by data obtained from mouse model of ISO inhibition BBN-induced mouse-invasive bladder cancer formation. These findings not only provide a novel insight into the understanding of mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such bladder cancer invasion through targeting the STAT1-FOXO1-MMP-2 axis. Cancer Prev Res; 9(7); 567-80. ©2016 AACR. ©2016 American Association for Cancer Research.
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Andrade, Ana Luiza Dias Leite de; Nonaka, Cassiano Francisco Weege; Gordón-Núñez, Manuel Antonio; Freitas, Roseana de Almeida; Galvão, Hébel Cavalcanti
2013-08-01
Different cell types and cytokines have been identified as contributors to the formation of periapical lesions. In this perspective, this study aimed to evaluate the immunoexpression of interleukin (IL)-17, transforming growth factor (TGF)-β1, and the forkhead box P3 (FoxP3) in periapical lesions, correlating them with the type of lesion, the intensity of the inflammatory infiltrate, and the thickness of the cystic epithelial lining. Twenty periapical granulomas (PGs), 20 radicular cysts (RCs), and 20 residual radicular cysts (RRCs) were submitted to immunohistochemical analysis using anti-IL-17, anti-TGF-β1, and anti-FoxP3 antibodies. In comparison with PGs and RCs, RRCs exhibited a lower immunoexpression of IL-17 and TGF-β1 (P = .021 and P < .001, respectively). The number of FoxP3+ cells increased in this order: RRCs, RCs, and PGs (P < .001). In comparison with lesions with inflammatory infiltrates grades I and II, lesions with inflammatory infiltrate grade III exhibited a higher number of FoxP3+ cells (P = .002). Similarly, in comparison with lesions with inflammatory infiltrates grades II and III, lesions with inflammatory infiltrate grade I showed a tendency for a lower expression of IL-17 and TGF-β1 (P = .085 and P = .051, respectively). For all groups, there was a positive correlation between the immunoexpressions of IL-17 and TGF-β1 (P < .05). Positive correlations between the number of FoxP3+ cells and the immunoexpressions of IL-17 and TGF-β1 (P < .05) were found only in PGs. Th17 and Treg cells seem to interact at the site of injury, suggesting the involvement of proinflammatory and immunoregulatory cytokines in the pathogenesis of periapical lesions. Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.
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Jia, Zhongwei; Wan, Fangning; Zhu, Yao; Shi, Guohai; Zhang, Hailiang; Dai, Bo; Ye, Dingwei
2018-06-01
Previous studies have demonstrated that several members of the Forkhead-box (FOX) family of genes are associated with tumor progression and metastasis. The objective of the current study was to screen candidate FOX family genes identified from analysis of molecular networks in clear cell renal cell carcinoma (ccRCC). The expression of FOX family genes as well as FOX family-associated genes was examined, and Kaplan-Meier survival analysis was performed in The Cancer Genome Atlas (TCGA) cohort (n=525). Patient characteristics, including sex, age, tumor diameter, laterality, tumor-node-metastasis, tumor grade, stage, white blood cell count, platelet count, the levels of hemoglobin, overall survival (OS) and disease-free survival (DFS), were collected for univariate and multivariate Cox proportional hazards ratio analyses. A total of seven candidate FOX family genes were selected from the TCGA database subsequent to univariate and multivariate Cox proportional hazards ratio analyses. FOXA1, FOXA2, FOXD1, FOXD4L2, FOXK2 and FOXL1 were associated with poor OS time, while FOXA1, FOXA2, FOXD1 and FOXK2 were associated with poor DFS time (P<0.05). FOXN2 was associated with favorable outcomes for overall and disease-free survival (P<0.05). In the gene cluster network analysis, the expression of FOX family-associated genes, including nuclear receptor coactivator ( NCOA ) 1 , NADH-ubiquinone oxidoreductase flavoprotein 3 ( NDUFV3 ), phosphatidylserine decarboxylase ( PISD ) and pyruvate kinase liver and red blood cell ( PKLR ), were independent prognostic factors for OS in patients with ccRCC. Results of the present study revealed that the expression of FOX family genes, including FOXA1, FOXA2, FOXD1, FOXD4L2, FOXK2 and FOXL1 , and FOX family-associated genes, including NCOA1, NDUFV3, PISD and PKLR , are independent prognostic factors for patients with ccRCC.
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Song, E Y; Han, S; Yang, B; Morris, G P; Bui, J D
2015-04-01
The proliferation rates of human T cells in vitro are affected by some factors such as initial T-cell number, dose of stimulating cells, and duration of culture. The transcription factor forkhead box P3 (FoxP3) has been used to identify regulatory T cells in humans and is thought to correlate with tolerance to allogeneic organ transplant. Thus, it is important to optimize conditions to expand FoxP3 cell proliferation to improve engraftment of allogeneic organ transplants. We studied proliferative responses and FoxP3 expression in divided T cells with the use of flow cytometric analysis of Ki-67 in culture of different concentrations of responding cells (6 × 10(6), 4 × 10(6), 2 × 10(6), 1 × 10(6), and 0.5 × 10(6)cells/mL), different types of stimulating cells (lymphocytes and low density cells), and different numbers of HLA mismatches. The proportion of CD3(+) cells, CD4(+)CD25(+) cells, and CD4(+)CD25(+)FoxP3(+) cells among mononuclear cells were highest at initial cell concentration of 2 × 10(6) responder cells/mL with lymphocytes as stimulators at day-5 mixed lymphocyte reaction (MLR). They were highest at a concentration of 4 × 10(6) responder cells/mL with low density cells as stimulators. The recovery (%), proportion of CD3(+) cells, CD4(+)CD25(+) cells, and CD4(+)CD25(+)FoxP3(+) cells with 2 HLA-DR incompatibility were significantly higher than those of 1 HLA-DR incompatibility at day-5 MLR. Initial cell concentration and HLA-DR incompatibility can affect the generation of FoxP3+ T cells in human MLR. These factors could be considered for efficient generation of Tregs for clinical trials in the future. Copyright © 2015 Elsevier Inc. All rights reserved.
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Zhao, Xiaoqin; Rong, Can; Pan, Fenghui; Xiang, Lizhi; Wang, Xinlei; Hu, Yun
2018-06-28
Increasing evidence indicates that long noncoding RNAs (lncRNAs) perform special biological functions by regulating gene expression through multiple pathways and molecular mechanisms. The aim of this study was to explore the expression characteristics of lncRNA uc.322 in pancreatic islet cells and its effects on the secretion function of islet cells. Bioinformatics analysis was used to detect the lncRNA uc.322 sequence, location, and structural features. Expression of lncRNA uc.322 in different tissues was detected by quantitative polymerase chain reaction analyses. Quantitative polymerase chain reaction, Western blot analysis, adenosine triphosphate determination, glucose-stimulated insulin secretion, and enzyme-linked immunosorbent assay were used to evaluate the effects of lncRNA uc.322 on insulin secretion. The results showed that the full-length of lncRNA uc.322 is 224 bp and that it is highly conserved in various species. Bioinformatics analysis revealed that lncRNA uc.322 is located on chr7:122893196-122893419 (GRCH37/hg19) within the SRY-related HMG-box 6 gene exon region. Compared with other tissues, lncRNA uc.322 is highly expressed in pancreatic tissue. Upregulation of lncRNA uc.322 expression increases the insulin transcription factors pancreatic and duodenal homeobox 1 and Forkhead box O1 expression, promotes insulin secretion in the extracellular fluid of Min6 cells, and increases the adenosine triphosphate concentration. On the other hand, knockdown of lncRNA uc.322 has opposite effects on Min6 cells. Overall, this study showed that upregulation of lncRNA uc.322 in islet β-cells can increase the expression of insulin transcription factors and promote insulin secretion, and it may be a new therapeutic target for diabetes. © 2018 Wiley Periodicals, Inc.
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Linares, María; Marín-García, Patricia; Martínez-Chacón, Gabriela; Pérez-Benavente, Susana; Puyet, Antonio; Diez, Amalia; Bautista, José M
2013-12-01
Oxidative stress has been attributed both a key pathogenic and rescuing role in cerebral malaria (CM). In a Plasmodium berghei ANKA murine model of CM, host redox signaling and functioning were examined during the course of neurological damage. Host antioxidant defenses were early altered at the transcriptional level indicated by the gradually diminished expression of superoxide dismutase-1 (sod-1), sod-2, sod-3 and catalase genes. During severe disease, this led to the dysfunctional activity of superoxide dismutase and catalase enzymes in damaged brain regions. Vitagene associated markers (heat shock protein 70 and thioredoxin-1) also showed a decaying expression pattern that paralleled reduced expression of the transcription factors Parkinson disease 7, Forkhead box O 3 and X-box binding protein 1 with a role in preserving brain redox status. However, the oxidative stress markers reactive oxygen/nitrogen species were not accumulated in the brains of CM mice and redox proteomics and immunohistochemistry failed to detect quantitative or qualitative differences in protein carbonylation. Thus, the loss of antioxidant capacity was compensated for in all cerebral regions by progressive upregulation of heme oxygenase-1, and in specific regions by early glutathione peroxidase-1 induction. This study shows for the first time a scenario of cooperative glutathione peroxidase and heme oxygenase-1 upregulation to suppress superoxide dismutase, catalase, heat shock protein-70 and thioredoxin-1 downregulation effects in experimental CM, counteracting oxidative damage and maintaining redox equilibrium. Our findings reconcile the apparent inconsistency between the lack of oxidative metabolite build up and reported protective effect of antioxidant therapy against CM. © 2013.
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Boxing It Up-a Cross-curricular Approach.
ERIC Educational Resources Information Center
Till, Wesley
1996-01-01
Reports on a class project that examined the manufacture of boxes and packaging to teach about design and technology. The class discovered basic manufacturing techniques by examining and disassembling cereal boxes. Field trips to stores provided more examples. Appraises the children's final projects and discusses acquiring materials. (MJP)
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MicroRNAs control hepatocyte proliferation during liver regeneration.
Song, Guisheng; Sharma, Amar Deep; Roll, Garrett R; Ng, Raymond; Lee, Andrew Y; Blelloch, Robert H; Frandsen, Niels M; Willenbring, Holger
2010-05-01
MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G(1) to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH. Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration.
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Association of REL Polymorphism with Cow's Milk Proteins Allergy in Pediatric Algerian Population.
Rahmoun, Nesrine; El Mecherfi, Kamel Eddine; Bouchetara, Assia; Lardjem Hetraf, Sara; Dahmani Amira, Chahinez; Adda Neggaz, Leila; Boudjema, Abdallah; Zemani-Fodil, Faouzia; Kheroua, Omar
2018-02-01
Cow's milk proteins allergy (CMPA) pathogenesis involves complex immunological mechanisms with the participation of several cells and molecules involved in food allergy. The association of polymorphisms in the interleukin 4, Forkhead box P3 and the avian reticuloendotheliosis genes was investigated in an infant population with CMPA of Western Algeria. We obtained DNA and clinical data from milk allergic subjects during active phase and from a group of non-atopic control subjects. Our findings showed that the allele G of the cRel gene intronic polymorphism at +7883 positions was significantly higher among cow's milk proteins allergic patients compared to control subjects. The results of this study suggest a possible association of CMPA with cRel G+7883T polymorphism.
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Nudel, Ron; Newbury, Dianne F
2013-01-01
The forkhead box P2 gene, designated FOXP2, is the first gene implicated in a speech and language disorder. Since its discovery, many studies have been carried out in an attempt to explain the mechanism by which it influences these characteristically human traits. This review presents the story of the discovery of the FOXP2 gene, including early studies of the phenotypic implications of a disruption in the gene. We then discuss recent investigations into the molecular function of the FOXP2 gene, including functional and gene expression studies. We conclude this review by presenting the fascinating results of recent studies of the FOXP2 ortholog in other species that are capable of vocal communication. WIREs Cogn Sci 2013, 4:547–560. doi: 10.1002/wcs.1247 PMID:24765219
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Lee, Donna M; Duensing, Anette
2018-02-01
Transcriptional regulation of the KIT receptor tyrosine kinase, a master regulator in gastrointestinal stromal tumors (GIST) and their precursors, the interstitial cells of Cajal (ICC), is part of a positive feedback loop involving the transcription factor ETV1. A new study now shows that the forkhead box (FOX) family transcription factor FOXF1 not only is an upstream regulator of ETV1 and hence ICC/GIST lineage-specific gene transcription, but also functions as lineage-specific pioneer factor with an active role in chromatin rearrangement to facilitate ETV1 binding and transcriptional activity. Cancer Discov; 8(2); 146-9. ©2018 AACR See related article by Ran et al., p. 234 . ©2018 American Association for Cancer Research.
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Lyu, J; Imachi, H; Iwama, H; Zhang, H; Murao, K
2016-05-01
ATP-binding cassette transporter A1 (ABCA1) in pancreatic beta cells influences insulin secretion and cholesterol homeostasis. The present study investigates whether insulin-like growth factor 1 (IGF-1), which mediates stimulation of ABCA1 gene expression, could also interfere with the phosphatidylinositol 3-kinase (PI3-K) cascade.ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and a reporter gene assay in rat insulin-secreting INS-1 cells incubated with IGF-1. The binding of forkhead box O1 (FoxO1) protein to the ABCA1 promoter was assessed by a chromatin immunoprecipitation (ChIP) assay. ABCA1 protein levels increased in response to rising concentrations of IGF-1. Real-time PCR analysis showed a significant increase in ABCA1 mRNA expression. However, both effects were suppressed after silencing the IGF-1 receptor. In parallel with its effect on endogenous ABCA1 mRNA levels, IGF-1 induced the activity of a reporter construct containing the ABCA1 promoter, while it was abrogated by LY294002, a specific inhibitor of PI3-K. Constitutively active Akt stimulated activity of the ABCA1 promoter, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity. A ChIP assay showed that FoxO1 mediated its transcriptional activity by directly binding to the ABCA1 promoter region. The knockdown of FoxO1 disrupted the effect of IGF-1 on ABCA1 expression. Furthermore, IGF-1 promoted cholesterol efflux and reduced the pancreatic lipotoxicity. These results demonstrate that the PI3-K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF-1 stimulation. © Georg Thieme Verlag KG Stuttgart · New York.
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Zhao, Yunjing; Liu, Xiaoliang; Sun, Hongwei; Wang, Yueping; Yang, Wenzhu; Ma, Hongwei
2015-12-01
The forkhead box protein P2 (FOXP2) gene encodes an important transcription factor that contains a polyglutamine (poly‑Q) tract and a forkhead DNA binding domain. It has been observed that FOXP2 is associated with speech sound disorder (SSD), and mutations that decrease the length of the poly‑Q tract were identified in the FOXP2 gene of SSD patients. However, the exact role of poly‑Q reduction is not well understood. In the present study, constructs expressing wild‑type and poly‑Q reduction mutants of FOXP2 were generated by polymerase chain reaction (PCR) using lentiviral vectors and transfected into the SH‑SY5Y neuronal cell line. Quantitative reverse transcription (qRT)‑PCR and western blotting indicated that infected cells stably expressed high levels of FOXP2. Using this cell model, the impact of FOXP2 on the expression of contactin‑associated protein‑like 2 (CNTNAP2) were investigated, and CNTNAP2 mRNA expression levels were observed to be significantly higher in cells expressing poly‑Q‑reduced FOXP2. In addition, the expression level of CASPR2, a mammalian homolog of Drosophila Neurexin IV, was increased in cells expressing the FOXP2 mutant. Demonstration of regulation by FOXP2 indicates that CNTNAP2 may also be involved in SSD.
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Zhou, Huanyu; Dickson, Matthew E.; Kim, Min Soo; Bassel-Duby, Rhonda; Olson, Eric N.
2015-01-01
Conversion of fibroblasts to functional cardiomyocytes represents a potential approach for restoring cardiac function after myocardial injury, but the technique thus far has been slow and inefficient. To improve the efficiency of reprogramming fibroblasts to cardiac-like myocytes (iCMs) by cardiac transcription factors [Gata4, Hand2, Mef2c, and Tbx5 (GHMT)], we screened 192 protein kinases and discovered that Akt/protein kinase B dramatically accelerates and amplifies this process in three different types of fibroblasts (mouse embryo, adult cardiac, and tail tip). Approximately 50% of reprogrammed mouse embryo fibroblasts displayed spontaneous beating after 3 wk of induction by Akt plus GHMT. Furthermore, addition of Akt1 to GHMT evoked a more mature cardiac phenotype for iCMs, as seen by enhanced polynucleation, cellular hypertrophy, gene expression, and metabolic reprogramming. Insulin-like growth factor 1 (IGF1) and phosphoinositol 3-kinase (PI3K) acted upstream of Akt whereas the mitochondrial target of rapamycin complex 1 (mTORC1) and forkhead box o3 (Foxo3a) acted downstream of Akt to influence fibroblast-to-cardiomyocyte reprogramming. These findings provide insights into the molecular basis of cardiac reprogramming and represent an important step toward further application of this technique. PMID:26354121
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Progress in the molecular and genetic modification breeding of beef cattle in China.
Tong, Bin; Zhang, Li; Li, Guang-Peng
2017-11-20
The studies of beef cattle breeding in China have been greatly improved with the rapid development of the international beef cattle industrialization. The beef cattle breeding technologies have rapidly transformed from traditional breeding to molecular marker-assisted breeding, genomic selection and genetic modification breeding. Hundreds of candidate genes and molecular markers associated with growth, meat quality, reproduction performance and diseases resistance have been identified, and some of them have already been used in cattle breeding. Genes and molecular markers associated with growth and development are focused on the growth hormone, muscle regulatory factors, myostatin and insulin-like growth factors. Meat quality is mediated by fatty acid transport and deposition related signals, calpains and calpain system, muscle regulatory factors and muscle growth regulation pathways. Reproduction performance is regulated by GnRH-FSH-LH, growth differentiation factor 9, prolactin receptor and forkhead box protein O1. Disease resistance is modulated by the major histocompatibility complex gene family, toll-like receptors, mannose-binding lectin and interferon gene signals. In this review, we summarize the most recent progress in beef cattle breeding in marker-assisted selection, genome-wide selection and genetic modification breeding, aiming to provide a reference for further genetic breeding research of beef cattle in China.
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Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.
Lovelace, Erica S; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard P; Zink, Erika M; Kim, Young-Mo; Kyle, Jennifer E; Webb-Robertson, Bobbie-Jo M; Waters, Katrina M; Metz, Thomas O; Farin, Federico; Oberlies, Nicholas H; Polyak, Stephen J
2015-08-28
Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e., 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, whereas silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.
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Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling
Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard; Zink, Erika M.; Kim, Young-Mo; Kyle, Jennifer E.; Webb-Robertson, Bobbie-Jo; Waters, Katrina M.; Metz, Thomas O.; Farin, Federico; Oberlies, Nicholas H.; Polyak, Stephen J.
2016-01-01
Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e. 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, while silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation. PMID:26186142
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Wang, Lixin; Brugge, Joan S; Janes, Kevin A
2011-10-04
Gene expression networks are complicated by the assortment of regulatory factors that bind DNA and modulate transcription combinatorially. Single-cell measurements can reveal biological mechanisms hidden by population averages, but their value has not been fully explored in the context of mRNA regulation. Here, we adapted a single-cell expression profiling technique to examine the gene expression program downstream of Forkhead box O (FOXO) transcription factors during 3D breast epithelial acinar morphogenesis. By analyzing patterns of mRNA fluctuations among individual matrix-attached epithelial cells, we found that a subset of FOXO target genes was jointly regulated by the transcription factor Runt-related transcription factor 1 (RUNX1). Knockdown of RUNX1 causes hyperproliferation and abnormal morphogenesis, both of which require normal FOXO function. Down-regulating RUNX1 and FOXOs simultaneously causes widespread oxidative stress, which arrests proliferation and restores normal acinar morphology. In hormone-negative breast cancers lacking human epidermal growth factor receptor 2 (HER2) amplification, we find that RUNX1 down-regulation is strongly associated with up-regulation of FOXO1, which may be required to support growth of RUNX1-negative tumors. The coordinate function of these two tumor suppressors may provide a failsafe mechanism that inhibits cancer progression.
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Biological properties of mud extracts derived from various spa resorts.
Spilioti, Eliana; Vargiami, Margarita; Letsiou, Sophia; Gardikis, Konstantinos; Sygouni, Varvara; Koutsoukos, Petros; Chinou, Ioanna; Kassi, Eva; Moutsatsou, Paraskevi
2017-08-01
Spa resorts are known for thousands of years for their healing properties and have been empirically used for the treatment of many inflammatory conditions. Mud is one of the most often used natural materials for preventive, healing and cosmetic reasons and although it has been used since the antiquity, little light has been shed on its physical, chemical and biological properties. In this study we examined the effect of mud extracts on the expression of adhesion molecules (CAMs) by endothelial cells as well as their effects on monocyte adhesion to activated endothelial cells. Most of mud extracts inhibited the expression of VCAM-1 by endothelial cells and reduced monocyte adhesion to activated endothelial cells, indicating a potent anti-inflammatory activity. Furthermore, the mud extracts were tested for their antimicrobial activity; however, most of them appeared inactive against S. aureus and S. epidermidis. One of the mud extracts (showing the best stabilization features) increased significantly the expression of genes involved in cell protection, longevity and hydration of human keratinocytes, such as, collagen 6A1, forkhead box O3, sirtuin-1, superoxide dismutase 1 and aquaporin-3. The present study reveals that mud exerts important beneficial effects including anti-inflammatory and anti-aging activity as well as moisturizing effects, implicating important cosmeceutical applications.
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Excessive fluoride reduces Foxo1 expression in dental epithelial cells of the rat incisor.
Gao, Jianghong; Ruan, Jianping; Gao, Liping
2014-10-01
Enamel fluorosis is characterized by hypomineralization, and forkhead box O1 (Foxo1) is essential for mouse enamel biomineralization. This study investigated the effect of fluoride on Foxo1 expression and its implications for enamel fluorosis. Mandibular incisors were extracted from Sprague Dawley rats treated for 3 months with water containing 0, 50, or 100 p.p.m. F⁻. Immunohistochemistry was used to localize and quantify FOXO1 expression in dental epithelial layer cells of the incisors. The effect of fluoride on expression of Foxo1, kallikrein-4 (Klk4), and amelotin (Amtn) mRNAs was analyzed by real-time RT-PCR, and western blotting was used to measure total and nuclear FOXO1 protein levels in mature dental epithelial cells. The results revealed that nuclear FOXO1 was mainly localized in the transition and the mature ameloblasts and exhibited weaker expression in the rats exposed to fluoride. In addition to the reduced levels of Foxo1, Klk4, and AmtnmRNAs, the protein levels of total and nuclearFOXO1 were decreased in the mature dental epithelial cells exposed to fluoride. Thus, excessive fluoride may have an effect on the expression levels of Foxo1 in dental epithelial cells and thereby affect hypomineralization of the enamel during fluorosis. © 2014 Eur J Oral Sci.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Chen, Liang; Department of Otolaryngology, Guangzhou General Hospital of PLA Guangzhou Command, Guangzhou 510010; Tang, Yanping
2013-06-14
Highlights: •miR-421 is upregulated in nasopharyngeal carcinoma. •miR-421 induces cell proliferation and apoptosis resistance. •FOXO4 is a direct and functional target of miR-421. -- Abstract: microRNAs have been demonstrated to play important roles in cancer development and progression. Hence, identifying functional microRNAs and better understanding of the underlying molecular mechanisms would provide new clues for the development of targeted cancer therapies. Herein, we reported that a microRNA, miR-421 played an oncogenic role in nasopharyngeal carcinoma. Upregulation of miR-421 induced, whereas inhibition of miR-421 repressed cell proliferation and apoptosis resistance. Furthermore, we found that upregulation of miR-421 inhibited forkhead box proteinmore » O4 (FOXO4) signaling pathway following downregulation of p21, p27, Bim and FASL expression by directly targeting FOXO4 3′UTR. Additionally, we demonstrated that FOXO4 expression is critical for miR-421-induced cell growth and apoptosis resistance. Taken together, our findings not only suggest that miR-421 promotes nasopharyngeal carcinoma cell proliferation and anti-apoptosis, but also uncover a novel regulatory mechanism for inactivation of FOXO4 in nasopharyngeal carcinoma.« less
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Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma.
Lang, Mingxiao; Wang, Xiuchao; Wang, Hongwei; Dong, Jie; Lan, Chungen; Hao, Jihui; Huang, Chongbiao; Li, Xin; Yu, Ming; Yang, Yanhui; Yang, Shengyu; Ren, He
2016-08-10
Arsenic trioxide (ATO) has been selected as a promising treatment not only in leukemia but also in solid tumors. Previous studies showed that the cytotoxicity of ATO mainly depends on the induction of reactive oxygen species. However, ATO has only achieved a modest effect in pancreatic ductal adenocarcinoma, suggesting that the existing radical scavenging proteins, such as hypoxia inducible factor-1, attenuate the effect. The goal of this study is to investigate the effect of combination treatment of ATO plus PX-478 (hypoxia-inducible factor-1 inhibitor) and its underlying mechanism. Here, we showed that PX-478 robustly strengthened the anti-growth and pro-apoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro. Meanwhile, in vivo mouse xenograft models also showed the synergistic effect of ATO plus PX-478 compared with any single agent. Further studies showed that the anti-tumor effect of ATO plus PX-478 was derived from the reactive oxygen species-induced apoptosis. We next confirmed that Hypoxia-inducible factor-1 cleared reactive oxygen species by its downstream target, forkhead box O transcription factors, and this effect may justify the strategy of ATO plus PX-478 in the treatment of pancreatic cancer. Copyright © 2016. Published by Elsevier Ireland Ltd.
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Depigmenting Effect of Resveratrol Is Dependent on FOXO3a Activation without SIRT1 Activation.
Kwon, Soon-Hyo; Choi, Hye-Ryung; Kang, Youn-A; Park, Kyoung-Chan
2017-06-07
Resveratrol exhibits not only anti-melanogenic property by inhibiting microphthalmia-associated transcription factor (MITF), but also anti-aging property by activating sirtuin-1 (SIRT1). In this study, the relationship between depigmenting effect of resveratrol and SIRT1/forkhead box O (FOXO) 3a activation and was investigated. Resveratrol suppressed melanogenesis by the downregulation of MITF and tyrosinase via ERK pathway. Results showed that the expression of both SIRT1 and FOXO3a were increased. It is reported that SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. However in our study, FOXO3a activation appeared earlier than that of SIRT1. Furthermore, the effect of resveratrol on the levels of MITF and tyrosinase was suppressed when melanocytes were pre-treated with SP600125 (JNK inhibitor). However, pre-treatment with SIRT1 inhibitor (EX527, or sirtinol) did not affect the levels of MITF and tyrosinase. Therefore, resveratrol inhibits melanogenesis through the activation of FOXO3a but not by the activation of SIRT1. Although SIRT1 activation by resveratrol is a well-known mechanism of resveratrol-induced antiaging effects, our study showed that not SIRT1 but FOXO3a activation is involved in depigmenting effects of resveratrol.
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Shrestha, Anup; Nepal, Saroj; Kim, Mi Jin; Chang, Jae Hoon; Kim, Sang-Hyun; Jeong, Gil-Saeng; Jeong, Chul-Ho; Park, Gyu Hwan; Jung, Sunghee; Lim, Jaecheong; Cho, Eunha; Lee, Soyoung; Park, Pil-Hoon
2016-02-01
Adiponectin predominantly secreted from adipose tissue has exhibited potent anti-proliferative properties in cancer cells via modulating cell cycle and apoptosis. FoxO3A, a Forkhead box O member of the transcription factor, plays a critical role in modulating expression of genes involved in cell death and/or survival. In this study, we investigated the role of FoxO3A signaling in anti-cancer activities of adiponectin. Herein, we have shown that treatment with globular adiponectin (gAcrp) increases p27 but decreases cyclinD1 expression in human hepatoma (HepG2) and breast (MCF-7) cancer cells. Gene ablation of FoxO3A prevented gAcrp-induced increase in p27 and decreased in cyclin D1 expression, and further ameliorated cell cycle arrest by gAcrp, indicating a critical role of FoxO3A in gAcrp-induced cell cycle arrest of cancer cells. Moreover, treatment with gAcrp also induced caspase-3/7 activation and increased Fas ligand (FasL) expression in both HepG2 and MCF-7 cells. Transfection with FoxO3A siRNA inhibited gAcrp-induced caspase-3/7 activation and FasL expression, suggesting that FoxO3A signaling also plays an important role in gAcrp-induced apoptosis of cancer cells. We also found that gene silencing of AMPK prevented gAcrp-induced nuclear translocation of FoxO3A in HepG2 and MCF-7 cells. In addition, suppression of AMPK also blocked gAcrp-induced cell cycle arrest and further attenuated gAcrp-induced caspase-3/7 activation, indicating that AMPK signaling plays a pivotal role in both gAcrp-induced cell cycle arrest and apoptosis via acting as an upstream signaling of FoxO3A. Taken together, our findings demonstrated that AMPK/FoxO3A axis plays a cardinal role in anti-proliferative effect of adiponectin in cancer cells. © 2015 Wiley Periodicals, Inc.
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2014-05-28
SECURITY CLASSIFICATION OF: Antimicrobial peptides or their synthetic mimics are a promising class of potential new antibiotics. Herein we assess the...effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial ?- peptide ...P.O. Box 12211 Research Triangle Park, NC 27709-2211 Antimicrobial peptidomimetics; Peptide –peptoid chimeras; Guanidinium cation; Bacterial
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A Calculus for Boxes and Traits in a Java-Like Setting
NASA Astrophysics Data System (ADS)
Bettini, Lorenzo; Damiani, Ferruccio; de Luca, Marco; Geilmann, Kathrin; Schäfer, Jan
The box model is a component model for the object-oriented paradigm, that defines components (the boxes) with clear encapsulation boundaries. Having well-defined boundaries is crucial in component-based software development, because it enables to argue about the interference and interaction between a component and its context. In general, boxes contain several objects and inner boxes, of which some are local to the box and cannot be accessed from other boxes and some can be accessible by other boxes. A trait is a set of methods divorced from any class hierarchy. Traits can be composed together to form classes or other traits. We present a calculus for boxes and traits. Traits are units of fine-grained reuse, whereas boxes can be seen as units of coarse-grained reuse. The calculus is equipped with an ownership type system and allows us to combine coarse- and fine-grained reuse of code by maintaining encapsulation of components.
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Shen, Xueyan; Cui, Jianzhou; Gong, Qingli
2011-12-01
Members of the Fox gene family of transcriptional regulators are essential for animal development and have been extensively studied in vertebrates. The mouse and human genomes contain at least 40 FOX genes which are divided into 19 subclasses based on the sequence similarity of the highly conserved forkhead domain. Using the genome sequence of the Takifugu rubripes and Tetraodon nigroviridis , we examined the genomic complement of fox genes in these organisms to gain insight into the evolutionary relationship of this gene family. We identified 53 fox genes in Tetraodon nigroviridis and Takifugu rubripes genome by searching the forkhead domain. These genes are divided into 18 subclasses as follows: 8 fox genes in subclass O; 6 in subclass P ; 4 in subclasses D, J, and N; 3 in subclasses A, B, C, E, F, and I; 2 in subclasses K, L, and Q; and 1 in subclasses G, H, M, and R. Together with the forkhead domain sequences of human, chicken, frog, zebrafish, medaka, and Caenorhabditis elegans, the phylogenetic relationship of the fox genes in Takifugu rubripes and Tetraodon nigroviridis were analyzed and compared. The genes structure, general features, and the three-dimensional model of these genes were also discussed.
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Lee, Eun-Kyu; Oh, Hyun-Hee; Choi, Cheol Soo; Kim, Sujong; Jun, Hee-Sook
2014-01-01
Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg−1 body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1. PMID:25610880
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Krivoruchko, Anastasia; Storey, Kenneth B
2013-11-01
The forkhead class O (FoxO) transcription factors are important regulators of multiple aspects of cellular metabolism. We hypothesized that activation of these transcription factors could play crucial roles in low oxygen survival in the anoxia-tolerant turtle, Trachemys scripta elegans. Two FoxOs, FoxO1 and FoxO3, were examined in turtle tissues in response to 5 and 20h of anoxic submergence using techniques of RT-PCR, western immunoblotting and DNA-binding assays to assess activation. Transcript levels of FoxO-responsive genes were also quantified using RT-PCR. FoxO1 was anoxia-responsive in the liver, with increases in transcript levels, protein levels, nuclear levels and DNA-binding of 1.7-4.8fold in response to anoxia. Levels of phosphorylated FoxO1 also decreased to 57% of control values in response to 5h of anoxia, indicating activation. FoxO3 was activated in the heart, kidney and liver in response to anoxia, with nuclear levels increasing by 1.5-3.7fold and DNA-binding activity increasing by 1.3-2.9fold. Transcript levels of two FoxO-target genes, p27kip1 and catalase, also rose by 2.4-2.5fold in the turtle liver under anoxia. The results suggest that the FoxO transcription factors are activated in response to anoxia in T. scripta elegans, potentially contributing to the regulation of stress resistance and metabolic depression. This study provides the first demonstration of activation of FoxOs in a natural model for vertebrate anoxia tolerance, further improving understanding of how tissues can survive without oxygen. © 2013.
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77 FR 10719 - Order Renewing Order Temporarily Denying Export Privileges
Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-23
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Inoue, Yosuke; Moriwaki, Kazumasa; Ueda, Yasuhiro; Takeuchi, Toshihisa; Higuchi, Kazuhide; Asahi, Michio
2018-01-08
O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors. Given that FOXM1 expression was reported to be elevated in gastric cancer, we examined the effect of high glucose or an inhibitor of O-GlcNAc hydrolase, Thiamet G (TMG), on FOXM1 protein expression in a human gastric cancer cell line, MKN45 cells, and confirmed that FOXM1 protein level and the cell proliferation were upregulated. To investigate the molecular mechanisms by which FOXM1 protein expression is regulated by O-GlcNAcylation, the effect of high glucose and TMG on FOXM1 ubiquitination was examined in MKN45 cells. As a result, the ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3β. High glucose and TMG treatment increased phospho-serine 9 GSK-3β, an inactive form, and the degradation of FOXM1 protein was suppressed by treatment of GSK-3β inhibitors in MKN45 cells. Taken together, we suggest that high glucose and elevated O-GlcNAcylation stabilize FOXM1 protein by its reduced degradation via GSK-3β inactivation in MKN45 cells, suggesting that the higher risk of gastric cancer in diabetic patients could be partially due to O-GlcNAcylation-mediated FOXM1 stabilization. Copyright © 2017 Elsevier Inc. All rights reserved.
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Zeng, Bingqing; Li, Yiwen; Niu, Bo; Wang, Xinyi; Cheng, Yufang; Zhou, Zhongzhen; You, Tingting; Liu, Yonggang; Wang, Haitao; Xu, Jiangping
2016-08-01
The selective serotonin reuptake inhibitor fluoxetine is neuroprotective in several brain injury models. It is commonly used to treat major depressive disorder and related conditions, but its mechanism of action remains incompletely understood. Activation of the phosphatidylinositol-3-kinase/protein kinase B/forkhead box O3a (PI3K/Akt/FoxO3a) and protein kinase A/cAMP-response element binding protein (PKA/CREB) signaling pathways has been strongly implicated in the pathogenesis of depression and might be the downstream target of fluoxetine. Here, we used PC12 cells exposed to corticosterone (CORT) to study the neuroprotective effects of fluoxetine and the involvement of the PI3K/Akt/FoxO3a and PKA/CREB signaling pathways. Our results show that CORT reduced PC12 cells viability by 70 %, and that fluoxetine showed a concentration-dependent neuroprotective effect. Neuroprotective effects of fluoxetine were abolished by inhibition of PI3K, Akt, and PKA using LY294002, KRX-0401, and H89, respectively. Treatment of PC12 cells with fluoxetine resulted in increased phosphorylation of Akt, FoxO3a, and CREB. Fluoxetine also dose-dependently rescued the phosphorylation levels of Akt, FoxO3a, and CREB, following administration of CORT (from 99 to 110, 56 to 170, 80 to 170 %, respectively). In addition, inhibition of PKA and PI3K/Akt resulted in decreased levels of p-CREB, p-Akt, and p-FoxO3a in the presence of fluoxetine. Furthermore, fluoxetine reversed CORT-induced upregulation of p53-upregulated modulator of apoptosis (Puma) and Bcl-2-interacting mediator of cell death (Bim) via the PI3K/Akt/FoxO3a signaling pathway. H89 treatment reversed the effect of fluoxetine on the mRNA level of brain-derived neurotrophic factor, which was decreased in the presence of CORT. Our data indicate that fluoxetine elicited neuroprotection toward CORT-induced cell death that involves dual regulation from PI3K/Akt/FoxO3a and PKA/CREB pathways.
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Development and maintenance of intestinal regulatory T cells.
Tanoue, Takeshi; Atarashi, Koji; Honda, Kenya
2016-05-01
Gut-resident forkhead box P3 (FOXP3)(+)CD4(+) regulatory T cells (Treg cells) are distinct from those in other organs and have gut-specific phenotypes and functions. Whereas Treg cells in other organs have T cell receptors (TCRs) specific for self antigens, intestinal Treg cells have a distinct set of TCRs that are specific for intestinal antigens, and these cells have pivotal roles in the suppression of immune responses against harmless dietary antigens and commensal microorganisms. The differentiation, migration and maintenance of intestinal Treg cells are controlled by specific signals from the local environment. In particular, certain members of the microbiota continuously provide antigens and immunoregulatory small molecules that modulate intestinal Treg cells. Understanding the development and the maintenance of intestinal Treg cells provides important insights into disease-relevant host-microorganism interactions.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-31
... Aviation Services, G 22 Dubai Airport Free Zone, P.O. Box 393754, Dubai, United Arab Emirates; and P.O. Box..., United Arab Emirates; Mahmoud Amini, G 22 Dubai Airport Free Zone, P.O. Box 393754, Dubai, United Arab... Montaigne 75008, Paris, France; Sirjanco Trading, P.O. Box 8709, Dubai, United Arab Emirates; Ali Eslamian...
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Pair distribution function (PDF) analysis of mesoporous α-Fe2O3 and Cr2O3.
Hill, Adrian H; Allieta, Mattia
2013-06-14
We have measured atomic pair distribution functions of novel mesoporous metal oxides, α-Fe2O3 and Cr2O3. These have an ordered pore mosaic as well as crystalline structure within the pore walls, making them an interesting class of materials to characterise. Comparison of "bulk" and mesoporous data sets has allowed an estimate of long range structural coherence to be derived; ≈125 Å and ≈290 Å for α-Fe2O3 and Cr2O3 respectively. Further "box-car" analysis has shown that above ≈40 Å both mesoporous samples deviate greatly from their bulk counterparts. This is attributed to the pores of the mesoporous structure creating voids in the pair-correlations, disrupting long range order.
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Kim, Sung-Mi; Grenert, James P.; Patterson, Cam; Correia, Maria Almira
2016-01-01
Genetic ablation of C-terminus of Hsc70-interacting protein (CHIP) E3 ubiquitin-ligase impairs hepatic cytochrome P450 CYP2E1 degradation. Consequent CYP2E1 gain of function accelerates reactive O2 species (ROS) production, triggering oxidative/proteotoxic stress associated with sustained activation of c-Jun NH2-terminal kinase (JNK)-signaling cascades, pro-inflammatory effectors/cytokines, insulin resistance, progressive hepatocellular ballooning and microvesicular steatosis. Despite this, little evidence of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) was found in CHIP−/−-mice over the first 8–9-months of life. We herein document that this lack of tissue injury is largely due to the concurrent up-regulation and/or activation of the adiponectin-5′-AMP-activated protein kinase (AMPK)-forkhead box O (FOXO)-signaling axis stemming from at the least three synergistic features: Up-regulated expression of adipose tissue adiponectin and its hepatic adipoR1/adipoR2 receptors, stabilization of hepatic AMPKα1-isoform, identified herein for the first time as a CHIP-ubiquitination substrate (unlike its AMPKα2-isoform), as well as nuclear stabilization of FOXOs, well-known CHIP-ubiquitination targets. Such beneficial predominance of the adiponectin-AMPK-FOXO-signaling axis over the sustained JNK-elevation and injurious insulin resistance in CHIP−/−-livers apparently counteracts/delays rapid progression of the hepatic microvesicular steatosis to the characteristic macrovesicular steatosis observed in clinical NASH and/or rodent NASH-models. PMID:27406999
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Han, Ihn; Choi, Eun Ha
2017-05-30
Non-thermal atmospheric pressure plasma is ionized matter, composed of highly reactive species that include positive ions, negative ions, free radicals, neutral atoms, and molecules. Recent reports have suggested that non-thermal biocompatible plasma (NBP) can selectively kill a variety of cancer cells, and promote stem cell differentiation. However as of yet, the regulation of proliferation and differentiation potential of NBP has been poorly understood.Here, we investigated the effects of NBP on the osteogenic differentiation of precursor cell lines of osteoblasts, MC3T3 E1 and SaOS-2. For in vitro osteogenic differentiation, precursor cell lines were treated with NBP, and cultured with osteogenic induction medium. After 10 days of treatment, the NBP was shown to be effective in osteogenic differentiation in MC3T3 E1 cells by von Kossa and Alizarin Red S staining assay. Real-time PCR was then performed to investigate the expression of osteogenic specific genes, Runx2, OCN, COL1, ALP and osterix in MC3T3 E1 cells after treatment with NBP for 4 days. Furthermore, analysis of the protein expression showed that NBP treatment significantly reduced PI3K/AKT signaling and MAPK family signaling. However, p38 controlled phosphorylation of transcription factor forkhead box O1 (FoxO1) that related to cell differentiation with increased phosphorylated p38. These results suggest that non-thermal atmospheric pressure plasma can induce osteogenic differentiation, and enhance bone formation.
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2012-03-22
Fabric 3.85% Polypropylene (PP) (Class 5 plastics, soda cups, yogurt boxes, syrup bottles, prescription bottles) 1.32% Yard waste 5.67% PVC (Class 3...plastics, milk jugs) 1.23% Cardboard 31.33% Polypropylene (PP) (Class 5 plastics, soda cups, yogurt boxes, syrup bottles, prescription bottles) 0.62
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Gopal, Keshav; Saleme, Bruno; Al Batran, Rami; Aburasayn, Hanin; Eshreif, Amina; Ho, Kim L; Ma, Wayne K; Almutairi, Malak; Eaton, Farah; Gandhi, Manoj; Park, Edwards A; Sutendra, Gopinath; Ussher, John R
2017-09-01
Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation and a critical regulator of metabolic flexibility during the fasting to feeding transition. PDH is regulated via both PDH kinases (PDHK) and PDH phosphatases, which phosphorylate/inactivate and dephosphorylate/activate PDH, respectively. Our goal was to determine whether the transcription factor forkhead box O1 (FoxO1) regulates PDH activity and glucose oxidation in the heart via increasing the expression of Pdk4 , the gene encoding PDHK4. To address this question, we differentiated H9c2 myoblasts into cardiac myocytes and modulated FoxO1 activity, after which Pdk4 /PDHK4 expression and PDH phosphorylation/activity were assessed. We assessed binding of FoxO1 to the Pdk4 promoter in cardiac myocytes in conjunction with measuring the role of FoxO1 on glucose oxidation in the isolated working heart. Both pharmacological (1 µM AS1842856) and genetic (siRNA mediated) inhibition of FoxO1 decreased Pdk4 /PDHK4 expression and subsequent PDH phosphorylation in H9c2 cardiac myocytes, whereas 10 µM dexamethasone-induced Pdk4 /PDHK4 expression was abolished via pretreatment with 1 µM AS1842856. Furthermore, transfection of H9c2 cardiac myocytes with a vector expressing FoxO1 increased luciferase activity driven by a Pdk4 promoter construct containing the FoxO1 DNA-binding element region, but not in a Pdk4 promoter construct lacking this region. Finally, AS1842856 treatment in fasted mice enhanced glucose oxidation rates during aerobic isolated working heart perfusions. Taken together, FoxO1 directly regulates Pdk4 transcription in the heart, thereby controlling PDH activity and subsequent glucose oxidation rates. NEW & NOTEWORTHY Although studies have shown an association between FoxO1 activity and pyruvate dehydrogenase kinase 4 expression, our study demonstrated that pyruvate dehydrogenase kinase 4 is a direct transcriptional target of FoxO1 (but not FoxO3/FoxO4) in the heart. Furthermore, we report here, for the first time, that FoxO1 inhibition increases glucose oxidation in the isolated working mouse heart. Copyright © 2017 the American Physiological Society.
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Schmetterer, Klaus G; Haiderer, Daniela; Leb-Reichl, Victoria M; Neunkirchner, Alina; Jahn-Schmid, Beatrice; Küng, Hans J; Schuch, Karina; Steinberger, Peter; Bohle, Barbara; Pickl, Winfried F
2011-01-01
Regulatory T (Treg) cells establish and maintain tolerance to self-antigens and many foreign antigens, such as allergens, by suppressing effector T-cell proliferation and function. We have previously shown that human T-cell receptor (TCR) αβ-chains specific for allergen-derived epitopes confer allergen specificity on peripheral blood T cells of individuals with and without allergy. To study the feasibility of generating allergen-specific human Treg cells by retroviral transduction of a transcription unit encoding forkhead box protein 3 (FOXP3) and allergen-specific TCR αβ-chains. cDNAs encoding the α and β-chains of a Bet v 1(142-153)-specific TCR (TCR alpha variable region 6/TCR beta variable region 20) and human FOXP3 were linked via picornaviral 2A sequences and expressed as single translational unit from an internal ribosomal entry site-green fluorescence protein-containing retroviral vector. Retrovirally transduced peripheral blood T cells were tested for expression of transgenes, Treg phenotype, and regulatory capacity toward allergen-specific effector T cells. Transduced T cells displayed a Treg phenotype with clear-cut upregulation of CD25, CD39, and cytotoxic T-lymphocyte antigen 4. The transduced cells were hyporesponsive in cytokine production and secretion and, like naturally occurring Treg cells, did not proliferate after antigen-specific or antigen-mimetic stimulation. However, proliferation was inducible upon exposure to exogenous IL-2. In coculture experiments, TRAV6(+)TRBV20(+)FOXP3(+) transgenic T cells, unlike FOXP3(+) single transgenic T cells or naturally occurring Treg cells, highly significantly suppressed T cell cytokine production and proliferation of corresponding allergen-specific effector T cells in an allergen-specific, dose-dependent manner. We demonstrate a transgenic approach to engineer human allergen-specific Treg cells that exert their regulatory function in an activation-dependent manner. Customized Treg cells might become useful for tolerance induction therapies in individuals with allergic and other immune-mediated diseases. Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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USDA-ARS?s Scientific Manuscript database
MADS-box transcription factors are key elements of the genetic networks controlling flower and fruit development. Among these, the class D clade are involved in seed, ovule, and funiculus development. The tomato genome comprises two class D genes, Sl-AGL11 and Sl-MBP3, both displaying high expressio...
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Construction of anatase/rutile TiO2 hollow boxes for highly efficient photocatalytic performance
NASA Astrophysics Data System (ADS)
Jia, Changchao; Zhang, Xiao; Yang, Ping
2018-02-01
Hollow TiO2 hierarchical boxes with suitable anatase and rutile ratios were designed for photocatalysis. The unique hierarchical structure was fabricated via a Topotactic synthetic method. CaTiO3 cubes were acted as the sacrificial templates to create TiO2 hollow hierarchical boxes with well-defined phase distribution. The phase composition of the hollow TiO2 hierarchical boxes is similar to that of TiO2 P25 nanoparticles (∼80% anatase, and 20% rutile). Compared with nanaoparticles, TiO2 hollow boxes with hierarchical structures exhibited an excellent performance in the photocatalytic degradation of methylene blue organic pollutant. Quantificationally, the degradation rate of the hollow boxes is higher than that of TiO2 P25 nanoparticles by a factor of 2.7. This is ascribed that hollow structure provide an opportunity for using incident light more efficiently. The surface hierarchical and well-organized porous structures are beneficial to supply more active sites and enough transport channels for reactant molecules. The boxes consist of single crystal anatase and rutile combined well with each other, which gives photon-generated carriers transfer efficiently.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Bin, Geng; Bo, Zhang; Jing, Wang
TNF-α is known to induce osteoblasts apoptosis, whereas mechanical stimulation has been shown to enhance osteoblast survival. In the present study, we found that mechanical stimulation in the form of fluid shear stress (FSS) suppresses TNF-α induced apoptosis in MC3T3-E1 cells. Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family that has been implicated in cell survival. We also demonstrated that FSS imposed by flow chamber in vitro leads to a markedly activation of ERK5, which was shown to be protective against TNF-α-induced apoptosis, whereas the transfection of siRNA against ERK5 (ERK5-siRNA) reversed themore » FSS-medicated anti-apoptotic effects. An initial FSS-mediated activation of ERK5 that phosphorylates AKT to increase its activity, and a following forkhead box O 3a (FoxO3a) was phosphorylated by activated AKT. Phosphorylated FoxO3a is sequestered in the cytoplasm, and prevents it from translocating to nucleus where it can increase the expression of FasL and Bim. The inhibition of AKT-FoxO3a signalings by a PI3K (PI3-kinase)/AKT inhibitor (LY294002) or the transfection of ERK5-siRNA led to the nuclear translocation of non-phosphorylated FoxO3a, and increased the protein expression of FasL and Bim. In addition, the activation of caspase-3 by TNF-α was significantly inhibited by aforementioned FSS-medicated mechanisms. In brief, the activation of ERK5-AKT-FoxO3a signaling pathways by FSS resulted in a decreased expression of FasL and Bim and an inhibition of caspase-3 activation, which exerts a protective effect that prevents osteoblasts from apoptosis. - Highlights: • Fluid shear stress inhibits osteoblast apoptosis induced by TNF-α. • Inhibition of ERK5 activity by transfection of ERK5 siRNA blocks FSS-mediated anti-apoptotic effect in osteoblast. • Activated ERK5-AKT-FoxO3a-Bim/FasL signaling pathways by FSS is required to protect osteoblast from apoptosis.« less
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Dumitriu, Alexandra; Latourelle, Jeanne C; Hadzi, Tiffany C; Pankratz, Nathan; Garza, Dan; Miller, John P; Vance, Jeffery M; Foroud, Tatiana; Beach, Thomas G; Myers, Richard H
2012-06-01
Parkinson disease (PD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. While the degeneration of dopaminergic neurons in PD mainly takes place in the substantia nigra pars compacta (SN) region, other brain areas, including the prefrontal cortex, develop Lewy bodies, the neuropathological hallmark of PD. We generated and analyzed expression data from the prefrontal cortex Brodmann Area 9 (BA9) of 27 PD and 26 control samples using the 44K One-Color Agilent 60-mer Whole Human Genome Microarray. All samples were male, without significant Alzheimer disease pathology and with extensive pathological annotation available. 507 of the 39,122 analyzed expression probes were different between PD and control samples at false discovery rate (FDR) of 5%. One of the genes with significantly increased expression in PD was the forkhead box O1 (FOXO1) transcription factor. Notably, genes carrying the FoxO1 binding site were significantly enriched in the FDR-significant group of genes (177 genes covered by 189 probes), suggesting a role for FoxO1 upstream of the observed expression changes. Single-nucleotide polymorphisms (SNPs) selected from a recent meta-analysis of PD genome-wide association studies (GWAS) were successfully genotyped in 50 out of the 53 microarray brains, allowing a targeted expression-SNP (eSNP) analysis for 52 SNPs associated with PD affection at genome-wide significance and the 189 probes from FoxO1 regulated genes. A significant association was observed between a SNP in the cyclin G associated kinase (GAK) gene and a probe in the spermine oxidase (SMOX) gene. Further examination of the FOXO1 region in a meta-analysis of six available GWAS showed two SNPs significantly associated with age at onset of PD. These results implicate FOXO1 as a PD-relevant gene and warrant further functional analyses of its transcriptional regulatory mechanisms.
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Dumitriu, Alexandra; Latourelle, Jeanne C.; Hadzi, Tiffany C.; Pankratz, Nathan; Garza, Dan; Miller, John P.; Vance, Jeffery M.; Foroud, Tatiana; Beach, Thomas G.; Myers, Richard H.
2012-01-01
Parkinson disease (PD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. While the degeneration of dopaminergic neurons in PD mainly takes place in the substantia nigra pars compacta (SN) region, other brain areas, including the prefrontal cortex, develop Lewy bodies, the neuropathological hallmark of PD. We generated and analyzed expression data from the prefrontal cortex Brodmann Area 9 (BA9) of 27 PD and 26 control samples using the 44K One-Color Agilent 60-mer Whole Human Genome Microarray. All samples were male, without significant Alzheimer disease pathology and with extensive pathological annotation available. 507 of the 39,122 analyzed expression probes were different between PD and control samples at false discovery rate (FDR) of 5%. One of the genes with significantly increased expression in PD was the forkhead box O1 (FOXO1) transcription factor. Notably, genes carrying the FoxO1 binding site were significantly enriched in the FDR–significant group of genes (177 genes covered by 189 probes), suggesting a role for FoxO1 upstream of the observed expression changes. Single-nucleotide polymorphisms (SNPs) selected from a recent meta-analysis of PD genome-wide association studies (GWAS) were successfully genotyped in 50 out of the 53 microarray brains, allowing a targeted expression–SNP (eSNP) analysis for 52 SNPs associated with PD affection at genome-wide significance and the 189 probes from FoxO1 regulated genes. A significant association was observed between a SNP in the cyclin G associated kinase (GAK) gene and a probe in the spermine oxidase (SMOX) gene. Further examination of the FOXO1 region in a meta-analysis of six available GWAS showed two SNPs significantly associated with age at onset of PD. These results implicate FOXO1 as a PD–relevant gene and warrant further functional analyses of its transcriptional regulatory mechanisms. PMID:22761592
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Galbo, Thomas; Olsen, Grith Skytte; Quistorff, Bjørn; Nishimura, Erica
2011-01-01
In type 2 Diabetes (T2D) free fatty acids (FFAs) in plasma are increased and hepatic insulin resistance is “selective”, in the sense that the insulin-mediated decrease of glucose production is blunted while insulin's effect on stimulating lipogenesis is maintained. We investigated the molecular mechanisms underlying this pathogenic paradox. Primary rat hepatocytes were exposed to palmitate for twenty hours. To establish the physiological relevance of the in vitro findings, we also studied insulin-resistant Zucker Diabetic Fatty (ZDF) rats. While insulin-receptor phosphorylation was unaffected, activation of Akt and inactivation of the downstream targets Glycogen synthase kinase 3α (Gsk3α and Forkhead box O1 (FoxO1) was inhibited in palmitate-exposed cells. Accordingly, dose-response curves for insulin-mediated suppression of the FoxO1-induced gluconeogenic genes and for de novo glucose production were right shifted, and insulin-stimulated glucose oxidation and glycogen synthesis were impaired. In contrast, similar to findings in human T2D, the ability of insulin to induce triglyceride (TG) accumulation and transcription of the enzymes that catalyze de novo lipogenesis and TG assembly was unaffected. Insulin-induction of these genes could, however, be blocked by inhibition of the atypical PKCs (aPKCs). The activity of the Akt-inactivating Protein Phosphatase 2A (PP2A) was increased in the insulin-resistant cells. Furthermore, inhibition of PP2A by specific inhibitors increased insulin-stimulated activation of Akt and phosphorylation of FoxO1 and Gsk3α. Finally, PP2A mRNA levels were increased in liver, muscle and adipose tissue, while PP2A activity was increased in liver and muscle tissue in insulin-resistant ZDF rats. In conclusion, our findings indicate that FFAs may cause a selective impairment of insulin action upon hepatic glucose metabolism by increasing PP2A activity. PMID:22087313
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Atomoxetine Prevents Dexamethasone-Induced Skeletal Muscle Atrophy in Mice
Jesinkey, Sean R.; Korrapati, Midhun C.; Rasbach, Kyle A.; Beeson, Craig C.
2014-01-01
Skeletal muscle atrophy remains a clinical problem in numerous pathologic conditions. β2-Adrenergic receptor agonists, such as formoterol, can induce mitochondrial biogenesis (MB) to prevent such atrophy. Additionally, atomoxetine, an FDA-approved norepinephrine reuptake inhibitor, was positive in a cellular assay for MB. We used a mouse model of dexamethasone-induced skeletal muscle atrophy to investigate the potential role of atomoxetine and formoterol to prevent muscle mass loss. Mice were administered dexamethasone once daily in the presence or absence of formoterol (0.3 mg/kg), atomoxetine (0.1 mg/kg), or sterile saline. Animals were euthanized at 8, 16, and 24 hours or 8 days later. Gastrocnemius muscle weights, changes in mRNA and protein expression of peroxisome proliferator–activated receptor-γ coactivator-1 α (PGC-1α) isoforms, ATP synthase β, cytochrome c oxidase subunit I, NADH dehydrogenase (ubiquinone) 1 β subcomplex, 8, ND1, insulin-like growth factor 1 (IGF-1), myostatin, muscle Ring-finger protein-1 (muscle atrophy), phosphorylated forkhead box protein O 3a (p-FoxO3a), Akt, mammalian target of rapamycin (mTOR), and ribosomal protein S6 (rp-S6; muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 hours after treatment in naïve mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1α-4-IGF1–Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 hours and repressed myostatin at 16 hours. In contrast to what was observed with acute treatment, chronic treatment (7 days) with atomoxetine increased p-Akt and p-FoxO3a, and sustained PGC-1α expression and skeletal muscle mass in dexamethasone-treated mice, in a manner comparable to formoterol. In conclusion, chronic treatment with a low dose of atomoxetine prevented dexamethasone-induced skeletal muscle wasting and supports a potential role in preventing muscle atrophy. PMID:25292181
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Wang, Qian; Wang, Ning; Dong, Mei; Chen, Fang; Li, Zhong; Chen, Yuanyuan
2014-07-01
GdCl3 (gadolinium chloride) has been shown to reduce blood glucose; however, the underlying mechanism remains unclear. Liver gluconeogenesis is an important pathway involved in the maintenance of glucose homoeostasis. The aim of the present study was to investigate the role of GdCl3 in hepatic gluconeogenesis and explore the precise molecular mechanism. Animals from a classical Type 2 diabetic mouse model, created by exposing C57BL/6J mice to a high-fat diet for 4 months, were treated with GdCl3 or saline. Body weight, blood glucose and insulin sensitivity were monitored. It was observed that GdCl3 significantly reduced blood glucose levels and improved insulin sensitivity. A pyruvate tolerance test showed further that GdCl3 suppressed gluconeogenesis in diabetic mice. In the livers of GdCl3-treated mice, the expression of Pepck (phosphoenolpyruvate carboxykinase) and G6pase (glucose-6-phosphatase), the key enzymes in gluconeogenesis, were dramatically reduced. Furthermore, experiments in hepatocarcinoma cells revealed that GdCl3 activated the Akt pathway to promote the phosphorylation of FoxO1 (forkhead box O1), leading to the suppression of gluconeogenesis by reducing the expression of PEPCK and G6Pase and resulting in decreased cellular production of glucose. Comparable results were observed in the livers of GdCl3-treated mice. In addition, we have shown that GdCl3 augmented the role of insulin to control hepatic glucose production. We conclude that GdCl3 reduces hyperglycaemia via the Akt/FoxO1-induced suppression of hepatic gluconeogenesis, both in Type 2 diabetic mice (in vivo) and in hepatocarcinoma cells (in vitro), suggesting that GdCl3 may be a potential therapeutic agent for diabetes.
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Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia.
Chassaing, N; Causse, A; Vigouroux, A; Delahaye, A; Alessandri, J-L; Boespflug-Tanguy, O; Boute-Benejean, O; Dollfus, H; Duban-Bedu, B; Gilbert-Dussardier, B; Giuliano, F; Gonzales, M; Holder-Espinasse, M; Isidor, B; Jacquemont, M-L; Lacombe, D; Martin-Coignard, D; Mathieu-Dramard, M; Odent, S; Picone, O; Pinson, L; Quelin, C; Sigaudy, S; Toutain, A; Thauvin-Robinet, C; Kaplan, Josseline; Calvas, Patrick
2014-10-01
Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Effect of pH on the Structure and DNA Binding of the FOXP2 Forkhead Domain.
Blane, Ashleigh; Fanucchi, Sylvia
2015-06-30
Forkhead box P2 (FOXP2) is a transcription factor expressed in cardiovascular, intestinal, and neural tissues during embryonic development and is implicated in language development. FOXP2 like other FOX proteins contains a DNA binding domain known as the forkhead domain (FHD). The FHD interacts with DNA by inserting helix 3 into the major groove. One of these DNA-protein interactions is a direct hydrogen bond that is formed with His554. FOXP2 is localized in the nuclear compartment that has a pH of 7.5. Histidine contains an imidazole side chain in which the amino group typically has a pKa of ~6.5. It seems possible that pH fluctuations around 6.5 may result in changes in the protonation state of His554 and thus the ability of the FOXP2 FHD to bind DNA. To investigate the effect of pH on the FHD, both the structure and the binding affinity were studied in the pH range of 5-9. This was done in the presence and absence of DNA. The structure was assessed using size exclusion chromatography, far-UV circular dichroism, and intrinsic and extrinsic fluorescence. The results indicated that while pH did not affect the secondary structure in the presence or absence of DNA, the tertiary structure was pH sensitive and the protein was less compact at low pH. Furthermore, the presence of DNA caused the protein to become more compact at low pH and also had the potential to increase the dimerization propensity. Fluorescence anisotropy was used to investigate the effect of pH on the FOXP2 FHD DNA binding affinity. It was found that pH had a direct effect on binding affinity. This was attributed to the altered hydrogen bonding patterns upon protonation or deprotonation of His554. These results could implicate pH as a means of regulating transcription by the FOXP2 FHD, which may also have repercussions for the behavior of this protein in cancer cells.
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Association of FOXO3A variation with human longevity confirmed in German centenarians
Flachsbart, Friederike; Caliebe, Amke; Kleindorp, Rabea; Blanché, Hélène; von Eller-Eberstein, Huberta; Nikolaus, Susanna; Schreiber, Stefan; Nebel, Almut
2009-01-01
The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin–IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms. A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al. (2008) Proc Natl Acad Sci USA 105:13987–13992]. However, this finding required replication in an independent population. Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans. PMID:19196970
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Wang, Wei; Zhou, Pang-Hu; Hu, Wei
2016-03-01
Forkhead box O4 (FOXO4) has been reported to be a novel tumor suppressor gene in gastrointestinal cancers; however, its role in clear‑cell renal carcinoma cells (ccRCC) has remained largely elusive. The present study assessed the expression levels of FOXO4 in RCC tissues and cells. Furthermore, the effects of vector‑mediated overexpression of FOXO4 on the apoptotic rate of the 786‑0 and Caki‑1 cell lines and the role of Bim in this process were investigated. The results demonstrated that the protein and mRNA expression levels of FOXO4 were decreased in renal cancer tissues and cell lines compared with those in normal tissues and cell lines. FOXO4 overexpression significantly increased the apoptotic rate of ccRCC cells in vitro, along with increased protein expression levels of Bim, cleaved‑caspase 3, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax) and cytochrome c, as well as a decrease in Bcl‑2 expression. Of note, the apoptotic effects of FOXO4 overexpression in 786‑0 cells were inhibited by small interfering RNA‑mediated knockdown of Bim. The results of the present study indicated that FOXO4 has an inhibitory effect in ccRCC, at least in part through inducing apoptosis via upregulation of Bim in the mitochondria-dependent pathway.
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Biomechanics and mechanical signaling in the ovary: a systematic review.
Shah, Jaimin S; Sabouni, Reem; Cayton Vaught, Kamaria C; Owen, Carter M; Albertini, David F; Segars, James H
2018-04-24
Mammalian oogenesis and folliculogenesis share a dynamic connection that is critical for gamete development. For maintenance of quiescence or follicular activation, follicles must respond to soluble signals (growth factors and hormones) and physical stresses, including mechanical forces and osmotic shifts. Likewise, mechanical processes are involved in cortical tension and cell polarity in oocytes. Our objective was to examine the contribution and influence of biomechanical signaling in female mammalian gametogenesis. We performed a systematic review to assess and summarize the effects of mechanical signaling and mechanotransduction in oocyte maturation and folliculogenesis and to explore possible clinical applications. The review identified 2568 publications of which 122 met the inclusion criteria. The integration of mechanical and cell signaling pathways in gametogenesis is complex. Follicular activation or quiescence are influenced by mechanical signaling through the Hippo and Akt pathways involving the yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene, the mammalian target of rapamycin (mTOR), and forkhead box O3 (FOXO3) gene. There is overwhelming evidence that mechanical signaling plays a crucial role in development of the ovary, follicle, and oocyte throughout gametogenesis. Emerging data suggest the complexities of mechanotransduction and the biomechanics of oocytes and follicles are integral to understanding of primary ovarian insufficiency, ovarian aging, polycystic ovary syndrome, and applications of fertility preservation.
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Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma.
Park, Soon Young; Piao, Yuji; Thomas, Craig; Fuller, Gregory N; de Groot, John F
2016-05-03
Cdc2-like kinase 2 (CLK2) is known as a regulator of RNA splicing that ultimately controls multiple physiological processes. However, the function of CLK2 in glioblastoma progression has not been described. Reverse-phase protein array (RPPA) was performed to identify proteins differentially expressed in CLK2 knockdown cells compared to controls. The RPPA results indicated that CLK2 knockdown influenced the expression of survival-, proliferation-, and cell cycle-related proteins in GSCs. Thus, knockdown of CLK2 expression arrested the cell cycle at the G1 and S checkpoints in multiple GSC lines. Depletion of CLK2 regulated the dephosphorylation of AKT and decreased phosphorylation of Forkhead box O3a (FOXO3a), which not only translocated to the nucleus but also increased p27 expression. In two glioblastoma xenograft models, the survival duration of mice with CLK2-knockdown GSCs was significantly longer than mice with control tumors. Additionally, tumor volumes were significantly smaller in CLK2-knockdown mice than in controls. Knockdown of CLK2 expression reduced the phosphorylation of FOXO3a and decreased Ki-67 in vivo. Finally, high expression of CLK2 protien was significantly associated with worse patient survival. These findings suggest that CLK2 plays a critical role in controlling the cell cycle and survival of glioblastoma via FOXO3a/p27.
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Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma
Thomas, Craig; Fuller, Gregory N.; de Groot, John F.
2016-01-01
Cdc2-like kinase 2 (CLK2) is known as a regulator of RNA splicing that ultimately controls multiple physiological processes. However, the function of CLK2 in glioblastoma progression has not been described. Reverse-phase protein array (RPPA) was performed to identify proteins differentially expressed in CLK2 knockdown cells compared to controls. The RPPA results indicated that CLK2 knockdown influenced the expression of survival-, proliferation-, and cell cycle-related proteins in GSCs. Thus, knockdown of CLK2 expression arrested the cell cycle at the G1 and S checkpoints in multiple GSC lines. Depletion of CLK2 regulated the dephosphorylation of AKT and decreased phosphorylation of Forkhead box O3a (FOXO3a), which not only translocated to the nucleus but also increased p27 expression. In two glioblastoma xenograft models, the survival duration of mice with CLK2-knockdown GSCs was significantly longer than mice with control tumors. Additionally, tumor volumes were significantly smaller in CLK2-knockdown mice than in controls. Knockdown of CLK2 expression reduced the phosphorylation of FOXO3a and decreased Ki-67 in vivo. Finally, high expression of CLK2 protien was significantly associated with worse patient survival. These findings suggest that CLK2 plays a critical role in controlling the cell cycle and survival of glioblastoma via FOXO3a/p27. PMID:27050366
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James
Silymarin (SM), a natural product, is touted as a liver protectant and preventer of both chronic inflammation and diseases. To define how SM elicits these effects at a systems level, we performed transcriptional profiling, metabolomics, and signaling studies in human liver and T cell lines. Multiple pathways associated with cellular stress and metabolism were modulated by SM treatment within 0.5 to four hours: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed suppressionmore » of glycolytic, TCA cycle, and amino acid metabolism by SM treatment. Antiinflammatory effects arose with prolonged (i.e. 24 hours) SM exposure, with suppression of multiple proinflammatory mRNAs and nuclear factor kappa B (NF-κB) and forkhead box O (FOXO) signaling. Studies with murine knock out cells revealed that SM inhibition of both mTOR and NF-κB was partially AMPK dependent, while SM inhibition of the mTOR pathway in part required DDIT4. Thus, SM activates stress and repair responses that culminate in an anti-inflammatory phenotype. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Therefore, natural products like SM may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.« less
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Adaptogens Stimulate Neuropeptide Y and Hsp72 Expression and Release in Neuroglia Cells
Panossian, Alexander; Wikman, Georg; Kaur, Punit; Asea, Alexzander
2011-01-01
The beneficial stress–protective effect of adaptogens is related to the regulation of homeostasis via mechanisms of action associated with the hypothalamic–pituitary–adrenal axis and the regulation of key mediators of the stress response, such as molecular chaperones, stress-activated c-Jun N-terminal protein kinase, forkhead box O transcription factor, cortisol, and nitric oxide (NO). However, it still remains unclear what the primary upstream targets are in response to stimulation by adaptogens. The present study addresses this gap in our knowledge and suggests that an important target for adaptogen mediated stress–protective effector functions is the stress hormone neuropeptide Y (NPY). We demonstrated that ADAPT-232, a fixed combination of adaptogens Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract SHR-5, and its active constituent salidroside, stimulated the expression of NPY and 72 kDa heat shock protein (Hsp72) in isolated human neuroglia cells. The central role of NPY was validated in experiments in which pre-treatment of human neuroglia cells with NPY-siRNA and HSF1-siRNA resulted in the significant suppression of ADAPT-232-induced NPY and Hsp72 release. Taken together our studies suggest that the stimulation and release of the stress hormones, NPY and Hsp72, into systemic circulation is an innate defense response against mild stressors (ADAPT-232), which increase tolerance and adaptation to stress. PMID:22347152
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Adaptogens stimulate neuropeptide y and hsp72 expression and release in neuroglia cells.
Panossian, Alexander; Wikman, Georg; Kaur, Punit; Asea, Alexzander
2012-01-01
The beneficial stress-protective effect of adaptogens is related to the regulation of homeostasis via mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of the stress response, such as molecular chaperones, stress-activated c-Jun N-terminal protein kinase, forkhead box O transcription factor, cortisol, and nitric oxide (NO). However, it still remains unclear what the primary upstream targets are in response to stimulation by adaptogens. The present study addresses this gap in our knowledge and suggests that an important target for adaptogen mediated stress-protective effector functions is the stress hormone neuropeptide Y (NPY). We demonstrated that ADAPT-232, a fixed combination of adaptogens Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract SHR-5, and its active constituent salidroside, stimulated the expression of NPY and 72 kDa heat shock protein (Hsp72) in isolated human neuroglia cells. The central role of NPY was validated in experiments in which pre-treatment of human neuroglia cells with NPY-siRNA and HSF1-siRNA resulted in the significant suppression of ADAPT-232-induced NPY and Hsp72 release. Taken together our studies suggest that the stimulation and release of the stress hormones, NPY and Hsp72, into systemic circulation is an innate defense response against mild stressors (ADAPT-232), which increase tolerance and adaptation to stress.
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Evolutionary acquisition of cysteines determines FOXO paralog-specific redox signaling.
Putker, Marrit; Vos, Harmjan R; van Dorenmalen, Kim; de Ruiter, Hesther; Duran, Ana G; Snel, Berend; Burgering, Boudewijn M T; Vermeulen, Michiel; Dansen, Tobias B
2015-01-01
Reduction-oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter can result in disulfide formation between protein hetero- or homodimers that alter protein function until the local cellular redox environment has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the Forkhead Box O4 (FOXO4) transcription factor. In this study, we sought to investigate whether redox signaling differentially controls the human FOXO3 and FOXO4 paralogs. We present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen, we identified previously unknown redox-dependent FOXO3 interaction partners. The nuclear import receptors Importin-7 (IPO7) and Importin-8 (IPO8) form a disulfide-dependent heterodimer with FOXO3, which is required for its reactive oxygen species-induced nuclear translocation. FOXO4 does not interact with IPO7 or IPO8. IPO7 and IPO8 control the nuclear import of FOXO3, but not FOXO4, in a redox-sensitive and disulfide-dependent manner. Our findings suggest that evolutionary acquisition of cysteines has contributed to regulatory divergence of FOXO paralogs, and that phylogenetic analysis can aid in the identification of cysteines involved in redox signaling.
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Enhanced procedural learning of speech sound categories in a genetic variant of FOXP2.
Chandrasekaran, Bharath; Yi, Han-Gyol; Blanco, Nathaniel J; McGeary, John E; Maddox, W Todd
2015-05-20
A mutation of the forkhead box protein P2 (FOXP2) gene is associated with severe deficits in human speech and language acquisition. In rodents, the humanized form of FOXP2 promotes faster switching from declarative to procedural learning strategies when the two learning systems compete. Here, we examined a polymorphism of FOXP2 (rs6980093) in humans (214 adults; 111 females) for associations with non-native speech category learning success. Neurocomputational modeling results showed that individuals with the GG genotype shifted faster to procedural learning strategies, which are optimal for the task. These findings support an adaptive role for the FOXP2 gene in modulating the function of neural learning systems that have a direct bearing on human speech category learning. Copyright © 2015 the authors 0270-6474/15/357808-05$15.00/0.
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Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses
Matarese, Giuseppe; Procaccini, Claudio; Menale, Ciro; Kim, Jae Geun; Kim, Jung Dae; Diano, Sabrina; Diano, Nadia; De Rosa, Veronica; Dietrich, Marcelo O.; Horvath, Tamas L.
2013-01-01
Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4+ T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3+) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response. PMID:23530205
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A Procedure for Evaluating Subpotable Water Reuse Potential at Army Fixed Facilities.
1981-11-01
characteristic of phosphate waste waters from fume scrubbers. + Flue gas desulfurization sludge liquors. 75 Table B5 Base Housing Water Supply Quality (Also...ENGINEERING RESEARCH LABORATORY 4A762720A896-B-008 P.O. Box 4005, Champaign, IL 61820 1I. CONTROLLING OFFICE NAME AND ADDRESS 12. REPORT DATE November 1981 13...NUMBER OF PAGES 102 4. MONITORING AGENCY NAME & ADDRESS(If different from Controlling Office) IS. SECURITY CLASS. (of til, report) UNCLASSIFIED 15
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Mechanisms of cisplatin-induced muscle atrophy
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp; Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501; Sagara, Atsunobu
Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only themore » muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.« less
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Yan, Fengxia; Liao, Rifang; Farhan, Mohd; Wang, Tinghuai; Chen, Jiashu; Wang, Zhong; Little, Peter J; Zheng, Wenhua
2016-12-01
Uveal melanoma (UM) is the most common primary intraocular malignant tumor of adults. It has high mortality rate due to liver metastasis. However, the epidemiology and pathogenesis of liver metastasis in UM are not elucidated and there is no effective therapy available for preventing the development of this disease. IGF-1 is a growth factor involved in cell proliferation, malignant transformation and inhibition of apoptosis. In previous report, IGF-1 receptor was found to be highly expressed in UM and this was related to tumor prognosis. FoxO3a is a Forkhead box O (FOXO) transcription factor and a downstream target of the IGF-1R/PI3K/Akt pathway involved in a number of physiological and pathological processes including cancer. However, the role of FoxO3a in UM is unknown. In the present study, we investigated fundamental mechanisms in the growth, migration and invasion of UM and the involvement of FoxO3a. IGF-1 increased the cell viability, invasion, migration and S-G2/M cell cycle phase accumulation of UM cells. Western blot analysis showed that IGF-1 led to activation of Akt and concomitant phosphorylation of FoxO3a. FoxO3a phosphorylation was associated with its translocation into the cytoplasm from the nucleus and its functional inhibition led to the inhibition of expression of Bim and p27, but an increase in the expression of Cyclin D1. The effects of IGF-1 on UM cells were reversed by LY294002 (a PI3K inhibitor) or Akt siRNA, and the overexpression of FoxO3a also attenuated basal invasion and migration of UM. Taken all together, these results suggest that inhibition of FoxO3a by IGF-1 via the PI3K/Akt pathway has an important role in IGF-1 induced proliferation and invasion of UM cells. These findings also support FoxO3a and IGF signaling may represent a valid target for investigating the development of new strategies for the treatment and prevention of the pathology of UM. Copyright © 2016. Published by Elsevier Masson SAS.
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Code of Federal Regulations, 2013 CFR
2013-01-01
... components: (1) Bonneville Power Administration, P.O. Box 3621-KDP-7, Portland, OR 97232. (2) Carlsbad Field Office, P.O. Box 3090, Carlsbad, NM 88221. (3) Chicago Office, 9800 S. Cass Avenue, Argonne, IL 60439. (4...) National Nuclear Security Administration Service Center, P.O. Box 5400, Albuquerque, NM 87185-5400. (9...
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Code of Federal Regulations, 2012 CFR
2012-01-01
... components: (1) Bonneville Power Administration, P.O. Box 3621-KDP-7, Portland, OR 97232. (2) Carlsbad Field Office, P.O. Box 3090, Carlsbad, NM 88221. (3) Chicago Office, 9800 S. Cass Avenue, Argonne, IL 60439. (4...) National Nuclear Security Administration Service Center, P.O. Box 5400, Albuquerque, NM 87185-5400. (9...
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Code of Federal Regulations, 2014 CFR
2014-01-01
... components: (1) Bonneville Power Administration, P.O. Box 3621-KDP-7, Portland, OR 97232. (2) Carlsbad Field Office, P.O. Box 3090, Carlsbad, NM 88221. (3) Chicago Office, 9800 S. Cass Avenue, Argonne, IL 60439. (4...) National Nuclear Security Administration Service Center, P.O. Box 5400, Albuquerque, NM 87185-5400. (9...
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77 FR 8861 - Pesticide Products; Receipt of Applications To Register New Uses
Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-15
... Protection, LLC, P.O. Box 18300, Greensboro, NC 27419. Active ingredient: Difenoconazole. Proposed Uses...: EPA- HQ-OPP-2011-0086. Company name and address: Syngenta Crop Protection, LLC, P.O. Box 18300... Protection, LLC, P.O. Box 18300, Greensboro, NC 27419. Active ingredient: Difenoconazole and Propiconazole...
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78 FR 13659 - Sierrita Gas Pipeline LLC; Notice OF Application
Federal Register 2010, 2011, 2012, 2013, 2014
2013-02-28
... (Sierrita), P.O. Box 1087, Colorado Springs, Colorado 80944, filed in the above referenced docket an... directed to Mr. Francisco Tarin, Director, Regulatory Affairs, Sierrita Gas Pipeline LLC, P.O. Box 1087... or David K. Dewey, Associate Counsel, Sierrita Gas Pipeline LLC, P.O. Box 1087, Colorado Springs...
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75 FR 52935 - Colorado Interstate Gas Company; Notice of Application
Federal Register 2010, 2011, 2012, 2013, 2014
2010-08-30
... Interstate Gas Company (CIG), P.O. Box 1087, Colorado Springs, Colorado 80944, pursuant to section 7(c) of.... Susan C. Stires, Director, Regulatory Affairs, Colorado Interstate Gas Company, P.O. Box 1087, Colorado... President and General Counsel, Colorado Interstate Gas Company; P.O. Box 1087, Colorado Springs, Colorado...
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Pan, Xiaoyue; Munshi, Mohamed Khalid; Iqbal, Jahangir; Queiroz, Joyce; Sirwi, Alaa Ahmed; Shah, Shrenik; Younus, Abdullah; Hussain, M Mahmood
2013-07-12
We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV(-/-) mice showed diurnal variations similar to apoAIV(+/+) mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV(-/-) mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV(-/-) mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV(-/-) mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.
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Zhang, Xiaoni; Wang, Qijian; Yang, Shaozong; Lin, Shengnan; Bao, Manzhu; Wu, Quanshu; Wang, Caiyun; Fu, Xiaopeng
2018-01-01
Dianthus is a large genus containing many species with high ornamental economic value. Extensive breeding strategies permitted an exploration of an improvement in the quality of cultivated carnation, particularly in flowers. However, little is known on the molecular mechanisms of flower development in carnation. Here, we report the identification and description of MADS-box genes in carnation (DcaMADS) with a focus on those involved in flower development and organ identity determination. In this study, 39 MADS-box genes were identified from the carnation genome and transcriptome by the phylogenetic analysis. These genes were categorized into four subgroups (30 MIKCc, two MIKC*, two Mα, and five Mγ). The MADS-box domain, gene structure, and conserved motif compositions of the carnation MADS genes were analysed. Meanwhile, the expression of DcaMADS genes were significantly different in stems, leaves, and flower buds. Further studies were carried out for exploring the expression of DcaMADS genes in individual flower organs, and some crucial DcaMADS genes correlated with their putative function were validated. Finally, a new expression pattern of DcaMADS genes in flower organs of carnation was provided: sepal (three class E genes and two class A genes), petal (two class B genes, two class E genes, and one SHORT VEGETATIVE PHASE (SVP)), stamen (two class B genes, two class E genes, and two class C), styles (two class E genes and two class C), and ovary (two class E genes, two class C, one AGAMOUS-LIKE 6 (AGL6), one SEEDSTICK (STK), one B sister, one SVP, and one Mα). This result proposes a model in floral organ identity of carnation and it may be helpful to further explore the molecular mechanism of flower organ identity in carnation. PMID:29617274
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Zhang, Xiaoni; Wang, Qijian; Yang, Shaozong; Lin, Shengnan; Bao, Manzhu; Bendahmane, Mohammed; Wu, Quanshu; Wang, Caiyun; Fu, Xiaopeng
2018-04-04
Dianthus is a large genus containing many species with high ornamental economic value. Extensive breeding strategies permitted an exploration of an improvement in the quality of cultivated carnation, particularly in flowers. However, little is known on the molecular mechanisms of flower development in carnation. Here, we report the identification and description of MADS-box genes in carnation ( DcaMADS ) with a focus on those involved in flower development and organ identity determination. In this study, 39 MADS-box genes were identified from the carnation genome and transcriptome by the phylogenetic analysis. These genes were categorized into four subgroups (30 MIKC c , two MIKC*, two Mα, and five Mγ). The MADS-box domain, gene structure, and conserved motif compositions of the carnation MADS genes were analysed. Meanwhile, the expression of DcaMADS genes were significantly different in stems, leaves, and flower buds. Further studies were carried out for exploring the expression of DcaMADS genes in individual flower organs, and some crucial DcaMADS genes correlated with their putative function were validated. Finally, a new expression pattern of DcaMADS genes in flower organs of carnation was provided: sepal (three class E genes and two class A genes), petal (two class B genes, two class E genes, and one SHORT VEGETATIVE PHASE ( SVP )), stamen (two class B genes, two class E genes, and two class C), styles (two class E genes and two class C), and ovary (two class E genes, two class C, one AGAMOUS-LIKE 6 ( AGL6 ), one SEEDSTICK ( STK ), one B sister , one SVP , and one Mα ). This result proposes a model in floral organ identity of carnation and it may be helpful to further explore the molecular mechanism of flower organ identity in carnation.
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Inhibition of FoxO1 acetylation by INHAT subunit SET/TAF-Iβ induces p21 transcription.
Chae, Yun-Cheol; Kim, Kee-Beom; Kang, Joo-Young; Kim, Se-Ryeon; Jung, Hyeon-Soo; Seo, Sang-Beom
2014-08-25
Post-translational modification of forkhead family transcription factor, FoxO1, is an important regulatory mode for its diverse activities. FoxO1 is acetylated by HAT coactivators and its transcriptional activity is decreased via reduced DNA binding affinity. Here, we report that SET/TAF-Iβ inhibited p300-mediated FoxO1 acetylation in an INHAT domain-dependent manner. SET/TAF-Iβ interacted with FoxO1 and activated transcription of FoxO1 target gene, p21. Moreover, SET/TAF-Iβ inhibited acetylation of FoxO1 and increased p21 transcription induced by oxidative stress. Our results suggest that SET/TAF-Iβ inhibits FoxO1 acetylation and activates its transcriptional activity toward p21. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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Fox (forkhead) genes are involved in the dorso-ventral patterning of the Xenopus mesoderm.
El-Hodiri, H; Bhatia-Dey, N; Kenyon, K; Ault, K; Dirksen, M; Jamrich, M
2001-01-01
Fox (forkhead/winged helix) genes encode a family of transcription factors that are involved in embryonic pattern formation, regulation of tissue specific gene expression and tumorigenesis. Several of them are transcribed during Xenopus embryogenesis and are important for the patterning of ectoderm, mesoderm and endoderm. We have isolated three forkhead genes that are activated during gastrulation and play an important role in the dorso-ventral patterning of the mesoderm. XFKH1 (FoxA4b), the first vertebrate forkhead gene to be implicated in embryonic pattern formation, is expressed in the Spemann-Mangold organizer region and later in the embryonic notochord. XFKH7, the Xenopus orthologue of the murine Mfh1(Foxc2), is expressed in the presomitic mesoderm, but not in the notochord or lateral plate mesoderm. Finally, XFD-13'(FoxF1b)1 is expressed in the lateral plate mesoderm, but not in the notochord or presomitic mesoderm. Expression pattern and functional experiments indicate that these three forkhead genes are involved in the dorso-ventral patterning of the mesoderm.
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1983-07-01
SECURITY CLASS. (of chi* report) Los Angeles District, Corps of Engineers Ucasfe P.O. Box 2711, Los Angeles, CA 90053 15&. DEL SI F1CATION/OWNGRAOI...greater potential for the possible occurrence of a large earthquake include the Whittier-Elsinore, Agua Caliente, San Jacinto, and the San Andreas...about 900,000 motor vehicles used within the county. 2.20 Air contaminants monitored within the San Diego Bay air basin include carbon monoxide (CO
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Rodil-Garcia, Patricia; Arellanes-Licea, Elvira del Carmen; Montoya-Contreras, Angélica; Salazar-Olivo, Luis A.
2017-01-01
Birth weight is an early predictor for metabolic diseases and microRNAs (miRNAs) are proposed as fetal programming participants. To evaluate the use of dried blood spots (DBS) on newborn screening cards (NSC) as a source of analyzable miRNAs, we optimized a commercial protocol to recover total miRNA from normal birth weight (NBW, n = 17–20), low birth weight (LBW, n = 17–20) and high birth weight (macrosomia, n = 17–20) newborns and analyzed the relative expression of selected miRNAs by stem-loop RT-qPCR. The possible role of miRNAs on the fetal programming of metabolic diseases was explored by bioinformatic tools. The optimized extraction of RNA resulted in a 1.2-fold enrichment of miRNAs respect to the commercial kit. miR-33b and miR-375 were overexpressed in macrosomia 9.8-fold (p < 0.001) and 1.7-fold, (p < 0.05), respectively and miR-454-3p was overexpressed in both LBW and macrosomia (19.7-fold, p < 0.001 and 10.8-fold, p < 0.001, respectively), as compared to NBW. Potential target genes for these miRNAs are associated to cyclic-guanosine monophosphate (cGMP)-dependent protein kinase (PKG), mitogen-activated protein kinase (MAPK), type 2 diabetes, transforming growth factor-β (TGF-β)and Forkhead box O protein (FoxO) pathways. In summary, we improved a protocol for analyzing miRNAs from NSC and provide the first evidence that birth weight modifies the expression of miRNAs associated to adult metabolic dysfunctions. Our work suggests archived NSC are an invaluable resource in the search for fetal programming biomarkers. PMID:29182561
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Smad3 induces atrogin-1, inhibits mTOR and protein synthesis, and promotes muscle atrophy in vivo.
Goodman, Craig A; McNally, Rachel M; Hoffmann, F Michael; Hornberger, Troy A
2013-11-01
Myostatin, a member of the TGF superfamily, is sufficient to induce skeletal muscle atrophy. Myostatin-induced atrophy is associated with increases in E3-ligase atrogin-1 expression and protein degradation and decreases in Akt/mechanistic target of rapamycin (mTOR) signaling and protein synthesis. Myostatin signaling activates the transcription factor Smad3 (Small Mothers Against Decapentaplegic), which has been shown to be necessary for myostatin-induced atrogin-1 expression and atrophy; however, it is not known whether Smad3 is sufficient to induce these events or whether Smad3 simply plays a permissive role. Thus, the aim of this study was to address these questions with an in vivo model. To accomplish this goal, in vivo transfection of plasmid DNA was used to create transient transgenic mouse skeletal muscles, and our results show for the first time that Smad3 expression is sufficient to stimulate atrogin-1 promoter activity, inhibit Akt/mTOR signaling and protein synthesis, and induce muscle fiber atrophy. Moreover, we propose that Akt/mTOR signaling is inhibited by a Smad3-induced decrease in microRNA-29 (miR-29) expression and a subsequent increase in the translation of phosphatase and tensin homolog (PTEN) mRNA. Smad3 is also sufficient to inhibit peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) promoter activity and to increase FoxO (Forkhead Box Protein, Subclass O)-mediated signaling and the promoter activity of plasminogen activator inhibitor 1 (PAI-1). Combined, this study provides the first evidence that Smad3 is sufficient to regulate many of the events associated with myostatin-induced atrophy and therefore suggests that Smad3 signaling may be a viable target for therapies aimed at preventing myostatin-induced muscle atrophy.
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Sun, Rulin; Zhang, Santao; Hu, Wenjun; Lu, Xing; Lou, Ning; Yang, Zhende; Chen, Shaoyong; Zhang, Xiaoping; Yang, Hongmei
2016-07-01
Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia. Copyright © 2016 the American Physiological Society.
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Toorie, Anika M.; Cyr, Nicole E.; Steger, Jennifer S.; Beckman, Ross; Farah, George; Nillni, Eduardo A.
2016-01-01
Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamic-pituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamic-pituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH. PMID:26755731
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ERIC Educational Resources Information Center
Willis, Patrick
2014-01-01
When high school students are asked what's the best part of science class, many will say it's the field trips. Students enjoy engaging in authentic, community-based science outside the classroom. To capitalize on this, Patrick Willis created the Bird Box Survey Project for his introductory field biology class. The project takes students…
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40 CFR Appendix II to Part 280 - List of Agencies Designated To Receive Notifications
Code of Federal Regulations, 2012 CFR
2012-07-01
... of Pollution Control and Ecology, P.O. Box 9583, Little Rock, Arkansas 72219, 501/562-7444 California (State Form), Executive Director, State Water Resources Control Board, P.O. Box 100, Sacramento... and Waste Management, Department of Natural Resources and Environmental Control, P.O. Box 1401, 89...
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40 CFR Appendix II to Part 280 - List of Agencies Designated To Receive Notifications
Code of Federal Regulations, 2013 CFR
2013-07-01
... of Pollution Control and Ecology, P.O. Box 9583, Little Rock, Arkansas 72219, 501/562-7444 California (State Form), Executive Director, State Water Resources Control Board, P.O. Box 100, Sacramento... and Waste Management, Department of Natural Resources and Environmental Control, P.O. Box 1401, 89...
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40 CFR Appendix II to Part 280 - List of Agencies Designated To Receive Notifications
Code of Federal Regulations, 2010 CFR
2010-07-01
... of Pollution Control and Ecology, P.O. Box 9583, Little Rock, Arkansas 72219, 501/562-7444 California (State Form), Executive Director, State Water Resources Control Board, P.O. Box 100, Sacramento... and Waste Management, Department of Natural Resources and Environmental Control, P.O. Box 1401, 89...
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40 CFR Appendix II to Part 280 - List of Agencies Designated To Receive Notifications
Code of Federal Regulations, 2011 CFR
2011-07-01
... of Pollution Control and Ecology, P.O. Box 9583, Little Rock, Arkansas 72219, 501/562-7444 California (State Form), Executive Director, State Water Resources Control Board, P.O. Box 100, Sacramento... and Waste Management, Department of Natural Resources and Environmental Control, P.O. Box 1401, 89...
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40 CFR Appendix II to Part 280 - List of Agencies Designated To Receive Notifications
Code of Federal Regulations, 2014 CFR
2014-07-01
... of Pollution Control and Ecology, P.O. Box 9583, Little Rock, Arkansas 72219, 501/562-7444 California (State Form), Executive Director, State Water Resources Control Board, P.O. Box 100, Sacramento... and Waste Management, Department of Natural Resources and Environmental Control, P.O. Box 1401, 89...
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75 FR 30806 - Colorado Interstate Gas Company; Notice of Application
Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-02
... Interstate Gas Company (CIG), P.O. Box 1087, Colorado Springs, Colorado 80944, filed with the Federal Energy... Susan C. Stires, Director, Regulatory Affairs, Colorado Interstate Gas Company, P.O. Box 1087, Colorado..., P.O. Box 1087, Colorado Springs, Colorado 80944 at 719-520-4898. Pursuant to section 157.9 of the...
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78 FR 13658 - Sierrita Gas Pipeline LLC; Notice of Application
Federal Register 2010, 2011, 2012, 2013, 2014
2013-02-28
... (Sierrita), P.O. Box 1087, Colorado Springs, Colorado 80944, filed in the above referenced docket an... Gas Pipeline LLC, P.O. Box 1087, Colorado Springs, Colorado 80944, by telephone at (719) 667-7517, by... General Counsel or David K. Dewey, Associate Counsel, Sierrita Gas Pipeline LLC, P.O. Box 1087, Colorado...
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Detection and quantification of RNA 2′-O-methylation and pseudouridylation
Karijolich, John
2016-01-01
RNA-guided RNA modification is a naturally occurring process that introduces 2′-O-methylation and pseudouridylation into rRNA, spliceosomal snRNA and several other types of RNA. The Box C/D ribonucleoproteins (RNP) and Box H/ACA RNP, each containing one unique guide RNA (Box C/D RNA or Box H/ACA RNA) and a set of core proteins, are responsible for 2′-O-methylation and pseudouridylation respectively. Box C/D RNA and Box H/ACA RNA provide the modification specificity through base pairing with their RNA substrate. These post-transcriptional modifications could profoundly alter the properties and functions of substrate RNAs. Thus it is desirable to establish reliable and standardized modification methods to study biological functions of modified nucleotides in RNAs. Here, we present several sensitive and efficient methods and protocols for detecting and quantifying post-transcriptional 2′-O-methylation and pseudouridylation. PMID:26853326
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Monoallelic expression of the human FOXP2 speech gene
Adegbola, Abidemi A.; Cox, Gerald F.; Bradshaw, Elizabeth M.; Hafler, David A.; Gimelbrant, Alexander; Chess, Andrew
2015-01-01
The recent descriptions of widespread random monoallelic expression (RMAE) of genes distributed throughout the autosomal genome indicate that there are more genes subject to RMAE on autosomes than the number of genes on the X chromosome where X-inactivation dictates RMAE of X-linked genes. Several of the autosomal genes that undergo RMAE have independently been implicated in human Mendelian disorders. Thus, parsing the relationship between allele-specific expression of these genes and disease is of interest. Mutations in the human forkhead box P2 gene, FOXP2, cause developmental verbal dyspraxia with profound speech and language deficits. Here, we show that the human FOXP2 gene undergoes RMAE. Studying an individual with developmental verbal dyspraxia, we identify a deletion 3 Mb away from the FOXP2 gene, which impacts FOXP2 gene expression in cis. Together these data suggest the intriguing possibility that RMAE impacts the haploinsufficiency phenotypes observed for FOXP2 mutations. PMID:25422445
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Monoallelic expression of the human FOXP2 speech gene.
Adegbola, Abidemi A; Cox, Gerald F; Bradshaw, Elizabeth M; Hafler, David A; Gimelbrant, Alexander; Chess, Andrew
2015-06-02
The recent descriptions of widespread random monoallelic expression (RMAE) of genes distributed throughout the autosomal genome indicate that there are more genes subject to RMAE on autosomes than the number of genes on the X chromosome where X-inactivation dictates RMAE of X-linked genes. Several of the autosomal genes that undergo RMAE have independently been implicated in human Mendelian disorders. Thus, parsing the relationship between allele-specific expression of these genes and disease is of interest. Mutations in the human forkhead box P2 gene, FOXP2, cause developmental verbal dyspraxia with profound speech and language deficits. Here, we show that the human FOXP2 gene undergoes RMAE. Studying an individual with developmental verbal dyspraxia, we identify a deletion 3 Mb away from the FOXP2 gene, which impacts FOXP2 gene expression in cis. Together these data suggest the intriguing possibility that RMAE impacts the haploinsufficiency phenotypes observed for FOXP2 mutations.
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FOXP3 gene variations and susceptibility to autism: A case-control study.
Safari, Mohammad Reza; Ghafouri-Fard, Soudeh; Noroozi, Rezvan; Sayad, Arezou; Omrani, Mir Davood; Komaki, Alireza; Eftekharian, Mohammad Mahdi; Taheri, Mohammad
2017-01-05
Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental disorders associated with immune system dysregulation. There are supporting evidences for the role of Forkhead Box P3 (FOXP3) gene as a lineage specification factor of regulatory T cells in the pathogenesis of ASD. The aim of this study was to explore possible relationship between genetic variants rs2232365 and rs3761548 of FOXP3 and ASD in 523 ASD patients versus 472 control individuals. Allele frequency analyses showed significant overpresentation of rs2232365-G allele in cases versus controls. In addition, rs2232365 GG genotype was associated with ASD in dominant inheritance model. Haplotype analysis revealed no significant association of any estimated block of rs2232365/rs3761548 with ASD. Our study indicated that rs2232365 is associated with ASD. Copyright © 2016 Elsevier B.V. All rights reserved.
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Effects of oxidative stress on hyperglycaemia-induced brain malformations in a diabetes mouse model.
Jin, Ya; Wang, Guang; Han, Sha-Sha; He, Mei-Yao; Cheng, Xin; Ma, Zheng-Lai; Wu, Xia; Yang, Xuesong; Liu, Guo-Sheng
2016-09-10
Pregestational diabetes mellitus (PGDM) enhances the risk of fetal neurodevelopmental defects. However, the mechanism of hyperglycaemia-induced neurodevelopmental defects is not fully understood. In this study, several typical neurodevelopmental defects were identified in the streptozotocin-induced diabetes mouse model. The neuron-specific class III beta-tubulin/forkhead box P1-labelled neuronal differentiation was suppressed and glial fibrillary acidic protein-labelled glial cell lineage differentiation was slightly promoted in pregestational diabetes mellitus (PGDM) mice. Various concentrations of glucose did not change the U87 cell viability, but glial cell line-derived neurotrophic factor expression was altered with varying glucose concentrations. Mouse maternal hyperglycaemia significantly increased Tunel(+) apoptosis but did not dramatically affect PCNA(+) cell proliferation in the process. To determine the cause of increased apoptosis, we determined the SOD activity, the expression of Nrf2 as well as its downstream anti-oxidative factors NQO1 and HO1, and found that all of them significantly increased in PGDM fetal brains compared with controls. However, Nrf2 expression in U87 cells was not significantly changed by different glucose concentrations. In mouse telencephalon, we observed the co-localization of Tuj-1 and Nrf2 expression in neurons, and down-regulating of Nrf2 in SH-SY5Y cells altered the viability of SH-SY5Y cells exposed to high glucose concentrations. Taken together, the data suggest that Nrf2-modulated antioxidant stress plays a crucial role in maternal hyperglycaemia-induced neurodevelopmental defects. Copyright © 2016 Elsevier Inc. All rights reserved.
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-12-19
... DEPARTMENT OF COMMERCE Bureau of Industry and Security Igor Bobel, Inmate -67253-066, FCI Loretto, Federal Correctional Institution, P.O. Box 1000, Loretto, PA 15940; Order Denying Export Privileges On May... a last known address at: Inmate -67253-066, FCI Loretto, Federal Correctional Institution, P.O. Box...
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Hegazy, Rehab; Salama, Abeer; Mansour, Dina; Hassan, Azza
2016-01-01
Hexavalent chromium (CrVI) is a heavy metal widely used in more than 50 industries. Nephrotoxicity is a major adverse effect of chromium poisoning. The present study investigated the potential renoprotective effect of lactoferrin (Lf) against potassium dichromate (PDC)-induced acute kidney injury (AKI) in rats. Beside, because previous studies suggest that interlukin-18 (IL-18) and insulin-like growth factor-1 (IGF-1) play important roles in promoting kidney damage, the present work aimed to evaluate the involvement of these two cytokines in PDC model of AKI and in the potential renoprotective effect of lactoferrin. Adult male albino Wistar rats were pretreated with Lf (200 mg/kg/day, p.o.) or (300 mg/kg/day, p.o.); the doses that are usually used in the experiment studies, for 14 days followed by a single dose of PDC (15 mg/kg, s.c.). PDC caused significant increase in serum urea, creatinine, and total protein levels. This was accompanied with decreased renal glutathione content, and increased renal malondialdehyde, IL-18, IL-4, nuclear factor kappa B (NFκB), IGF-1, and the phosphorylated form of forkhead box protein O1 (FoxO1) levels. Moreover, normal expression IFN-γ mRNA and enhanced expression of TNF-α mRNA was demonstrated in renal tissues. Histopathological investigations provoked deleterious changes in the renal tissues. Tubular epithelial hyperplasia and apoptosis were demonstrated immunohistochemically by positive proliferating cell nuclear antigen (PCNA), Bax, and Caspase-3 expression, respectively. Pretreatment of rats with Lf in both doses significantly corrected all previously mentioned PDC-induced changes with no significant difference between both doses. In conclusion, the findings of the present study demonstrated the involvement of oxidative stress, inflammatory reactions, tubular hyperplasia and apoptosis in PDC-induced AKI. It suggested a role of IL-18 through stimulation of IL-4-induced inflammatory pathway, and IGF-1 through triggering FoxO1-induced cell proliferation. Moreover, the study revealed that Lf protected the kidney against Cr-induced AKI in rats and significantly showed antioxidant, anti-inflammatory, and anti-proliferative properties with down-regulation of IL-18 and IGF-1.
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Cho, Jun-Ho; Pan, Chi-Jiunn; Anduaga, Javier
2017-01-01
A deficiency in glucose-6-phosphatase-α (G6Pase-α) in glycogen storage disease type Ia (GSD-Ia) leads to impaired glucose homeostasis and metabolic manifestations including hepatomegaly caused by increased glycogen and neutral fat accumulation. A recent report showed that G6Pase-α deficiency causes impairment in autophagy, a recycling process important for cellular metabolism. However, the molecular mechanism underlying defective autophagy is unclear. Here we show that in mice, liver-specific knockout of G6Pase-α (L-G6pc-/-) leads to downregulation of sirtuin 1 (SIRT1) signaling that activates autophagy via deacetylation of autophagy-related (ATG) proteins and forkhead box O (FoxO) family of transcriptional factors which transactivate autophagy genes. Consistently, defective autophagy in G6Pase-α-deficient liver is characterized by attenuated expressions of autophagy components, increased acetylation of ATG5 and ATG7, decreased conjugation of ATG5 and ATG12, and reduced autophagic flux. We further show that hepatic G6Pase-α deficiency results in activation of carbohydrate response element-binding protein, a lipogenic transcription factor, increased expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a lipid regulator, and suppressed expression of PPAR-α, a master regulator of fatty acid β-oxidation, all contributing to hepatic steatosis and downregulation of SIRT1 expression. An adenovirus vector-mediated increase in hepatic SIRT1 expression corrects autophagy defects but does not rectify metabolic abnormalities associated with G6Pase-α deficiency. Importantly, a recombinant adeno-associated virus (rAAV) vector-mediated restoration of hepatic G6Pase-α expression corrects metabolic abnormalities, restores SIRT1-FoxO signaling, and normalizes defective autophagy. Taken together, these data show that hepatic G6Pase-α deficiency-mediated down-regulation of SIRT1 signaling underlies defective hepatic autophagy in GSD-Ia. PMID:28558013
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Ohkawara, Hiroshi; Ishibashi, Toshiyuki; Sugimoto, Koichi; Ikeda, Kazuhiko; Ogawa, Kazuei; Takeishi, Yasuchika
2014-01-01
Membrane type 1–matrix metalloproteinase (MT1-MMP) functions as a signaling molecule in addition to a proteolytic enzyme. Our hypothesis was that MT1-MMP cooperates with protein kinase B (Akt) in tumor necrosis factor (TNF)-α-induced signaling pathways of vascular responses, including tissue factor (TF) procoagulant activity and endothelial apoptosis, in cultured human aortic endothelial cells (ECs). TNF-α (10 ng/mL) induced a decrease in Akt phosphorylation within 60 minutes in ECs. A chemical inhibitor of MMP, TIMP-2 and selective small interfering RNA (siRNA)-mediated suppression of MT1-MMP reversed TNF-α-triggered transient decrease of Akt phosphorylation within 60 minutes, suggesting that MT1-MMP may be a key regulator of Akt phosphorylation in TNF-α-stimulated ECs. In the downstream events, TNF-α increased TF antigen and activity, and suppressed the expression of thrombomodulin (TM) antigen. Inhibition of Akt markedly enhanced TNF-α-induced expression of TF antigen and activity, and further reduced the expression of TM antigen. Silencing of MT1-MMP by siRNA also reversed the changed expression of TF and TM induced by TNF-α. Moreover, TNF-α induced apoptosis of ECs through Akt- and forkhead box protein O1 (FoxO1)-dependent signaling pathway and nuclear factor-kB (NF-kB) activation. Knockdown of MT1-MMP by siRNA reversed apoptosis of ECs by inhibiting TNF-α-induced Akt-dependent regulation of FoxO1 in TNF-α-stimulated ECs. Immunoprecipitation demonstrated that TNF-α induced the changes in the associations between the cytoplasmic fraction of MT1-MMP and Akt in ECs. In conclusion, we show new evidence that MT1-MMP/Akt signaling axis is a key modifier for TNF-α-induced signaling pathways for modulation of procoagulant activity and apoptosis of ECs. PMID:25162582
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Coordination of NF-kappaB and NFAT antagonism by the forkhead transcription factor Foxd1.
Lin, Ling; Peng, Stanford L
2006-04-15
Forkhead transcription factors play critical roles in the maintenance of immune homeostasis. In this study, we demonstrate that this regulation most likely involves intricate interactions between the forkhead family members and inflammatory transcription factors: the forkhead member Foxd1 coordinates the regulation of the activity of two key inflammatory transcription factors, NF-AT and NF-kappaB, with Foxd1 deficiency resulting in multiorgan, systemic inflammation, exaggerated Th cell-derived cytokine production, and T cell proliferation in autologous MLRs. Foxd1-deficient T cells possess increased activity of both NF-AT and NF-kappaB: the former correlates with the ability of Foxd1 to regulate casein kinase 1, an NF-AT inhibitory kinase; the latter with the ability of Foxd1 to regulate Foxj1, which regulates the NF-kappaB inhibitory subunit IkappaB beta. Thus, Foxd1 modulates inflammatory reactions and prevents autoimmunity by directly regulating anti-inflammatory regulators of the NF-AT pathway, and by coordinating the suppression of the NF-kappaB pathway via Foxj1. These findings indicate the presence of a general network of forkhead proteins that enforce T cell quiescence.
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Internet-Based Injury Profile Developer (IPD) User’s Manual, Version 1.0
2002-10-01
NAVAL HEALTH RESEARCH CENTER Internet-based Injury Profile Developer (IPD) User’s Manual Version 1.0 M. Knapp M. Galarneau...NAVAL HEALTH RESEARCH CENTER P. O. BOX 85122 SAN DIEGO, CA 92186-5122...Kizakevich2 1Naval Health Research Center P.O. Box 85122 San Diego, CA 92182-5122 2Research Triangle Institute P.O. Box 12194
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-01
... 56, Room 2300, P.O. Box 25426, Denver, CO 80225-0426, (720) 544- 2903/TDD (800) 659-3656. Delaware... Place, P.O. Box 147010, Gainesville, FL 32614-7010, (352) 338-3400/TDD (352) 338- 3499. Georgia USDA... (318) 473-7655. Maine USDA Rural Development State Office, 967 Illinois Avenue, Suite 4, P.O. Box 405...
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Massi, Daniela; Romano, Emanuela; Rulli, Eliana; Merelli, Barbara; Nassini, Romina; De Logu, Francesco; Bieche, Ivan; Baroni, Gianna; Cattaneo, Laura; Xue, Gongda; Mandalà, Mario
2017-06-01
The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified. Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients. We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03-0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54-131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10-0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09-0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%. Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Minimal Phenotype of Mice Homozygous for a Null Mutation in the Forkhead/Winged Helix Gene, Mf2
Kume, Tsutomu; Deng, Keyu; Hogan, Brigid L. M.
2000-01-01
Mf2 (mesoderm/mesenchyme forkhead 2) encodes a forkhead/winged helix transcription factor expressed in numerous tissues of the mouse embryo, including paraxial mesoderm, somites, branchial arches, vibrissae, developing central nervous system, and developing kidney. We have generated mice homozygous for a null mutation in the Mf2 gene (Mf2lacZ) to examine its role during embryonic development. The lacZ allele also allows monitoring of Mf2 gene expression. Homozygous null mutants are viable and fertile and have no major developmental defects. Some mutants show renal abnormalities, including kidney hypoplasia and hydroureter, but the penetrance of this phenotype is only 40% or lower, depending on the genetic background. These data suggest that Mf2 can play a unique role in kidney development, but there is functional redundancy in this organ and other tissues with other forkhead/winged helix genes. PMID:10648626
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Minimal phenotype of mice homozygous for a null mutation in the forkhead/winged helix gene, Mf2.
Kume, T; Deng, K; Hogan, B L
2000-02-01
Mf2 (mesoderm/mesenchyme forkhead 2) encodes a forkhead/winged helix transcription factor expressed in numerous tissues of the mouse embryo, including paraxial mesoderm, somites, branchial arches, vibrissae, developing central nervous system, and developing kidney. We have generated mice homozygous for a null mutation in the Mf2 gene (Mf2(lacZ)) to examine its role during embryonic development. The lacZ allele also allows monitoring of Mf2 gene expression. Homozygous null mutants are viable and fertile and have no major developmental defects. Some mutants show renal abnormalities, including kidney hypoplasia and hydroureter, but the penetrance of this phenotype is only 40% or lower, depending on the genetic background. These data suggest that Mf2 can play a unique role in kidney development, but there is functional redundancy in this organ and other tissues with other forkhead/winged helix genes.
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Jeong, Sin-Gu; Cho, Goang-Won
2015-05-15
Cellular senescence is characterized by functional decline induced by cumulative damage to DNA, proteins, lipids, and carbohydrates. Previous studies have reported that replicative senescence is caused by excessive amounts of reactive oxygen species (ROS) produced as a result of aerobic energy metabolism. In this study, we established human bone marrow mesenchymal stromal cells (hBM-MSCs) in replicative senescence after culture over a long term to investigate the relationship between ROS levels and stem cell potential and to determine whether differentiation potential can be restored by antioxidant treatment. Intracellular ROS levels were increased in hBM-MSCs; this was accompanied by a decrease in the expression of the antioxidant enzymes catalase and superoxide dismutase (SOD)1 and 2 and of phosphorylated forkhead box O1 (p-FOXO1) as well as an increase in the expression of p53 and p16, along with a reduction in differentiation potential. When the antioxidant ascorbic acid was used to eliminate excess ROS, the levels of antioxidant enzymes (catalase, SOD1 and 2, p-FOXO1, and p53) were partly restored. Moreover, differentiation into adipocytes and osteocytes was higher in hBM-MSCs treated with ascorbic acid than in the untreated control cells. These results suggest that the decline in differentiation potential caused by increased endogenous ROS production during in vitro expansion can be reversed by treatment with antioxidants such as ascorbic acid. Copyright © 2015 Elsevier Inc. All rights reserved.
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SIRT1 and FOXO1 mRNA expression in PBMC correlates to physical activity in COPD patients
Taka, Chihiro; Hayashi, Ryuji; Shimokawa, Kazuki; Tokui, Kotaro; Okazawa, Seisuke; Kambara, Kenta; Inomata, Minehiko; Yamada, Toru; Matsui, Shoko; Tobe, Kazuyuki
2017-01-01
Background Physical activity (PA) is considered as one of the most important prognostic predictors in chronic obstructive pulmonary disease (COPD) patients. Longevity gene, SIRT1, is reported to be involved in the pathogenesis of COPD by regulating the signaling pathways of oxidative stress, inflammation, and aging. We hypothesize that SIRT1 and related genes are also associated with the benefits of PA in COPD patients. Methods Eighteen COPD outpatients were enrolled in this study, and their PA level was assessed with an accelerometer. We assessed the SIRT1 and related genes mRNA expression levels in the peripheral blood mononuclear cells (PBMCs) of the subjects. We carried out respiratory function testing, blood gas analysis, the 6-minute walk test, and measurement of the cross-sectional area of the erector spinae muscles (ESMCSA) by chest computed tomography. We analyzed the association of PA with the results of each of the examinations. Results The mean age was 72±9 years, and the mean forced expiratory volume in 1 second was 1.4±0.56 L (52%±19% predicted). Our findings revealed a correlation between the daily PA and ESMCSA. The SIRT1 and Forkhead box O (FOXO)1 mRNA expression levels in PBMCs were positively correlated with moderate-PA time (r=0.60, p=0.008 for SIRT1 and r=0.59, p=0.01 for FOXO1). PMID:29138552
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Li, Ying-Na; Guo, Yu; Xi, Miao-Miao; Yang, Pei; Zhou, Xue-Ying; Yin, Shuang; Hai, Chun-Xu; Li, Jin-Gang; Qin, Xu-Jun
2014-01-01
Reactive oxygen species (ROS) are closely related to the aging process. In our previous studies, we found that the saponins from Aralia taibaiensis have potent antioxidant activity, suggesting the potential protective activity on the aging. However, the protective effect of the saponins and the possible underlying molecular mechanism remain unknown. In the present study, we employed a D-galactose-induced aging rat model to investigate the protective effect of the saponins. We found that D-galactose treatment induced obvious aging-related changes such as the decreased thymus and spleen coefficients, the increased advanced glycation end products (AGEs) level, senescence-associated β-galactosidase (SAβ-gal) activity, and malondialdehyde (MDA) level. Further results showed that Forkhead box O3a (FOXO3a), nuclear factor-erythroid 2-related factor 2 (Nrf2), and their targeted antioxidants such as superoxide dismutase 2 (SOD2), catalase (CAT), glutathione reductase (GR), glutathione (GSH), glutamate-cysteine ligase (GCL), and heme oxygenase 1 (HO-1) were all inhibited in the aging rats induced by D-galactose treatment. Saponins supplementation showed effective protection on these changes. These results demonstrate that saponins from Aralia taibaiensis attenuate the D-galactose-induced rat aging. By activating FOXO3a and Nrf2 pathways, saponins increase their downstream multiple antioxidants expression and function, at least in part contributing to the protection on the D-galactose-induced aging in rats. PMID:24669284
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Belguise, Karine; Sonenshein, Gail E.
2007-01-01
The vast majority of primary human breast cancer tissues display aberrant nuclear NF-κB c-Rel expression. A causal role for c-Rel in mammary tumorigenesis has been demonstrated using a c-Rel transgenic mouse model; however, tumors developed with a long latency, suggesting a second event is needed to trigger tumorigenesis. Here we show that c-Rel activity in the mammary gland is repressed by estrogen receptor α (ERα) signaling, and we identify an epigenetic mechanism in breast cancer mediated by activation of what we believe is a novel PKCθ-Akt pathway that leads to downregulation of ERα synthesis and derepression of c-Rel. ERα levels were lower in c-Rel–induced mammary tumors compared with normal mammary gland tissue. PKCθ induced c-Rel activity and target gene expression and promoted growth of c-Rel- and c-RelxCK2α–driven mouse mammary tumor–derived cell lines. RNA expression levels of PKCθ and c-Rel target genes were inversely correlated with ERα levels in human breast cancer specimens. PKCθ activated Akt, thereby inactivating forkhead box O protein 3a (FOXO3a) and leading to decreased synthesis of its target genes, ERα and p27Kip1. Thus we have shown that activation of PKCθ inhibits the FOXO3a/ERα/p27Kip1 axis that normally maintains an epithelial cell phenotype and induces c-Rel target genes, thereby promoting proliferation, survival, and more invasive breast cancer. PMID:18037997
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Kim, Arang; Yun, Jung-Mi
2017-08-01
Hyperglycemia leads to diabetes and its diabetic complications. In this study, we investigated the synergistic effects of luteolin and fisetin on proinflammatory cytokine secretion and its underlying epigenetic regulation in human monocytes exposed to hyperglycemic (HG) concentrations. Human monocytic cells (THP-1) were cultured under controlled (14.5 mM mannitol), normoglycemic (5.5 mM glucose), or HG (20 mM glucose) conditions in the absence or presence of the two phytochemicals for 48 h. Whereas HG conditions significantly induced histone acetylation, nuclear factor-kappa B (NF-κB) activation, interleukin 6, and tumor necrosis factor-α release from THP-1 cells; combination treatments with the two phytochemicals (500 nM fisetin, and l μM and 500 nM luteolin) suppressed NF-κB activity and inflammatory cytokine release. Fisetin, luteolin, and their combination treatments also significantly decreased the activity of histone acetyltransferase, a known NF-κB coactivator; inhibited reactive oxygen species production; and activated sirtuin (SIRT)1 and forkhead box O3a (FOXO3a) expressions (P < .05). Thus, combination treatments with the two phytochemicals inhibited HG condition-induced cytokine production in monocytes, through epigenetic changes involving NF-κB activation. We, therefore, suggest that combination treatments with luteolin and fisetin may be a potential candidate for the treatment and prevention of diabetes and its complications.
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Cold exposure increases slow-type myosin heavy chain 1 (MyHC1) composition of soleus muscle in rats.
Mizunoya, Wataru; Iwamoto, Yohei; Sato, Yusuke; Tatsumi, Ryuichi; Ikeuchi, Yoshihide
2014-03-01
The aim of this study was to examine the effects of cold exposure on rat skeletal muscle fiber type, according to myosin heavy chain (MyHC) isoform and metabolism-related factors. Male Wistar rats (7 weeks old) were housed individually at 4 ± 2°C as a cold-exposed group or at room temperature (22 ± 2°C) as a control group for 4 weeks. We found that cold exposure significantly increased the slow-type MyHC1 content in the soleus muscle (a typical slow-type fiber), while the intermediate-type MyHC2A content was significantly decreased. In contrast to soleus, MyHC composition of extensor digitorum longus (EDL, a typical fast-type fiber) and gastrocnemius (a mix of slow-type and fast-type fibers) muscle did not change from cold exposure. Cold exposure increased mRNA expression of mitochondrial uncoupling protein 3 (UCP3) in both the soleus and EDL. Cold exposure also increased mRNA expression of myoglobin, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) and forkhead box O1 (FOXO1) in the soleus. Upregulation of UCP3 and PGC1α proteins were observed with Western blotting in the gastrocnemius. Thus, cold exposure increased metabolism-related factors in all muscle types that were tested, but MyHC isoforms changed only in the soleus. © 2013 Japanese Society of Animal Science.
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Puukila, Stephanie; Bryan, Sean; Laakso, Anna; Abdel-Malak, Jessica; Gurney, Carli; Agostino, Adrian; Belló-Klein, Adriane; Prasad, Kailash; Khaper, Neelam
2015-01-01
Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG), a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 μ5M iron for 24 hours and/or a 24 hour pre-treatment of 500 μ M SDG. Cardiac iron overload resulted in increased oxidative stress and gene expression of the inflammatory mediators tumor necrosis factor-α, interleukin-10 and interferon γ, as well as matrix metalloproteinases-2 and -9. Increased apoptosis was evident by increased active caspase 3/7 activity and increased protein expression of Forkhead box O3a, caspase 3 and Bax. Cardiac iron overload also resulted in increased protein expression of p70S6 Kinase 1 and decreased expression of AMP-activated protein kinase. Pre-treatment with SDG abrogated the iron-induced increases in oxidative stress, inflammation and apoptosis, as well as the increased p70S6 Kinase 1 and decreased AMP-activated protein kinase expression. The decrease in superoxide dismutase activity by iron treatment was prevented by pre-treatment with SDG in the presence of iron. Based on these findings we conclude that SDG was cytoprotective in an in vitro model of iron overload induced redox-inflammatory damage, suggesting a novel potential role for SDG in cardiac iron overload. PMID:25822525
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Puukila, Stephanie; Bryan, Sean; Laakso, Anna; Abdel-Malak, Jessica; Gurney, Carli; Agostino, Adrian; Belló-Klein, Adriane; Prasad, Kailash; Khaper, Neelam
2015-01-01
Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG), a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 μ5M iron for 24 hours and/or a 24 hour pre-treatment of 500 μ M SDG. Cardiac iron overload resulted in increased oxidative stress and gene expression of the inflammatory mediators tumor necrosis factor-α, interleukin-10 and interferon γ, as well as matrix metalloproteinases-2 and -9. Increased apoptosis was evident by increased active caspase 3/7 activity and increased protein expression of Forkhead box O3a, caspase 3 and Bax. Cardiac iron overload also resulted in increased protein expression of p70S6 Kinase 1 and decreased expression of AMP-activated protein kinase. Pre-treatment with SDG abrogated the iron-induced increases in oxidative stress, inflammation and apoptosis, as well as the increased p70S6 Kinase 1 and decreased AMP-activated protein kinase expression. The decrease in superoxide dismutase activity by iron treatment was prevented by pre-treatment with SDG in the presence of iron. Based on these findings we conclude that SDG was cytoprotective in an in vitro model of iron overload induced redox-inflammatory damage, suggesting a novel potential role for SDG in cardiac iron overload.
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MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4*
Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan
2015-01-01
Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. PMID:25657009
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Mandai, Shintaro; Mori, Takayasu; Nomura, Naohiro; Furusho, Taisuke; Arai, Yohei; Kikuchi, Hiroaki; Sasaki, Emi; Sohara, Eisei; Rai, Tatemitsu; Uchida, Shinichi
2018-06-14
With-no-lysine (K) (WNK) kinases, which are mutated in the inherited form of hypertension pseudohypoaldosteronism type II, are essential regulators of membrane ion transporters. Here, we report that WNK1 positively regulates skeletal muscle cell hypertrophy via mediating the function of the pro-longevity transcription factor forkhead box protein O4 (FOXO4) independent of the conventional WNK signaling pathway linking SPS/STE20-related proline-alanine-rich kinase (SPAK)/oxidative stress response kinase 1 (OSR1) to downstream effector ion transporters. Small interfering RNA (siRNA)-mediated silencing of WNK1, but not SPAK/OSR1 kinases, induced myotube atrophy and remarkable increases in the mRNA expression of the muscle atrophy ubiquitin ligases MAFbx and MuRF1 in C2C12 mouse skeletal muscle cells. WNK1 silencing also increased FOXO4 nuclear localization, and co-transfection of Foxo4-targeted siRNA completely reversed the myotube atrophy and upregulation of atrogene transcription induced by WNK1 silencing. We further illustrated that WNK1 protein abundance in skeletal muscle was increased by chronic voluntary wheel running exercise (hypertrophic stimulus) and markedly decreased by adenine-induced chronic kidney disease (atrophic stimulus) in mice. These findings suggest that WNK1 is involved in the physiological regulation of mammalian skeletal muscle hypertrophy and atrophy via interactions with FOXO4. The WNK1-FOXO4 axis may be a potential therapeutic target in human diseases causing sarcopenia.
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Li, Xiang-Yong; Liu, Ying-Hua; Wang, Bin; Chen, Chih-Yu; Zhang, Hong-Man; Kang, Jing X
2018-01-01
The current system of food production is linked to both the increasing prevalence of chronic disease and the deterioration of the environment, and thereby calls for novel ways of producing nutritious foods in a sustainable manner. In the "longevity village" of Bama, China, we have identified two plant foods, hemp seed and bitter vegetable (Sonchus oleraceus), that are commonly consumed by its residents and grow abundantly in unfarmed land without fertilizers or pesticides. Here, we show that a diet composed of these two foods (the "HB diet") provides a sufficient variety of nutrients and confers significant health benefits. Aged mice allowed ad libitum access to the HB diet not only had longer life spans and improved cognitive function but were also protected against age-related metabolic syndrome, fatty liver, gut dysbiosis and chronic inflammation compared to aged mice fed a control Western diet. Furthermore, longevity-related genes (including 5'adenosine monophosphate-activated protein kinase, sirtuin 1, nuclear respiratory factor 1 and forkhead box O3) were significantly up-regulated, while aging-related genes (including mammalian target of rapamycin and nuclear factor kappa B) were down-regulated. These results demonstrate that the HB diet is capable of promoting health and longevity, and present a sustainable source of healthy foods that can help control the prevalence of chronic diseases and reduce agricultural impact on the environment. Copyright © 2017 Elsevier Inc. All rights reserved.
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Giamas, Georgios; Filipović, Aleksandra; Jacob, Jimmy; Messier, Walter; Zhang, Hua; Yang, Dongyun; Zhang, Wu; Shifa, Belul Assefa; Photiou, Andrew; Tralau-Stewart, Cathy; Castellano, Leandro; Green, Andrew R; Coombes, R Charles; Ellis, Ian O; Ali, Simak; Lenz, Heinz-Josef; Stebbing, Justin
2011-06-01
Therapies targeting estrogen receptor α (ERα, encoded by ESR1) have transformed the treatment of breast cancer. However, large numbers of women relapse, highlighting the need for the discovery of new regulatory targets modulating ERα pathways. An siRNA screen identified kinases whose silencing alters the estrogen response including those previously implicated in regulating ERα activity (such as mitogen-activated protein kinase and AKT). Among the most potent regulators was lemur tyrosine kinase-3 (LMTK3), for which a role has not previously been assigned. In contrast to other modulators of ERα activity, LMTK3 seems to have been subject to Darwinian positive selection, a noteworthy result given the unique susceptibility of humans to ERα+ breast cancer. LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter. LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro. Silencing of LMTK3 reduced tumor volume in an orthotopic mouse model and abrogated proliferation of ERα+ but not ERα- cells, indicative of its role in ERα activity. In human cancers, LMTK3 abundance and intronic polymorphisms were significantly associated with disease-free and overall survival and predicted response to endocrine therapies. These findings yield insights into the natural history of breast cancer in humans and reveal LMTK3 as a new therapeutic target.
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Saben, Jessica L.; Asghar, Zeenat; Rhee, Julie S.; Drury, Andrea; Scheaffer, Suzanne
2016-01-01
The most significant increase in metabolic syndrome over the previous decade occurred in women of reproductive age, which is alarming given that metabolic syndrome is associated with reproductive problems including subfertility and early pregnancy loss. Individuals with metabolic syndrome often consume excess fructose, and several studies have concluded that excess fructose intake contributes to metabolic syndrome development. Here, we examined the effects of increased fructose consumption on pregnancy outcomes in mice. Female mice fed a high-fructose diet (HFrD) for 6 weeks developed glucose intolerance and mild fatty liver but did not develop other prominent features of metabolic syndrome such as weight gain, hyperglycemia, and hyperinsulinemia. Upon mating, HFrD-exposed mice had lower pregnancy rates and smaller litters at midgestation than chow-fed controls. To explain this phenomenon, we performed artificial decidualization experiments and found that HFrD consumption impaired decidualization. This appeared to be due to decreased circulating progesterone as exogenous progesterone administration rescued decidualization. Furthermore, HFrD intake was associated with decreased bone morphogenetic protein 2 expression and signaling, both of which were restored by exogenous progesterone. Finally, expression of forkhead box O1 and superoxide dismutase 2 [Mn] proteins were decreased in the uteri of HFrD-fed mice, suggesting that HFrD consumption promotes a prooxidative environment in the endometrium. In summary, these data suggest that excess fructose consumption impairs murine fertility by decreasing steroid hormone synthesis and promoting an adverse uterine environment. PMID:26677880
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Great Blue Herons in Puget Sound
2007-06-01
Island) (Eissinger unpubl. data). Herons have been documented nesting in at least 18 tree species in Washington , including 8 deciduous , 9...Partnership WDFW - P.O. Box 43145, Olympia Washington 98504-3145 U.S. Army Corps of Engineers - P.O. Box 3755, Seattle Washington , 98124-3755 2007-06... Washington Sea Grant - 3716 Brooklyn Avenue NE, Box 355060, Seattle Washington 98195-6716 University of Washington School of Oceanography - Box 357940
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-04-02
... DEPARTMENT OF COMMERCE Bureau of Industry and Security Marc Knapp, Inmate --06450-015, FCI Safford, P.O. Box 9000, Safford, AZ 85548; Order Denying Export Privileges On September 13, 2011, in the U.S..., with the last known address at: Inmate --06450-015, FCI Safford, P.O. Box 9000, Safford, AZ 85548, and...
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NASA Astrophysics Data System (ADS)
von Schneidemesser, E.; Coates, J.; Denier van der Gon, H. A. C.; Visschedijk, A. J. H.; Butler, T. M.
2016-06-01
Non-methane volatile organic compounds (NMVOCs) are detrimental to human health owing to the toxicity of many of the NMVOC species, as well as their role in the formation of secondary air pollutants such as tropospheric ozone (O3) and secondary organic aerosol. The speciation and amount of NMVOCs emitted into the troposphere are represented in emission inventories (EIs) for input to chemical transport models that predict air pollutant levels. Much of the information in EIs pertaining to speciation of NMVOCs is likely outdated, but before taking on the task of providing an up-to-date and highly speciated EI, a better understanding of the sensitivity of models to the change in NMVOC input would be highly beneficial. According to the EIs, the solvent sector is the most important sector for NMVOC emissions. Here, the sensitivity of modelled tropospheric O3 to NMVOC emission inventory speciation was investigated by comparing the maximum potential difference in O3 produced using a variety of reported solvent sector EI speciations in an idealized study using a box model. The sensitivity was tested using three chemical mechanisms that describe O3 production chemistry, typically employed for different types of modelling scales - point (MCM v3.2), regional (RADM2), and global (MOZART-4). In the box model simulations, a maximum difference of 15 ppbv (ca. 22% of the mean O3 mixing ratio of 69 ppbv) between the different EI speciations of the solvent sector was calculated. In comparison, for the same EI speciation, but comparing the three different mechanisms, a maximum difference of 6.7 ppbv was observed. Relationships were found between the relative contribution of NMVOC compound classes (alkanes and oxygenated species) in the speciations to the amount of Ox produced in the box model. These results indicate that modelled tropospheric O3 is sensitive to the speciation of NMVOCs as specified by emission inventories, suggesting that detailed updates to the EI speciation information would be warranted. Furthermore, modelled tropospheric O3 was also sensitive to the choice of chemical mechanism and further evaluation of both of these sensitivities in more realistic chemical-transport models is needed.
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Damage Tolerance Evaluation of the Anti-Camout Rib (ACR) Torq-Set Recess Fasteners
1983-01-01
Prod Gp Alcoa George P. VoSs Mr. Russell E. Mack 500 S. Main St P.O. Box 840 Akron OH 44318 Lancaster PA 17604 Bitz Inc Alcoa Technical Center Mr. Rick ...J. Doyle The Boeing Co AVRADCOM/DRDAV-EQA Mail Stop 5A-02 P.O. Box 209 P.O. Box 3707 Seattle WA 98124 Seattle WA 98124 Manuel A. Biera E. F. Riordan
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47 CFR 1.1152 - Schedule of annual regulatory fees and filing locations for wireless radio services.
Code of Federal Regulations, 2010 CFR
2010-10-01
...) (47 CFR, Part 90) (a) New, Renew/Mod (FCC 601 & 159) $40.00 FCC, P.O. Box 979097, St. Louis, MO 63197-9000. (b) New, Renew/Mod (Electronic Filing) (FCC 601 & 159) 40.00 FCC, P.O. Box 979097, St. Louis, MO 63197-9000. (c) Renewal Only (FCC 601 & 159) 40.00 FCC, P.O. Box 979097, St. Louis, MO 63197-9000. (d...
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Pitts-Singer, T. L.
2017-01-01
The blue orchard bee, Osmia lignaria (Say), is a solitary bee that is an excellent pollinator of tree fruit orchards. Due to the annual rising costs of honey bee hive rentals, many orchardists are eager to develop management tools and practices to support O. lignaria as an alternative pollinator. Establishing O. lignaria pollination as a sustainable industry requires careful consideration of both bee and orchard management. Here, we test the effect of artificial nest box distribution on in-orchard propagation of O. lignaria in Utah commercial tart cherry orchards. Two nest box distributions were compared across three paired, 1.2-ha plots. One distribution, traditionally employed by O. lignaria consultants, included a centrally located tote for mass-nesting with smaller, surrounding ‘satellite’ nest boxes at orchard margins. The other distribution was composed of smaller, more equally distributed nest boxes throughout the 1.2-ha plots. Significantly higher propagation of O. lignaria was observed in the latter nest box distribution, although all treatments resulted in bee return exceeding the number of bees initially released. These findings provide support for the use of O. lignaria in tart cherry orchards, and demonstrate how simple changes to bee set-up and management can influence propagation efforts. PMID:28365763
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Tran, Stella; Wang, Ying; Lamba, Pankaj; Zhou, Xiang; Boehm, Ulrich; Bernard, Daniel J.
2013-01-01
Forkhead box L2 (Foxl2), a member of the forkhead transcription factor family, plays important roles in pituitary follicle-stimulating hormone synthesis and in ovarian maintenance and function. Mutations in the human FOXL2 gene cause eyelid malformations and premature ovarian failure. FOXL2/Foxl2 is expressed in pituitary gonadotrope and thyrotrope cells, the perioptic mesenchyme of the developing eyelid, and ovarian granulosa cells. The mechanisms governing this cell-restricted expression have not been described. We mapped the Foxl2 transcriptional start site in immortalized murine gonadotrope-like cells, LβT2, by 5’ rapid amplification of cDNA ends and then PCR amplified approximately 1 kb of 5’ flanking sequence from murine genomic DNA. When ligated into a reporter plasmid, the proximal promoter conferred luciferase activity in both homologous (LβT2) and, unexpectedly, heterologous (NIH3T3) cells. In silico analyses identified a CpG island in the proximal promoter and 5’ untranslated region, suggesting that Foxl2 transcription might be regulated epigenetically. Indeed, pyrosequencing and quantitative analysis of DNA methylation using real-time PCR revealed Foxl2 proximal promoter hypomethylation in homologous compared to some, though not all, heterologous cell lines. The promoter was also hypomethylated in purified murine gonadotropes. In vitro promoter methylation completely silenced reporter activity in heterologous and homologous cells. Collectively, the data suggest that differential proximal promoter DNA methylation may contribute to cell-specific Foxl2 expression in some cellular contexts. However, gonadotrope-specific expression of the gene cannot be explained by promoter hypomethylation alone. PMID:24098544
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Fujita, Eriko; Tanabe, Yuko; Shiota, Akira; Ueda, Masatsugu; Suwa, Kiyotaka; Momoi, Mariko Y.; Momoi, Takashi
2008-01-01
Previous studies have demonstrated that mutation in the forkhead domain of the forkhead box P2 (FOXP2) protein (R553H) causes speech-language disorders. To further analyze FOXP2 function in speech learning, we generated a knockin (KI) mouse for Foxp2 (R552H) [Foxp2 (R552H)-KI], corresponding to the human FOXP2 (R553H) mutation, by homologous recombination. Homozygous Foxp2 (R552H)-KI mice showed reduced weight, immature development of the cerebellum with incompletely folded folia, Purkinje cells with poor dendritic arbors and less synaptophysin immunoreactivity, and achieved crisis stage for survival 3 weeks after birth. At postnatal day 10, these mice also showed severe ultrasonic vocalization (USV) and motor impairment, whereas the heterozygous Foxp2 (R552H)-KI mice exhibited modest impairments. Similar to the wild-type protein, Foxp2 (R552H) localized in the nuclei of the Purkinje cells and the thalamus, striatum, cortex, and hippocampus (CA1) neurons of the homozygous Foxp2 (R552H)-KI mice (postnatal day 10), and some of the neurons showed nuclear aggregates of Foxp2 (R552H). In addition to the immature development of the cerebellum, Foxp2 (R552H) nuclear aggregates may further compromise the function of the Purkinje cells and cerebral neurons of the homozygous mice, resulting in their death. In contrast, heterozygous Foxp2 (R552H)-KI mice, which showed modest impairment of USVs with different USV qualities and which did not exhibit nuclear aggregates, should provide insights into the common molecular mechanisms between the mouse USV and human speech learning and the relationship between the USV and motor neural systems. PMID:18287060
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Evaluating pharmaceutical waste disposal in pediatric units.
Almeida, Maria Angélica Randoli de; Wilson, Ana Maria Miranda Martins; Peterlini, Maria Angélica Sorgini
2016-01-01
To verify the disposal of pharmaceutical waste performed in pediatric units. A descriptive and observational study conducted in a university hospital. The convenience sample consisted of pharmaceuticals discarded during the study period. Handling and disposal during preparation and administration were observed. Data collection took place at pre-established times and was performed using a pre-validated instrument. 356 drugs disposals were identified (35.1% in the clinic, 31.8% in the intensive care unit, 23.8% in the surgical unit and 9.3% in the infectious diseases unit). The most discarded pharmacological classes were: 22.7% antimicrobials, 14.8% electrolytes, 14.6% analgesics/pain killers, 9.5% diuretics and 6.7% antiulcer agents. The most used means for disposal were: sharps' disposable box with a yellow bag (30.8%), sink drain (28.9%), sharps' box with orange bag (14.3%), and infectious waste/bin with a white bag (10.1%). No disposal was identified after drug administration. A discussion of measures that can contribute to reducing (healthcare) waste volume with the intention of engaging reflective team performance and proper disposal is necessary. Verificar o descarte dos resíduos de medicamentos realizado em unidades pediátricas. Estudo descritivo e observacional, realizado em um hospital universitário. A amostra de conveniência foi constituída pelos medicamentos descartados durante o período de estudo. Observaram-se a manipulação e o descarte durante o preparo e a administração. A coleta dos dados ocorreu em horários preestabelecidos e realizada por meio de instrumento pré-validado. Identificaram-se 356 descartes de medicamentos (35,1% na clínica, 31,8% na unidade de cuidados intensivos, 23,8% na cirúrgica e 9,3% na infectologia). As classes farmacológicas mais descartadas foram: 22,7% antimicrobianos, 14,8% eletrólitos, 14,6% analgésicos, 9,5% diuréticos e 6,7% antiulcerosos. Vias mais utilizadas: caixa descartável para perfurocortante com saco amarelo (30,8%), ralo da pia (28,9%), caixa de perfurocortante com saco laranja (14,3%) e lixeira infectante com saco branco (10,1%). Não foi identificado descarte após a administração dos fármacos. Faz-se necessária a discussão de medidas que contribuam para a redução do volume de resíduos, com o intuito de engajar a atuação reflexiva da equipe e o descarte adequado.
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Lin, Xinjun; Shi, Hong; Cui, Yi; Wang, Xiaoning; Zhang, Jieping; Yu, Wenzhen; Wei, Min
2018-07-01
The present study aimed to evaluate the impact of dendrobium mixture (DMix) on the gene and protein expression of insulin signaling pathway-associated factors in the livers of diabetic rats. The molecular mechanisms by which DMix inhibits gluconeogenesis were also investigated. A total of 47 female Wistar rats were used in the present study. Of these, 11 rats were randomly selected as healthy controls and diabetes was induced in the remaining 36 rats by administering a high-fat and high-sugar diet for 6 weeks, followed by two intraperitoneal injections of streptozotocin. The 36 rats were screened for diabetes and then randomly divided into three groups: Model, metformin and DMix groups. Following 12 weeks of treatment, the fasting blood glucose (FBG), glycosylated serum protein (GSP), serum insulin, blood lipids [total cholesterol (Tch) and triglycerides (TG)], alanine transaminase (ALT) and aspartate transaminase (AST) were assessed. In addition, hematoxylin and eosin staining was used for histomorphological examination of the liver tissues. The mRNA expression of insulin receptor (InsR), forkhead box protein O1 (FoxO1), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) in the liver was measured with reverse transcription-quantitative polymerase chain reaction and the protein expression of InsR, phosphoinositide-3-kinase (PI3K), phosphorylated (p)-PI3K, protein kinase B (Akt), p-Akt, FoxO1, PEPCK and G6Pase in the liver was measured by western blot analysis. The FBG, GSP, InsR, Tch, TG, ALT and AST levels were significantly lower in the DMix-treated group compared with the model group (P<0.05). In addition, DMix treatment notably improved liver histopathology and significantly increased the gene and protein expression of InsR, PI3K and Akt (P<0.05). DMix treatment also significantly reduced the gene and protein expression of FoxO1, PEPCK and G6Pase (P<0.05). DMix effectively reduced FBG and blood lipids and significantly improved liver function and insulin resistance in diabetic rats, possibly by regulating the gene and protein expression of molecules associated with the PI3K/Akt signaling pathway.
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77 FR 13077 - Order Temporarily Denying Export Privileges
Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-05
.... Box 9645, Q4-280, Sharjah Airport International Free Zone, Sharjah, United Arab Emirates. Do-It FZC, P.O. Box 9645, Q4-280, Sharjah Airport International Free Zone, Sharjah, United Arab Emirates... International Free Zone, Sharjah, United Arab Emirates. 5. Do-It FZC, P.O. Box 9645, Q4-280, Sharjah Airport...
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7 CFR Appendix A to Part 661 - Availability of Information
Code of Federal Regulations, 2013 CFR
2013-01-01
... and copying of a record or for copies of records shall be made to the Deputy Administrator for.... Box 832, Athens, Ga. 30603. State Conservationist, 300 Moana Blvd., Ala., Room 4316, P.O. Box 50004... Conservationist, Federal Bldg., Durham, N.H. 03824. State Conservationist, 1370 Hamilton St., P.O. Box 219...
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7 CFR Appendix A to Part 661 - Availability of Information
Code of Federal Regulations, 2012 CFR
2012-01-01
... and copying of a record or for copies of records shall be made to the Deputy Administrator for.... Box 832, Athens, Ga. 30603. State Conservationist, 300 Moana Blvd., Ala., Room 4316, P.O. Box 50004... Conservationist, Federal Bldg., Durham, N.H. 03824. State Conservationist, 1370 Hamilton St., P.O. Box 219...
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7 CFR Appendix A to Part 661 - Availability of Information
Code of Federal Regulations, 2014 CFR
2014-01-01
... and copying of a record or for copies of records shall be made to the Deputy Administrator for.... Box 832, Athens, Ga. 30603. State Conservationist, 300 Moana Blvd., Ala., Room 4316, P.O. Box 50004... Conservationist, Federal Bldg., Durham, N.H. 03824. State Conservationist, 1370 Hamilton St., P.O. Box 219...
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Artz, Derek R; Allan, Matthew J; Wardell, Gordon I; Pitts-Singer, Theresa L
2014-12-01
Intensively managed, commercial orchards offer resources for managed solitary bees within agricultural landscapes and provide a means to study bee dispersal patterns, spatial movement, nest establishment, and reproduction. In 2012, we studied the impact of 1) the color of nest boxes covaried with four nest box density treatments and 2) the number of bee release sites covaried with two nest box density treatments on the reproductive success of Osmia lignaria Say in a California almond orchard pollinated by a mixture of O. lignaria and Apis mellifera L. Nest box color influenced the number of nests, total cells, and cells with male and female brood. More nests and cells were produced in light blue nest boxes than in orange or yellow nest boxes. The covariate nest box density also had a significant effect on brood production. The number of release sites did not affect O. lignaria nesting and reproduction, but the number of cavities in nest boxes influenced reproduction. Overall, the color of nest boxes and their distribution, but not the number of release sites, can greatly affect O. lignaria nest establishment and reproductive success in a commercial almond orchard. The ability to locate nesting sites in a homogenous, large orchard landscape may also be facilitated by the higher frequency of nest boxes with low numbers of cavities, and by the ability to detect certain nest box colors that best contrast with the blooming trees. © 2014 Entomological Society of America.
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Nine Optical Black-Box Experiments for Lower-Secondary Students
ERIC Educational Resources Information Center
Rode, Henning; Friege, Gunnar
2017-01-01
In this paper a sequence of nine, easy to manufacture optical black-box experiments with increasing levels of difficulty, and supportive frameworks for physics classes are introduced. They have been evaluated in a lower-secondary school at the end of optics lessons. A black-box is a kind of experimental task where the inner structure is not…
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John Henry--The Steel Driving Man
ERIC Educational Resources Information Center
Murphy, David E.; Gulley, Laura L.
2005-01-01
The story of John Henry provided the setting for sixth-grade class to participate in a John Henry Day of mathematics experiments. The students collected data from experiments where students competed against machines and technology. The student analyzed the data by comparing two box plots, a box plot of human data, and a box plot of machine or…
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NASA Technical Reports Server (NTRS)
Yamada, Atsuko; Martindale, Mark Q.
2002-01-01
Ctenophores are thoroughly modern animals whose ancestors are derived from a separate evolutionary branch than that of other eumetazoans. Their major longitudinal body axis is the oral-aboral axis. An apical sense organ, called the apical organ, is located at the aboral pole and contains a highly innervated statocyst and photodetecting cells. The apical organ integrates sensory information and controls the locomotory apparatus of ctenophores, the eight longitudinal rows of ctene/comb plates. In an effort to understand the developmental and evolutionary organization of axial properties of ctenophores we have isolated a forkhead gene from the Brain Factor 1 (BF-1) family. This gene, ctenoBF-1, is the first full-length nuclear gene reported from ctenophores. This makes ctenophores the most basal metazoan (to date) known to express definitive forkhead class transcription factors. Orthologs of BF-1 in vertebrates, Drosophila, and Caenorhabditis elegans are expressed in anterior neural structures. Surprisingly, in situ hybridizations with ctenoBF-1 antisense riboprobes show that this gene is not expressed in the apical organ of ctenophores. CtenoBF-1 is expressed prior to first cleavage. Transcripts become localized to the aboral pole by the 8-cell stage and are inherited by ectodermal micromeres generated from this region at the 16- and 32-cell stages. Expression in subsets of these cells persists and is seen around the edge of the blastopore (presumptive mouth) and in distinct ectodermal regions along the tentacular poles. Following gastrulation, stomodeal expression begins to fade and intense staining becomes restricted to two distinct domains in each tentacular feeding apparatus. We suggest that the apical organ is not homologous to the brain of bilaterians but that the oral pole of ctenophores corresponds to the anterior pole of bilaterian animals.
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Effects of oxidative stress on hyperglycaemia-induced brain malformations in a diabetes mouse model
DOE Office of Scientific and Technical Information (OSTI.GOV)
Jin, Ya; Wang, Guang; Han, Sha-Sha
Pregestational diabetes mellitus (PGDM) enhances the risk of fetal neurodevelopmental defects. However, the mechanism of hyperglycaemia-induced neurodevelopmental defects is not fully understood. In this study, several typical neurodevelopmental defects were identified in the streptozotocin-induced diabetes mouse model. The neuron-specific class III beta-tubulin/forkhead box P1-labelled neuronal differentiation was suppressed and glial fibrillary acidic protein-labelled glial cell lineage differentiation was slightly promoted in pregestational diabetes mellitus (PGDM) mice. Various concentrations of glucose did not change the U87 cell viability, but glial cell line-derived neurotrophic factor expression was altered with varying glucose concentrations. Mouse maternal hyperglycaemia significantly increased Tunel{sup +} apoptosis but didmore » not dramatically affect PCNA{sup +} cell proliferation in the process. To determine the cause of increased apoptosis, we determined the SOD activity, the expression of Nrf2 as well as its downstream anti-oxidative factors NQO1 and HO1, and found that all of them significantly increased in PGDM fetal brains compared with controls. However, Nrf2 expression in U87 cells was not significantly changed by different glucose concentrations. In mouse telencephalon, we observed the co-localization of Tuj-1 and Nrf2 expression in neurons, and down-regulating of Nrf2 in SH-SY5Y cells altered the viability of SH-SY5Y cells exposed to high glucose concentrations. Taken together, the data suggest that Nrf2-modulated antioxidant stress plays a crucial role in maternal hyperglycaemia-induced neurodevelopmental defects. - Highlights: • Typical neurodevelopmental defects could be observed in STZ-treated mouse fetuses. • Nrf2 played a crucial role in hyperglycaemia-induced brain malformations. • The effects of hyperglycaemia on neurons and glia cells were not same.« less
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1986-06-01
P.O. Box 2007 3101 E. Alejo Rd. Palm Springs, CA 92262 Telephone: (619) 327-1571 Date Evaluated June 1979 Summary The BABYbird Ventilator, Model 5900...air. Procurement Manufacturer 15 Product and Manufacturer Infant AIRbird Resuscitator Medical Products Oivision/3M P.O. Box 2007 3101 E. Alejo Rd. Palm...Silicone Bag Medical Products Division/3M P.O. Box 20073101 E. Alejo Rd Palm Springs, CA 92262 Telephone: (619) 327-1571 Date Evaluated July 1978 Sumary
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... 0043 Arthritis Foundation P.O. Box 7669 Atlanta GA Atlanta, GA 30357 help@arthritis.org http://www.arthritis.org ... 0043 Arthritis Foundation P.O. Box 7669 Atlanta GA Atlanta, GA 30357 help@arthritis.org http://www. ...
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Baehr, Leslie M.; West, Daniel W. D.; Marshall, Andrea G.; Marcotte, George R.; Baar, Keith
2017-01-01
Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (−9 to −38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. NEW & NOTEWORTHY In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy. PMID:28336537
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Cho, John E.; Fournier, Mario; Da, Xiaoyu
2010-01-01
Increased expression of forkhead box O (Foxo) transcription factors were reported in cultured myotubes and mouse limb muscle with corticosteroid (CS) treatment. We previously reported that administration of CS to rats resulted in muscle fiber atrophy only by day 7. The aim of this study, therefore, was to evaluate the time-course changes in the expression of Foxo transcription factors and muscle-specific ubiquitin E3 ligases in rat limb muscle following CS administration. Triamcinolone (TRI; 1 mg · kg−1 · day−1 im) was administered for 1, 3, or 7 days. Control (CTL) rats were given saline. Muscle mRNA was analyzed by real-time RT-PCR. Compared with CTL, body weights of TRI-treated animals decreased by 3, 12, and 21% at days 1, 3, and 7, respectively. Muscle IGF-1 mRNA levels decreased by 33, 65, and 58% at days 1, 3, and 7 in TRI-treated rats compared with CTL. Levels of phosphorylated Akt were 28, 50, and 36% lower in TRI animals at these time points. Foxo1 mRNA increased progressively by 1.2-, 1.4-, and 2.5-fold at days 1, 3, and 7 in TRI animals. Similar changes were noted in the expression of Foxo3a mRNA (1.3-, 1.4-, and 2.6-fold increments). By contrast, Foxo4 mRNA was not significantly changed in TRI animals. With TRI, muscle atrophy F box/Atrogin-1 increased by 1.8-, 4.1-, and 7.5-fold at days 1, 3, and 7 compared with CTL rats. By contrast, muscle RING finger 1 increased only from day 7 (2.7-fold). Gradual reduction in IGF-I expression with TRI over the time series paralleled that of Akt. These findings are consistent with a progressive stimulus to muscle protein degradation and the need to process/remove disassembled muscle proteins via the ubiquitin-proteasome system. Elucidating the dynamic catabolic responses to CS challenge is important in understanding the mechanisms underlying muscle atrophy and therapeutic measures to offset this. PMID:19850732
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... Aicardi Syndrome Foundation P.O. Box 3202 St. Charles IL St. Charles, IL 60174 web@aicardisyndrome.org http://www.aicardisyndrome. ... Aicardi Syndrome Foundation P.O. Box 3202 St. Charles IL St. Charles, IL 60174 web@aicardisyndrome.org ...
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Virant-Klun, Irma; Stimpfel, Martin
2016-01-01
Small stem cells with diameters of up to 5 μm previously isolated from adult human ovaries indicated pluripotency and germinal lineage, especially primordial germ cells, and developed into primitive oocyte-like cells in vitro. Here, we show that a comparable population of small stem cells can be found in the ovarian tissue of women with borderline ovarian cancer, which, in contrast to small stem cells in “healthy” ovaries, formed spontaneous tumour-like structures and expressed some markers related to pluripotency and germinal lineage. The gene expression profile of these small putative cancer stem cells differed from similar cells sorted from “healthy” ovaries by 132 upregulated and 97 downregulated genes, including some important forkhead box and homeobox genes related to transcription regulation, developmental processes, embryogenesis, and ovarian cancer. These putative cancer stem cells are suggested to be a novel population of ovarian tumour-initiating cells in humans. PMID:27703207
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Sheikine, Yuri; Woda, Craig B; Lee, Pui Y; Chatila, Talal A; Keles, Sevgi; Charbonnier, Louis-Marie; Schmidt, Birgitta; Rosen, Seymour; Rodig, Nancy M
2015-07-01
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder is an autoimmune disease caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor. These mutations affect the normal function of circulating regulatory T cells. IPEX is characterized by profound immune dysregulation leading to dermatitis, enteropathy, multiple endocrinopathies and failure to thrive. Different forms of renal injury have also been noted in these patients but these have been described to a very limited extent. Three patients with IPEX with characteristic renal findings and mutations in FOXP3, including one novel mutation, are described. Case presentations are followed by a review of the renal manifestations noted in IPEX and the range of therapeutic options for this disorder. We recommend that IPEX be considered in the differential diagnosis of young children who present with signs of immune dysregulation with a concomitant renal biopsy demonstrating immune complex deposition in a membranous-like pattern and/or interstitial nephritis.
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Regulatory T-cell stability and plasticity in mucosal and systemic immune systems.
Murai, M; Krause, P; Cheroutre, H; Kronenberg, M
2010-09-01
Regulatory T cells (Treg) express the forkhead box p3 (Foxp3) transcription factor and suppress pathological immune responses against self and foreign antigens, including commensal microorganisms. Foxp3 has been proposed as a master key regulator for Treg, required for their differentiation, maintenance, and suppressive functions. Two types of Treg have been defined. Natural Treg (nTreg) are usually considered to be a separate sublineage arising during thymus differentiation. Induced Treg (iTreg) originate upon T cell receptor (TCR) stimulation in the presence of tumor growth factor beta. Although under homeostatic conditions most Treg in the periphery are nTreg, special immune challenges in the intestine promote more frequently the generation of iTreg. Furthermore, recent observations have challenged the notion that Treg are a stable sublineage, and they suggest that, particularly under lymphopenic and/or inflammatory conditions, Treg may lose Foxp3 and/or acquire diverse effector functions, especially in the intestine, which may contribute to uncontrolled inflammation.
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Functional defect in regulatory T cells in myasthenia gravis
Thiruppathi, Muthusamy; Rowin, Julie; Jiang, Qin Li; Sheng, Jian Rong; Prabhakar, Bellur S.; Meriggioli, Matthew N.
2012-01-01
Forkhead box P3 (FOXP3)+ is a transcription factor necessary for the function of regulatory T cells (Treg cells). Treg cells maintain immune homeostasis and self-tolerance, and play an important role in the prevention of autoimmune disease. Here, we discuss the role of Treg cells in the pathogenesis of myasthenia gravis (MG) and review evidence indicating that a significant defect in Treg cell in vitro suppressive function exists in MG patients, without an alteration in circulating frequency. This functional defect is associated with a reduced expression of key functional molecules such as FOXP3 on isolated Treg cells and appears to be more pronounced in immunosuppression-naive MG patients. In vitro administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced the suppressive function of Treg cells and up-regulated FOXP3 expression. These findings indicate a clinically relevant Treg cell–intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target. PMID:23252899
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[Molecular genetics of functional articulation disorder in children].
Zhao, Yun-Jing; Ma, Hong-Wei
2012-04-01
Genetic factors are an important cause of functional articulation disorder in children. This article reviews some genes and chromosome regions associated with a genetic susceptibility to functional articulation disorders. The forkhead box P2 (FOXP2) gene on chromosome 7 is introduced in details including its structure, expression and function. The relationship between the FOXP2 gene and developmental apraxia of speech is discussed. As a transcription factor, FOXP2 gene regulates the expression of many genes. CNTNAP2 as an important target gene of FOXP2 is a key gene influencing language development. Functional articulation disorder may be developed to dyslexia, therefore some candidate regions and genes related to dyslexia, such as 3p12-13, 15q11-21, 6p22 and 1p34-36, are also introduced. ROBO1 gene in 3p12.3, ZNF280D gene, TCF12 gene, EKN1 gene in 15q21, and KIAA0319 gene in 6p22 have been candidate genes for the study of functional articulation disorder.
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Boyle, N K; Pitts-Singer, T L
2017-01-01
The blue orchard bee, Osmia lignaria (Say), is a solitary bee that is an excellent pollinator of tree fruit orchards. Due to the annual rising costs of honey bee hive rentals, many orchardists are eager to develop management tools and practices to support O. lignaria as an alternative pollinator. Establishing O. lignaria pollination as a sustainable industry requires careful consideration of both bee and orchard management. Here, we test the effect of artificial nest box distribution on in-orchard propagation of O. lignaria in Utah commercial tart cherry orchards. Two nest box distributions were compared across three paired, 1.2-ha plots. One distribution, traditionally employed by O. lignaria consultants, included a centrally located tote for mass-nesting with smaller, surrounding 'satellite' nest boxes at orchard margins. The other distribution was composed of smaller, more equally distributed nest boxes throughout the 1.2-ha plots. Significantly higher propagation of O. lignaria was observed in the latter nest box distribution, although all treatments resulted in bee return exceeding the number of bees initially released. These findings provide support for the use of O. lignaria in tart cherry orchards, and demonstrate how simple changes to bee set-up and management can influence propagation efforts. Published by Oxford University Press on behalf of the Entomological Society of America 2017. This work is written by US Government employees and is in the public domain in the US.
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7 CFR Appendix A to Part 661 - Availability of Information
Code of Federal Regulations, 2010 CFR
2010-01-01
... Conservation Service, State Office Location State Conservationist, Wright Building, 138 South Gay St., P.O. Box..., Ariz. 85025. State Conservationist, Federal Bldg., Room 5029, 700 West Capitol St., P.O. Box 2323... Towers, Suite 2-4, 9 East Loockerman St., Dover, Del. 19901. State Conservationist, Federal Bldg., P.O...
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77 FR 39159 - Airworthiness Directives; Empresa Brasileria de Aeronáutica S.A. (EMBRAER) Airplanes
Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-02
... Lima, 2170, S[atilde]o Jos[eacute] dos Campos--SP, CEP: 12227-901--PO Box 36/2, BRASIL; fax ++55 12.... Brigadeiro Faria Lima, 2170, S[atilde]o Jos[eacute] dos Campos--SP, CEP: 12227-901--P.O. Box 36/2, BRASIL...
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de Lira, Claudio Andre Barbosa; Peixinho-Pena, Luiz Fernando; Vancini, Rodrigo Luiz; de Freitas Guina Fachina, Rafael Júlio; de Almeida, Alexandre Aparecido; Andrade, Marília dos Santos; da Silva, Antonio Carlos
2013-01-01
The present study aimed to describe heart rate (HR) responses during a simulated Olympic boxing match and examine physiological parameters of boxing athletes. Ten highly trained Olympic boxing athletes (six men and four women) performed a maximal graded exercise test on a motorized treadmill to determine maximal oxygen uptake (52.2 mL · kg−1 · min−1 ± 7.2 mL · kg−1 · min−1) and ventilatory thresholds 1 and 2. Ventilatory thresholds 1 and 2 were used to classify the intensity of exercise based on respective HR during a boxing match. In addition, oxygen uptake (V̇O2) was estimated during the match based on the HR response and the HR-V̇O2 relationship obtained from a maximal graded exercise test for each participant. On a separate day, participants performed a boxing match lasting three rounds, 2 minutes each, with a 1-minute recovery period between each round, during which HR was measured. In this context, HR and V̇O2 were above ventilatory threshold 2 during 219.8 seconds ± 67.4 seconds. There was an increase in HR and V̇O2 as a function of round (round 3 < round 2 < round 1, P < 0.0001). These findings may direct individual training programs for boxing practitioners and other athletes. PMID:24379723
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de Lira, Claudio Andre Barbosa; Peixinho-Pena, Luiz Fernando; Vancini, Rodrigo Luiz; de Freitas Guina Fachina, Rafael Júlio; de Almeida, Alexandre Aparecido; Andrade, Marília Dos Santos; da Silva, Antonio Carlos
2013-01-01
The present study aimed to describe heart rate (HR) responses during a simulated Olympic boxing match and examine physiological parameters of boxing athletes. Ten highly trained Olympic boxing athletes (six men and four women) performed a maximal graded exercise test on a motorized treadmill to determine maximal oxygen uptake (52.2 mL · kg(-1) · min(-1) ± 7.2 mL · kg(-1) · min(-1)) and ventilatory thresholds 1 and 2. Ventilatory thresholds 1 and 2 were used to classify the intensity of exercise based on respective HR during a boxing match. In addition, oxygen uptake (V̇O2) was estimated during the match based on the HR response and the HR-V̇O2 relationship obtained from a maximal graded exercise test for each participant. On a separate day, participants performed a boxing match lasting three rounds, 2 minutes each, with a 1-minute recovery period between each round, during which HR was measured. In this context, HR and V̇O2 were above ventilatory threshold 2 during 219.8 seconds ± 67.4 seconds. There was an increase in HR and V̇O2 as a function of round (round 3 < round 2 < round 1, P < 0.0001). These findings may direct individual training programs for boxing practitioners and other athletes.
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Effect of betaine on hepatic insulin resistance through FOXO1-induced NLRP3 inflammasome.
Kim, Dae Hyun; Kim, Seong Min; Lee, Bonggi; Lee, Eun Kyeong; Chung, Ki Wung; Moon, Kyoung Mi; An, Hye Jin; Kim, Kyung Mok; Yu, Byung Pal; Chung, Hae Young
2017-07-01
In the present study, we attempted to elucidate whether molecular modulation of inflammation by betaine through the forkhead box O1 (FOXO1)-induced NLRP3 inflammasome improves insulin resistance. Betaine is a major water-soluble component of Lycium chinense. It mainly functions as an oxidative metabolite of choline by suppressing superoxide-induced free radicals by donating methyl groups. The FOXO1 transcription factor regulates various genes involved in cellular metabolic processes related to cell death as well as oxidative stress responses through binding to the thioredoxin-interacting protein (TXNIP). Betaine is known to inhibit FOXO1 phosphorylation through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) in liver cells exposed to insulin. To elucidate the molecular mechanism of inactivation of insulin-induced FOXO1 by the antioxidant betaine, we used HepG2 cells and the liver of db/db mice treated with betaine at a dose of 50 mg/kg/day for 3 weeks. We found that the activation of NLRP3 inflammasome genes was reduced by betaine, which resulted in the suppression of reactive species (RS) production in liver cells. In addition, betaine inhibited insulin-induced PI3K/AKT and FOXO1 activation. Therefore, betaine suppressed the cytokine interleukin-1β production by inhibiting the activation of the NLRP3 inflammasome via interaction of FOXO1 and TXNIP. Our results suggest that betaine inhibits the FOXO1 binding to TXNIP, leading to the suppression of RS-induced NLRP3 inflammasome activation in a diabetic liver. Copyright © 2017 Elsevier Inc. All rights reserved.
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Lu, Tong; Chai, Qiang; Yu, Ling; d’Uscio, Livius V.; Katusic, Zvonimir S.; He, Tongrong; Lee, Hon-Chi
2012-01-01
Activity of the vascular large conductance Ca2+-activated K+ (BK) channel is tightly regulated by its accessory β1 subunit (BK-β1). Downregulation of BK-β1 expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)–dependent F-box–only protein (FBXO) expression. However, the upstream signaling regulating this process is unclear. Overproduction of reactive oxygen species (ROS) is a common finding in diabetic vasculopathy. We hypothesized that ROS signaling cascade facilitates the FOXO-3a/FBXO-mediated BK-β1 degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-β1 expression in streptozotocin (STZ)-induced diabetic mouse arteries and in human coronary smooth muscle cells (SMCs) cultured with high glucose was attributable to an increase in protein kinase C (PKC)-β and NADPH oxidase expressions and accompanied by attenuation of Akt phosphorylation and augmentation of atrogin-1 expression. Treatment with ruboxistaurin (a PKCβ inhibitor) or with GW501516 (a peroxisome proliferator–activated receptor δ activator) reduced atrogin-1 expression and restored BK channel-mediated coronary vasodilation in diabetic mice. Our results suggested that oxidative stress inhibited Akt signaling and facilitated the FOXO-3a/FBXO-dependent BK-β1 degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-β1 degradation and protected coronary function in diabetes. PMID:22586590
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Pauli, José R.; Cintra, Dennys E.; de Souza, Claudio T.; Ropelle, Eduardo R.; R. da Silva, Adelino S.
2015-01-01
The purpose of this study was to verify the effects of overtraining (OT) on insulin, inflammatory and gluconeogenesis signaling pathways in the livers of mice. Rodents were divided into control (CT), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR). Rotarod, incremental load, exhaustive and grip force tests were used to evaluate performance. Thirty-six hours after a grip force test, the livers were extracted for subsequent protein analyses. The phosphorylation of insulin receptor beta (pIRbeta), glycogen synthase kinase 3 beta (pGSK3beta) and forkhead box O1 (pFoxo1) increased in OTR/down versus CT. pGSK3beta was higher in OTR/up versus CT, and pFoxo1 was higher in OTR/up and OTR versus CT. Phosphorylation of protein kinase B (pAkt) and insulin receptor substrate 1 (pIRS–1) were higher in OTR/up versus CT and OTR/down. The phosphorylation of IκB kinase alpha and beta (pIKKalpha/beta) was higher in all OT protocols versus CT, and the phosphorylation of stress-activated protein kinases/Jun amino-terminal kinases (pSAPK-JNK) was higher in OTR/down versus CT. Protein levels of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) and hepatocyte nuclear factor 4alpha (HNF-4alpha) were higher in OTR versus CT. In summary, OTR/down improved the major proteins of insulin signaling pathway but up-regulated TRB3, an Akt inhibitor, and its association with Akt. PMID:26445495
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Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease
Souza-Mello, Vanessa
2015-01-01
Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs. PMID:26052390
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Wang, Ning; Zhang, Jiahui; Qin, Mengting; Yi, Wenjing; Yu, Shuang; Chen, Yi; Guan, Jing; Zhang, Rui
2018-03-01
Pancreatic β cells are sensitive to oxidative stress, which is one of the predominant causes of cell damage and the emergence of diabetes. The identification of effective therapeutic strategies to protect pancreatic cells from oxidative stress has increased interest in the screening of antioxidants from natural products. The present study aimed to investigate the protective effects of morin against streptozotocin (STZ)‑induced cell damage in a rat insulinoma cell line (RINm5F pancreatic β cells) and to identify the underlying mechanisms. The results indicated that morin inhibited the increase in intracellular reactive oxygen species, attenuated the activity of poly (ADP‑ribose) polymerase, restored intracellular nicotinamide adenine dinucleotide levels and reduced the apoptotic cell death of STZ‑treated pancreatic β cells. Treatment with morin significantly upregulated catalase in pancreatic β cells, and ameliorated the STZ‑induced loss of catalase at the genetic, protein and enzymatic level. In further experiments, morin induced the phosphorylation of 5' adenosine monophosphate‑activated protein kinase (AMPK), which subsequently promoted the translocation of forkhead box O3 (FOXO3) to the nucleus. Specific small interfering RNAs (siRNAs) against AMPK and FOXO3 suppressed morin‑induced catalase expression. Furthermore, catalase‑specific siRNA abolished the protective effects of morin against STZ‑stimulated cell death. Taken together, these results indicated that morin protected RINm5F cells from STZ‑induced cell damage by triggering the phosphorylation of AMPK, thus resulting in subsequent activation of FOXO3 and induction of catalase.
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MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4.
Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan
2015-03-27
Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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Chung, Ki Wung; Choi, Yeon Ja; Park, Min Hi; Jang, Eun Ji; Kim, Dae Hyun; Park, Byung Hyun; Yu, Byung Pal; Chung, Hae Young
2015-08-01
Stresses, such as exposure to ultraviolet radiation and those associated with aging, are known to cause premature cellular senescence that is characterized by growth arrest and morphological and gene expression changes. This study was designed to investigate the protective effect of Sirtuin1 (SIRT1) on the UVB-induced premature senescence. Under in vitro experimental conditions, exposure to a subcytotoxic dose of UVB enhanced human skin fibroblasts senescence, as characterized by increased β-galactosidase activity and increased levels of senescence-associated proteins. However, adenovirus-mediated SIRT1 overexpression significantly protected fibroblasts from UVB-induced cellular deterioration. Exposure to UVB-induced cell senescence was associated with oxidative stress and p38 mitogen-activated protein kinase activation. Molecular analysis demonstrated that deacetylation of Forkhead box O3α (FOXO3α) by SIRT1 changed the transcriptional activity of FOXO3α and increased resistance to the oxidative stress. In addition, SIRT1 suppressed UVB-induced p53 acetylation and its transcriptional activity, which directly affected the cell cycle arrest induced by UVB. Further study demonstrated that SIRT1 activation inhibited cell senescence in the skin of the HR1 hairless mouse exposed to UVB. The study identifies a new role for SIRT1 in the UVB-induced senescence of skin fibroblats and provides a potential target for skin protection through molecuar insights into the mechanisms responsible for UVB-induced photoaging. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Wang, Hai-Lian; Li, Chun-Yang; Zhang, Bin; Liu, Yuan-De; Lu, Bang-Min; Shi, Zheng; An, Na; Zhao, Liang-Kai; Zhang, Jing-Jing; Bao, Jin-Ku; Wang, Yi
2014-01-01
Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of β-cells in mice following 70% partial pancreatectomy (PPx), and to explore the mechanisms of mangiferin-induced β-cell proliferation. For this purpose, adult C57BL/6J mice after 7–14 days post-PPx, or a sham operation were subjected to mangiferin (30 and 90 mg/kg body weight) or control solvent injection. Mangiferin-treated mice exhibited an improved glycemia and glucose tolerance, increased serum insulin levels, enhanced β-cell hyperplasia, elevated β-cell proliferation and reduced β-cell apoptosis. Further dissection at the molecular level showed several key regulators of cell cycle, such as cyclin D1, D2 and cyclin-dependent kinase 4 (Cdk4) were significantly up-regulated in mangiferin-treated mice. In addition, critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (Ngn3), glucose transporter 2 (GLUT-2), Forkhead box protein O1 (Foxo-1), and glucokinase (GCK), were found to be promoted by mangiferin at both the mRNA and protein expression level. Thus, mangiferin administration markedly facilitates β-cell proliferation and islet regeneration, likely by regulating essential genes in the cell cycle and the process of islet regeneration. These effects therefore suggest that mangiferin bears a therapeutic potential in preventing and/or treating the diabetes. PMID:24853132
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Wang, Hai-Lian; Li, Chun-Yang; Zhang, Bin; Liu, Yuan-De; Lu, Bang-Min; Shi, Zheng; An, Na; Zhao, Liang-Kai; Zhang, Jing-Jing; Bao, Jin-Ku; Wang, Yi
2014-05-20
Mangiferin, a xanthonoid found in plants including mangoes and iris unguicularis, was suggested in previous studies to have anti-hyperglycemic function, though the underlying mechanisms are largely unknown. This study was designed to determine the therapeutic effect of mangiferin by the regeneration of β-cells in mice following 70% partial pancreatectomy (PPx), and to explore the mechanisms of mangiferin-induced β-cell proliferation. For this purpose, adult C57BL/6J mice after 7-14 days post-PPx, or a sham operation were subjected to mangiferin (30 and 90 mg/kg body weight) or control solvent injection. Mangiferin-treated mice exhibited an improved glycemia and glucose tolerance, increased serum insulin levels, enhanced β-cell hyperplasia, elevated β-cell proliferation and reduced β-cell apoptosis. Further dissection at the molecular level showed several key regulators of cell cycle, such as cyclin D1, D2 and cyclin-dependent kinase 4 (Cdk4) were significantly up-regulated in mangiferin-treated mice. In addition, critical genes related to β-cell regeneration, such as pancreatic and duodenal homeobox 1 (PDX-1), neurogenin 3 (Ngn3), glucose transporter 2 (GLUT-2), Forkhead box protein O1 (Foxo-1), and glucokinase (GCK), were found to be promoted by mangiferin at both the mRNA and protein expression level. Thus, mangiferin administration markedly facilitates β-cell proliferation and islet regeneration, likely by regulating essential genes in the cell cycle and the process of islet regeneration. These effects therefore suggest that mangiferin bears a therapeutic potential in preventing and/or treating the diabetes.
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Yang, Ye; Bao, Wei; Sang, Zhengyu; Yang, Yongbing; Lu, Meng; Xi, Xiaowei
2018-01-01
Mutations in the gene encoding AT-rich interactive domain 1A (ARID1A) are frequently observed in endometrial cancer (EC) but the molecular mechanisms linking the genetic changes remain to be fully understood. The present study aimed to elucidate the influence of ARID1A mutations on signaling pathways. Missense, synonymous and nonsense heterozygous ARID1A mutations in the EC HEC-1-A cell line were verified by Sanger sequencing. Mutated ARID1A small interfering RNA was transfected into HEC-1-A cells. Biochemical microarray analysis revealed 13 upregulated pathways, 17 downregulated pathways, 14 significantly affected disease states and functions, 662 upstream and 512 downstream genes in mutated ARID1A-depleted HEC-1-A cells, among which the mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin-like growth factor-1 (IGF1) signaling pathways were the 2 most downregulated pathways. Furthermore, the forkhead box protein O1 pathway was upregulated, while the IGF1 receptor, insulin receptor substrate 1 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit b pathways were downregulated. Carcinoma tumorigenesis, tumor cell mitosis and tumor cell death were significantly upregulated disease states and functions, while cell proliferation and tumor growth were significantly downregulated. The results of the present study suggested that ARID1A may be a potential prognostic and therapeutic molecular drug target for the prevention of EC progression. PMID:29399196
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-26
..., Line 1: Replaced ``Street/RFD , P.O. Box, or URB'' with ``(Street/RFD , URB, or P.O. Box, Apt/Unit, In Care Of or Attn (e.g., In Care Of--Jane Doe, Apt 100))''. [cir] Mailing Address, Address Line 2... applicable. (e.g., In Care Of--Jane Doe, Apt 100)'' with ``(If applicable)''. In the photograph box, the...
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1992-03-01
Oty_ Population City Population San Jose 782,248 Santa Clara 92,090 San Francisco 763,800 Daly City 91,209 Oakland 372,000 San Mateo 84,829...Oakland Tribune P.O. Box 24424 Oakland, CA 94623 (415) 645-2000/2771 DAILY NEWSPAPERS (cont’d) Editor San Jose Mercury-News P.O. Box 5533 750 Ridder...Park Drive San Jose , CA 95190 (408) 920-5000/288-8060 Editor San Mateo Times P.O. Box 5400 1080 S. Amphlett San Mateo, CA 94402 (415) 348
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Ozone-induced gene expression occurs via ethylene-dependent and -independent signalling.
Grimmig, Bernhard; Gonzalez-Perez, Maria N; Leubner-Metzger, Gerhard; Vögeli-Lange, Regina; Meins, Fred; Hain, Rüdiger; Penuelas, Josep; Heidenreich, Bernd; Langebartels, Christian; Ernst, Dieter; Sandermann, Heinrich
2003-03-01
Recent studies suggest that ethylene is involved in signalling ozone-induced gene expression. We show here that application of ozone increased glucuronidase (GUS) expression of chimeric reporter genes regulated by the promoters of the tobacco class I beta-1,3-glucanases (GLB and Gln2) and the grapevine resveratrol synthase (Vst1) genes in transgenic tobacco leaves. 5'-deletion analysis of the class I beta-1,3-glucanase promoter revealed that ozone-induced gene regulation is mainly mediated by the distal enhancer region containing the positively acting ethylene-responsive element (ERE). In addition, application of 1-methylcyclopropene (1-MCP), an inhibitor of ethylene action, blocked ozone-induced class I beta-1,3-glucanase promoter activity. Enhancer activity and ethylene-responsiveness depended on the integrity of the GCC boxes, cis-acting elements present in the ERE of the class I beta-1,3-glucanase and the basic-type pathogenesis-related PR-1 protein (PRB-1b) gene promoters. The minimal PRB-1b promoter containing only the ERE with intact GCC boxes, was sufficient to confer 10-fold ozone inducibility to a GUS-reporter gene, while a substitution mutation in the GCC box abolished ozone responsiveness. The ERE region of the class I beta-1,3-glucanase promoter containing two intact GCC boxes confered strong ozone inducibility to a minimal cauliflower mosaic virus (CaMV) 35S RNA promoter, whereas two single-base substitution in the GCC boxes resulted in a complete loss of ozone inducibility. Taken together, these datastrongly suggest that ethylene is signalling ozone-induced expression of class I beta-l,3-glucanase and PRB-1b genes. Promoter analysis of the stilbene synthase Vst1 gene unravelled different regions for ozone and ethylene-responsiveness. Application of 1-MCP blocked ethylene-induced Vst1 induction, but ozone induction was not affected. This shows that ozone-induced gene expression occurs via at least two different signalling mechanisms and suggests an additional ethylene independent signalling pathway for ozone-induced expression of genes involved in phytoalexin biosynthesis.
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-09-02
... CONTACT: The Bison Ecology and Management Office, Yellowstone National Park, P.O. Box 168, Yellowstone... comments to the Bison Ecology and Management Office, Center for Resources, P.O. Box 168, Yellowstone...
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-09-26
...: Valent U.S.A. Corporation, P.O. Box 8025, Walnut Creek, CA 94596. Active ingredient: Clothianidin..., P.O. Box 8025, Walnut Creek, CA 94596. Active ingredient: Clothianidin. Product Type: Insecticide...
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ERIC Educational Resources Information Center
Science Teacher, 1988
1988-01-01
Reviews two computer software packages for use in physical science, physics, and chemistry classes. Includes "Physics of Model Rocketry" for Apple II, and "Black Box" for Apple II and IBM compatible computers. "Black Box" is designed to help students understand the concept of indirect evidence. (CW)
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7 CFR Appendix A to Part 661 - Availability of Information
Code of Federal Regulations, 2011 CFR
2011-01-01
... Towers, Suite 2-4, 9 East Loockerman St., Dover, Del. 19901. State Conservationist, Federal Bldg., P.O... Conservationist, Federal Bldg., Durham, N.H. 03824. State Conservationist, 1370 Hamilton St., P.O. Box 219...., 310 New Bern Ave., Fifth Floor-P.O. Box 27307, Raleigh, N.C. 27611. State Conservationist, Federal...
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Dissecting signalling by individual Akt/PKB isoforms, three steps at once.
Osorio-Fuentealba, Cesar; Klip, Amira
2015-09-01
The serine/threonine kinase Akt/PKB (protein kinase B) is key for mammalian cell growth, survival, metabolism and oncogenic transformation. The diverse level and tissue expression of its three isoforms, Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ, make it daunting to identify isoform-specific actions in vivo and even in isolated tissues/cells. To date, isoform-specific knockout and knockdown have been the best strategies to dissect their individual overall functions. In a recent article in the Biochemical Journal, Kajno et al. reported a new strategy to study isoform selectivity in cell lines. Individual Akt/PKB isoforms in 3T3-L1 pre-adipocytes are first silenced via shRNA and stable cellular clones lacking one or the other isoform are selected. The stably silenced isoform is then replaced by a mutant engineered to be refractory to inhibition by MK-2206 (Akt1(W80A) or Akt2(W80A)). Akt1(W80A) or Akt2(W80A) are functional and effectively recruited to the plasma membrane in response to insulin. The system affords the opportunity to acutely control the activity of the endogenous non-silenced isoform through timely addition of MK-2206. Using this approach, it is confirmed that Akt1/PKBα is the preferred isoform sustaining adipocyte differentiation, but both Akt1/PKBα and Akt2/PKBβ can indistinctly support insulin-dependent FoxO1 (forkhead box O1) nuclear exclusion. Surprisingly, either isoform can also support insulin-dependent glucose transporter (GLUT) 4 translocation to the membrane, in contrast with the preferential role of Akt2/PKBβ assessed by knockdown studies. The new strategy should allow analysis of the plurality of Akt/PKB functions in other cells and in response to other stimuli. It should also be amenable to high-throughput studies to speed up advances in signal transmission by this pivotal kinase. © 2015 Authors; published by Portland Press Limited.
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Rorato, Rodrigo; Borges, Beatriz de Carvalho; Uchoa, Ernane Torres; Antunes-Rodrigues, José; Elias, Carol Fuzeti; Elias, Lucila Leico Kagohara
2017-07-04
Metabolic endotoxemia contributes to low-grade inflammation in obesity, which causes insulin resistance due to the activation of intracellular proinflammatory pathways, such as the c-Jun N-terminal Kinase (JNK) cascade in the hypothalamus and other tissues. However, it remains unclear whether the proinflammatory process precedes insulin resistance or it appears because of the development of obesity. Hypothalamic low-grade inflammation was induced by prolonged lipopolysaccharide (LPS) exposure to investigate if central insulin resistance is induced by an inflammatory stimulus regardless of obesity. Male Wistar rats were treated with single (1 LPS) or repeated injections (6 LPS) of LPS (100 μg/kg, IP) to evaluate the phosphorylation of the insulin receptor substrate-1 (IRS1), Protein kinase B (AKT), and JNK in the hypothalamus. Single LPS increased the expression of pIRS1, pAKT, and pJNK, whereas the repeated LPS treatment failed to recruit pIRS1 and pAKT. The 6 LPS treated rats showed increased total JNK and pJNK. The 6 LPS rats became unresponsive to the hypophagic effect induced by central insulin administration (12 μM/5 μL, ICV). Prolonged exposure to LPS (24 h) impaired the insulin-induced AKT phosphorylation and the translocation of the transcription factor forkhead box protein O1 (FoxO1) from the nucleus to the cytoplasm of the cultured hypothalamic GT1-7 cells. Central administration of the JNK inhibitor (20 μM/5 μL, ICV) restored the ability of insulin to phosphorylate IRS1 and AKT in 6 LPS rats. The present data suggest that an increased JNK activity in the hypothalamus underlies the development of insulin resistance during prolonged exposure to endotoxins. Our study reveals that weight gain is not mandatory for the development of hypothalamic insulin resistance and the blockade of proinflammatory pathways could be useful for restoring the insulin signaling during prolonged low-grade inflammation as seen in obesity.
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Song, Chao; Zhao, Jiamin; Fu, Beibei; Li, Dan; Mao, Tingchao; Peng, Wei; Wu, Haibo; Zhang, Yong
2017-11-01
Mitochondrial reactive oxygen species (ROS) production has been implicated in the pathogenesis of fluoride toxicity in liver. Melatonin, an indolamine synthesized in the pineal gland, was previously shown to protect against sodium fluoride (NaF)-induced hepatotoxicity. This study investigated the protective effects of melatonin pretreatment on NaF-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Reducing mitochondrial ROS by melatonin substantially attenuated NaF-induced NADPH oxidase 4 (Nox4) upregulation and cytotoxicity in L-02 cells. Melatonin exerted its hepatoprotective effects by upregulating Sirtuin 3 (Sirt3) expression level and its activity. Melatonin increased the activity of manganese superoxide dismutase (SOD2) by promoting Sirt3-mediated deacetylation and promoted SOD2 expression through Sirt3-regulated DNA-binding activity of forkhead box O3 (FoxO3a), thus inhibiting the production of mitochondrial ROS induced by NaF. Notably, increased peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) by melatonin activated the Sirt3 expression, which was regulated by an estrogen-related receptor (ERR) binding element (ERRE) mapped to Sirt3 promoter region. Analysis of the cell signaling pathway profiling systems and specific pathway inhibition indicated that melatonin enhances PGC-1α expression by activating the PI3K/AKT signaling pathway. Importantly, inhibition of melatonin receptor (MT)-1 blocked the melatonin-activated PI3K/AKT-PGC-1α-Sirt3 signaling. Mechanistic study revealed that the protective effects of melatonin were associated with down-regulation of JNK1/2 phosphorylation. Our findings provided a theoretical basis that melatonin mitigated NaF-induced hepatotoxicity, which, in part, was mediated through the activation of the Sirt3 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.
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Oxidative stress reduces trophoblast FOXO1 and integrin β3 expression that inhibits cell motility.
Chen, Chie-Pein; Chen, Cheng-Yi; Wu, Yi-Hsin; Chen, Chia-Yu
2018-06-08
Preeclampsia is a serious pregnancy complication associated with placental oxidative stress and impaired trophoblast migration. The mechanism of defective trophoblast migration remains unknown. Forkhead box O1 (FOXO1) is a transcription factor. Integrin β3 is involved in cell motility. We hypothesized that FOXO1 mediates expression of trophoblast integrin β3, which could be impaired by oxidative stress and have implications in preeclampsia. The expressions of FOXO1 and integrin β3 were significantly reduced in preeclamptic placentas (n = 15) compared to that of controls (n = 15; p < 0.01). HTR-8/SVneo and JEG-3 trophoblasts were transfected to express wild-type FOXO1-WT or constitutively-expressed nuclear mutant form, FOXO1-AAA. The FOXO1 in HTR-8/SVneo and 3A-Sub-E trophoblasts was silenced by small interfering RNA. AKT-mediated phosphorylation inactivated FOXO1, but FOXO1-AAA was not phosphorylated. The expression of trophoblast integrin β3 was significantly elevated by FOXO1 overexpression and inhibited by FOXO1 knockdown. FOXO1 regulates integrin β3 at the transcriptional level via binding to the putative FOXO1 response element site between position -1154 to -1139 (TGAGATGTTTTGAAAG) in HTR-8/SVneo trophoblasts. The level of phosphorylated FOXO1 was decreased, and the FOXO1 level was increased in trophoblasts treated with AKT inhibitor MK2206, leading to upregulation of integrin β3. The capabilities of trophoblast adhesion and migration were enhanced by FOXO1-overexpression or MK2206, and inhibited by silencing FOXO1 or oxidative stress with H 2 O 2 . These results suggest that FOXO1 enhances trophoblast integrin β3 expression, and mediates cell adhesion and migration. By affecting the expression of FOXO1 and cell motility in trophoblasts, oxidative stress plays a role in the development of preeclampsia. Copyright © 2018 Elsevier Inc. All rights reserved.
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47 CFR 1.1156 - Schedule of regulatory fees and filing locations for international services.
Code of Federal Regulations, 2014 CFR
2014-10-01
... Stations (Geostationary Orbit) $122,400 FCC, International, P.O. Box 979084, St. Louis, MO 63197-9000. Space Stations (Non-Geostationary Orbit) 132,850 FCC, International, P.O. Box 979084, St. Louis, MO...
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47 CFR 1.1156 - Schedule of regulatory fees and filing locations for international services.
Code of Federal Regulations, 2013 CFR
2013-10-01
... Stations (Geostationary Orbit) $139,100 FCC, International, P.O. Box 979084, St. Louis, MO 63197-9000. Space Stations (Non-Geostationary Orbit) 149,875 FCC, International, P.O. Box 979084, St. Louis, MO...
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47 CFR 1.1156 - Schedule of regulatory fees and filing locations for international services.
Code of Federal Regulations, 2012 CFR
2012-10-01
... Stations (Geostationary Orbit) $132,875 FCC, International, P.O. Box 979084, St. Louis, MO 63197-9000. Space Stations (Non-Geostationary Orbit) 143,150 FCC, International, P.O. Box 979084, St. Louis, MO...
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77 FR 14776 - El Paso Natural Gas Company; Notice of Amendment to Presidential Permit
Federal Register 2010, 2011, 2012, 2013, 2014
2012-03-13
... Natural Gas Company (El Paso), P.O. Box 1087, Colorado Springs, Colorado, filed an application in Docket..., Director, Regulatory Affairs, El Paso Western Pipelines, Two North Nevada Avenue, P.O. Box 1087, Colorado...
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75 FR 62515 - El Paso Natural Gas Company; Notice of Application
Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-12
... Paso Natural Gas Company (EPNG), P.O. Box 1087, Colorado Springs, Colorado 80944, filed in the above... Paso Natural Gas Company, P.O. Box 1087, Colorado Springs, Colorado 80944 at (719) 667-7514 or by fax...
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ERIC Educational Resources Information Center
Kurtz, Kevin
1996-01-01
Describes a California elementary school's plan to help teachers develop portfolios for year-end assessments. Teachers toss notes from parents, student work samples, photographs of class activities, lesson materials, and other "artifacts" into cardboard boxes. They help each other sort by four subject categories and develop final…
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OXIDATIVE STRESS: BIOMARKERS AND NOVEL THERAPEUTIC PATHWAYS
Maiese, Kenneth; Chong, Zhao Zhong; Hou, Jinling; Shang, Yan Chen
2010-01-01
Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO) and members of the mammalian forkhead transcription factors of the O class (FoxOs) may offer the greatest promise for new treatment regimens since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. However, biological outcome with EPO and FoxOs may sometimes be both unexpected and undesirable that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as complicated role EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation. PMID:20064603
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Erythropoietin and diabetes mellitus
Maiese, Kenneth
2015-01-01
Erythropoietin (EPO) is a 30.4 kDa growth factor and cytokine that governs cell proliferation, immune modulation, metabolic homeostasis, vascular function, and cytoprotection. EPO is under investigation for the treatment of variety of diseases, but appears especially suited for the treatment of disorders of metabolism that include diabetes mellitus (DM). DM and the complications of this disease impact a significant portion of the global population leading to disability and death with currently limited therapeutic options. In addition to its utility for the treatment of anemia, EPO can improve cardiac function, reduce fatigue, and improve cognition in patients with DM as well as regulate cellular energy metabolism, obesity, tissue repair and regeneration, apoptosis, and autophagy in experimental models of DM. Yet, EPO can have adverse effects that involve the vasculature system and unchecked cellular proliferation. Critical to the cytoprotective capacity and the potential for a positive clinical outcome with EPO are the control of signal transduction pathways that include protein kinase B, the mechanistic target of rapamycin, Wnt signaling, mammalian forkhead transcription factors of the O class, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), and AMP activated protein kinase. Therapeutic strategies that can specifically target and control EPO and its signaling pathways hold great promise for the development of new and effective clinical treatments for DM and the complications of this disorder. PMID:26516410
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Trap style influences wild pig behavior and trapping success
Williams, B.L.; Holtfreter, R.W.; Ditchkoff, S.S.; Grand, J.B.
2011-01-01
Despite the efforts of many natural resource professionals, wild pig (Sus scrofa) populations are expanding in many areas of the world. Although many creative techniques for controlling pig populations are being explored, trapping has been and still is themost commonly usedmethod of population control formany public and private land managers. We conducted an observational study to examine the efficiency of 2 frequently used trap styles: a small, portable box-style trap and a larger, semi-permanent, corral-style trap.We used game cameras to examine patterns of trap entry by wild pigs around each style of trap, and we conducted a trapping session to compare trapping success between trap styles. Adult female and juvenile wild pigs entered both styles of trap more readily than did adult males, and adult males seemed particularly averse to entering box traps. Less than 10% of adult male visits to box traps resulted in entries, easily the least percentage of any class at any style of trap. Adult females entered corral traps approximately 2.2 times more often per visit than box traps and re-entered corral traps >2 times more frequently. Juveniles entered and reentered both box and corral traps at similar rates. Overall (all-class) entry-per-visit rates at corral traps (0.71) were nearly double that of box traps (0.37). Subsequent trapping data supported these preliminary entry data; the capture rate for corral traps was >4 times that of box traps. Our data suggest that corral traps are temporally and economically superior to box traps with respect to efficiency; that is, corral traps effectively trap more pigs per trap night at a lower cost per pig than do box traps. ?? 2011 The Wildlife Society.
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1990-06-01
was used to spike the following items of equipment: 0 powder boxes o steam-heated risers o steam-heated discharge valves o steel pipe o aluminum pipe...expose it to the internal surfaces. For pipe ( aluminum and steel), one end of the pipe section was covered with parafilm wax. Spike solution was added...spike the following items of equipment: "o powder box "o steam-heated riser "o steam-heated discharge valve "O steel pipe "o aluminum pipe Prior to
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76 FR 39068 - Wrangell-Petersburg Resource Advisory Committee
Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-05
... Nolan Center in Wrangell, Alaska. Written comments may be submitted as described under Supplementary... CONTACT: Christopher Savage, Petersburg District Ranger, P.O. Box 1328, Petersburg, Alaska 99833, phone... Christopher Savage, Petersburg District Ranger, P.O. Box 1328, Petersburg, Alaska 99833, or Robert Dalrymple...
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Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-03
... Protection, LLC, P.O. Box 18300, Greensboro, NC 27419- 8300. 9198 The Andersons Lawn Fertilizer Division, Inc., P.O. Box 119, Maumee, OH 43537. 11603 Agan Chemical Manufacturing, Ltd., 3120 Highwoods Blvd., Suite...
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75 FR 57297 - Petitions for Modification of Existing Mandatory Safety Standards
Federal Register 2010, 2011, 2012, 2013, 2014
2010-09-20
.... 15-16663 and Mine No. 24, MSHA I.D. No. 15-19296, Rt. 292, P.O. Box 190, Lovely, Kentucky 41231. All....O. Box 148, Vansant, Virginia 24656 . Mine: No. 10 Mine, MSHA I.D. No. 44-07217, located in...
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... 888-232-6348 In English , en Español CDC National Prevention Information Network (NPIN) P.O. Box 6003 Rockville, MD 20849-6003 E-mail: npin-info@cdc.gov American Sexual Health Association (ASHA) P. O. Box 13827 Research Triangle Park, NC 27709-3827 1-800-783-9877 Sources ...
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Using Data Analysis to Explore Class Enrollment.
ERIC Educational Resources Information Center
Davis, Gretchen
1990-01-01
Describes classroom activities and shows that statistics is a practical tool for solving real problems. Presents a histogram, a stem plot, and a box plot to compare data involving class enrollments. (YP)
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Mizielińska, Małgorzata; Kowalska, Urszula; Jarosz, Michał; Sumińska, Patrycja
2018-01-01
Portions of fresh Baltic cod fillets were packed into cellulose boxes (control samples), which were covered with Methyl Hydroxypropyl Celluloses (MHPC) coating with 2% polylysine. The cellulose boxes had square PE films and were enclosed in MHPC coating containing ZnO nanoparticles. The cod fillets were stored at 5 °C and examined after 72 h and 144 h storage times. Results obtained in this study showed that the textural parameters of the cod fillets increased, with both Springiness and Cohesiveness found greater after 144 h of storage for all analysed packaging materials. The Gumminess of fillets increased after storage, but the lowest increase was noted in cod samples that were stored in boxes containing PE films with ZnO nanoparticles. It was found that water loss from the cod fillets in these boxes was also lowest. The Adhesiveness of the fish samples stored in boxes devoid of active coatings also increased. In contrast to the packaging material devoid of active coatings, the storage of fillets in active coating boxes resulted in a decrease of adhesiveness. Microbial analysis showed that packaging material containing nano-ZnO was found to be more active against mesophilic and psychotropic bacterial cells than the coatings with polylysine after 72 h and 144 h of storage. PMID:29534544
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Mizielińska, Małgorzata; Kowalska, Urszula; Jarosz, Michał; Sumińska, Patrycja
2018-03-12
Portions of fresh Baltic cod fillets were packed into cellulose boxes (control samples), which were covered with Methyl Hydroxypropyl Celluloses (MHPC) coating with 2% polylysine. The cellulose boxes had square PE films and were enclosed in MHPC coating containing ZnO nanoparticles. The cod fillets were stored at 5 °C and examined after 72 h and 144 h storage times. Results obtained in this study showed that the textural parameters of the cod fillets increased, with both Springiness and Cohesiveness found greater after 144 h of storage for all analysed packaging materials. The Gumminess of fillets increased after storage, but the lowest increase was noted in cod samples that were stored in boxes containing PE films with ZnO nanoparticles. It was found that water loss from the cod fillets in these boxes was also lowest. The Adhesiveness of the fish samples stored in boxes devoid of active coatings also increased. In contrast to the packaging material devoid of active coatings, the storage of fillets in active coating boxes resulted in a decrease of adhesiveness. Microbial analysis showed that packaging material containing nano-ZnO was found to be more active against mesophilic and psychotropic bacterial cells than the coatings with polylysine after 72 h and 144 h of storage.
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Mystery Boxes: Helping Children Improve Their Reasoning
ERIC Educational Resources Information Center
Rule, Audrey C.
2007-01-01
This guest editorial describes ways teachers can use guessing games about an unknown item in a "mystery box" to help children improve their abilities to listen to others, recall information, ask purposeful questions, classify items by class, make inferences, synthesize information, and draw conclusions. The author presents information…
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-04-17
... Gatewick Freight & Cargo Services, a/k/a/ Gatewick Aviation Services, G 22 Dubai Airport Free Zone, P.O... Airport Free Zone, P.O. Box 393754, Dubai, United Arab Emirates; and P.O. Box 52404, Dubai, United Arab.... Kerman Aviation, a/k/a GIE Kerman Aviation, 42 Avenue Montaigne 75008, Paris, France. Sirjanco Trading, P...
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50 CFR 679.90 - Allocation, use, and transfer of Amendment 80 QS permits.
Code of Federal Regulations, 2010 CFR
2010-10-01
..., NMFS, P.O. Box 21668, Juneau, AK 99802-1668; (ii) Fax: 907-586-7354; or (iii) Hand delivery or carrier: NMFS, Room 713, 709 West 9th Street, Juneau, AK 99801. (2) Application forms. Application forms are... Administrator, c/o Restricted Access Management Program, NMFS, P.O. Box 21668, Juneau, AK 99802-1668; (ii) Fax...
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50 CFR 679.90 - Allocation, use, and transfer of Amendment 80 QS permits.
Code of Federal Regulations, 2011 CFR
2011-10-01
..., NMFS, P.O. Box 21668, Juneau, AK 99802-1668; (ii) Fax: 907-586-7354; or (iii) Hand delivery or carrier: NMFS, Room 713, 709 West 9th Street, Juneau, AK 99801. (2) Application forms. Application forms are... Administrator, c/o Restricted Access Management Program, NMFS, P.O. Box 21668, Juneau, AK 99802-1668; (ii) Fax...
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50 CFR 679.90 - Allocation, use, and transfer of Amendment 80 QS permits.
Code of Federal Regulations, 2012 CFR
2012-10-01
... Restricted Access Management Program, NMFS, P.O. Box 21668, Juneau, AK 99802-1668; (ii) Fax: 907-586-7354; or (iii) Hand delivery or carrier: NMFS, Room 713, 709 West 9th Street, Juneau, AK 99801. (2) Application... Administrator, c/o Restricted Access Management Program, NMFS, P.O. Box 21668, Juneau, AK 99802-1668; (ii) Fax...
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Beyer, Andrea R; VieBrock, Lauren; Rodino, Kyle G; Miller, Daniel P; Tegels, Brittney K; Marconi, Richard T; Carlyon, Jason A
2015-10-01
A rising theme among intracellular microbes is the delivery of ankyrin repeat-containing effectors (Anks) that interact with target proteins to co-opt host cell functions. Orientia tsutsugamushi, an obligate intracellular bacterium and the etiologic agent of scrub typhus, encodes one of the largest Ank repertoires of any sequenced microorganism. They have been previously identified as type 1 secretion system substrates. Here, in silico and manual sequence analyses revealed that a large proportion of O. tsutsugamushi strain Ikeda Anks bear a eukaryotic/poxvirus-like F-box motif, which is known to recruit host cell SCF1 ubiquitin ligase machinery. We assessed the Anks for the ability to serve as F-box proteins. Coimmunoprecipitation assays demonstrated that F-box-containing Anks interact with overexpressed and/or endogenous SCF1 components. When coexpressed with FLAG-Ank4_01 or FLAG-Ank9, a glutathione S-transferase (GST)-tagged version of the SCF1 component SKP1 localized to subcellular sites of FLAG-Ank accumulation. The abilities of recombinant Anks to interact and colocalize with SKP1 were F-box dependent. GST-SKP1 precipitated O. tsutsugamushi-derived Ank9 from infected host cells, verifying both that the pathogen expresses Ank9 during infection and the protein's capability to bind SKP1. Aligning O. tsutsugamushi, poxviral, and eukaryotic F-box sequences delineated three F-box residues that are highly conserved and likely to be functionally important. Substitution of these residues ablated the ability of GFP-Ank9 to interact with GST-SKP1. These results demonstrate that O. tsutsugamushi strain Ikeda Anks can co-opt host cell polyubiquitination machinery, provide the first evidence that an O. tsutsugamushi Ank does so during infection, and advance overall understanding of microbial F-box proteins. Ankyrin repeat-containing proteins (Anks) are important virulence factors of intracellular bacteria that mediate protein-protein interactions with host cell targets. Orientia tsutsugamushi, which causes a debilitating infection called scrub typhus in one of the most densely populated regions of the world, encodes one of the largest Ank armamentariums of any sequenced bacterium. This study demonstrates that O. tsutsugamushi strain Ikeda Anks also bear F-box motifs that interact with host cell polyubiquitination machinery. By proving that an Orientia-derived Ank interacts with SKP1 in infected cells, this evidences the first bona fide Orientia effector and the first example of an endogenous F-box-containing Ank-mammalian-host ligand interaction for any intracellular bacterium. Also, importantly, this work identifies key residues that are essential for microbial F-box function. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Beyer, Andrea R.; VieBrock, Lauren; Rodino, Kyle G.; Miller, Daniel P.; Tegels, Brittney K.; Marconi, Richard T.
2015-01-01
ABSTRACT A rising theme among intracellular microbes is the delivery of ankyrin repeat-containing effectors (Anks) that interact with target proteins to co-opt host cell functions. Orientia tsutsugamushi, an obligate intracellular bacterium and the etiologic agent of scrub typhus, encodes one of the largest Ank repertoires of any sequenced microorganism. They have been previously identified as type 1 secretion system substrates. Here, in silico and manual sequence analyses revealed that a large proportion of O. tsutsugamushi strain Ikeda Anks bear a eukaryotic/poxvirus-like F-box motif, which is known to recruit host cell SCF1 ubiquitin ligase machinery. We assessed the Anks for the ability to serve as F-box proteins. Coimmunoprecipitation assays demonstrated that F-box-containing Anks interact with overexpressed and/or endogenous SCF1 components. When coexpressed with FLAG-Ank4_01 or FLAG-Ank9, a glutathione S-transferase (GST)-tagged version of the SCF1 component SKP1 localized to subcellular sites of FLAG-Ank accumulation. The abilities of recombinant Anks to interact and colocalize with SKP1 were F-box dependent. GST-SKP1 precipitated O. tsutsugamushi-derived Ank9 from infected host cells, verifying both that the pathogen expresses Ank9 during infection and the protein's capability to bind SKP1. Aligning O. tsutsugamushi, poxviral, and eukaryotic F-box sequences delineated three F-box residues that are highly conserved and likely to be functionally important. Substitution of these residues ablated the ability of GFP-Ank9 to interact with GST-SKP1. These results demonstrate that O. tsutsugamushi strain Ikeda Anks can co-opt host cell polyubiquitination machinery, provide the first evidence that an O. tsutsugamushi Ank does so during infection, and advance overall understanding of microbial F-box proteins. IMPORTANCE Ankyrin repeat-containing proteins (Anks) are important virulence factors of intracellular bacteria that mediate protein-protein interactions with host cell targets. Orientia tsutsugamushi, which causes a debilitating infection called scrub typhus in one of the most densely populated regions of the world, encodes one of the largest Ank armamentariums of any sequenced bacterium. This study demonstrates that O. tsutsugamushi strain Ikeda Anks also bear F-box motifs that interact with host cell polyubiquitination machinery. By proving that an Orientia-derived Ank interacts with SKP1 in infected cells, this evidences the first bona fide Orientia effector and the first example of an endogenous F-box-containing Ank–mammalian-host ligand interaction for any intracellular bacterium. Also, importantly, this work identifies key residues that are essential for microbial F-box function. PMID:26170417
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Flower development of Phalaenopsis orchid involves functionally divergent SEPALLATA-like genes
Pan, Zhao-Jun; Chen, You-Yi; Du, Jian-Syun; Chen, Yun-Yu; Chung, Mei-Chu; Tsai, Wen-Chieh; Wang, Chun-Neng; Chen, Hong-Hwa
2014-01-01
The Phalaenopsis orchid produces complex flowers that are commercially valuable, which has promoted the study of its flower development. E-class MADS-box genes, SEPALLATA (SEP), combined with B-, C- and D-class MADS-box genes, are involved in various aspects of plant development, such as floral meristem determination, organ identity, fruit maturation, seed formation and plant architecture. Four SEP-like genes were cloned from Phalaenopsis orchid, and the duplicated PeSEPs were grouped into PeSEP1/3 and PeSEP2/4. All PeSEPs were expressed in all floral organs. PeSEP2 expression was detectable in vegetative tissues. The study of protein–protein interactions suggested that PeSEPs may form higher order complexes with the B-, C-, D-class and AGAMOUS LIKE6-related MADS-box proteins to determine floral organ identity. The tepal became a leaf-like organ when PeSEP3 was silenced by virus-induced silencing, with alterations in epidermis identity and contents of anthocyanin and chlorophyll. Silencing of PeSEP2 had minor effects on the floral phenotype. Silencing of the E-class genes PeSEP2 and PeSEP3 resulted in the downregulation of B-class PeMADS2-6 genes, which indicates an association of PeSEP functions and B-class gene expression. These findings reveal the important roles of PeSEP in Phalaenopsis floral organ formation throughout the developmental process by the formation of various multiple protein complexes. PMID:24571782
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FOXQ1 promotes gastric cancer metastasis through upregulation of Snail.
Zhang, Jing; Liu, Yimin; Zhang, Jia; Cui, Xiaohai; Li, Gang; Wang, Jiansheng; Ren, Hong; Zhang, Yunfeng
2016-06-01
Gastric cancer (GC) is one of the most common cancers, and the second most common cause of cancer deaths worldwide. Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family and its upregulation is closely correlated with tumor progression and prognosis of multiple cancer types, including GC. FOXQ1 has been shown to regulate EMT and function in human cancers. However, the role of FOXQ1 in regulating EMT in GC and the exactly mechanism has not been clarified. The purpose of this study was to investigate the effects of FOXQ1 on EMT in human GC. FOXQ1 protein was detected by immunohistochemistry in human GC specimens and their clinical significance evaluated. We examined the cell biology and molecular biology changes after overexpression and knockdown of FOXQ1 in gastric cancer cells in vitro. To further understand the underlying mechanisms of EMT promoted by FOXQ1, we examined the changes of target genes of FOXQ1 after overexpression and knockdown of FOXQ1 in gastric cancer cells. In the present study, we demonstrate that FOXQ1 is overexpressed in GC tissues and its expression level is closely correlated with histologic differentiation, pTNM stage, and lymphatic metastasis of GC. Kaplan-Meier survival analysis showed that a high expression level of FOXQ1 resulted in a significantly poor prognosis of GC patients. FOXQ1 modulated GC cell invasion in vitro, and induced E-cadherin repression. FOXQ1 also upregulated the expression of vimentin in vitro. The Snail signaling pathway was likely involved in the induction of EMT by FOXQ1 in GC. Our results demonstrate that FOXQ1 is a prognostic marker for patients with GC, FOXQ1 over-expression is involved in acquisition of the mesenchymal phenotype of gastric cancer cells, and that subsequent Snail expression is essential for induction of EMT. The results suggest that FOXQ1 is a potential therapeutic target for the development of therapies for GC.
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-10-17
... Dr. Ruth Lunn, Director, ORoC, DNTP, NIEHS, P.O. Box 12233, MD K2-14, Research Triangle Park, NC..., ORoC, DNTP, NIEHS, P.O. Box 12233, MD K2-14, Research Triangle Park, NC 27709; telephone (919) 316...
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Crack Velocities in Natural Rubber.
1982-05-01
vulcanized natural rubber (3). The surprisingly low value for natural rubber was attributed to highly anisotropic elastic behavior at high strains...Dr. R.L. Rabie Hercules Incorporated WX-2, MS-952 Alleghany Ballistic Lab Los Alamos National Lab. P.O. Box 210 P.O. Box 1663 Washington, D.C. 21502
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77 FR 27227 - Notice of Agreements Filed
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2012-05-09
... Authority, P.O. Box 2562; Houston, TX 77252. Synopsis: The agreement sets forth certain discounted rates and... Houston Authority, P.O. Box 2562; Houston, TX 77252. Synopsis: The agreement sets forth certain discounted rates and charges applicable to Bayport Container Lines Americas, Inc.'s container vessels calling at...
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Pelvic Inflammatory Disease (PID) Fact Sheet
... 232-6348 In English , en Español Resources: CDC National Prevention Information Network (NPIN) P.O. Box 6003 Rockville, MD 20849-6003 E-mail npin-info@cdc.gov American Sexual Health Association (ASHA) P. O. Box 13827 Research Triangle Park, NC 27709-3827 1-800-783-9877 Related ...
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Analytical Representations of Blast Damage for Several Types of Targets
1978-10-01
Office Box 195 Washington, D.C. Oak Ridge, Tennessee 37830 Mr. Eugene Kopf (1) Dr. Richard Garwin (1) Defense Advanced Research Projects IBM Fellow...Ridge National Laboratory Center for Planning & Research, Inc. Post Office Box X 750 Welch Road Oak Ridge, Tennessee 37830 Palo Alto, California 94304 Dr...Dr. Conrad V. Chester(i Oak Ridge National Laboratory Building 450C-S, Roan S-24o0 Post Office Box E O •k Ridge, Tennessee 37830 Institute for Defense
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Unique Aspects of Flight Testing Unmanned Aircraft Systems
2010-04-01
or instruments on the air vehicle. This technique has included placing small compass in the corner of the camera field of view, and adding attitude...Salisbury SP4 0JQ Lautrupbjerg 1-5, 2750 Ballerup Attn: Biblioteket P.O. Box 25 SLOVAQUIE ESPAGNE NO-2007 Kjeller Akadémia ozbrojených síl SDG ...Ljubljana PO Box 18 Royal Netherlands Military 197 21 Praha 9 Academy Library SPAIN P.O. Box 90.002 SDG TECEN / DGAM DENMARK 4800 PA Breda C
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Harris, Nathaniel A; Rapoport, Robert M; Zuccarello, Mario; Maggio, John E
2018-06-01
The formation of the bilirubin oxidation products (BOXes), BOX A ([4-methyl-5-oxo-3-vinyl-(1,5-dihydropyrrol-2-ylidene)acetamide]) and BOX B (3-methyl-5-oxo-4-vinyl-(1,5-dihydropyrrol-2-ylidene)acetamide), as well as MVM (4-methyl-3-vinylmaleimide) were synthesized by oxidation of bilirubin with H 2 O 2 without and with FeCl 3 , respectively. Compound identity was confirmed with NMR and mass spectrometry (MS; less than 1 ppm, tandem MS up to MS 4 ). UV absorption profiles, including λ max , and extinction coefficient (ε; estimated using NMR) for BOX A, BOX B, and MVM in H 2 O, 15% CH 3 CN plus 10 mM CF 3 CO 2 H, CH 3 CN, CHCl 3 , CH 2 Cl 2 , and 0.9% NaCl were determined. At longer wavelengths, λ max 's for 1) BOX A were little affected by the solvent, ranging from 295-297 nm; 2) BOX B, less polar solvent yielded λ max 's of lower wavelength, with values ranging from 308-313 nm, and 3) MVM, less polar solvent yielded λ max 's of higher wavelength, with values ranging from 318-327 nm. Estimated ε's for BOX A and BOX B were approximately 5- to 10-fold greater than for MVM.
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50 CFR 29.21-2 - Application procedures.
Code of Federal Regulations, 2012 CFR
2012-10-01
... Wildlife Service, 500 Gold Avenue, P.O. Box 1306, Albuquerque, New Mexico 87103. (3) For the States of..., 300 Westgate Center Drive, Hadley, Massachusetts 01035. (6) For the States of Colorado, Kansas... Wildlife Service, P.O. Box 25486, Denver Federal Center, Denver, Colorado 80225. (7) For the State of...
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50 CFR 2.2 - Locations of regional offices.
Code of Federal Regulations, 2013 CFR
2013-10-01
... the States of Arizona, New Mexico, Oklahoma, and Texas), 500 Gold Avenue SW., Room 9018 (P.O. Box 1306... States of Colorado, Kansas, Montana, Nebraska, North Dakota, South Dakota, Utah and Wyoming), 134 Union Boulevard (P.O. Box 25486), Lakewood, Colorado 80228. (g) Alaska Regional Office (Region 7—comprising the...
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50 CFR 2.2 - Regional offices.
Code of Federal Regulations, 2014 CFR
2014-10-01
... the States of Arizona, New Mexico, Oklahoma, and Texas), 500 Gold Avenue SW., Room 9018 (P.O. Box 1306... States of Colorado, Kansas, Montana, Nebraska, North Dakota, South Dakota, Utah and Wyoming), 134 Union Boulevard (P.O. Box 25486), Lakewood, Colorado 80228. (g) Alaska Regional Office (Region 7—comprising the...
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UpTempO Buoys for Understanding and Prediction
2014-09-30
between the Delrin plastic pod housing and the thermistor epoxy potting. (b) Buoy ship deployment. Three Metocean-manufactured UpTempO buoys were ship...2 and 3). The box is held together with only glue and paper tape. The sensor cable is housed in an inner cardboard box that eventually separates
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75 FR 5930 - Proposed Flood Elevation Determinations
Federal Register 2010, 2011, 2012, 2013, 2014
2010-02-05
... include BFEs located on the stream reach between the referenced locations above. Please refer to the... 20472. ADDRESSES City of Fort Ransom Maps are available for inspection at P.O. Box 17, Fort Ransom, ND 58033. City of Lisbon Maps are available for inspection at P.O. Box 1079, Lisbon, ND 58054...
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Code of Federal Regulations, 2011 CFR
2011-07-01
... Department of Pollution Control and Ecology, 8001 National Drive, P.O. Box 9583, Little Rock, AR 72209. (F... State Department of Ecology (Ecology), P.O. Box 47600, Olympia, WA 98504-7600, http://www.ecy.wa.gov... not delegated. NSPS Subparts Delegated to Washington Air Agencies Subpart 1 Washington Ecology 2 BCAA...
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Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-09
..., Sao Jose dos Campos--SP, CEP: 12227-901--P.O. Box: 38/2, BRASIL, telephone: ++55 12 3927-5383; fax... Support, Av. Brig. Farina Lima, 2170, Sao Jose dos Campos--SP, CEP: 12227-901--P.O. Box: 38/2, BRASIL...
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78 FR 21934 - El Paso Natural Gas Company, L.L.C.; Notice of Request Under Blanket Authorization
Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-12
..., 2013, El Paso Natural Gas Company, L.L.C. (El Paso), P.O. Box 1087, Colorado Springs, CO 80944, filed..., Regulatory Affairs Department, El Paso Natural Gas Company, L.L.C., P.O. Box 1087, Colorado Springs, CO 80944...
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Detailed 3D representations for object recognition and modeling.
Zia, M Zeeshan; Stark, Michael; Schiele, Bernt; Schindler, Konrad
2013-11-01
Geometric 3D reasoning at the level of objects has received renewed attention recently in the context of visual scene understanding. The level of geometric detail, however, is typically limited to qualitative representations or coarse boxes. This is linked to the fact that today's object class detectors are tuned toward robust 2D matching rather than accurate 3D geometry, encouraged by bounding-box-based benchmarks such as Pascal VOC. In this paper, we revisit ideas from the early days of computer vision, namely, detailed, 3D geometric object class representations for recognition. These representations can recover geometrically far more accurate object hypotheses than just bounding boxes, including continuous estimates of object pose and 3D wireframes with relative 3D positions of object parts. In combination with robust techniques for shape description and inference, we outperform state-of-the-art results in monocular 3D pose estimation. In a series of experiments, we analyze our approach in detail and demonstrate novel applications enabled by such an object class representation, such as fine-grained categorization of cars and bicycles, according to their 3D geometry, and ultrawide baseline matching.
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Fox proteins are modular competency factors for facial cartilage and tooth specification.
Xu, Pengfei; Balczerski, Bartosz; Ciozda, Amanda; Louie, Kristin; Oralova, Veronika; Huysseune, Ann; Crump, J Gage
2018-06-26
Facial form depends on the precise positioning of cartilage, bone, and tooth fields in the embryonic pharyngeal arches. How complex signaling information is integrated to specify these cell types remains a mystery. We find that modular expression of Forkhead domain transcription factors (Fox proteins) in the zebrafish face arises through integration of Hh, Fgf, Bmp, Edn1 and Jagged-Notch pathways. Whereas loss of C-class Fox proteins results in reduced upper facial cartilages, loss of F-class Fox proteins results in distal jaw truncations and absent midline cartilages and teeth. We show that Fox proteins are required for Sox9a to promote chondrogenic gene expression. Fox proteins are sufficient in neural crest-derived cells for cartilage development, and neural crest-specific misexpression of Fox proteins expands the cartilage domain but inhibits bone. These results support a modular role for Fox proteins in establishing the competency of progenitors to form cartilage and teeth in the face. © 2018. Published by The Company of Biologists Ltd.
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Ge, Chen-Xu; Yu, Rong; Xu, Min-Xuan; Li, Pei-Qin; Fan, Chen-Yu; Li, Jian-Mei; Kong, Ling-Dong
2016-01-05
Betaine has been proven effective in treating nonalcoholic fatty liver disease (NAFLD) in animal models, however, its molecular mechanisms remain elusive. The aims of this study were to explore the mechanisms mediating the anti-inflammatory and anti-lipogenic actions of betaine in fructose-fed rats. In this study, betaine improved insulin resistance, reduced body weight gain and serum lipid levels, and prevented hepatic lipid accumulation in fructose-fed rats. It up-regulated hepatic expression of liver X receptor-alpha (LXRα) and peroxisome proliferator-activated receptor-alpha (PPARα), with the attenuation of the changes of their target genes, including hepatic carnitine palmitoyl transferase (CPT) 1α, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1, apolipoprotein B, sterol regulatory element-binding protein 1c and adipocyte differentiation-related protein, involved in fatty acid oxidation and lipid storage in these model rats. Furthermore, betaine alleviated ER stress and inhibited acetyl-CoA carboxylase α, CPT II, stearoyl-CoA desaturase 1 and fatty acid synthase expression involved in fatty acid synthesis in the liver of fructose-fed rats. Betaine suppressed hepatic gluconeogenesis in fructose-fed rats by moderating protein kinase B -forkhead box protein O1 pathway, as well as p38 mitogen-activated protein kinase and mammalian target of rapamycin activity. Moreover, betaine inhibited hepatic nuclear factor kappa B /nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation-mediated inflammation in this animal model. These results demonstrated that betaine ameliorated hepatic lipid accumulation, gluconeogenesis, and inflammation through restoring LXRα and PPARα expression and alleviating ER stress in fructose-fed rats. This study provides the potential mechanisms of betaine involved in the treatment of NAFLD. Copyright © 2015 Elsevier B.V. All rights reserved.
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Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Dinh, Chi H L; Wang, Hongqin; Cheng, Licai; Huang, Xu-Feng
2015-09-05
High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that bardoxolone methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR. BM prevented HF diet-induced insulin resistance and alterations in the protein levels of protein tyrosine phosphatase 1B (PTP1B), forkhead box protein O1 (FOXO1) and BDNF, and expression of the insulin receptor (IR), IRS-1 and glucose-6-phosphatase (G6Pase) genes. Furthermore, BM prevented fat accumulation in the liver and decreases in the β-oxidation gene, peroxisomal acyl-coenzyme A oxidase 1 (ACOX) in mice fed a HF diet. In the livers of HF fed mice, BM administration prevented HF diet-induced macrophage infiltration, inflammation as indicated by reduced IL-6 and signal transducer and activator of transcription 3 (STAT3) protein levels and TNFα mRNA expression, and increased nuclear factor-like 2 (Nrf2) mRNA expression and nuclear protein levels. These findings suggest that BM prevents HF diet induced insulin resistance and the development of hepatic steatosis in mice fed a chronic HF diet through modulation of molecules involved in insulin signalling, lipid metabolism and inflammation in the liver. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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van Doorn, Remco; Dijkman, Remco; Vermeer, Maarten H; Out-Luiting, Jacoba J; van der Raaij-Helmer, Elisabeth M H; Willemze, Rein; Tensen, Cornelis P
2004-08-15
Sézary syndrome (Sz) is a malignancy of CD4+ memory skin-homing T cells and presents with erythroderma, lymphadenopathy, and peripheral blood involvement. To gain more insight into the molecular features of Sz, oligonucleotide array analysis was performed comparing gene expression patterns of CD4+ T cells from peripheral blood of patients with Sz with those of patients with erythroderma secondary to dermatitis and healthy controls. Using unsupervised hierarchical clustering gene, expression patterns of T cells from patients with Sz were classified separately from those of benign T cells. One hundred twenty-three genes were identified as significantly differentially expressed and had an average fold change exceeding 2. T cells from patients with Sz demonstrated decreased expression of the following hematopoietic malignancy-linked tumor suppressor genes: TGF-beta receptor II, Mxi1, Riz1, CREB-binding protein, BCL11a, STAT4, and Forkhead Box O1A. Moreover, the tyrosine kinase receptor EphA4 and the potentially oncogenic transcription factor Twist were highly and selectively expressed in T cells of patients with Sz. High expression of EphA4 and Twist was also observed in lesional skin biopsy specimens of a subset of patients with cutaneous T cell lymphomas related to Sz, whereas their expression was nearly undetectable in benign T cells or in skin lesions of patients with inflammatory dermatoses. Detection of EphA4 and Twist may be used in the molecular diagnosis of Sz and related cutaneous T-cell lymphomas. Furthermore, the membrane-bound EphA4 receptor may serve as a target for directed therapeutic intervention.
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Michalkova, Veronika; Mireji, Paul; Attardo, Geoffrey M.; Moulton, John K.; Wilson, Thomas G.; Aksoy, Serap
2014-01-01
Tsetse flies are viviparous insects that nurture a single intrauterine progeny per gonotrophic cycle. The developing larva is nourished by the lipid-rich, milk-like secretions from a modified female accessory gland (milk gland). An essential feature of the lactation process involves lipid mobilization for incorporation into the milk. In this study, we examined roles for juvenile hormone (JH) and insulin/IGF-like (IIS) signaling pathways during tsetse pregnancy. In particular, we examined the roles for these pathways in regulating lipid homeostasis during transitions between non-lactating (dry) and lactating periods. The dry period occurs over the course of oogenesis and embryogenesis, while the lactation period spans intrauterine larvigenesis. Genes involved in the JH and IIS pathways were upregulated during dry periods, correlating with lipid accumulation between bouts of lactation. RNAi suppression of Forkhead Box Sub Group O (FOXO) expression impaired lipolysis during tsetse lactation and reduced fecundity. Similar reduction of the JH receptor Methoprene tolerant (Met), but not its paralog germ cell expressed (gce), reduced lipid accumulation during dry periods, indicating functional divergence between Met and gce during tsetse reproduction. Reduced lipid levels following Met knockdown led to impaired fecundity due to inadequate fat reserves at the initiation of milk production. Both the application of the JH analog (JHA) methoprene and injection of insulin into lactating females increased stored lipids by suppressing lipolysis and reduced transcripts of lactation-specific genes, leading to elevated rates of larval abortion. To our knowledge, this study is the first to address the molecular physiology of JH and IIS in a viviparous insect, and specifically to provide a role for JH signaling through Met in the regulation of lipid metabolism. PMID:23499946
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Baumann, Aaron A; Benoit, Joshua B; Michalkova, Veronika; Mireji, Paul; Attardo, Geoffrey M; Moulton, John K; Wilson, Thomas G; Aksoy, Serap
2013-06-15
Tsetse flies are viviparous insects that nurture a single intrauterine progeny per gonotrophic cycle. The developing larva is nourished by the lipid-rich, milk-like secretions from a modified female accessory gland (milk gland). An essential feature of the lactation process involves lipid mobilization for incorporation into the milk. In this study, we examined roles for juvenile hormone (JH) and insulin/IGF-like (IIS) signaling pathways during tsetse pregnancy. In particular, we examined the roles for these pathways in regulating lipid homeostasis during transitions between non-lactating (dry) and lactating periods. The dry period occurs over the course of oogenesis and embryogenesis, while the lactation period spans intrauterine larvigenesis. Genes involved in the JH and IIS pathways were upregulated during dry periods, correlating with lipid accumulation between bouts of lactation. RNAi suppression of Forkhead Box Sub Group O (FOXO) expression impaired lipolysis during tsetse lactation and reduced fecundity. Similar reduction of the JH receptor Methoprene tolerant (Met), but not its paralog germ cell expressed (gce), reduced lipid accumulation during dry periods, indicating functional divergence between Met and gce during tsetse reproduction. Reduced lipid levels following Met knockdown led to impaired fecundity due to inadequate fat reserves at the initiation of milk production. Both the application of the JH analog (JHA) methoprene and injection of insulin into lactating females increased stored lipids by suppressing lipolysis and reduced transcripts of lactation-specific genes, leading to elevated rates of larval abortion. To our knowledge, this study is the first to address the molecular physiology of JH and IIS in a viviparous insect, and specifically to provide a role for JH signaling through Met in the regulation of lipid metabolism during insect lactation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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Ryan, John J; Archer, Stephen L
2014-06-20
The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension. RV hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation, fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis, adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-brain natriuretic peptide levels, troponin release, elevated catecholamine levels, RV dilatation, and late gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of G-protein receptor kinase-mediated downregulation, desensitization, and uncoupling of β-adrenoreceptors. RV ischemia may result from capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a forkhead box protein O1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of pyruvate dehydrogenase kinase, fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis, adrenergic signaling, and phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary vascular disease. © 2014 American Heart Association, Inc.
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Wu, Ting; Zhang, Zhenhai; Yuan, Zhangqin; Lo, Li Jan; Chen, Jun; Wang, Yizhen; Peng, Jinrong
2013-01-01
Meat quality is determined by properties such as carcass color, tenderness and drip loss. These properties are closely associated with meat composition, which includes the types of muscle fiber and content of intramuscular fat (IMF). Muscle fibers are the main contributors to meat mass, while IMF not only contributes to the sensory properties but also to the plethora of physical, chemical and technological properties of meat. However, little is known about the molecular mechanisms that determine meat composition in different pig breeds. In this report we show that Jinhua pigs, a Chinese breed, contains much higher levels of IMF than do Landrace pigs, a Danish breed. We analyzed global gene expression profiles in the longissimus dorsi muscles in Jinhua and Landrace breeds at the ages of 30, 90 and 150 days. Cross-comparison analysis revealed that genes that regulate fatty acid biosynthesis (e.g., fatty acid synthase and stearoyl-CoA desaturase) are expressed at higher levels in Jinhua pigs whereas those that regulate myogenesis (e.g., myogenic factor 6 and forkhead box O1) are expressed at higher levels in Landrace pigs. Among those genes which are highly expressed in Jinhua pigs at 90 days (d90), we identified a novel gene porcine FLJ36031 (pFLJ), which functions as a positive regulator of fat deposition in cultured intramuscular adipocytes. In summary, our data showed that the up-regulation of fatty acid biosynthesis regulatory genes such as pFLJ and myogenesis inhibitory genes such as myostatin in the longissimus dorsi muscles of Jinhua pigs could explain why this local breed produces meat with high levels of IMF.
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Yuan, Zhangqin; Lo, Li Jan; Chen, Jun; Wang, Yizhen; Peng, Jinrong
2013-01-01
Meat quality is determined by properties such as carcass color, tenderness and drip loss. These properties are closely associated with meat composition, which includes the types of muscle fiber and content of intramuscular fat (IMF). Muscle fibers are the main contributors to meat mass, while IMF not only contributes to the sensory properties but also to the plethora of physical, chemical and technological properties of meat. However, little is known about the molecular mechanisms that determine meat composition in different pig breeds. In this report we show that Jinhua pigs, a Chinese breed, contains much higher levels of IMF than do Landrace pigs, a Danish breed. We analyzed global gene expression profiles in the longissimus dorsi muscles in Jinhua and Landrace breeds at the ages of 30, 90 and 150 days. Cross-comparison analysis revealed that genes that regulate fatty acid biosynthesis (e.g., fatty acid synthase and stearoyl-CoA desaturase) are expressed at higher levels in Jinhua pigs whereas those that regulate myogenesis (e.g., myogenic factor 6 and forkhead box O1) are expressed at higher levels in Landrace pigs. Among those genes which are highly expressed in Jinhua pigs at 90 days (d90), we identified a novel gene porcine FLJ36031 (pFLJ), which functions as a positive regulator of fat deposition in cultured intramuscular adipocytes. In summary, our data showed that the up-regulation of fatty acid biosynthesis regulatory genes such as pFLJ and myogenesis inhibitory genes such as myostatin in the longissimus dorsi muscles of Jinhua pigs could explain why this local breed produces meat with high levels of IMF. PMID:23301040
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Mitochondria and FOXO3: breath or die.
Hagenbuchner, Judith; Ausserlechner, Michael J
2013-01-01
Forkhead box O (FOXO) transcription factors are regulators of cell-type specific apoptosis and cell cycle arrest but also control longevity and reactive oxygen species (ROS). ROS-control by FOXO is mediated by transcriptional activation of detoxifying enzymes such as Superoxide dismutase 2 (SOD2), Catalase or Sestrins or by the repression of mitochondrial respiratory chain proteins resulting in reduced mitochondrial activity. FOXO3 also regulates the adaptation to hypoxia by reducing mitochondrial mass and oxygen consumption during HIF-1α activation. In neuronal tumor cells, FOXO3 triggers ROS-accumulation as a consequence of transient mitochondrial outer membrane permeabilization, which is essential for FOXO3-induced apoptosis in these cells. Cellular ROS levels are affected by the FOXO-targets Bim, BclxL, and Survivin. All three proteins localize to mitochondria and affect mitochondrial membrane potential, respiration and cellular ROS levels. Bim-activation by FOXO3 causes mitochondrial depolarization resulting in a transitory decrease of respiration and ROS production. Survivin, on the other hand, actively changes mitochondrial architecture, respiration-efficacy and energy metabolism. This ability distinguishes Survivin from other anti-apoptotic proteins such as BclxL, which inhibits ROS by inactivating Bim but does not alter mitochondrial function. Importantly, FOXO3 simultaneously also activates ROS-detoxification via induction of SESN3. In this paper we discuss the hypothesis that the delicate balance between ROS-accumulation by Bim-triggered mitochondrial damage, mitochondrial architecture and ROS-detoxifying proteins determines cell fate. We provide evidence for a FOXO self-reactivating loop and for novel functions of FOXO3 in controlling mitochondrial respiration of neuronal cells, which further supports the current view that FOXO transcription factors are information-integrating sentinels of cellular stress and critical modulators of cell homeostasis.
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Effects of Iron Overload on the Bone Marrow Microenvironment in Mice
Zhao, Mingfeng; Li, Deguan; Chai, Xiao; Cao, Xiaoli; Meng, Juanxia; Chen, Jie; Xiao, Xia; Li, Qing; Mu, Juan; Shen, Jichun; Meng, Aimin
2015-01-01
Objective Using a mouse model, Iron Overload (IO) induced bone marrow microenvironment injury was investigated, focusing on the involvement of reactive oxygen species (ROS). Methods Mice were intraperitoneally injected with iron dextran (12.5, 25, or 50mg) every three days for two, four, and six week durations. Deferasirox(DFX)125mg/ml and N-acetyl-L-cysteine (NAC) 40mM were co-administered. Then, bone marrow derived mesenchymal stem cells (BM-MSCs) were isolated and assessed for proliferation and differentiation ability, as well as related gene changes. Immunohistochemical analysis assessed the expression of haematopoietic chemokines. Supporting functions of BM-MSCs were studied by co-culture system. Results In IO condition (25mg/ml for 4 weeks), BM-MSCs exhibited proliferation deficiencies and unbalanced osteogenic/adipogenic differentiation. The IO BM-MSCs showed a longer double time (2.07±0.14 days) than control (1.03±0.07 days) (P<0.05). The immunohistochemical analysis demonstrated that chemokine stromal cell-derived factor-1, stem cell factor -1, and vascular endothelial growth factor-1 expression were decreased. The co-cultured system demonstrated that bone marrow mononuclear cells (BMMNCs) co-cultured with IO BM-MSCs had decreased colony forming unit (CFU) count (p<0.01), which indicates IO could lead to decreased hematopoietic supporting functions of BM-MSCs. This effect was associated with elevated phosphatidylinositol 3 kinase (PI3K) and reduced of Forkhead box protein O3 (FOXO3) mRNA expression, which could induce the generation of ROS. Results also demonstrated that NAC or DFX treatment could partially attenuate cell injury and inhibit signaling pathway striggered by IO. Conclusion These results demonstrated that IO can impair the bone marrow microenvironment, including the quantity and quality of BM-MSCs. PMID:25774923
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Savikj, Mladen; Ruby, Maxwell A; Kostovski, Emil; Iversen, Per O; Zierath, Juleen R; Krook, Anna; Widegren, Ulrika
2018-06-01
Despite the well-known role of satellite cells in skeletal muscle plasticity, the effect of spinal cord injury on their function in humans remains unknown. We determined whether spinal cord injury affects the intrinsic ability of satellite cells to differentiate and produce metabolically healthy myotubes. We obtained vastus lateralis biopsies from eight spinal cord-injured and six able-bodied individuals. Satellite cells were isolated, grown and differentiated in vitro. Gene expression was measured by quantitative PCR. Abundance of differentiation markers and regulatory proteins was determined by Western blotting. Protein synthesis and fatty acid oxidation were measured by radioactive tracer-based assays. Activated satellite cells (myoblasts) and differentiated myotubes derived from skeletal muscle of able-bodied and spinal cord-injured individuals expressed similar (P > 0.05) mRNA levels of myogenic regulatory factors. Myogenic differentiation factor 1 expression was higher in myoblasts from spinal cord-injured individuals. Desmin and myogenin protein content was increased upon differentiation in both groups, while myotubes from spinal cord-injured individuals contained more type I and II myosin heavy chain. Phosphorylated and total protein levels of Akt-mechanistic target of rapamycin and forkhead box protein O signalling axes and protein synthesis rate in myotubes were similar (P > 0.05) between groups. Additionally, fatty acid oxidation of myotubes from spinal cord-injured individuals was unchanged (P > 0.05) compared to able-bodied controls. Our results indicate that the intrinsic differentiation capacity of satellite cells and metabolic characteristics of myotubes are preserved following spinal cord injury. This may inform potential interventions targeting satellite cell activation to alleviate skeletal muscle atrophy. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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Vázquez-Manrique, Rafael P.; Farina, Francesca; Cambon, Karine; Dolores Sequedo, María; Parker, Alex J.; Millán, José María; Weiss, Andreas; Déglon, Nicole; Neri, Christian
2016-01-01
The adenosine monophosphate activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. However, in Huntington's disease (HD), AMPK may be activated in the striatum of HD mice at a late, post-symptomatic phase of the disease, and high-dose regiments of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide may worsen neuropathological and behavioural phenotypes. Here, we revisited the role of AMPK in HD using models that recapitulate the early features of the disease, including Caenorhabditis elegans neuron dysfunction before cell death and mouse striatal cell vulnerability. Genetic and pharmacological manipulation of aak-2/AMPKα shows that AMPK activation protects C. elegans neurons from the dysfunction induced by human exon-1 huntingtin (Htt) expression, in a daf-16/forkhead box O-dependent manner. Similarly, AMPK activation using genetic manipulation and low-dose metformin treatment protects mouse striatal cells expressing full-length mutant Htt (mHtt), counteracting their vulnerability to stress, with reduction of soluble mHtt levels by metformin and compensation of cytotoxicity by AMPKα1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-γ1 to mouse striata slows down the neurodegenerative effects of mHtt. Collectively, these data highlight the importance of considering the dynamic of HD for assessing the therapeutic potential of stress-response targets in the disease. We postulate that AMPK activation is a compensatory response and valid approach for protecting dysfunctional and vulnerable neurons in HD. PMID:26681807
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Zeng, Baosheng; Huang, Yuping; Xu, Jun; Shiotsuki, Takahiro; Bai, Hua; Palli, Subba Reddy; Huang, Yongping; Tan, Anjiang
2017-07-14
Forkhead box O (FOXO) functions as the terminal transcription factor of the insulin signaling pathway and regulates multiple physiological processes in many organisms, including lifespan in insects. However, how FOXO interacts with hormone signaling to modulate insect growth and development is largely unknown. Here, using the transgene-based CRISPR/Cas9 system, we generated and characterized mutants of the silkworm Bombyx mori FOXO ( BmFOXO ) to elucidate its physiological functions during development of this lepidopteran insect. The BmFOXO mutant (FOXO-M) exhibited growth delays from the first larval stage and showed precocious metamorphosis, pupating at the end of the fourth instar (trimolter) rather than at the end of the fifth instar as in the wild-type (WT) animals. However, different from previous reports on precocious metamorphosis caused by juvenile hormone (JH) deficiency in silkworm mutants, the total developmental time of the larval period in the FOXO-M was comparable with that of the WT. Exogenous application of 20-hydroxyecdysone (20E) or of the JH analog rescued the trimolter phenotype. RNA-seq and gene expression analyses indicated that genes involved in JH degradation but not in JH biosynthesis were up-regulated in the FOXO-M compared with the WT animals. Moreover, we identified several FOXO-binding sites in the promoter of genes coding for JH-degradation enzymes. These results suggest that FOXO regulates JH degradation rather than its biosynthesis, which further modulates hormone homeostasis to control growth and development in B. mori In conclusion, we have uncovered a pivotal role for FOXO in regulating JH signaling to control insect development. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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Inhibition of FOXO1/3 promotes vascular calcification.
Deng, Liang; Huang, Lu; Sun, Yong; Heath, Jack M; Wu, Hui; Chen, Yabing
2015-01-01
Vascular calcification is a characteristic feature of atherosclerosis, diabetes mellitus, and end-stage renal disease. We have demonstrated that activation of protein kinase B (AKT) upregulates runt-related transcription factor 2 (Runx2), a key osteogenic transcription factor that is crucial for calcification of vascular smooth muscle cells (VSMC). Using mice with SMC-specific deletion of phosphatase and tensin homolog (PTEN), a major negative regulator of AKT, the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO (forkhead box O)-mediated Runx2 upregulation and VSMC calcification. SMC-specific PTEN deletion mice were generated by crossing PTEN floxed mice with SM22α-Cre transgenic mice. The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo. Runx2 knockdown did not affect proliferation but blocked calcification of the PTEN-deficient VSMC, suggesting that PTEN deletion promotes Runx2-depedent VSMC calcification that is independent of proliferation. At the molecular level, PTEN deficiency increased the amount of Runx2 post-transcriptionally by inhibiting Runx2 ubiquitination. AKT activation increased phosphorylation of FOXO1/3 that led to nuclear exclusion of FOXO1/3. FOXO1/3 knockdown in VSMC phenocopied the PTEN deficiency, demonstrating a novel function of FOXO1/3, as a downstream signaling of PTEN/AKT, in regulating Runx2 ubiquitination and VSMC calcification. Using heterozygous SMC-specific PTEN-deficient mice and atherogenic ApoE(-/-) mice, we further demonstrated AKT activation, FOXO phosphorylation, and Runx2 ubiquitination in vascular calcification in vivo. Our studies have determined a new causative effect of SMC-specific PTEN deficiency on vascular calcification and demonstrated that FOXO1/3 plays a crucial role in PTEN/AKT-modulated Runx2 ubiquitination and VSMC calcification. © 2014 American Heart Association, Inc.
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Burgos-Ramos, Emma; González-Rodríguez, Agueda; Canelles, Sandra; Baquedano, Eva; Frago, Laura M; Revuelta-Cervantes, Jesús; Gómez-Ambrosi, Javier; Frühbeck, Gema; Chowen, Julie A; Argente, Jesús; Valverde, Angela M; Barrios, Vicente
2012-03-01
Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2(-/-)) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2(-/-) mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2(-/-) mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2(-/-). Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2(-/-) mice, with FOXO1 showing mainly nuclear localization in D IRS2(-/-) and cytoplasmic in ND IRS2(-/-) mice. D IRS2(-/-) mice exhibited higher hypothalamic inflammation markers than ND IRS2(-/-) mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes.
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Kristensen, Malene M; Davidsen, Peter K; Vigelsø, Andreas; Hansen, Christina N; Jensen, Lars J; Jessen, Niels; Bruun, Jens M; Dela, Flemming; Helge, Jørn W
2017-03-01
Obesity is central in the development of insulin resistance. However, the underlying mechanisms still need elucidation. Dysregulated microRNAs (miRNAs; post-transcriptional regulators) in adipose tissue may present an important link. The miRNA expression in subcutaneous adipose tissue from 19 individuals with severe obesity (10 women and 9 men) before and after a 15-week weight loss intervention was studied using genome-wide microarray analysis. The microarray results were validated with RT-qPCR, and pathway enrichment analysis of in silico predicted targets was performed to elucidate the biological consequences of the miRNA dysregulation. Lastly, the messenger RNA (mRNA) and/or protein expression of multiple predicted targets as well as several proteins involved in lipolysis were investigated. The intervention led to upregulation of miR-29a-3p and miR-29a-5p and downregulation of miR-20b-5p. The mRNA and protein expression of predicted targets was not significantly affected by the intervention. However, negative correlations between miR-20b-5p and the protein levels of its predicted target, acyl-CoA synthetase long-chain family member 1, were observed. Several other miRNA-target relationships correlated negatively, indicating possible miRNA regulation, including miR-29a-3p and lipoprotein lipase mRNA levels. Proteins involved in lipolysis were not affected by the intervention. Weight loss influenced several miRNAs, some of which were negatively correlated with predicted targets. These dysregulated miRNAs may affect adipocytokine signaling and forkhead box protein O signaling. © 2017 The Obesity Society.
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Ye, Zhi; Wang, Na; Xia, Pingping; Wang, E; Liao, Juan; Guo, Qulian
2013-04-01
Parecoxib, a novel COX-2 inhibitor, functions as a neuroprotective agent and rescues neurons from cerebral ischemic reperfusion injury-induced apoptosis. However, the molecular mechanisms underlying parecoxib neuroprotection remain to be elucidated. There is growing evidence that endoplasmic reticulum (ER) stress plays an important role in neuronal death caused by brain ischemia. However, very little is known about the role of parecoxib in mediating pathophysiological reactions to ER stress induced by ischemic reperfusion injury. Therefore, in the present study, we investigated whether delayed administration of parecoxib attenuates brain damage via suppressing ER stress-induced cell death. Adult male Sprague-Dawley rats were administered parecoxib (10 or 30 mg kg(-1), IP) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion (MCAO) for three consecutive days. The expressions of glucose-regulated protein 78 (GRP78) and oxygen-regulated protein 150 (ORP150) and C/EBP-homologous protein (CHOP) and forkhead box protein O 1 (Foxo1) in cytoplasmic and nuclear fraction were determined by Western blotting. The levels of caspase-12 expression were checked by immunohistochemistry analysis, served as a marker for ER stress-induced apoptosis. Parecoxib significantly suppressed cerebral ischemic injury-induced nuclear translocation of CHOP and Foxo1 and attenuated the immunoreactivity of caspase-12 in ischemic penumbra. Furthermore, the protective effect of delayed administration of parecoxib was accompanied by an increased GRP78 and ORP150 expression. Therefore, our study suggested that elevation of GRP78 and ORP150, and suppression of CHOP and Foxo1 nuclear translocation may contribute to parecoxib-mediated neuroprotection during ER stress responses.
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Brinkmann, Christian; Przyklenk, Axel; Metten, Alexander; Schiffer, Thorsten; Bloch, Wilhelm; Brixius, Klara; Gehlert, Sebastian
2017-11-01
Mitophagy is a form of autophagy for the elimination of mitochondria. Mitochondrial content and function are reduced in the skeletal muscle of patients with type 2 diabetes mellitus (T2DM). Physical training has been shown to restore mitochondrial capacity in T2DM patients, but the role of mitophagy has not been examined in this context. This study analyzes the impact of a 3-month endurance training on important skeletal muscle mitophagy regulatory proteins and oxidative phosphorylation (OXPHOS) complexes in T2DM patients. Muscle biopsies were obtained from eight overweight/obese T2DM men (61±10 years) at T1 (6 weeks pre-training), T2 (1 week pre-training), and T3 (3 to 4 days post-training). Protein contents were determined by Western blotting. The training increased mitochondrial complex II significantly (T2-T3: +29%, p = 0.037). The protein contents of mitophagy regulatory proteins (phosphorylated form of forkhead box O3A (pFOXO3A), mitochondrial E3 ubiquitin protein ligase-1 (MUL1), Bcl-2/adenovirus E1B 19-kD interacting protein-3 (BNIP3), microtubule-associated protein 1 light chain-3B (the ratio LC3B-II/LC3B-I was determined)) did not differ significantly between T1, T2, and T3. The results imply that training-induced changes in OXPHOS subunits (significant increase in complex II) are not accompanied by changes in mitophagy regulatory proteins in T2DM men. Future studies should elucidate whether acute exercise might affect mitophagic processes in T2DM patients (and whether a transient regulation of mitophagy regulatory proteins is evident) to fully clarify the role of physical activity and mitophagy for mitochondrial health in this particular patient group.
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Crossland, Hannah; Constantin-Teodosiu, Dumitru; Gardiner, Sheila M; Greenhaff, Paul L
2017-07-01
The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5 ± 0.1 mg·kg -1 ·day -1 ) for 2 weeks before and during 24 h continuous intravenous infusion of LPS (15 μg·kg -1 ·h -1 ) or saline. Rosi blunted LPS-induced increases in muscle tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA by 70% ( P <0.05) and 64% ( P <0.01) respectively. Furthermore, Rosi suppressed the LPS-induced reduction in phosphorylated AKT and phosphorylated Forkhead box O (FOXO) 1 protein, as well as the up-regulation of muscle RING finger 1 (MuRF1; P <0.01) mRNA and the LPS-induced increase in 20S proteasome activity ( P <0.05). Accordingly, LPS reduced the muscle protein:DNA ratio (∼30%, P <0.001), which Rosi offset. Increased muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA ( P <0.001) and muscle lactate accumulation ( P <0.001) during endotoxaemia were suppressed by Rosi. Thus, pre-treatment with Rosi reduced muscle cytokine accumulation and blunted muscle protein loss and lactate accumulation during endotoxaemia, and at least in part by reducing activation of molecular events known to increase muscle protein breakdown and mitochondrial pyruvate use. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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Resveratrol modulates the angiogenic response to exercise training in skeletal muscles of aged men.
Gliemann, Lasse; Olesen, Jesper; Biensø, Rasmus Sjørup; Schmidt, Jakob Friis; Akerstrom, Thorbjorn; Nyberg, Michael; Lindqvist, Anna; Bangsbo, Jens; Hellsten, Ylva
2014-10-15
In animal studies, the polyphenol resveratrol has been shown to influence several pathways of importance for angiogenesis in skeletal muscle. The aim of the present study was to examine the angiogenic effect of resveratrol supplementation with parallel exercise training in aged men. Forty-three healthy physically inactive aged men (65 ± 1 yr) were divided into 1) a training group that conducted 8 wk of intense exercise training where half of the subjects received a daily intake of either 250 mg trans-resveratrol (n = 14) and the other half received placebo (n = 13) and 2) a nontraining group that received either 250 mg trans-resveratrol (n = 9) or placebo (n = 7). The group that trained with placebo showed a ~20% increase in the capillary-to-fiber ratio, an increase in muscle protein expression of VEGF, VEGF receptor-2, and tissue inhibitor of matrix metalloproteinase (TIMP-1) but unaltered thrombospodin-1 levels. Muscle interstitial VEGF and thrombospodin-1 protein levels were unchanged after the training period. The group that trained with resveratrol supplementation did not show an increase in the capillary-to-fiber ratio or an increase in muscle VEGF protein. Muscle TIMP-1 protein levels were lower in the training and resveratrol group than in the training and placebo group. Both training groups showed an increase in forkhead box O1 protein. In nontraining groups, TIMP-1 protein was lower in the resveratrol-treated group than the placebo-treated group after 8 wk. In conclusion, these data show that exercise training has a strong angiogenic effect, whereas resveratrol supplementation may limit basal and training-induced angiogenesis. Copyright © 2014 the American Physiological Society.
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DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway.
Zhou, Ting-Ting; Ma, Fei; Shi, Xiao-Fan; Xu, Xin; Du, Te; Guo, Xiao-Dan; Wang, Gai-Hong; Yu, Liang; Rukachaisirikul, Vatcharin; Hu, Li-Hong; Chen, Jing; Shen, Xu
2017-08-01
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including Gαs, Gαi and Gαq. Gαs-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Gαi-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Gαq-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4( 1H )-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in db/db mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT-inhibited gluconeogenesis by regulating the Gαq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca 2+ )/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Gαq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM. © 2017 Society for Endocrinology.
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Yan, Caifeng; Chen, Jinfeng; Li, Min; Xuan, Wenying; Su, Dongming; You, Hui; Huang, Yujie; Chen, Nuoqi; Liang, Xiubin
2016-07-01
MicroRNA-9 (miR-9) is involved in the regulation of pancreatic beta cell function. However, its role in gluconeogenesis is still unclear. Our objective was to investigate the role of miR-9 in hepatic glucose production (HGP). MiR-9 expression was measured in livers of high-fat diet (HFD) mice and ob/ob mice. The methylation status of the miR-9-3 promoter regions in hepatocytes was determined by the methylation-specific PCR procedure. The binding activity of DNA methyltransferase (DNMT)1, DNMT3a and DNMT3b on the miR-9-3 promoter was detected by chromatin immunoprecipitation (ChIP) and quantitative real-time PCR assays. HGP was evaluated in vitro and in vivo. Glucose tolerance, insulin tolerance and pyruvate tolerance tests were also performed. Reduced miR-9 expression and hypermethylation of the miR-9-3 promoter were observed in the livers of obese mice. Further study showed that the binding of DNMT1, but not of DNMT3a and DNMT3b, to the miR-9-3 promoter was increased in hepatocytes from ob/ob mice. Knockdown of DNMT1 alleviated the decrease in hepatic miR-9 expression in vivo and in vitro. Overexpression of hepatic miR-9 improved insulin sensitivity in obese mice and inhibited HGP. In addition, deletion of hepatic miR-9 led to an increase in random and fasting blood glucose levels in lean mice. Importantly, silenced forkhead box O1 (FOXO1) expression reversed the gluconeogenesis and glucose production in hepatocytes induced by miR-9 deletion. Our observations suggest that the decrease in miR-9 expression contributes to an inappropriately activated gluconeogenesis in obese mice.
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Khan, Sabbir; Kumar, Sandeep; Jena, Gopabandhu
2016-06-01
Recent evidences highlighted the role of histone deacetylases (HDACs) in insulin-resistance, gluconeogenesis and islet function. HDACs can modulate the expression of various genes, which directly or indirectly affect glucose metabolism. This study was aimed to evaluate the role of valproic acid (VPA) on fat deposition, insulin-resistance and gluconeogenesis in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet and low dose streptozotocin. VPA at the doses of 150 and 300 mg/kg/day and metformin (positive control) 150 mg/kg twice daily for 10 weeks were administered by oral gavage. Insulin-resistance, dyslipidemia and glycemia were evaluated by biochemical estimations, while fat accumulation and structural alteration were assessed by histopathology. Protein expression and insulin signaling were evaluated by western blot and immunohistochemistry. VPA treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, fat deposition in brown adipose tissue, white adipose tissue and liver, which are comparable to metformin treatment. Further, VPA inhibited the gluconeogenesis and glucagon expression as well as restored the histopathological alterations in pancreas and liver. Our findings provide new insights on the anti-diabetic role of VPA in type-2 diabetes mellitus by the modulation of insulin signaling and forkhead box protein O1 (FOXO1)-mediated gluconeogenesis. Since VPA is a well established clinical drug, the detailed molecular mechanisms of the present findings can be further investigated for possible clinical use. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.
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Martínez de Morentin, Pablo B.; Lage, Ricardo; González-García, Ismael; Ruíz-Pino, Francisco; Martins, Luís; Fernández-Mallo, Diana; Gallego, Rosalía; Fernø, Johan; Señarís, Rosa; Saha, Asish K.; Tovar, Sulay; Diéguez, Carlos; Nogueiras, Rubén; Tena-Sempere, Manuel
2015-01-01
During gestation, hyperphagia is necessary to cope with the metabolic demands of embryonic development. There were three main aims of this study: Firstly, to investigate the effect of pregnancy on hypothalamic fatty acid metabolism, a key pathway for the regulation of energy balance; secondly, to study whether pregnancy induces resistance to the anorectic effect of fatty acid synthase (FAS) inhibition and accumulation of malonyl-coenzyme A (CoA) in the hypothalamus; and, thirdly, to study whether changes in hypothalamic AMPK signaling are associated with brown adipose tissue (BAT) thermogenesis during pregnancy. Our data suggest that in pregnant rats, the hypothalamic fatty acid pathway shows an overall state that should lead to anorexia and elevated BAT thermogenesis: decreased activities of AMP-activated protein kinase (AMPK), FAS, and carnitine palmitoyltransferase 1, coupled with increased acetyl-CoA carboxylase function with subsequent elevation of malonyl-CoA levels. This profile seems dependent of estradiol levels but not prolactin or progesterone. Despite the apparent anorexic and thermogenic signaling in the hypothalamus, pregnant rats remain hyperphagic and display reduced temperature and BAT function. Actually, pregnant rats develop resistance to the anorectic effects of central FAS inhibition, which is associated with a reduction of proopiomelanocortin (POMC) expression and its transcription factors phospho-signal transducer and activator of transcription 3, and phospho-forkhead box O1. This evidence demonstrates that pregnancy induces a state of resistance to the anorectic and thermogenic actions of hypothalamic cellular signals of energy surplus, which, in parallel to the already known refractoriness to leptin effects, likely contributes to gestational hyperphagia and adiposity. PMID:25535827
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Zhu, Yao; Huang, Jing Jing; Zhang, Xiao Xiao; Yan, Yu; Yin, Xiao Wei; Ping, Gu; Jiang, Wei Ming
2018-05-30
Qing Gan Zi Shen Tang (QGZST) is a famous traditional Chinese medicine formula in the Jiangsu Province Hospital of Traditional Chinese Medicine for its efficacy in treating hypertension, obesity, hyperlipidemia and insulin resistance. The current study further evaluated the effects and possible mechanisms of QGZST on epididymal white adipose tissue (eWAT) dysfunction in a high-fat-diet (HFD)-fed-spontaneously hypertensive rat (SHR) model. Results showed that QGZST significantly decreased the systolic blood pressure (SBP), mean arterial blood pressure (MAP), body weights and adipocyte size of HFD-fed SHRs. Moreover, QGZST remarkably reduced the serum levels of cholesterol, triglyceride, low-density lipoprotein cholesterol, fasting glucose, fasting insulin and HOMA-IR index, increased serum high-density lipoprotein cholesterol levels and improved glucose intolerance in HFD-fed SHRs. Furthermore, QGZST dramatically attenuated HFD-fed-induced hypersecretion of proinflammatory cytokines and hypoproduction of adiponectin in SHRs. Mechanistically, QGZST stimulated the activity of Sirtuin 1 (SIRT1) and Forkhead box protein O1 (FOXO1) and suppress the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT-enhancer-binding proteins-α(C/EBP-α), fatty acid binding protein 4 (FABP4), acetylated nuclear factor-kappa-B-p65 (acetyl-NF-кB-p65) and protein-tyrosine phosphatase 1B (PTP1B). More than that, QGZST also prevented acetyl-NF-кB-p65 nuclear accumulation. Collectively, our research demonstrated for the first time that QGZST is able to alleviate eWAT dysfunction with up-regulation of SIRT1 in HFD-fed SHRs, which might supply further insight into QGZST-mediated anti-hypertension and anti-obesity effects. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
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Lokireddy, Sudarsanareddy; Mouly, Vincent; Butler-Browne, Gillian; Gluckman, Peter D; Sharma, Mridula; Kambadur, Ravi; McFarlane, Craig
2011-12-01
Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of "cachectic-like" muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting. Therefore, in this present study we describe in further detail the mechanisms behind myostatin regulation of human skeletal muscle wasting using an in vitro human primary myotube atrophy model. Treatment of human myotube populations with myostatin promoted dramatic myotubular atrophy. Mechanistically, myostatin-induced myotube atrophy resulted in reduced p-AKT concomitant with the accumulation of active dephosphorylated Forkhead Box-O (FOXO1) and FOXO3. We further show that addition of myostatin results in enhanced activation of atrogin-1 and muscle-specific RING finger protein 1 (MURF1) and reduced expression of both myosin light chain (MYL) and myosin heavy chain (MYH). In addition, we found that myostatin-induced loss of MYL and MYH proteins is dependent on the activity of the proteasome and mediated via SMAD3-dependent regulation of FOXO1 and atrogin-1. Therefore, these data suggest that the mechanism through which myostatin promotes muscle wasting is very well conserved between species, and that myostatin-induced human myotube atrophy is mediated through inhibition of insulin-like growth factor (IGF)/phosphoinositide 3-kinase (PI3-K)/AKT signaling and enhanced activation of the ubiquitin-proteasome pathway and elevated protein degradation.
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FABP4 induces asthmatic airway epithelial barrier dysfunction via ROS-activated FoxM1.
Wu, Gaohui; Yang, Liteng; Xu, Yi; Jiang, Xiaohong; Jiang, Xiaomin; Huang, Lisha; Mao, Ling; Cai, Shaoxi
2018-01-01
Functional abnormal airway epithelial cells, along with activated inflammatory cells, resulting in chronic airway inflammation, are considered as the characteristic of asthma. Fatty Acid Binding Protein 4 (FABP4) takes part in glucose and lipid homeostasis, and also have an important role in allergic airway inflammation. However, whether FABP4 influence barrier function of airway epithelial cells is unknown. In vivo, a HDM-induced murine model of asthma was obtained to assessed airway inflammation and protein expression of E-cadherin and Forkhead Box M1 (FoxM1). In vitro, 16-HBE was cultured and was treated with hrFABP4, siFABP4, FABPF4 inhibitor BMS, or FoxM1 inhibitor RCM-1. IL-4, IL-5, and IL-13 level was determined by ELISA. Transepithelial electrical resistance (TER), paracellular permeability and E-cadherin-special immunofluorescence were measured to value airway epithelial barrier function. Intracellular ROS production was determined by DCF-DA fluorescence. FABP4 inhibitor BMS alleviate airway inflammation and destruction of E-cad in allergic mouse. Treatment with HDM or hrFABP4 aggravated inflammatory response, damaged airway epithelial barrier, which could be inhibited by siFABP4 and BMS. Treatment with HDM or hrFABP4 also enhanced levels of FoxM1, and Inhibited FoxM1 suppressed HDM- and hrFABP4-induced inflammation and airway epithelial barrier dysfunction. In addition, H 2 O 2 promoted FoxM1 expression, HDM and hrFABP4 induced-FoxM1 could be inhibited by NAC, leading to decreased inflammation and improved airway epithelial barrier. Upregulated ROS induced by FABP4 was of significance in activating FoxM1 leading to airway inflammation and epithelial barrier dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.
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Prakash, Prem; Singh, Vishal; Jain, Manish; Rana, Minakshi; Khanna, Vivek; Barthwal, Manoj Kumar; Dikshit, Madhu
2014-03-15
High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α/β, peroxisome proliferator-activated receptor (PPAR)-α, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-β, fatty acid synthase (FAS) and PPARγ genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-γ] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1α/β and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury. Copyright © 2014 Elsevier B.V. All rights reserved.
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Effects of spaceflight on murine skeletal muscle gene expression
Allen, David L.; Bandstra, Eric R.; Harrison, Brooke C.; Thorng, Seiha; Stodieck, Louis S.; Kostenuik, Paul J.; Morony, Sean; Lacey, David L.; Hammond, Timothy G.; Leinwand, Leslie L.; Argraves, W. Scott; Bateman, Ted A.; Barth, Jeremy L.
2009-01-01
Spaceflight results in a number of adaptations to skeletal muscle, including atrophy and shifts toward faster muscle fiber types. To identify changes in gene expression that may underlie these adaptations, we used both microarray expression analysis and real-time polymerase chain reaction to quantify shifts in mRNA levels in the gastrocnemius from mice flown on the 11-day, 19-h STS-108 shuttle flight and from normal gravity controls. Spaceflight data also were compared with the ground-based unloading model of hindlimb suspension, with one group of pure suspension and one of suspension followed by 3.5 h of reloading to mimic the time between landing and euthanization of the spaceflight mice. Analysis of microarray data revealed that 272 mRNAs were significantly altered by spaceflight, the majority of which displayed similar responses to hindlimb suspension, whereas reloading tended to counteract these responses. Several mRNAs altered by spaceflight were associated with muscle growth, including the phosphatidylinositol 3-kinase regulatory subunit p85α, insulin response substrate-1, the forkhead box O1 transcription factor, and MAFbx/atrogin1. Moreover, myostatin mRNA expression tended to increase, whereas mRNA levels of the myostatin inhibitor FSTL3 tended to decrease, in response to spaceflight. In addition, mRNA levels of the slow oxidative fiber-associated transcriptional coactivator peroxisome proliferator-associated receptor (PPAR)-γ coactivator-1α and the transcription factor PPAR-α were significantly decreased in spaceflight gastrocnemius. Finally, spaceflight resulted in a significant decrease in levels of the microRNA miR-206. Together these data demonstrate that spaceflight induces significant changes in mRNA expression of genes associated with muscle growth and fiber type. PMID:19074574
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FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase
Doan, Khanh V.; Kinyua, Ann W.; Yang, Dong Joo; Ko, Chang Mann; Moh, Sang Hyun; Shong, Ko Eun; Kim, Hail; Park, Sang-Kyu; Kim, Dong-Hoon; Kim, Inki; Paik, Ji-Hye; DePinho, Ronald A.; Yoon, Seul Gi; Kim, Il Yong; Seong, Je Kyung; Choi, Yun-Hee; Kim, Ki Woo
2016-01-01
Dopaminergic (DA) neurons are involved in the integration of neuronal and hormonal signals to regulate food consumption and energy balance. Forkhead transcriptional factor O1 (FoxO1) in the hypothalamus plays a crucial role in mediation of leptin and insulin function. However, the homoeostatic role of FoxO1 in DA system has not been investigated. Here we report that FoxO1 is highly expressed in DA neurons and mice lacking FoxO1 specifically in the DA neurons (FoxO1 KODAT) show markedly increased energy expenditure and interscapular brown adipose tissue (iBAT) thermogenesis accompanied by reduced fat mass and improved glucose/insulin homoeostasis. Moreover, FoxO1 KODAT mice exhibit an increased sucrose preference in concomitance with higher dopamine and norepinephrine levels. Finally, we found that FoxO1 directly targets and negatively regulates tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of the catecholamine synthesis, delineating a mechanism for the KO phenotypes. Collectively, these results suggest that FoxO1 in DA neurons is an important transcriptional factor that directs the coordinated control of energy balance, thermogenesis and glucose homoeostasis. PMID:27681312
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Kato, Taigo; Inoue, Hiroyuki; Imoto, Seiya; Tamada, Yoshinori; Miyamoto, Takashi; Matsuo, Yo; Nakamura, Yusuke; Park, Jae-Hyun
2016-01-01
T–lymphokine-activated killer cell–originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects. PMID:26933922
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Kato, Taigo; Inoue, Hiroyuki; Imoto, Seiya; Tamada, Yoshinori; Miyamoto, Takashi; Matsuo, Yo; Nakamura, Yusuke; Park, Jae-Hyun
2016-04-05
T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects.
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High expression of FOXP3 in primary melanoma is associated with tumour progression.
Gerber, A L; Münst, A; Schlapbach, C; Shafighi, M; Kiermeir, D; Hüsler, R; Hunger, R E
2014-01-01
The antitumour immune response plays an important role in the prognosis of melanoma. High numbers of circulating regulatory T cells have been associated with rapid disease progression. To assess the influence of forkhead box protein (FOXP)3, CD1a and langerin expression on the prognosis of primary melanoma. We analysed 185 primary melanomas by immunohistochemical staining for expression of the regulatory T-cell marker FOXP3 and the dendritic cell markers langerin and CD1a, and correlated marker expression with clinical outcome. Disease-free survival and overall survival were significantly longer in patients expressing low levels of FOXP3 in the primary melanoma, whereas they were associated with high expression of CD1a. The negative prognostic value of FOXP3 expression was independent of the Breslow tumour thickness. Langerin expression did not correlate with the clinical outcome. High expression of FOXP3 in the primary melanoma may be used as an additional independent prognostic marker for early tumour progression in patients with melanoma. © 2013 British Association of Dermatologists.
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Watanabe, Hideo; Francis, Joshua M.; Woo, Michele S.; Etemad, Banafsheh; Lin, Wenchu; Fries, Daniel F.; Peng, Shouyong; Snyder, Eric L.; Tata, Purushothama Rao; Izzo, Francesca; Schinzel, Anna C.; Cho, Jeonghee; Hammerman, Peter S.; Verhaak, Roel G.; Hahn, William C.; Rajagopal, Jayaraj; Jacks, Tyler; Meyerson, Matthew
2013-01-01
The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To study the transcriptional impact of NKX2-1 amplification, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma and analyzed DNA-binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation. Integration of these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1. Further cistromic and overexpression analyses indicated that NKX2-1 can cooperate with the forkhead box transcription factor FOXA1 to regulate LMO3 gene expression. RNAi analysis of NKX2-1-amplified cells compared with nonamplified cells demonstrated that LMO3 mediates cell survival downstream from NKX2-1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transcriptional signal transducer in NKX2-1-amplified lung adenocarcinomas. PMID:23322301
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Aas, Ida Bergva; Austbø, Lars; Falk, Knut; Hordvik, Ivar; Koppang, Erling Olaf
2017-11-01
Central and peripheral immune tolerance is together with defense mechanisms a hallmark of all lymphoid tissues. In fish, such tolerance is especially important in the gills, where the intimate contact between gill tissue and the aqueous environment would otherwise lead to continual immune stimulation by innocuous antigens. In this paper, we focus on the expression of genes associated with immune regulation by the interbranchial lymphoid tissue (ILT) in an attempt to understand its role in maintaining immune homeostasis. Both healthy and virus-challenged fish were investigated, and transcript levels were examined from laser-dissected ILT, gills, head kidney and intestine. Lack of Aire expression in the ILT excluded its involvement in central tolerance and any possibility of its being an analogue to the thymus. On the other hand, the ILT appears to participate in peripheral immune tolerance due to its relatively high expression of forkhead box protein 3 (Foxp3) and other genes associated with regulatory T cells (Tregs) and immune suppression. Copyright © 2017 Elsevier Ltd. All rights reserved.
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FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis.
Tan, BeeShin; Anaka, Matthew; Deb, Siddhartha; Freyer, Claudia; Ebert, Lisa M; Chueh, Anderly C; Al-Obaidi, Sheren; Behren, Andreas; Jayachandran, Aparna; Cebon, Jonathan; Chen, Weisan; Mariadason, John M
2014-01-15
The Forkhead box P3 (FOXP3) transcription factor is the key driver of regulatory T cell (Treg cells) differentiation and immunosuppressive function. In addition, FOXP3 has been reported to be expressed in many tumors, including melanoma. However, its role in tumorigenesis is conflicting, with both tumor suppressive and tumor promoting functions described. The aim of the current study was to characterize the expression and function of FOXP3 in melanoma. FOXP3 expression was detected by immunohistochemistry (IHC) in 12% (18/146) of stage III and IV melanomas. However expression was confined to fewer than 1% of cells in these tumors. Stable over-expression of FOXP3 in the SK-MEL-28 melanoma cell line reduced cell proliferation and clonogenicity in vitro, and reduced xenograft growth in vivo. FOXP3 over-expression also increased pigmentation and the rate of apoptosis of SK-MEL-28 cells. Based on its infrequent expression in human melanoma, and its growth inhibitory and pro-apoptotic effect in over-expressing melanoma cells, we conclude that FOXP3 is not likely to be a key tumor suppressor or promoter in melanoma.
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Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.
Bacon, C; Schneider, M; Le Magueresse, C; Froehlich, H; Sticht, C; Gluch, C; Monyer, H; Rappold, G A
2015-05-01
Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.
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Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response.
Laidlaw, Brian J; Lu, Yisi; Amezquita, Robert A; Weinstein, Jason S; Vander Heiden, Jason A; Gupta, Namita T; Kleinstein, Steven H; Kaech, Susan M; Craft, Joe
2017-10-20
CD4 + follicular regulatory T (T fr ) cells suppress B cell responses through modulation of follicular helper T (T fh ) cells and germinal center (GC) development. We found that T fr cells can also promote the GC response through provision of interleukin-10 (IL-10) after acute infection with lymphocytic choriomeningitis virus (LCMV). Sensing of IL-10 by B cells was necessary for optimal development of the GC response. GC B cells formed in the absence of T reg cell-derived IL-10 displayed an altered dark zone state and decreased expression of the transcription factor Forkhead box protein 1 (FOXO1). IL-10 promoted nuclear translocation of FOXO1 in activated B cells. These data indicate that T fr cells play a multifaceted role in the fine-tuning of the GC response and identify IL-10 as an important mediator by which T fr cells support the GC reaction. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Liu, Kuisheng; Sun, Yuanyuan; Liu, Dahai; Ye, Shoudong
2017-08-26
Inhibition of Wnt/β-catenin signaling facilitates the derivation of mouse epiblast stem cells (EpiSCs), as well as dramatically promotes EpiSC self-renewal. The specific mechanism, however, is still unclear. Here, we showed that IWR1, a Wnt/β-catenin signaling inhibitor, allowed long-term self-renewal of EpiSCs in serum medium in combination with ROCK inhibitor Y27632. Through transcriptome data analysis, we arrived at a set of candidate transcription factors induced by IWR1. Among these, Forkhead box D3 (Foxd3) was most abundant. Forced expression of Foxd3 could recapitulate the self-renewal-promoting effect of IWR1 in EpiSCs. Conversely, knockdown of Foxd3 profoundly compromised responsiveness to IWR1, causing extinction of pluripotency markers and emergence of differentiation phenotype. Foxd3 thus is necessary and sufficient to mediate self-renewal downstream of Wnt/β-catenin signaling inhibitor. These findings highlight an important role for Foxd3 in regulating EpiSCs and will expand current understanding of the primed pluripotency. Copyright © 2017 Elsevier Inc. All rights reserved.
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Lozano, Reymundo; Vino, Arianna; Lozano, Cristina; Fisher, Simon E; Deriziotis, Pelagia
2015-12-01
FOXP1 (forkhead box protein P1) is a transcription factor involved in the development of several tissues, including the brain. An emerging phenotype of patients with protein-disrupting FOXP1 variants includes global developmental delay, intellectual disability and mild to severe speech/language deficits. We report on a female child with a history of severe hypotonia, autism spectrum disorder and mild intellectual disability with severe speech/language impairment. Clinical exome sequencing identified a heterozygous de novo FOXP1 variant c.1267_1268delGT (p.V423Hfs*37). Functional analyses using cellular models show that the variant disrupts multiple aspects of FOXP1 activity, including subcellular localization and transcriptional repression properties. Our findings highlight the importance of performing functional characterization to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders. Moreover, our data support the hypothesis that de novo variants represent significant causal factors in severe sporadic disorders and extend the phenotype seen in individuals with FOXP1 haploinsufficiency.
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Tian, Natasha M; Pratt, Thomas; Price, David J
2008-12-01
Mammalian binocular vision relies on the divergence of retinal ganglion cell axons at the optic chiasm, with strictly controlled numbers projecting contralaterally and ipsilaterally. In mouse, contralateral projections arise from the entire retina, whereas ipsilateral projections arise from ventrotemporal retina. We investigate how development of these patterns of projection is regulated by the contralateral determinant Foxg1, a forkhead box transcription factor expressed in nasal retina and at the chiasm. In nasal retina, loss of Foxg1 causes increased numbers of ipsilateral projections and ectopic expression of the ipsilateral determinants Zic2, Ephb1 and Foxd1, indicating that nasal retina is competent to express an ipsilateral program that is normally suppressed by Foxg1. Using co-cultures that combine Foxg1-expressing with Foxg1-null retinal explants and chiasm cells, we provide functional evidence that Foxg1 promotes contralateral projections through actions in nasal retina, and that in chiasm cells, Foxg1 is required for the generation of a hitherto unrecognized activity supporting RGC axon growth.
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Treg functional stability and its responsiveness to the microenvironment
Barbi, Joseph; Pardoll, Drew M.; Pan, Fan
2014-01-01
Summary Regulatory T cells (Tregs) prevent autoimmunity and tissue damage resulting from excessive or unnecessary immune activation through their suppressive function. While their importance for proper immune control is undeniable, the stability of the Treg lineage has recently become a controversial topic. Many reports have shown dramatic loss of the signature Treg transcription factor Forkhead box protein 3 (Foxp3) and Treg function under various inflammatory conditions. Other recent studies demonstrate that most Tregs are extremely resilient in their expression of Foxp3 and the retention of suppressive function. While this debate is unlikely to be settled in the immediate future, improved understanding of the considerable heterogeneity within the Foxp3+ Treg population and how Treg subsets respond to ranging environmental cues may be keys to reconciliation. In this review, we discuss the diverse mechanisms responsible for the observed stability or instability of Foxp3+ Treg identity and function. These include transcriptional and epigenetic programs, transcript targeting and posttranslational modifications that appear responsive to numerous elements of the microenvironment. These mechanisms for Treg functional modulation add to the discussion of Treg stability. PMID:24712463
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Liu, Yu; Han, Lili; Bai, Yahui; Du, Wei; Yang, Bo
2018-02-01
miRNAs were reported as oncogene or tumour suppressors in various cancers and played important roles in tumour development and progression. Dysregulated miR-133 has been reported in several cancers, however, the expression and biological function of miR-133 in glioma remained unclear. In this study, we found that miR-133 expression level was significantly decreased in glioma tissues and cell lines by RT-qPCR. Then miR-133 mimics were used to evaluate the effects of miR-133 on cell proliferation and invasion in vitro. We found that overexpressed miR-133 could significantly suppress cell growth, and invasion in U87 cells. Additionally, we found that forkhead box C1 (FOXC1) was overexpressed in glioma tissue and it was directly regulated by miR-133. Overall, this study is the first proof to demonstrate that miR-133 function as tumour suppressor in glioma and inhibit cell proliferation and invasioned by directly targeting FOXC1, implying miR-133 as a potential therapeutic target for glioma.
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miR-133 inhibits pituitary tumor cell migration and invasion via down-regulating FOXC1 expression.
Wang, D S; Zhang, H Q; Zhang, B; Yuan, Z B; Yu, Z K; Yang, T; Zhang, S Q; Liu, Y; Jia, X X
2016-03-24
Many studies have shown that microRNA (miR)-133 functions as a tumor suppressor in a variety of metastatic cancers, including breast cancer, gastric cancer, and liver fibrosis. However, the influence of miR-133 on pituitary tumor malignancy has not yet been reported. The purpose of this study was to explore the role of miR-133 in pituitary tumor cell migration and invasive ability and the molecular mechanisms involved. Our findings suggest that in pituitary adenoma cell lines, through direct targeting and negative control of forkhead box C1 (FOXC1), miR-133 can inhibit pituitary adenoma cell migration and invasion. In addition, epithelial-to-mesenchymal transition can be induced by miR-133. Additionally, a negative correlation was found between FOXC1 and miR-133 expression when comparing their expression levels between cancerous tissue and adjacent normal tissue. This suggests that miR-133 can inhibit cell migration and invasion by directly targeting FOXC1, implying that miR-133 could be a potential therapeutic target for treatment of invasive pituitary adenoma.
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Navarro, S; Cossalter, G; Chiavaroli, C; Kanda, A; Fleury, S; Lazzari, A; Cazareth, J; Sparwasser, T; Dombrowicz, D; Glaichenhaus, N; Julia, V
2011-01-01
The prevalence of asthma has steadily increased during the last decade, probably as the result of changes in the environment, including reduced microbial exposure during infancy. Accordingly, experimental studies have shown that deliberate infections with live pathogens prevent the development of allergic airway diseases in mice. Bacterial extracts are currently used in children suffering from repeated upper respiratory tract infections. In the present study, we have investigated whether bacterial extracts, commercially available as Broncho-Vaxom (BV), could prevent allergic airway disease in mice. Oral treatment with BV suppressed airway inflammation through interleukin-10 (IL-10)-dependent and MyD88 (myeloid differentiation primary response gene (88))-dependent mechanisms and induced the conversion of FoxP3 (forkhead box P3)(-) T cells into FoxP3(+) regulatory T cells. Furthermore, CD4(+) T cells purified from the trachea of BV-treated mice conferred protection against airway inflammation when adoptively transferred into sensitized mice. Therefore, treatment with BV could possibly be a safe and efficient strategy to prevent the development of allergic diseases in children.
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Zhang, X; Zhang, L; Du, Y; Zheng, H; Zhang, P; Sun, Y; Wang, Y; Chen, J; Ding, P; Wang, N; Yang, C; Huang, T; Yao, X; Qiao, Q; Gu, H; Cai, G; Cai, S; Zhou, X; Hu, W
2017-01-01
Epithelial–mesenchymal transition (EMT) is a critical event in metastasis of colorectal cancer (CRC). Rho/ROCKs signaling has a pivotal role in orchestrating actin cytoskeleton, leading to EMT and cancer invasion. However, the underlying mechanisms for ROCKs activation are not fully understood. Here, we identified FOXM1D, a novel isoform of Forkhead box M1 (FOXM1) that has a pivotal role in ROCKs activation by directly interacting with coiled-coil region of ROCK2. FOXM1D overexpression significantly polymerizes actin assembly and impairs E-cadherin expression, resulting in EMT and metastasis in xenograft mouse model and knockdown of FOXM1D has the opposite effect. Moreover, a high FOXM1D level correlates closely with clinical CRC metastasis. FOXM1D-induced ROCKs activation could be abrogated by the ROCKs inhibitors Y-27632 and fasudil. These observations indicate that the FOXM1D–ROCK2 interaction is crucial for Rho/ROCKs signaling and provide novel insight into actin cytoskeleton regulation and therapeutic potential for CRC metastasis. PMID:27399334
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Katz, Gil; Voss, Kelsey; Yan, Toria F; Kim, Yong Chan; Kortum, Robert L; Scott, David W; Snow, Andrew L
2018-05-01
Restimulation-induced cell death (RICD) is an apoptotic program that regulates effector T cell expansion, triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). Although CD4 + regulatory T cells (Tregs) consume IL-2 and experience frequent TCR stimulation, they are highly resistant to RICD. Resistance in Tregs is dependent on the forkhead box P3 (FOXP3) transcription factor, although the mechanism remains unclear. T cells from patients with X-linked lymphoproliferative disease (XLP-1), that lack the adaptor molecule SLAM-associated protein (SAP), are also resistant to RICD. Here we demonstrate that normal Tregs express very low levels of SAP compared to conventional T cells. FOXP3 reduces SAP expression by directly binding to and repressing the SH2D1A (SAP) promoter. Indeed, ectopic SAP expression restores RICD sensitivity in human FOXP3 + Tregs. Our findings illuminate the mechanism behind FOXP3-mediated RICD resistance in Tregs, providing new insight into their long-term persistence. Published by Elsevier Inc.
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Park, YoungJoon; Won, SeongSik; Nam, Min; Chung, Joo-Ho; Kwack, KyuBum
2014-12-01
Expression levels of monoamine oxidase A (MAOA), the enzyme that related to monoamine neurotransmitters metabolism such as serotonin, are related to schizophrenia and autism spectrum disorder. Forkhead box protein P2 (FOXP2), a transcription factor, is associated with abnormal language development and is expressed in several areas of the central nervous system in response to serotonin. For this reason, we undertook interaction analysis between MAOA and FOXP2 in autism spectrum disorder, including testing the verbal communication score of the childhood autism rating scale. In interaction analysis, the FOXP2-TCGC (rs12531289-rs1350135-rs10230087-rs2061183) diplotype and MAOA-TCG (rs6323-rs1801291-rs3027407) haplotype were significantly associated with autism spectrum disorder in males. However, when the interaction term was omitted, neither MAOA nor FOXP2 was associated with autism spectrum disorder or verbal communication. These results indicate that language and speech ability is affected by an interaction between FOXP2 and MAOA, but not by either gene separately. © The Author(s) 2013.
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Xu, Sha-Sha; Liu, Qing-Mei; Xiao, An-Feng; Maleki, Soheila J; Alcocer, Marcos; Gao, Yuan-Yuan; Cao, Min-Jie; Liu, Guang-Ming
2017-04-19
In the present study, the anti-food allergy activity of Eucheuma cottonii sulfated oligosaccharide (ESO) was investigated. ESO was obtained by enzymatic degradation and purified by column chromatography. RBL-2H3 cells and BALB/c mouse model were used to test the anti-food allergy activity of ESO. The effects of ESO on the regulatory T (Treg) cells and bone marrow-derived mast cells (BMMCs) were investigated by flow cytometry. The results of in vivo assay showed that ESO decreased the levels of mast cell protease-1 and histamine and inhibited the levels of specific IgE by 77.7%. In addition, the production of interleukin (IL)-4 and IL-13 was diminished in the ESO groups compared to the non-ESO-treated group. Furthermore, ESO could up-regulate Treg cells by 22.2-97.1%. In conclusion, ESO decreased the allergy response in mice by reducing basophil degranulation, up-regulating Treg cells via Forkhead box protein 3 (Foxp3), and releasing IL-10. ESO may have preventive and therapeutic potential in allergic disease.
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Chen, Meng-Ting; Sun, He-Fen; Li, Liang-Dong; Zhao, Yang; Yang, Li-Peng; Gao, Shui-Ping; Jin, Wei
2018-06-01
Cancer metastasis and relapse are the primary cause of mortality for patients with breast cancer. The present study performed quantitative proteomic analysis on the differentially expressed proteins between highly metastatic breast cancer cells and parental cells. It was revealed that forkhead box P2 (FOXP2), a transcription factor in neural development, may become a potential inhibitor of breast cancer metastasis. The results demonstrated that patients with a lower level of FOXP2 expression had significantly poorer relapse-free survival (P=0.0047). The transcription of FOXP2 was also significantly downregulated in breast cancer tissue compared with normal breast tissue (P=0.0005). In addition, FOXP2 may inhibit breast cancer cell migration and invasion in vitro . It was also revealed that the underlying mechanism may include the epithelial-mesenchymal transition process driven by the tumor growth factor β/SMAD signaling pathway. In conclusion, the present study identified FOXP2 as a novel suppressor and prognostic marker of breast cancer metastasis. These results may provide further insight into breast cancer prevention and the development of novel treatments.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Chu, Tian-Li; Zhao, Hong-Meng; Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin
2014-04-04
Highlights: • FOXD3 is down-regulated in breast cancer tissues. • FOXD3 inhibits breast cancer cell proliferation and invasion. • FoxD3 deficiency induces epithelial–mesenchymal transition. - Abstract: The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3more » expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial–mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy.« less
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Tregs: Where We Are and What Comes Next?
Zhao, Hai; Liao, Xuelian; Kang, Yan
2017-01-01
Regulatory T cells are usually recognized as a specialized subset of CD4 + T cells functioning in establishment and maintenance of immune tolerance. Meanwhile, there is emerging evidence that regulatory T cells (Tregs) are also present in various non-lymphoid tissues, and that they have unique phenotypes credited with activities distinct from regulatory function. Their development and function have been described in plenty of manuscripts in the past two decades. However, with the deepening of research in recent years, emerging evidence revealed some novel mechanisms about how Tregs exert their activities. First, we discuss the expanding family of regulatory lymphocytes briefly and then, try to interpret how fork-head box P3 (Foxp3), a master regulator of the regulatory pathway in the development and function of regulatory T cells, functions. Subsequently, another part of our focus is varieties of tissue Tregs. Next, we primarily discuss recent research on how Tregs work and their faceted functions in terms of soluble mediators, functional proteins, and inhibitory receptors. In particular, unless otherwise noted, the term "Treg" is used here to refer specially to the "CD4 + CD25 + Foxp3 +" regulatory cells.
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A holistic review on the autoimmune disease vitiligo with emphasis on the causal factors.
Patel, Seema; Rauf, Abdur; Khan, Haroon; Meher, Biswa Ranjan; Hassan, Syed Shams Ul
2017-08-01
Vitiligo is an idiopathic systemic autoimmune disease affecting skin, hair and oral mucosa. This genetic yet acquired disease characterized by melanin loss is a cause of morbidity across all races. Though thyroid disturbance has been recognized as a key trigger of this pathology, an array of other factors plays critical role in its manifestation. Multiple hormones (corticotropin-releasing hormone, adrenocorticotropic hormone, α-melanocyte-stimulating hormone, melatonin, calcitriol, testosterone, estrogen), genes (Human leukocyte antigen (HLA), Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), Forkhead box D3 (FOXD3), Cluster of differentiation 117 (CD117), Estrogen receptor (ESR) 1, Cyclooxygenase-2 (COX2), Vitiligo-associated protein 1 (VIT1)), and lifestyle choices (stress, diet, cosmetic products, and medications) have been suspected as drivers of this disorder. The pathological mechanisms have been understood in recent times, with the aid of genomic studies; however a universally-effective therapy is yet to be achieved. This review discusses these under-investigated facets of vitiligo onset and progression; hence, it is expected to enrich vitiligo research. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
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ERIC Educational Resources Information Center
Rule, Audrey C.; Crisafulli, Sherry; DeCare, Heather; DeLeo, Tonya; Eastman, Keri; Farrell, Liz; Geblein, Jennifer; Gioia, Chelsea; Joyce, Ashley; Killian, Kali; Knoop, Kelly; LaRocca, Alison; Meyer, Katie; Miller, Julianne; Roth, Vicki; Throo, Julie; Van Arsdale, Jim; Walker, Malissa
2007-01-01
Descriptive vocabulary is needed for communication and mental processing of science observations. Elementary preservice teachers in a science methods class at a mid-sized public college in central New York State increased their descriptive vocabularies through a course assignment of making a descriptive adjective object box. This teaching material…
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49 CFR 174.101 - Loading Class 1 (explosive) materials.
Code of Federal Regulations, 2010 CFR
2010-10-01
... point on a small area of another box. (b) Explosive bombs, unfuzed projectiles, rocket ammunition and... large metal packages of incendiary bombs, each weighing 226 kg (500 pounds) or more, may be loaded in stock cars or in flat bottom gondola cars only if they are adequately braced. Boxed bombs, rocket...
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Technologies for Teaching and Learning about Box Plots and Statistical Analysis
ERIC Educational Resources Information Center
Forster, Patricia A.
2007-01-01
This paper analyses technology-based instruction on data-analysis with box plots. Examples of instruction taken from the research literature inform a study of two classes of 17 year-old students (upper secondary) in which the mathematical relationships that their teachers targeted are distinguished as being, or not being, relevant to statistical…
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Augmented twin-nonlinear two-box behavioral models for multicarrier LTE power amplifiers.
Hammi, Oualid
2014-01-01
A novel class of behavioral models is proposed for LTE-driven Doherty power amplifiers with strong memory effects. The proposed models, labeled augmented twin-nonlinear two-box models, are built by cascading a highly nonlinear memoryless function with a mildly nonlinear memory polynomial with cross terms. Experimental validation on gallium nitride based Doherty power amplifiers illustrates the accuracy enhancement and complexity reduction achieved by the proposed models. When strong memory effects are observed, the augmented twin-nonlinear two-box models can improve the normalized mean square error by up to 3 dB for the same number of coefficients when compared to state-of-the-art twin-nonlinear two-box models. Furthermore, the augmented twin-nonlinear two-box models lead to the same performance as previously reported twin-nonlinear two-box models while requiring up to 80% less coefficients.
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50 CFR 2.2 - Locations of regional offices.
Code of Federal Regulations, 2011 CFR
2011-10-01
...—comprising the States of Arizona, New Mexico, Oklahoma and Texas), 500 Gold Avenue, SW, Room 9018 (P.O. Box... Regional Office (Region 6—comprising the States of Colorado, Kansas, Montana, Nebraska, North Dakota, South Dakota, Utah and Wyoming), 134 Union Boulevard (P.O. Box 25486), Denver Federal Center, Denver, Colorado...
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50 CFR 2.2 - Locations of regional offices.
Code of Federal Regulations, 2012 CFR
2012-10-01
...—comprising the States of Arizona, New Mexico, Oklahoma and Texas), 500 Gold Avenue, SW, Room 9018 (P.O. Box... Regional Office (Region 6—comprising the States of Colorado, Kansas, Montana, Nebraska, North Dakota, South Dakota, Utah and Wyoming), 134 Union Boulevard (P.O. Box 25486), Denver Federal Center, Denver, Colorado...
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50 CFR 2.2 - Locations of regional offices.
Code of Federal Regulations, 2010 CFR
2010-10-01
...—comprising the States of Arizona, New Mexico, Oklahoma and Texas), 500 Gold Avenue, SW, Room 9018 (P.O. Box... Regional Office (Region 6—comprising the States of Colorado, Kansas, Montana, Nebraska, North Dakota, South Dakota, Utah and Wyoming), 134 Union Boulevard (P.O. Box 25486), Denver Federal Center, Denver, Colorado...
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7 CFR 980.117 - Import regulations; onions.
Code of Federal Regulations, 2010 CFR
2010-01-01
... Texas points Officer-in-charge, 1301 West Expressway, Alamo, Tex. 78516. Phone 512-787-4091 or 512-787-6881 1 All Arizona points Officer-in-charge, P.O. Box 1614, Nogales, Ariz. 85621. Phone 602-287-4783 1.... Phone 213-688-2489 3 All Hawaii points Officer-in-charge, P.O. Box 22159, Pawaa Substation, Honolulu...
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5 CFR Appendix A to Part 582 - List of Agents Designated To Accept Legal Process
Code of Federal Regulations, 2011 CFR
2011-01-01
... Center, Office of General Counsel, Attention: Code L, P.O. Box 998002, Cleveland, OH 44199-8002, (216... Agency (DCAA) and the Defense Logistics Agency (DLA) who are employed outside the United States: See..., Bureau of Reclamation. Administrative Service Center, Department of the Interior, P.O. Box 272030, 7201...
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5 CFR Appendix A to Part 582 - List of Agents Designated To Accept Legal Process
Code of Federal Regulations, 2013 CFR
2013-01-01
... Center, Office of General Counsel, Attention: Code L, P.O. Box 998002, Cleveland, OH 44199-8002, (216... Agency (DCAA) and the Defense Logistics Agency (DLA) who are employed outside the United States: See..., Bureau of Reclamation. Administrative Service Center, Department of the Interior, P.O. Box 272030, 7201...
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5 CFR Appendix A to Part 582 - List of Agents Designated To Accept Legal Process
Code of Federal Regulations, 2012 CFR
2012-01-01
... Center, Office of General Counsel, Attention: Code L, P.O. Box 998002, Cleveland, OH 44199-8002, (216... Agency (DCAA) and the Defense Logistics Agency (DLA) who are employed outside the United States: See..., Bureau of Reclamation. Administrative Service Center, Department of the Interior, P.O. Box 272030, 7201...
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5 CFR Appendix A to Part 582 - List of Agents Designated To Accept Legal Process
Code of Federal Regulations, 2010 CFR
2010-01-01
... Center, Office of General Counsel, Attention: Code L, P.O. Box 998002, Cleveland, OH 44199-8002, (216... Agency (DCAA) and the Defense Logistics Agency (DLA) who are employed outside the United States: See..., Bureau of Reclamation. Administrative Service Center, Department of the Interior, P.O. Box 272030, 7201...
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5 CFR Appendix A to Part 582 - List of Agents Designated To Accept Legal Process
Code of Federal Regulations, 2014 CFR
2014-01-01
... Center, Office of General Counsel, Attention: Code L, P.O. Box 998002, Cleveland, OH 44199-8002, (216... Agency (DCAA) and the Defense Logistics Agency (DLA) who are employed outside the United States: See..., Bureau of Reclamation. Administrative Service Center, Department of the Interior, P.O. Box 272030, 7201...
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30 CFR 218.51 - How to make payments.
Code of Federal Regulations, 2010 CFR
2010-07-01
....O. Box 5640, Denver, CO 80217-5640. (3) For all other Federal and Indian lease payments other than... Management, P.O. Box 5810, Denver, CO 80217-5810. (e) Where to send a non-EFT payment when you use a courier or overnight delivery service. You should send this type of payment to: Minerals Management Service...
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40 CFR 49.24 - Federal Implementation Plan Provisions for Navajo Generating Station, Navajo Nation.
Code of Federal Regulations, 2011 CFR
2011-07-01
... in a log. (f) Reporting and recordkeeping requirements. Unless otherwise stated all requests, reports... shall be submitted to the Director, Navajo Environmental Protection Agency, P.O. Box 339, Window Rock... to the Director, Navajo Environmental Protection Agency, by mail to: P.O. Box 339, Window Rock...
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75 FR 13282 - Pesticide Products; Registration Applications
Federal Register 2010, 2011, 2012, 2013, 2014
2010-03-19
.... Company name and address: Arysta LifeScience, North Americal LLC, 15401 Weston Parkway, Suite 150, Cary... CropScience, P.O. Box 12014, 2 T.W. Alexander Drive, Research Triangle Park, NC 27709. Active...: EPA-HQ-OPP-2008-0262. Company name and address: Bayer CropScience, P.O. Box 12014, 2T.W. Alexander...
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75 FR 11884 - Pesticide Products; Registration Applications
Federal Register 2010, 2011, 2012, 2013, 2014
2010-03-12
.... Company Name and Address: Arysta LifeScience North America, 15401 Weston Parkway, Suite 150, Cary, NC... Number: EPA-HQ-OPP-2009-0279. Company Name and Address: Bayer CropScience, P.O. Box 12014, 2 T.W...: Bayer CropScience, P.O. Box 12014, 2 T.W. Alexander Drive, Research Triangle Park, NC 27709. Active...
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40 CFR Appendix A to Subpart E of... - References
Code of Federal Regulations, 2011 CFR
2011-07-01
... Servicing, ANSI/ISO/ASQC Q9001-1994. Available from American Society for Quality, P.O. Box 3005, Milwaukee... Environmental Data and Technology Programs—Requirements with guidance for use, ANSI/ASQC E4-2004. Available from American Society for Quality, P.O. Box 3005, Milwaukee, WI 53202 (http://qualitypress.asq.org). (3) Quality...
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76 FR 16415 - Product Cancellation Order for Certain Pesticide Registrations
Federal Register 2010, 2011, 2012, 2013, 2014
2011-03-23
... Cube Resins other than rotenone. Rotenone. 000869-00186 Green Light Rotenone... Cube Resins other than..., Inc., P.O. Box 1019, Salem, VA 24153-3805. 270 Farnam Companies, Inc., 301 West Osborn Road, Phoenix, AZ 85013. 769 Value Gardens Supply, LLC, P.O. Box 585, Saint Joseph, MO 64502. 869 Green Light...
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40 CFR Appendix A to Subpart A of... - References
Code of Federal Regulations, 2014 CFR
2014-07-01
...-1994. Available from American Society for Quality, P.O. Box 3005, Milwaukee, WI 53202 (http... P.O. Box 3005, Milwaukee, WI 53202 (http://qualitypress.asq.org). (3) Dimensioning and Tolerancing... available at http://www.epa.gov/ttn/amtic/pmqainf.html. [62 FR 38784, July 18, 1997, as amended at 71 FR...
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40 CFR Appendix A to Subpart A of... - References
Code of Federal Regulations, 2012 CFR
2012-07-01
...-1994. Available from American Society for Quality, P.O. Box 3005, Milwaukee, WI 53202 (http... P.O. Box 3005, Milwaukee, WI 53202 (http://qualitypress.asq.org). (3) Dimensioning and Tolerancing... available at http://www.epa.gov/ttn/amtic/pmqainf.html. [62 FR 38784, July 18, 1997, as amended at 71 FR...
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40 CFR Appendix A to Subpart A of... - References
Code of Federal Regulations, 2013 CFR
2013-07-01
...-1994. Available from American Society for Quality, P.O. Box 3005, Milwaukee, WI 53202 (http... P.O. Box 3005, Milwaukee, WI 53202 (http://qualitypress.asq.org). (3) Dimensioning and Tolerancing... available at http://www.epa.gov/ttn/amtic/pmqainf.html. [62 FR 38784, July 18, 1997, as amended at 71 FR...
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75 FR 62458 - Revision of Class E Airspace; Tanana, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-12
...-0588 Airspace Docket No. 10-AAL-16] Revision of Class E Airspace; Tanana, AK AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule. SUMMARY: This action revises Class E airspace at Tanana, AK. The... West 7th Avenue, Box 14, Anchorage, AK 99513-7587; telephone number (907) 271-5898; fax: (907) 271-2850...
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75 FR 77574 - Proposed Revision of Class E Airspace; Savoonga, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-13
...-1103Airspace Docket No. 10-AAL-18] Proposed Revision of Class E Airspace; Savoonga, AK AGENCY: Federal Aviation... proposes to revise Class E airspace at Savoonga, AK. The amendment of three Standard Instrument Approach... Operations, Federal Aviation Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587. FOR...
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76 FR 66178 - Revision of Class E Airspace; Umiat, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-26
...-0750; Airspace Docket No. 11-AAL-08] Revision of Class E Airspace; Umiat, AK AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule. SUMMARY: This action revises Class E airspace at Umiat, AK, due to...-538G, Federal Aviation Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587; telephone...
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76 FR 49387 - Proposed Amendment of Class E Airspace; Umiat, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-10
...-0750 Airspace Docket No. 11-AAL-08] Proposed Amendment of Class E Airspace; Umiat, AK AGENCY: Federal... proposes to revise Class E airspace at Umiat, AK. The cancellation of two special Instrument Approach... Operations, Federal Aviation Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587. FOR...
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75 FR 32271 - Revision of Class E Airspace; Nenana, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-08
...-0081; Airspace Docket No. 10-AAL-3] Revision of Class E Airspace; Nenana, AK AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule. SUMMARY: This action revises Class E airspace at Nenana, AK, to..., Federal Aviation Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587; telephone number...
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75 FR 77573 - Proposed Revision of Class E Airspace; Shungnak, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2010-12-13
...-1104 Airspace Docket No. 10-AAL-19] Proposed Revision of Class E Airspace; Shungnak, AK AGENCY: Federal... proposes to revise Class E airspace at Shungnak, AK. The amendment of Standard Instrument Approach... Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587. FOR FURTHER INFORMATION CONTACT: Martha...
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75 FR 12679 - Revision of Class E Airspace; Iliamna, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2010-03-17
...-1036; Airspace Docket No. 09-AAL-17] Revision of Class E Airspace; Iliamna, AK AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final rule. SUMMARY: This action revises Class E airspace at Iliamna, AK, to..., Federal Aviation Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587; telephone number...
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75 FR 33165 - Revision of Class E Airspace; Galena, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2010-06-11
...-0299; Airspace Docket No. 10-AAL-9] Revision of Class E Airspace; Galena, AK AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final Rule. SUMMARY: This action revises Class E airspace at Galena, AK, to...-538G, Federal Aviation Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587; telephone...
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76 FR 21832 - Proposed Revision of Class E Airspace; Yakutat, AK
Federal Register 2010, 2011, 2012, 2013, 2014
2011-04-19
...-0244 Airspace Docket No. 11-AAL-05] Proposed Revision of Class E Airspace; Yakutat, AK AGENCY: Federal... proposes to revise Class E airspace at Yakutat, AK. The revision of eight Standard Instrument Approach... Administration, 222 West 7th Avenue, Box 14, Anchorage, AK 99513-7587. FOR FURTHER INFORMATION CONTACT: Martha...
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1985-05-01
Bulman Army Research Office Royal Military College of Science P.O. Box 12211 Land Systems Group Research Triangle Park, NC 27709-2211 Shrivenham...Development Center P.O. Box 210 SMCAR-TSB Cumberland, M 21502 Dover, NJ 078fI1-5001 Tonney hlung Paul L. Fritch Armament Research & Development Center... Box 1201 Edward M. Patton San Jose, CA 95108 Battelle, Pacific Northwest Labs Battelle Road Frak Kiihl Richland, WA 99352 , Armament Research
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Sheikh, M Osman; Thieker, David; Chalmers, Gordon; Schafer, Christopher M; Ishihara, Mayumi; Azadi, Parastoo; Woods, Robert J; Glushka, John N; Bendiak, Brad; Prestegard, James H; West, Christopher M
2017-11-17
Skp1 is a conserved protein linking cullin-1 to F-box proteins in SCF ( S kp1/ C ullin-1/ F -box protein) E3 ubiquitin ligases, which modify protein substrates with polyubiquitin chains that typically target them for 26S proteasome-mediated degradation. In Dictyostelium (a social amoeba), Toxoplasma gondii (the agent for human toxoplasmosis), and other protists, Skp1 is regulated by a unique pentasaccharide attached to hydroxylated Pro-143 within its C-terminal F-box-binding domain. Prolyl hydroxylation of Skp1 contributes to O 2 -dependent Dictyostelium development, but full glycosylation at that position is required for optimal O 2 sensing. Previous studies have shown that the glycan promotes organization of the F-box-binding region in Skp1 and aids in Skp1's association with F-box proteins. Here, NMR and MS approaches were used to determine the glycan structure, and then a combination of NMR and molecular dynamics simulations were employed to characterize the impact of the glycan on the conformation and motions of the intrinsically flexible F-box-binding domain of Skp1. Molecular dynamics trajectories of glycosylated Skp1 whose calculated monosaccharide relaxation kinetics and rotational correlation times agreed with the NMR data indicated that the glycan interacts with the loop connecting two α-helices of the F-box-combining site. In these trajectories, the helices separated from one another to create a more accessible and dynamic F-box interface. These results offer an unprecedented view of how a glycan modification influences a disordered region of a full-length protein. The increased sampling of an open Skp1 conformation can explain how glycosylation enhances interactions with F-box proteins in cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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Mortality resulting from head injury in professional boxing.
Baird, Lissa C; Newman, C Benjamin; Volk, Hunter; Svinth, Joseph R; Conklin, Jordan; Levy, Michael L
2010-11-01
The majority of boxing-related fatalities result from traumatic brain injury. Biomechanical forces in boxing result in rotational acceleration with resultant subdural hematoma and diffuse axonal injury. Given the inherent risk and the ongoing criticism boxing has received, we evaluated mortalities associated with professional boxing. We used the Velaquez Fatality Collection of boxing injuries and supplementary sources to analyze mortality from 1950 to 2007. Variables evaluated included age at time of death, association with knockout or other outcome of match, rounds fought, weight class, location of fight, and location of pretermial event. There were 339 mortalities between 1950 and 2007 (mean age, 24 ± 3.8 years); 64% were associated with knockout and 15% with technical knockout. A higher percentage occurred in the lower weight classes. The preterminal event occurred in the ring (61%), in the locker room (17%), and outside the arena (22%), We evaluated for significant changes after 1983 when championship bouts were reduced from 15 to 12 rounds. There was a significant decline in mortality after 1983. We found no significant variables to support that this decline is related to a reduction in rounds. Rather, we hypothesize the decline to be the result of a reduction in exposure to repetitive head trauma (shorter careers and fewer fights), along with increased medical oversight and stricter safety regulations. Increased efforts should be made to improve medical supervisions of boxers. Mandatory central nervous system imaging after a knockout could lead to a significant reduction in associated mortality.
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Mortality resulting from head injury in professional boxing: case report.
Baird, Lissa C; Newman, C Benjamin; Volk, Hunter; Svinth, Joseph R; Conklin, Jordan; Levy, Michael L
2010-08-01
The majority of boxing-related fatalities result from traumatic brain injury. Biomechanical forces in boxing result in rotational acceleration with resultant subdural hematoma and diffuse axonal injury. Given the inherent risk and the ongoing criticism boxing has received, we evaluated mortalities associated with professional boxing. We used the Velazquez Fatality Collection of boxing injuries and supplementary sources to analyze mortality from 1950 to 2007. Variables evaluated included age at time of death, association with knockout or other outcome of match, rounds fought, weight class, location of fight, and location of preterminal event. There were 339 mortalities between 1950 and 2007 (mean age, 24 +/- 3.8 years); 64% were associated with knockout and 15% with technical knockout. A higher percentage occurred in the lower weight classes. The preterminal event occurred in the ring (61%), in the locker room (17%), and outside the arena (22%). We evaluated for significant changes after 1983 when championship bouts were reduced from 15 to 12 rounds. There was a significant decline in mortality after 1983. We found no significant variables to support that this decline is related to a reduction in rounds. Rather, we hypothesize the decline to be the result of a reduction in exposure to repetitive head trauma (shorter careers and fewer fights), along with increased medical oversight and stricter safety regulations. Increased efforts should be made to improve medical supervision of boxers. Mandatory central nervous system imaging after a knockout could lead to a significant reduction in associated mortality.
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Weiler, Sofia M E; Pinna, Federico; Wolf, Thomas; Lutz, Teresa; Geldiyev, Aman; Sticht, Carsten; Knaub, Maria; Thomann, Stefan; Bissinger, Michaela; Wan, Shan; Rössler, Stephanie; Becker, Diana; Gretz, Norbert; Lang, Hauke; Bergmann, Frank; Ustiyan, Vladimir; Kalin, Tatiana V; Singer, Stephan; Lee, Ju-Seog; Marquardt, Jens U; Schirmacher, Peter; Kalinichenko, Vladimir V; Breuhahn, Kai
2017-06-01
Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves. We analyzed changes in expression of these signature genes, at mRNA and protein levels, after small interfering RNA-mediated silencing of YAP in Sk-Hep1, SNU182, HepG2, or pancreatic cancer cells, as well as incubation with thiostrepton (an inhibitor of forkhead box M1 [FOXM1]) or verteporfin (inhibitor of the interaction between YAP and TEA domain transcription factor 4 [TEAD4]). We performed co-immunoprecipitation and chromatin immunoprecipitation experiments. We collected liver tissues from mice that express a constitutively active form of YAP (YAP S127A ) and analyzed gene expression signatures and histomorphologic parameters associated with chromosomal instability. Mice were given injections of thiostrepton and livers were collected and analyzed by immunoblotting, immunohistochemistry, histology, and real-time polymerase chain reaction. We performed immunohistochemical analyses on tissue microarrays of 105 HCCs and 7 nontumor liver tissues. Gene expression patterns associated with chromosome instability, called CIN25 and CIN70, were detected in HCCs from patients with shorter survival time or early cancer recurrence. TEAD4 and YAP were required for CIN25 and CIN70 signature expression via induction and binding of FOXM1. Disrupting the interaction between YAP and TEAD4 with verteporfin, or inhibiting FOXM1 with thiostrepton, reduced the chromosome instability gene expression patterns. Hyperplastic livers and tumors from YAP S127A mice had increased CIN25 and CIN70 gene expression patterns, aneuploidy, and defects in mitosis. Injection of YAP S127A mice with thiostrepton reduced liver overgrowth and signs of chromosomal instability. In human HCC tissues, high levels of nuclear YAP correlated with increased chromosome instability gene expression patterns and aneuploidy. By analyzing cell lines, genetically modified mice, and HCC tissues, we found that YAP cooperates with FOXM1 to contribute to chromosome instability. Agents that disrupt this pathway might be developed as treatments for liver cancer. Transcriptome data are available in the Gene Expression Omnibus public database (accession numbers: GSE32597 and GSE73396). Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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ERIC Educational Resources Information Center
Pound, Linda
1989-01-01
Investigated the intentions underlying practice in the classes of 24 nursery teachers. Many of the teachers valued cognitive growth and saw children's developing social competence as supporting that growth. (RJC)
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ERIC Educational Resources Information Center
Santos, Joel; Centurio, Tina
2012-01-01
What happens in the first week of school could very well set the stage for the rest of the school year. Setting high standards for science activities based in inquiry can start on the first day of science class and develop as the year unfolds. With the use of simple, readily available, inexpensive materials, an efficient mystery box lesson can be…
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Nonlocality distillation and postquantum theories with trivial communication complexity.
Brunner, Nicolas; Skrzypczyk, Paul
2009-04-24
We first present a protocol for deterministically distilling nonlocality, building upon a recent result of Forster et al. [Phys. Rev. Lett. 102, 120401 (2009)10.1103/PhysRevLett.102.120401]. Our protocol, which is optimal for two-copy distillation, works efficiently for a specific class of postquantum nonlocal boxes, which we term correlated nonlocal boxes. In the asymptotic limit, all correlated nonlocal boxes are distilled to the maximally nonlocal box of Popescu and Rohrlich. Then, taking advantage of a result of Brassard et al. [Phys. Rev. Lett. 96, 250401 (2006)10.1103/PhysRevLett.96.250401] we show that all correlated nonlocal boxes make communication complexity trivial, and therefore appear very unlikely to exist in nature. Astonishingly, some of these nonlocal boxes are arbitrarily close to the set of classical correlations. This result therefore gives new insight to the problem of why quantum nonlocality is limited.
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Augmented Twin-Nonlinear Two-Box Behavioral Models for Multicarrier LTE Power Amplifiers
2014-01-01
A novel class of behavioral models is proposed for LTE-driven Doherty power amplifiers with strong memory effects. The proposed models, labeled augmented twin-nonlinear two-box models, are built by cascading a highly nonlinear memoryless function with a mildly nonlinear memory polynomial with cross terms. Experimental validation on gallium nitride based Doherty power amplifiers illustrates the accuracy enhancement and complexity reduction achieved by the proposed models. When strong memory effects are observed, the augmented twin-nonlinear two-box models can improve the normalized mean square error by up to 3 dB for the same number of coefficients when compared to state-of-the-art twin-nonlinear two-box models. Furthermore, the augmented twin-nonlinear two-box models lead to the same performance as previously reported twin-nonlinear two-box models while requiring up to 80% less coefficients. PMID:24624047
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Federal Register 2010, 2011, 2012, 2013, 2014
2012-07-24
... Facilities Engineering Command Southeast, NAS Key West Air Operations EIS Project Manager, P.O. Box 30... Facilities Engineering Command Southeast, NAS Key West Air Operations EIS Project Manager, P.O. Box 30, Building 903, NAS Jacksonville, FL 32212 or electronically via the project Web site ( http://www.keywesteis...
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43 CFR 1821.10 - Where are BLM offices located?
Code of Federal Regulations, 2012 CFR
2012-10-01
..., 222 West 7th Avenue, #13, Anchorage, Alaska 99513-7599—Alaska. Arizona State Office, One North Central... Boulevard, Reno, Nevada 89502-7147, P.O. Box 12000, Reno, Nevada 89520-0006—Nevada. New Mexico State Office, 1474 Rodeo Road, Santa Fe, New Mexico 87505, P.O. Box 27115, Santa Fe, New Mexico 87502-0115—Kansas...
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43 CFR 1821.10 - Where are BLM offices located?
Code of Federal Regulations, 2014 CFR
2014-10-01
..., 222 West 7th Avenue, #13, Anchorage, Alaska 99513-7599—Alaska. Arizona State Office, One North Central... Boulevard, Reno, Nevada 89502-7147, P.O. Box 12000, Reno, Nevada 89520-0006—Nevada. New Mexico State Office, 310 Dinosaur Trail, Santa Fe, NM 87508, P.O. Box 27115, Santa Fe, New Mexico 87502-0115—Kansas, New...
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43 CFR 1821.10 - Where are BLM offices located?
Code of Federal Regulations, 2011 CFR
2011-10-01
..., 222 West 7th Avenue, #13, Anchorage, Alaska 99513-7599—Alaska. Arizona State Office, One North Central... Boulevard, Reno, Nevada 89502-7147, P.O. Box 12000, Reno, Nevada 89520-0006—Nevada. New Mexico State Office, 1474 Rodeo Road, Santa Fe, New Mexico 87505, P.O. Box 27115, Santa Fe, New Mexico 87502-0115—Kansas...
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43 CFR 1821.10 - Where are BLM offices located?
Code of Federal Regulations, 2013 CFR
2013-10-01
..., 222 West 7th Avenue, #13, Anchorage, Alaska 99513-7599—Alaska. Arizona State Office, One North Central... Boulevard, Reno, Nevada 89502-7147, P.O. Box 12000, Reno, Nevada 89520-0006—Nevada. New Mexico State Office, 310 Dinosaur Trail, Santa Fe, NM 87508, P.O. Box 27115, Santa Fe, New Mexico 87502-0115—Kansas, New...
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39 CFR 912.9 - Final denial of claim.
Code of Federal Regulations, 2011 CFR
2011-07-01
... with the Chief Counsel, National Tort Center, U.S. Postal Service, P.O. Box 66640, St. Louis, MO 63141... the Chief Counsel, National Tort Center, U.S. Postal Service, P.O. Box 66640, St. Louis, MO 63141-0640. (d) Only one request for reconsideration of a final denial may be filed. A claimant shall have no...
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75 FR 70225 - El Paso Natural Gas Company; Notice of Application
Federal Register 2010, 2011, 2012, 2013, 2014
2010-11-17
... Natural Gas Company (EPNG), P.O. Box 1087, Colorado Springs, Colorado 80944, filed in the above referenced docket an application, pursuant to section 7(c)(1)(b) of the Natural Gas Act (NGA) and Rule 207(a)(5) of... directed to Susan C. Stires, Director, Regulatory Affairs, El Paso Natural Gas Company, P.O. Box 1087...
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76 FR 49505 - Notice of Lodging of a Consent Decree Under the Clean Water Act
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-10
... or eliminate unlawful SSOs and CSOs into various rivers and streams, as well as discharges to... P.O. Box 7611, U.S. Department of Justice, Washington, DC 20044-7611. The comments should refer to... by mailing a request to the Consent Decree Library, P.O. Box 7611, [[Page 49506
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30 CFR 1218.51 - How to make payments.
Code of Federal Regulations, 2011 CFR
2011-07-01
...: Office of Natural Resources Revenue, P.O. Box 5640, Denver, CO 80217-5640. (3) For all other Federal and... Resources Revenue, P.O. Box 5810, Denver, CO 80217-5810. (e) Where to send a non-EFT payment when you use a courier or overnight delivery service. You should send this type of payment to: Office of Natural...
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40 CFR 49.24 - Federal Implementation Plan Provisions for Navajo Generating Station, Navajo Nation.
Code of Federal Regulations, 2010 CFR
2010-07-01
... observations, and any corrective actions taken shall be noted in a log. (f) Reporting and recordkeeping... Environmental Protection Agency, P.O. Box 339, Window Rock, Arizona 86515, (928) 871 -7692, (928) 871-7996... Protection Agency, by mail to: P.O. Box 339, Window Rock, Arizona 86515, or by facsimile to: (928) 871-7996...
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78 FR 24197 - Product Cancellation Order for Certain Pesticide Registrations
Federal Register 2010, 2011, 2012, 2013, 2014
2013-04-24
...; NY050002; OH030003). IN 46268-1054. 66330 Arysta Life Science North America, LLC, 15401 Weston Parkway... (ME090004) Bayer CropScience LP, 2 T.W. Alexander Dr., P.O. Box 12014, Research Triangle Park, NC 27709. 432 Bayer Environmental Science, 2 T.W. Alexander Dr., P.O. Box 12014, Research Triangle Park, NC 27709. 675...
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31 CFR 100.17 - Location of Federal Reserve banks and branches.
Code of Federal Regulations, 2010 CFR
2010-07-01
...), Miami, FL 33152 Nashville Branch—301 Eighth Avenue, North, Nashville, TN 37203 New Orleans Branch—525 St. Charles Avenue (P.O. Box 61630), New Orleans, LA 70161 Chicago—230 South LaSalle Street (P.O. Box 834... branches. Federal Reserve Bank and Address Boston—600 Atlantic Avenue, Boston, MA 02106 New York—33 Liberty...
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Antimisting Kerosene: Low Temperature Degradation and Blending
1988-06-01
400 7th Street, SW. (P-5) Pinellas Park, FL 33565 Washington, DC 20590 R. Landel Peter Meiklem Jet Propulsion Lab British Embassy 4800 Oak Grove...Lockheed Saudia - CC 836 Department 7475/Bu.Lding 229L P.O. Box #167 P.O. Box 551, Plant 2 Jeddah Burbank, CA 91520 SAUDI ARABIA C-9 John Pullskins E