ScreenPro FH: from the Czech MedPed to international collaboration. ScreenPro FH is a participating project of the EAS-FHCS.

PubMed

Ceska, R; Freiberger, T; Vaclova, M; Aleksicova, T; Votavova, L; Vrablik, M

2017-04-05

This article describes the evolution of our understanding of familial hypercholesterolemia (FH) in the Central, Eastern, and Southern Europe (CESE) region, and the dissemination of this understanding to other countries. Using the ScreenPro FH project as an example, we would like to illustrate the progression from national objectives, to regional networking and, finally, to international collaboration via the Familial Hypercholesterolemia Studies Collaboration (FHSC) project under the leadership of the European Atherosclerosis Society (EAS). It is essential to improve our ability to diagnose FH. In this regard, the EAS and its FHSC project must be commended for their educational and organizational activities which, above all, are dedicated to the creation of a global FH patient registry. In the CESE region, FH diagnostics and treatment situation are markedly different than in Western Europe or North America. Since the Czech MedPed project (Make Early Diagnoses to Prevent Early Deaths in Medical Pedigrees) has been so successful (with results not only comparable to, but, for some parameters, even surpassing the results of many Western countries) we decided to apply the Czech experience to the CESE region. Thus, the ScreenPro FH project was created. The aim of ScreenPro FH is to create a specialist network in the CESE region. The primary objective of the ScreenPro FH project was to dramatically reduce the number of premature deaths due to clinical complications of atherosclerosis in FH patients. At present, ScreenPro FH comprises 18 member countries with a total population of 500,000,000; which, in terms of the FH population, represents 1-2 million patients.

miR-339-5p inhibits alcohol-induced brain inflammation through regulating NF-κB pathway.

PubMed

Zhang, Yu; Wei, Guangkuan; Di, Zhiyong; Zhao, Qingjie

2014-09-26

Alcohol-induced neuroinflammation is mediated by the innate immunesystem. Pro-inflammatory responses to alcohol are modulated by miRNAs. The miRNA miR-339-5p has previously been found to be upregulated in alcohol-induced neuroinflammation. However, little has been elucidated on the regulatory functions of this miRNA in alcohol-induced neuroinflammation. We investigated the function of miR-339-5p in alcohol exposed brain tissue and isolated microglial cells using ex vivo and in vitro techniques. Our results show that alcohol induces transcription of miR 339-5p, IL-6, IL-1β and TNF-α in mouse brain tissue and isolated microglial cells by activating NF-κB. Alcohol activation of NF-κB allows for nuclear translocation of the NF-κB subunit p65 and expression of pro-inflammatory mediators. miR-339-5p inhibited expression of these pro-inflammatory factors through the NF-κB pathway by abolishing IKK-β and IKK-ε activity. Copyright © 2014 Elsevier Inc. All rights reserved.

The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes.

PubMed

Watchorn, Tammy M; Dowidar, Nabil; Dejong, Cornelis H C; Waddell, Ian D; Garden, O James; Ross, James A

2005-10-01

A novel proteoglycan, proteolysis inducing factor (PIF), is capable of inducing muscle proteolysis during the process of cancer cachexia, and of inducing an acute phase response in human hepatocytes. We investigated whether PIF is able to activate pro-inflammatory pathways in human Kupffer cells, the resident macrophages of the liver, and in monocytes, resulting in the production of pro-inflammatory cytokines. Normal liver tissue was obtained from patients undergoing partial hepatectomy and Kupffer cells were isolated. Monocytes were isolated from peripheral blood. Following exposure to native PIF, pro-inflammatory cytokine production from Kupffer cells and monocytes was measured and the NF-kappaB and STAT3 transcriptional pathways were investigated using electrophoretic mobility shift assays. We demonstrate that PIF is able to activate the transcription factor NF-kappaB and NF-kappaB-inducible genes in human Kupffer cells, and in monocytes, resulting in the production of pro-inflammatory cytokines such as TNF-alpha, IL-8 and IL-6. PIF enhances the expression of the cell surface molecules LFA-1 and CD14 on macrophages. PIF also activates the transcription factor STAT3 in Kupffer cells. The pro-inflammatory effects of PIF, mediated via NF-kappaB and STAT3, are important in macrophage behaviour and may contribute to the inflammatory pro-cachectic process in the liver.

NF-kappaB: Two Sides of the Same Coin.

PubMed

Pires, Bruno R B; Silva, Rafael C M C; Ferreira, Gerson M; Abdelhay, Eliana

2018-01-09

Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target.

Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erez, Neta, E-mail: netaerez@post.tau.ac.il; Glanz, Sarah; Raz, Yael

Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, themore » role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.« less

Chokeberry (Aronia melanocarpa (Michx.) Elliot) concentrate inhibits NF-κB and synergizes with selenium to inhibit the release of pro-inflammatory mediators in macrophages.

PubMed

Appel, Kurt; Meiser, Peter; Millán, Estrella; Collado, Juan Antonio; Rose, Thorsten; Gras, Claudia C; Carle, Reinhold; Muñoz, Eduardo

2015-09-01

Black chokeberry has been known to play a protective role in human health due to its high polyphenolic content including anthocyanins and caffeic acid derivatives. In the present study, we first characterized the polyphenolic content of a commercial chokeberry concentrate and investigated its effect on LPS-induced NF-κB activation and release of pro-inflammatory mediators in macrophages in the presence or the absence of sodium selenite. Examination of the phytochemical profile of the juice concentrate revealed high content of polyphenols (3.3%), including anthocyanins, proanthocyanidins, phenolic acids, and flavonoids. Among them, cyanidin-3-O-galactoside and caffeoylquinic acids were identified as the major compounds. Data indicated that chokeberry concentrate inhibited both the release of TNFα, IL-6 and IL-8 in human peripheral monocytes and the activation of the NF-κB pathway in RAW 264.7 macrophage cells. Furthermore, chokeberry synergizes with sodium selenite to inhibit NF-κB activation, cytokine release and PGE2 synthesis. These findings suggest that selenium added to chokeberry juice enhances significantly its anti-inflammatory activity, thus revealing a sound approach in order to tune the use of traditional herbals by combining them with micronutrients. Copyright © 2015 Elsevier B.V. All rights reserved.

Pro-sustainability choices and child deaths averted: from project experience to investment strategy.

PubMed

Sarriot, Eric G; Swedberg, Eric A; Ricca, James G

2011-05-01

The pursuit of the Millennium Development Goals and advancing the 'global health agenda' demand the achievement of health impact at scale through efficient investments. We have previously offered that sustainability-a necessary condition for successful expansion of programmes-can be addressed in practical terms. Based on benchmarks from actual child survival projects, we assess the expected impact of translating pro-sustainability choices into investment strategies. We review the experience of Save the Children US in Guinea in terms of investment, approach to sustainability and impact. It offers three benchmarks for impact: Entry project (21 lives saved of children under age five per US$100 000), Expansion project (37 LS/US$100k), and Continuation project (100 LS/US$100k). Extrapolating this experience, we model the impact of a traditional investment scenario against a pro-sustainability scenario and compare the deaths averted per dollar spent over five project cycles. The impact per dollar spent on a pro-sustainability strategy is 3.4 times that of a traditional one over the long run (range from 2.2 to 5.7 times in a sensitivity analysis). This large efficiency differential between two investment approaches offers a testable hypothesis for large-scale/long-term studies. The 'bang for the buck' of health programmes could be greatly increased by following a pro-sustainability investment strategy.

Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages.

PubMed

Salari, Samira; Seibert, Tara; Chen, Yong-Xiang; Hu, Tieqiang; Shi, Chunhua; Zhao, Xiaoling; Cuerrier, Charles M; Raizman, Joshua E; O'Brien, Edward R

2013-01-01

Heat shock protein 27 (HSP27) shows attenuated expression in human coronary arteries as the extent of atherosclerosis progresses. In mice, overexpression of HSP27 reduces atherogenesis, yet the precise mechanism(s) are incompletely understood. Inflammation plays a central role in atherogenesis, and of particular interest is the balance of pro- and anti-inflammatory factors produced by macrophages. As nuclear factor-kappa B (NF-κB) is a key immune signaling modulator in atherogenesis, and macrophages are known to secrete HSP27, we sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling in macrophages. Treatment of THP-1 macrophages with rHSP27 resulted in the degradation of an inhibitor of NF-κB, IκBα, nuclear translocation of the NF-κB p65 subunit, and increased NF-κB transcriptional activity. Treatment of THP-1 macrophages with rHSP27 yielded increased expression of a variety of genes, including the pro-inflammatory factors, IL-1β, and TNF-α. However, rHSP27 also increased the expression of the anti-inflammatory factors IL-10 and GM-CSF both at the mRNA and protein levels. Our study suggests that in macrophages, activation of NF-κB signaling by rHSP27 is associated with upregulated expression and secretion of key pro- and anti-inflammatory cytokines. Moreover, we surmise that it is the balance in expression of these mediators and antagonists of inflammation, and hence atherogenesis, that yields a favorable net effect of HSP27 on the vessel wall.

Integrated proteomics identified novel activation of dynein IC2-GR-COX-1 signaling in neurofibromatosis type I (NF1) disease model cells.

PubMed

Hirayama, Mio; Kobayashi, Daiki; Mizuguchi, Souhei; Morikawa, Takashi; Nagayama, Megumi; Midorikawa, Uichi; Wilson, Masayo M; Nambu, Akiko N; Yoshizawa, Akiyasu C; Kawano, Shin; Araki, Norie

2013-05-01

Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up- or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural

ONC201 selectively induces apoptosis in cutaneous T-cell lymphoma cells via activating pro-apoptotic integrated stress response and inactivating JAK/STAT and NF-κB pathways

PubMed Central

Ni, Xiao; Zhang, Xiang; Hu, Cheng-Hui; Langridge, Timothy; Tarapore, Rohinton S.; Allen, Joshua E.; Oster, Wolfgang; Duvic, Madeleine

2017-01-01

Cutaneous T-cell lymphomas (CTCLs) are extremely symptomatic and still incurable, and more effective and less toxic therapies are urgently needed. ONC201, an imipridone compound, has shown efficacy in pre-clinical studies in multiple advanced cancers. This study was to evaluate the anti-tumor activity of ONC201 on CTCL cells. The effect of ONC201 on the cell growth and apoptosis were evaluated in CTCL cell lines (n=8) and primary CD4+ malignant T cells isolated from CTCL patients (n=5). ONC201 showed a time-dependent cell growth inhibition in all treated cell lines with a concentration range of 1.25-10.0 μM. ONC201 also induced apoptosis in tested cells with a narrow concentration range of 2.5-10.0 μM, evidenced by increased Annexin V+ cells, accompanied by accumulated sub-G1 portions. ONC201 only induced apoptosis in CD4+ malignant T cells, not in normal CD4+ T cells. The activating transcription factor 4 (ATF4), a hallmark of integrated stress response, was upregulated in response to ONC201 whereas Akt was downregulated. In addition, molecules in JAK/STAT and NF-κB pathways, as well as IL-32β, were downregulated following ONC201 treatment. Thus, ONC201 exerts a potent and selective anti-tumor effect on CTCL cells. Its efficacy may involve activating integrated stress response through ATF4 and inactivating JAK/STAT and NF-κB pathways. PMID:28977902

ONC201 selectively induces apoptosis in cutaneous T-cell lymphoma cells via activating pro-apoptotic integrated stress response and inactivating JAK/STAT and NF-κB pathways.

PubMed

Ni, Xiao; Zhang, Xiang; Hu, Cheng-Hui; Langridge, Timothy; Tarapore, Rohinton S; Allen, Joshua E; Oster, Wolfgang; Duvic, Madeleine

2017-09-22

Cutaneous T-cell lymphomas (CTCLs) are extremely symptomatic and still incurable, and more effective and less toxic therapies are urgently needed. ONC201, an imipridone compound, has shown efficacy in pre-clinical studies in multiple advanced cancers. This study was to evaluate the anti-tumor activity of ONC201 on CTCL cells. The effect of ONC201 on the cell growth and apoptosis were evaluated in CTCL cell lines (n=8) and primary CD4 + malignant T cells isolated from CTCL patients (n=5). ONC201 showed a time-dependent cell growth inhibition in all treated cell lines with a concentration range of 1.25-10.0 μM. ONC201 also induced apoptosis in tested cells with a narrow concentration range of 2.5-10.0 μM, evidenced by increased Annexin V + cells, accompanied by accumulated sub-G1 portions. ONC201 only induced apoptosis in CD4 + malignant T cells, not in normal CD4 + T cells. The activating transcription factor 4 (ATF4), a hallmark of integrated stress response, was upregulated in response to ONC201 whereas Akt was downregulated. In addition, molecules in JAK/STAT and NF-κB pathways, as well as IL-32β, were downregulated following ONC201 treatment. Thus, ONC201 exerts a potent and selective anti-tumor effect on CTCL cells. Its efficacy may involve activating integrated stress response through ATF4 and inactivating JAK/STAT and NF-κB pathways.

miR-339-5p inhibits alcohol-induced brain inflammation through regulating NF-κB pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yu; Wei, Guangkuan; Di, Zhiyong

Graphical abstract: - Highlights: • Alcohol upregulates miR-339-5p expression. • miR-339-5p inhibits the NF-kB pathway. • miR-339-5p interacts with and blocks activity of IKK-beat and IKK-epsilon. • miR-339-5p modulates IL-1β, IL-6 and TNF-α. - Abstract: Alcohol-induced neuroinflammation is mediated by the innate immunesystem. Pro-inflammatory responses to alcohol are modulated by miRNAs. The miRNA miR-339-5p has previously been found to be upregulated in alcohol-induced neuroinflammation. However, little has been elucidated on the regulatory functions of this miRNA in alcohol-induced neuroinflammation. We investigated the function of miR-339-5p in alcohol exposed brain tissue and isolated microglial cells using ex vivo and in vitromore » techniques. Our results show that alcohol induces transcription of miR 339-5p, IL-6, IL-1β and TNF-α in mouse brain tissue and isolated microglial cells by activating NF-κB. Alcohol activation of NF-κB allows for nuclear translocation of the NF-κB subunit p65 and expression of pro-inflammatory mediators. miR-339-5p inhibited expression of these pro-inflammatory factors through the NF-κB pathway by abolishing IKK-β and IKK-ε activity.« less

NF-kappaB: Two Sides of the Same Coin

PubMed Central

Silva, Rafael C. M. C.; Ferreira, Gerson M.; Abdelhay, Eliana

2018-01-01

Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target. PMID:29315242

Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κb, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines.

PubMed

Ahmad, Sheikh Fayaz; Attia, Sabry M; Bakheet, Saleh A; Zoheir, Khairy M A; Ansari, Mushtaq Ahmad; Korashy, Hesham M; Abdel-Hamied, Hala E; Ashour, Abdelkader E; Abd-Allah, Adel R A

2015-04-01

Naringin has been reported to possess diverse pharmacological properties, including anti-arthritic and anti-inflammatory activities. The aim of the present study was to determine the potential anti-inflammatory effect of naringin in a mouse model of carrageenan-induced pleurisy. A single dose of naringin (40 and 80 mg/kg) was administered per oral (p.o.) 1 h before carrageenan (Cg) administration. Pro- and anti-inflammatory cytokines were analysed in pleural fluid. We also assessed the effects of naringin on the expression levels of iNOS, inducible cyclooxygenase isoform (COX-2), ICAM-1, MIP-2, PGE2, STAT3, TGF-β1, nuclear factor kappa B (NF-κB) and inhibitor of kappa B (IκBα) in lung tissue. The histological examinations revealed anti-inflammatory effect of naringin while Cg group deteriorated. Naringin downregulated Th1 and upregulated Th2 cytokines. Western blot analyses revealed increased protein expression of NF-κB, STAT3 and COX-2 and decreased IκBα in response to Cg treatment, which were reversed by the treatment with naringin. In the Cg group, mRNA expression levels of pro-inflammatory mediators upregulated and anti-inflammatory mediators downregulated. Naringin reversed these actions.

Vitamin D attenuates pro-inflammatory TNF-α cytokine expression by inhibiting NF-кB/p65 signaling in hypertrophied rat hearts.

PubMed

Al-Rasheed, Nawal M; Al-Rasheed, Nouf M; Bassiouni, Yieldez A; Hasan, Iman H; Al-Amin, Maha A; Al-Ajmi, Hanaa N; Mohamad, Raeesa A

2015-06-01

A growing body of evidence suggests that immune activation and inflammatory mediators may play a key role in the development and progression of left ventricle (LV) hypertrophy. The present study was designed to test the hypothesis that the cardioprotective effect of cholecalciferol (Vit-D3) is mediated via the regulation of messenger RNA (mRNA) expression of pro-inflammatory cytokines. Rats were randomly divided into four groups: control group received normal saline (0.9 % NaCl) i.p. for 14 days; Vit-D3 group received Vit-D3 at a dose of 12 μg/kg/day by gavage for 14 days; ISO group received saline for 7 days, and at day 7, ISO (5 mg/kg/day) was injected i.p. for 7 consecutive days to induce cardiac hypertrophy; and Vit-D3 + ISO group was treated with Vit-D3 for 14 days, and at day 7, ISO was administered for 7 consecutive days. Heart/body weight ratio, troponin-T, creatine kinase-MB, and tumor necrosis factor-α (TNF-α) levels of LV tissue were estimated. Levels of mRNA expression of NF-кB (NF-кB)/p65 and inhibitory kappa B (IкB)-α were determined by real-time PCR. Vit-D3 administration before and during induction of cardiac hypertrophy significantly reduced (P < 0.001) cardiac biomarkers. The histopathological examination further confirmed these results. In addition, Vit-D3 significantly decreased (P < 0.001) NF-кB-p65 mRNA expression and increased (P < 0.01) IкB-α mRNA expression in LV tissues compared to ISO group. Based on these findings, it was concluded that the administration of cholecalciferol markedly attenuated the development of ISO-induced cardiac hypertrophy likely through downregulation of TNF-α /NF-кb/p65 signaling pathways. However, it should be pointed out that other signaling pathways may contribute to the cardioprotective effect of Vit-D3 which requires further investigation.

Integration of gel-based proteome data with pProRep.

PubMed

Laukens, Kris; Matthiesen, Rune; Lemière, Filip; Esmans, Eddy; Onckelen, Harry Van; Jensen, Ole Nørregaard; Witters, Erwin

2006-11-15

pProRep is a web application integrating electrophoretic and mass spectral data from proteome analyses into a relational database. The graphical web-interface allows users to upload, analyse and share experimental proteome data. It offers researchers the possibility to query all previously analysed datasets and can visualize selected features, such as the presence of a certain set of ions in a peptide mass spectrum, on the level of the two-dimensional gel. The pProRep package and instructions for its use can be downloaded from http://www.ptools.ua.ac.be/pProRep. The application requires a web server that runs PHP 5 (http://www.php.net) and MySQL. Some (non-essential) extensions need additional freely available libraries: details are described in the installation instructions.

proBAMconvert: A Conversion Tool for proBAM/proBed.

PubMed

Olexiouk, Volodimir; Menschaert, Gerben

2017-07-07

The introduction of new standard formats, proBAM and proBed, improves the integration of genomics and proteomics information, thus aiding proteogenomics applications. These novel formats enable peptide spectrum matches (PSM) to be stored, inspected, and analyzed within the context of the genome. However, an easy-to-use and transparent tool to convert mass spectrometry identification files to these new formats is indispensable. proBAMconvert enables the conversion of common identification file formats (mzIdentML, mzTab, and pepXML) to proBAM/proBed using an intuitive interface. Furthermore, ProBAMconvert enables information to be output both at the PSM and peptide levels and has a command line interface next to the graphical user interface. Detailed documentation and a completely worked-out tutorial is available at http://probam.biobix.be .

Unification and Enhancement of Planetary Robotic Vision Ground Processing: The EC FP7 Project PRoVisG

NASA Astrophysics Data System (ADS)

Paar, G.

2009-04-01

At present, mainly the US have realized planetary space missions with essential robotics background. Joining institutions, companies and universities from different established groups in Europe and two relevant players from the US, the EC FP7 Project PRoVisG started in autumn 2008 to demonstrate the European ability of realizing high-level processing of robotic vision image products from the surface of planetary bodies. PRoVisG will build a unified European framework for Robotic Vision Ground Processing. State-of-art computer vision technology will be collected inside and outside Europe to better exploit the image data gathered during past, present and future robotic space missions to the Moon and the Planets. This will lead to a significant enhancement of the scientific, technologic and educational outcome of such missions. We report on the main PRoVisG objectives and the development status: - Past, present and future planetary robotic mission profiles are analysed in terms of existing solutions and requirements for vision processing - The generic processing chain is based on unified vision sensor descriptions and processing interfaces. Processing components available at the PRoVisG Consortium Partners will be completed by and combined with modules collected within the international computer vision community in the form of Announcements of Opportunity (AOs). - A Web GIS is developed to integrate the processing results obtained with data from planetary surfaces into the global planetary context. - Towards the end of the 39 month project period, PRoVisG will address the public by means of a final robotic field test in representative terrain. The European tax payers will be able to monitor the imaging and vision processing in a Mars - similar environment, thus getting an insight into the complexity and methods of processing, the potential and decision making of scientific exploitation of such data and not least the elegancy and beauty of the resulting image products

The pro-resolving lipid mediator Maresin 1 protects against cerebral ischemia/reperfusion injury by attenuating the pro-inflammatory response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xian, Wenjing; Wu, Yan; Xiong, Wei

Inflammation plays a crucial role in acute ischemic stroke pathogenesis. Macrophage-derived Maresin 1 (MaR1) is a newly uncovered mediator with potent anti-inflammatory abilities. Here, we investigated the effect of MaR1 on acute inflammation and neuroprotection in a mouse brain ischemia reperfusion (I/R) model. Male C57 mice were subjected to 1-h middle cerebral artery occlusion (MCAO) and reperfusion. By the methods of 2,3,5-triphenyltetrazolium chloride, haematoxylin and eosin or Fluoro-Jade B staining, neurological deficits scoring, ELISA detection, immunofluorescence assay and western blot analysis, we found that intracerebroventricular injection of MaR1 significantly reduced the infarct volume and neurological defects, essentially protected the brainmore » tissue and neurons from injury, alleviated pro-inflammatory reactions and NF-κB p65 activation and nuclear translocation. Taken together, our results suggest that MaR1 significantly protects against I/R injury probably by inhibiting pro-inflammatory reactions. - Highlights: • MaR1 significantly protects against ischemia reperfusion injury. • MaR1 inhibits pro-inflammatory cytokines and chemokines and reducing glial activation and neutrophil infiltration. • These effects at least partially occurred via suppression of the NF-κB p65 signalling pathway.« less

Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-κB activation.

PubMed

Yamaguchi, Masayoshi; Weitzmann, M Neale

2011-01-01

Several bone protective factors are reported to exhibit stimulatory activities on bone formation coupled with inhibitory effects on bone resorption; one such factor is vitamin K2. Vitamin K species [K1 (phylloquinone) and K2 (menaquinone)] have long been associated with bone protective activities and are receiving intense interest as nutritional supplements for the prevention or amelioration of bone disease in humans. However, the mechanisms of vitamin K action on the skeleton are poorly defined. Activation of the nuclear factor κB (NF-κB) signal transduction pathway is essential for osteoclast formation and resorption. By contrast, NF-κB signaling potently antagonizes osteoblast differentiation and function, prompting us to speculate that NF-κB antagonists may represent a novel class of dual anti-catabolic and pro-anabolic agents. We now show that vitamin K2 action on osteoblast and osteoclast formation and activity is accomplished by down-regulating basal and cytokine-induced NF-κB activation, by increasing IκB mRNA, in a γ-carboxylation-independent manner. Furthermore, vitamin K2 prevented repression by tumor necrosis factor α (TNFα) of SMAD signaling induced by either transforming growth factor ß (TGFß) or bone morphogenetic protein-2 (BMP-2). Vitamin K2 further antagonized receptor activator of NF-κB (RANK) ligand (RANKL)-induced NF-κB activation in osteoclast precursors. Our data provide a novel mechanism to explain the dual pro-anabolic and anti-catabolic activities of vitamin K2, and may further support the concept that pharmacological modulation of NF-κB signal transduction may constitute an effective mechanism for ameliorating pathological bone loss and for promoting bone health.

Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway.

PubMed

Park, Ji-Hyun; Seo, Young Ho; Jang, Jung-Hee; Jeong, Chul-Ho; Lee, Sooyeun; Park, Byoungduck

2017-12-11

Methamphetamine (METH) is a commonly abused drug that may result in neurotoxic effects. Recent studies have suggested that involvement of neuroinflammatory processes in brain dysfunction is induced by misuse of this drug. However, the mechanism underlying METH-induced inflammation and neurotoxicity in neurons is still unclear. In this study, we investigated whether asiatic acid (AA) effected METH-mediated neuroinflammation and neurotoxicity in dopaminergic neuronal cells. And we further determined whether the effect involved in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) pathway. We used the human dopaminergic neuroblastoma SH-SY5Y cell line, murine microglial BV2 cell line, and primary culture of rat embryo mesencephalic neurons. Pro-inflammatory cytokine production was monitored by ELISA and RT/real-time PCR. The cell cycle distribution and mitochondrial membrane integrity was analyzed by flow cytometry. We used immunoblotting, DNA-binding activity, and immunofluorescence staining to analyze the effect of AA on activation of the NF-κB, STAT3, MAPK-ERK, and apoptosis signaling pathways. METH induced TNF receptor (TNFR) expression and led to morphological changes of cells. Additionally, this drug increased pro-inflammatory cytokine (TNFα and IL-6) expression. AA significantly suppressed METH-induced TNFR expression in concentration dependent. Increased secretion of TNFα and IL-6 was inhibited in METH-stimulated neuronal cells by AA administration. AA showed significant protection against METH-induced translocation of NF-κB/STAT3 and ERK phosphorylation. AA inhibited METH-induced proteolytic fragmentation of caspase-3 and PARP. The pro-apoptotic protein Bax was significantly decreased, while the anti-apoptotic protein Bcl-xL was increased by AA treatment in METH-stimulated cells. A similar protective effect of AA on

Deacetylases and NF-κB in Redox Regulation of Cigarette Smoke induced Lung Inflammation: Implications in Pathogenesis of COPD

PubMed Central

Rajendrasozhan, Saravanan; Yang, Se-Ran; Edirisinghe, Indika; Yao, Hongwei; Adenuga, David; Rahman, Irfan

2009-01-01

Oxidative stress has been implicated in the pathogenesis of several inflammatory lung disorders including chronic obstructive pulmonary disease (COPD) due to its effect on pro-inflammatory gene transcription. Cigarette smoke-mediated oxidative stress activates NF-κB-dependent transcription of pro-inflammatory mediators either through activation of inhibitor κB-α kinase (IKK) and/or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-κB-co-activator complex formation results in targeted increase in chromatin modifications, such as histone acetylation leading to inflammatory gene transcription. NF-κB-dependent gene expression, at least in part, is regulated by changes in deacetylases such as histone deacetylases (HDACs) and sirtuins. Cigarette smoke and oxidants also alter the levels/activity of HDAC by post-translational modifications and in doing so further induces gene expression of pro-inflammatory mediators. In addition, cigarette smoke/oxidants can reduce glucocorticoid sensitivity by attenuating HDAC2 activity and expression, which may account for the glucocorticoid insensitivity in patients with COPD. Understanding the mechanisms of NF-κB regulation, and the balance between histone acetylation and deacetylation may lead to the development of novel therapies based on the pharmacological manipulation of IKK and deacetylases in lung inflammation and injury. PMID:18220485

ProNormz--an integrated approach for human proteins and protein kinases normalization.

PubMed

Subramani, Suresh; Raja, Kalpana; Natarajan, Jeyakumar

2014-02-01

The task of recognizing and normalizing protein name mentions in biomedical literature is a challenging task and important for text mining applications such as protein-protein interactions, pathway reconstruction and many more. In this paper, we present ProNormz, an integrated approach for human proteins (HPs) tagging and normalization. In Homo sapiens, a greater number of biological processes are regulated by a large human gene family called protein kinases by post translational phosphorylation. Recognition and normalization of human protein kinases (HPKs) is considered to be important for the extraction of the underlying information on its regulatory mechanism from biomedical literature. ProNormz distinguishes HPKs from other HPs besides tagging and normalization. To our knowledge, ProNormz is the first normalization system available to distinguish HPKs from other HPs in addition to gene normalization task. ProNormz incorporates a specialized synonyms dictionary for human proteins and protein kinases, a set of 15 string matching rules and a disambiguation module to achieve the normalization. Experimental results on benchmark BioCreative II training and test datasets show that our integrated approach achieve a fairly good performance and outperforms more sophisticated semantic similarity and disambiguation systems presented in BioCreative II GN task. As a freely available web tool, ProNormz is useful to developers as extensible gene normalization implementation, to researchers as a standard for comparing their innovative techniques, and to biologists for normalization and categorization of HPs and HPKs mentions in biomedical literature. URL: http://www.biominingbu.org/pronormz. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibition of the pro-inflammatory NF-κB pathway by a grape seed and grape marc meal extract in intestinal epithelial cells.

PubMed

Gessner, D K; Ringseis, R; Siebers, M; Keller, J; Kloster, J; Wen, G; Eder, K

2012-12-01

In pigs and other monogastric animal, the weaning phase is commonly accompanied by an increased susceptibility to gut disorders such as diarrhoea owing to the induction of an inflammatory process in the intestine during weaning. Given the unfavourable effects of intestinal inflammation on feed consumption, digestive capacity of the intestine and growth of animals, controlling intestinal inflammation is a reasonable approach for the maintenance of performance characteristics of livestock animals. Therefore, this study aimed to study the anti-inflammatory potential of a commercial polyphenol-rich grape seed (GS) and grape marc (GM) meal-based feed additive in a well-established in vitro intestinal epithelium model (polarized Caco-2 cells). The anti-inflammatory potential was evaluated by studying the effect of an ethanolic extract obtained from the GS and GM meal-based feed additive (GSGME) on the pro-inflammatory transcription factor NF-κB, which is considered to play a key role in the induction of weaning-associated intestinal inflammation. The highest non-cytotoxic concentrations of the ethanolic GSGME dose dependently reduced TNFα-induced NF-κB transactivation and decreased TNFα-induced mRNA levels of the NF-κB target genes IL-1β, IL-8, MCP-1 and CXCL1 in Caco-2 intestinal cells (p < 0.05). No effect of the ethanolic GSGME was observed on the cytoprotective Nrf2 pathway in Caco-2 cells as evidenced by an unaltered Nrf2 transactivation and unchanged mRNA levels of Nrf2 target genes, such as GPX-2, NQO1, CYP1A1 and UGT1A1. In conclusion, this study shows that an ethanolic GSGME exerts anti-inflammatory effects in intestinal cells under in vitro conditions. Thus, polyphenol-rich GSGM meal-based feed additives may be useful for the inhibition or prevention of inflammatory processes in the intestine of livestock animals, in particular during states with inappropriate NF-κB activation in the intestinal tissue, such as the weaning phase. Future studies are

NF-κB Regulates Caspase-4 Expression and Sensitizes Neuroblastoma Cells to Fas-Induced Apoptosis

PubMed Central

Yang, Hai-Jie; Wang, Mian; Wang, Lei; Cheng, Bin-Feng; Lin, Xiao-Yu; Feng, Zhi-Wei

2015-01-01

Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-κB signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-κB activation in Fas killing and the effect of NF-κB activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-κB signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-κB activation was shown to be pro-apoptotic, as suggested by the reduction of Fas-induced cell death with either a dominant negative form of IκBα (DN-IκBα) or an IκB kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-κB signaling, we found that DN-IκBα only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-κB activity by p65 (RelA) overexpression increased the expression of caspase-4 at both mRNA and protein levels. More directly, results from dual luciferase reporter assay demonstrated the regulation of caspase-4 promoter activity by NF-κB. When caspase-4 activity was blocked by its dominant negative (DN) form, Fas-induced cell death was substantially reduced. Consistently, the cleavage of PARP and caspase-3 induced by Fas was also reduced. In contrast, the cleavage of caspase-8 remained unaffected in caspase-4 DN cells, although caspase-8 inhibitor could rescue Fas-induced cell death. Collectively, these data suggest that caspase-4 activity is required for Fas-induced cell apoptosis and caspase-4 may act upstream of PARP and caspase-3 and downstream of caspase-8. Overall, we demonstrate that NF-κB can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-κB pro-apoptotic pathway in neuroblastoma cells. PMID:25695505

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Shuai; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208; Lv, Jiaju

2012-03-30

Highlights: Black-Right-Pointing-Pointer Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. Black-Right-Pointing-Pointer Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. Black-Right-Pointing-Pointer CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-{kappa}B) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-{kappa}B activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responsesmore » in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-{kappa}B activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNF{alpha})-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-{kappa}B transcriptional activity in RASMCs; however, did not affect the TNF{alpha}-induced NF-{kappa}B activity. Intriguingly, the TNF{alpha}-induced I{kappa}B phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of I{kappa}B{alpha} and I{kappa}B{beta} proteins, it did not alter the kinetics of TNF{alpha}-induced I{kappa}B protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-{kappa}B activity and TNF{alpha}-induced I{kappa}B kinase activation without affecting TNF{alpha}-induced NF-{kappa}B activity in VSMCs. In addition, knocking down of Cyld suppressed TNF{alpha}-induced activation of mitogen activated

Proline oxidase silencing induces proline-dependent pro-survival pathways in MCF-7 cells

PubMed Central

Zareba, Ilona; Celinska-Janowicz, Katarzyna; Surazynski, Arkadiusz; Miltyk, Wojciech; Palka, Jerzy

2018-01-01

Proline degradation by proline dehydrogenase/proline oxidase (PRODH/POX) contributes to apoptosis or autophagy. The identification of specific pathway of apoptosis/survival regulation is the aim of this study. We generated knocked-down PRODH/POX MCF-7 breast cancer cells (MCF-7shPRODH/POX). PRODH/POX silencing did not affect cell viability. However, it contributed to decrease in DNA and collagen biosynthesis, increase in prolidase activity and intracellular proline concentration as well as increase in the expression of iNOS, NF-κB, mTOR, HIF-1α, COX-2, AMPK, Atg7 and Beclin-1 in MCF-7shPRODH/POX cells. In these cells, glycyl-proline (GlyPro, substrate for prolidase) further inhibited DNA and collagen biosynthesis, maintained high prolidase activity, intracellular concentration of proline and up-regulated HIF-1α, AMPK, Atg7 and Beclin-1, compared to GlyPro-treated MCF-7 cells. In MCF-7 cells, GlyPro increased collagen biosynthesis, concentration of proline and expression of caspase-3, cleaved caspases -3 and -9, iNOS, NF-κB, COX-2 and AMPKβ. PRODH/POX knock-down contributed to pro-survival autophagy pathways in MCF-7 cells and GlyPro-derived proline augmented this process. However, GlyPro induced apoptosis in PRODH/POX-expressing MCF-7 cells as detected by up-regulation of active caspases -3 and -9. The data suggest that PRODH/POX silencing induces autophagy in MCF-7 cells and GlyPro-derived proline supports this process. PMID:29568391

Removal of Pharmaceutical and Personal Care Products (PPCPs) from Municipal Waste Water with Integrated Membrane Systems, MBR-RO/NF

PubMed Central

Wang, Yonggang; Wang, Xu; Li, Mingwei; Dong, Jing; Sun, Changhong; Chen, Guanyi

2018-01-01

This study focuses on the application of combining membrane bioreactor (MBR) treatment with reverse osmosis (RO) or nanofiltration (NF) membrane treatment for removal of pharmaceuticals and personal care products (PPCPs) in municipal wastewater. Twenty-seven PPCPs were measured in real influent with lowest average concentration being trimethoprim (7.12 ng/L) and the highest being caffeine (18.4 ng/L). The results suggest that the MBR system effectively removes the PPCPs with an efficiency of between 41.08% and 95.41%, and that the integrated membrane systems, MBR-RO/NF, can achieve even higher removal rates of above 95% for most of them. The results also suggest that, due to the differences in removal mechanisms of NF/RO membrane, differences of removal rates exist. In this study, the combination of MBR-NF resulted in the removal of 13 compounds to below detection limits and MBR-RO achieved even better results with removal of 20 compounds to below detection limits. PMID:29401723

Removal of Pharmaceutical and Personal Care Products (PPCPs) from Municipal Waste Water with Integrated Membrane Systems, MBR-RO/NF.

PubMed

Wang, Yonggang; Wang, Xu; Li, Mingwei; Dong, Jing; Sun, Changhong; Chen, Guanyi

2018-02-05

This study focuses on the application of combining membrane bioreactor (MBR) treatment with reverse osmosis (RO) or nanofiltration (NF) membrane treatment for removal of pharmaceuticals and personal care products (PPCPs) in municipal wastewater. Twenty-seven PPCPs were measured in real influent with lowest average concentration being trimethoprim (7.12 ng/L) and the highest being caffeine (18.4 ng/L). The results suggest that the MBR system effectively removes the PPCPs with an efficiency of between 41.08% and 95.41%, and that the integrated membrane systems, MBR-RO/NF, can achieve even higher removal rates of above 95% for most of them. The results also suggest that, due to the differences in removal mechanisms of NF/RO membrane, differences of removal rates exist. In this study, the combination of MBR-NF resulted in the removal of 13 compounds to below detection limits and MBR-RO achieved even better results with removal of 20 compounds to below detection limits.

Chemical Production of Excited NF.

DTIC Science & Technology

1982-07-01

purpose other than in connection with a definitely Government -related procure - ment, the United States Government incurs no responsibility or any...AD- AIIB 017 ROCKWELL INTERNATIONAL THOUSAND OAKS CA SCIENCE CENTER F/S -7/NF CHEMICAL PRODUC TION OF E XC ITED NF( U ) JUL 82 R D COOMBE , fl PATEL...Captain Ernest Kunstadt (ARAP) was the Laboratory Project Officer-in-Charge. When Government drawings, specifications, or other data are used for any

Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-κB activation.

PubMed

Marwick, John A; Mills, Ross; Kay, Oliver; Michail, Kyriakos; Stephen, Jillian; Rossi, Adriano G; Dransfield, Ian; Hirani, Nikhil

2018-06-04

Apoptotic cells modulate the function of macrophages to control and resolve inflammation. Here, we show that neutrophils induce a rapid and sustained suppression of NF-κB signalling in the macrophage through a unique regulatory relationship which is independent of apoptosis. The reduction of macrophage NF-κB activation occurs through a blockade in transforming growth factor β-activated kinase 1 (TAK1) and IKKβ activation. As a consequence, NF-κB (p65) phosphorylation is reduced, its translocation to the nucleus is inhibited and NF-κB-mediated inflammatory cytokine transcription is suppressed. Gene Set Enrichment Analysis reveals that this suppression of NF-κB activation is not restricted to post-translational modifications of the canonical NF-κB pathway, but is also imprinted at the transcriptional level. Thus neutrophils exert a sustained anti-inflammatory phenotypic reprogramming of the macrophage, which is reflected by the sustained reduction in the release of pro- but not anti- inflammatory cytokines from the macrophage. Together, our findings identify a novel apoptosis-independent mechanism by which neutrophils regulate the mediator profile and reprogramming of monocytes/macrophages, representing an important nodal point for inflammatory control.

Influence of deoxynivalenol on NF-kappaB activation and IL-8 secretion in human intestinal Caco-2 cells.

PubMed

Van De Walle, Jacqueline; Romier, Béatrice; Larondelle, Yvan; Schneider, Yves-Jacques

2008-04-01

Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. In human intestinal Caco-2 cells, DON activates the mitogen-activated protein kinases (MAPKs). We hypothesized a link between DON ingestion and intestinal inflammation, and used Caco-2 cells to assess the effects of DON, at plausible intestinal concentrations (250-10,000 ng/ml), on inflammatory mediators acting downstream the MAPKs cascade i.e. activation of nuclear factor-kappaB (NF-kappaB) and interleukin-8 (IL-8) secretion. In addition, Caco-2 cells were co-exposed to pro-inflammatory stimuli in order to mimic an inflamed intestinal epithelium. Dose-dependent increases in NF-kappaB activity and IL-8 secretion were observed, reaching 1.4- and 7.6-fold, respectively using DON at 10 microg/ml. Phosphorylation of inhibitor-kappaB (IkappaB) increased (1.6-fold) at DON levels <0.5 microg/ml. Exposure of Caco-2 cells to pro-inflammatory agents, i.e. 25 ng/ml interleukin-1beta, 100 ng/ml tumor necrosis factor-alpha or 10 microg/ml lipopolysaccharides, activated NF-kappaB and increased IL-8 secretion. Synergistic interactions between these stimuli and DON were observed. These data show that DON induces NF-kappaB activation and IL-8 secretion dose-dependently in Caco-2 cells, and this effect was accentuated upon pro-inflammatory stimulation, suggesting DON exposure could cause or exacerbate intestinal inflammation.

TNFα- and IKKβ-mediated TANK/I-TRAF phosphorylation: implications for interaction with NEMO/IKKγ and NF-κB activation

PubMed Central

Bonif, Marianne; Meuwis, Marie-Alice; Close, Pierre; Benoit, Valérie; Heyninck, Karen; Chapelle, Jean-Paul; Bours, Vincent; Merville, Marie-Paule; Piette, Jacques; Beyaert, Rudi; Chariot, Alain

2005-01-01

Pro-inflammatory cytokines trigger signalling cascades leading to NF-κB (nuclear factor-κB)-dependent gene expression through IKK [IκB (inhibitory κB) kinase]-dependent phosphorylation and subsequent degradation of the IκB proteins and via induced phosphorylation of p65. These signalling pathways rely on sequentially activated kinases which are assembled by essential and non-enzymatic scaffold proteins into functional complexes. Here, we show that the pro-inflammatory cytokine TNFα (tumour necrosis factor α) promotes TANK [TRAF (TNF receptor-associated factor) family member associated NF-κB activator] recruitment to the IKK complex via a newly characterized C-terminal zinc finger. Moreover, we show that TANK is phosphorylated by IKKβ upon TNFα stimulation and that this modification negatively regulates TANK binding to NEMO (NF-κB essential modulator). Interestingly, reduced TANK expression by RNA interference attenuates TNFα-mediated induction of a subset of NF-κB target genes through decreased p65 transactivation potential. Therefore the scaffold protein TANK is required for the cellular response to TNFα by connecting upstream signalling molecules to the IKKs and p65, and its subsequent IKKβ-mediated phosphorylation may be a mechanism to terminate the TANK-dependent wave of NF-κB activation. PMID:16336209

Integrated Programs and Pro-Environmental Behaviour

ERIC Educational Resources Information Center

Smith, Tiffany

2008-01-01

Research suggested that "nature experience as an education method played a role in developing environmental value and attitudes, and was influential in pro-environmental behaviour." Few of these studies however, assessed the long-term influences of outdoor education experiences on participants' pro-environmental behaviour. The Outward…

A probabilistic NF2 relational algebra for integrated information retrieval and database systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fuhr, N.; Roelleke, T.

The integration of information retrieval (IR) and database systems requires a data model which allows for modelling documents as entities, representing uncertainty and vagueness and performing uncertain inference. For this purpose, we present a probabilistic data model based on relations in non-first-normal-form (NF2). Here, tuples are assigned probabilistic weights giving the probability that a tuple belongs to a relation. Thus, the set of weighted index terms of a document are represented as a probabilistic subrelation. In a similar way, imprecise attribute values are modelled as a set-valued attribute. We redefine the relational operators for this type of relations such thatmore » the result of each operator is again a probabilistic NF2 relation, where the weight of a tuple gives the probability that this tuple belongs to the result. By ordering the tuples according to decreasing probabilities, the model yields a ranking of answers like in most IR models. This effect also can be used for typical database queries involving imprecise attribute values as well as for combinations of database and IR queries.« less

Haloperidol Suppresses NF-kappaB to Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Response in RAW 264 Cells

PubMed Central

Yamamoto, Shunsuke; Ohta, Noriyuki; Matsumoto, Atsuhiro; Horiguchi, Yu; Koide, Moe; Fujino, Yuji

2016-01-01

Background Haloperidol, a tranquilizing agent, is administered both to treat symptoms of psychotic disorders and to sedate agitated and delirious patients. Notably, haloperidol has been suggested to inhibit the immune response through unknown mechanisms. We hypothesized that the sedative modulates the immune response via NF-κB. Material/Methods Using flow cytometry, we analyzed the effects of haloperidol on expression CD80 and CD86 in RAW 264 cells and in primary macrophages derived from bone marrow. Secretion of interleukin (IL)-1β, IL-6, and IL-12 p40 was measured by enzyme-linked immunosorbent assay. In addition, NF-κB activation was evaluated using a reporter assay based on secretory embryonic alkaline phosphatase. Finally, synthetic antagonists were used to identify the dopamine receptor that mediates the effects of haloperidol. Results Haloperidol inhibited NF-κB activation, and thereby suppressed expression of CD80, as well as secretion of IL-1β, IL-6, and IL-12 p40. CD80 and IL-6 levels were similarly attenuated by a D2-like receptor antagonist, but not by a D1-like receptor antagonist. Conclusions The data strongly suggest that haloperidol inhibits the immune response by suppressing NF-κB signaling via the dopamine D2 receptor. PMID:26842661

Haloperidol Suppresses NF-kappaB to Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Response in RAW 264 Cells.

PubMed

Yamamoto, Shunsuke; Ohta, Noriyuki; Matsumoto, Atsuhiro; Horiguchi, Yu; Koide, Moe; Fujino, Yuji

2016-02-04

BACKGROUND Haloperidol, a tranquilizing agent, is administered both to treat symptoms of psychotic disorders and to sedate agitated and delirious patients. Notably, haloperidol has been suggested to inhibit the immune response through unknown mechanisms. We hypothesized that the sedative modulates the immune response via NF-κB. MATERIAL AND METHODS Using flow cytometry, we analyzed the effects of haloperidol on expression CD80 and CD86 in RAW 264 cells and in primary macrophages derived from bone marrow. Secretion of interleukin (IL)-1β, IL-6, and IL-12 p40 was measured by enzyme-linked immunosorbent assay. In addition, NF-κB activation was evaluated using a reporter assay based on secretory embryonic alkaline phosphatase. Finally, synthetic antagonists were used to identify the dopamine receptor that mediates the effects of haloperidol. RESULTS Haloperidol inhibited NF-κB activation, and thereby suppressed expression of CD80, as well as secretion of IL-1β, IL-6, and IL-12 p40. CD80 and IL-6 levels were similarly attenuated by a D2-like receptor antagonist, but not by a D1-like receptor antagonist. CONCLUSIONS The data strongly suggest that haloperidol inhibits the immune response by suppressing NF-kB signaling via the dopamine D2 receptor.

New Dimensions of The PACA (Pro-Am Collaborative Astronomy) Project

NASA Astrophysics Data System (ADS)

Yanamandra-Fisher, P. A.

2017-12-01

The Pro-Am Collaborative Astronomy (PACA) project evolved from the observational campaign of comet C/2012 S1 or C/ISON in 2013 to pro-am observing campaigns and polarimetric exploration in 2017. These include support of observing campaigns of current comets, legacy data, historical comets, planets, solar corona; and interconnected with social media, data and citizen scientists. A four dimensional framework has been developed to ensure the success of each unique PACA observing campaign, starting with identification of key science observations; creation of a global core observer network, utilizing the latest in technology and finally development of outreach and citizen science programs. A set of shareable documents addressing observational strategies; consistent standards for data; data access, use, and storage, to align with the needs of professional observers. Several interesting results emerged from the synergistic inclusion of both social media and amateur astronomers: (1) the establishment of a network of astronomers and related professionals, that can be galvanized into action on short notice to support observing campaigns; (2) assist in various science investigations pertinent to the campaign; (3) provide an alert-sounding mechanism should the need arise; (4) immediate outreach and dissemination of results via our media/blogger members; (5) provide a forum for discussions between the imagers and modelers to help strategize the observing campaign for maximum benefit. One of the challenges faced by all aspects of the PACA Project is how to archive and mine the volume of data generated for each campaign - and a potential citizen science project. I will highlight key aspects of past PACA campaigns: C/2013 A1 (C/SidingSpring) ; 67P/Churyumov-Gerasimenko (CG), target for ESA/Rosetta mission; and our current campaign PACA_PolNet, a multi-site polarimetric network to observe the Total Solar Eclipse on 21 August 2017, in partnership with the project Citizen CATE.

LPS-induced NF-{kappa}B expression in THP-1Blue cells correlates with neopterin production and activity of indoleamine 2,3-dioxygenase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schroecksnadel, Sebastian; Jenny, Marcel; Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck

2010-09-03

Research highlights: {yields} LPS induces NF-{kappa}B, neopterin formation and tryptophan degradation in THP-1 cells. {yields} Close dose- and time-dependent correlations exist between these biochemical events. {yields} Data provides some evidence for a parallel induction of them upon TLR stimulation. {yields} Results can be of considerable relevance also in vivo. -- Abstract: Neopterin production is induced in human monocyte-derived macrophages and dendritic cells upon stimulation with Th1-type cytokine interferon-{gamma} (IFN-{gamma}). In parallel, IFN-{gamma} induces the tryptophan-(trp)-degrading enzyme indoleamine 2,3-dioxygenase (IDO) and triggers the formation of reactive oxygen species (ROS). Translocation of the signal transduction element nuclear factor-{kappa}B (NF-{kappa}B) is induced bymore » ROS and accelerates the pro-inflammatory response by activation of other pro-inflammatory pathways. Therefore, a close relationship between NF-{kappa}B expression, the production of neopterin and the degradation of trp can be assumed, although this has not been demonstrated so far. In the present in vitro study we compared the influence of lipopolysaccharide (LPS) on NF-{kappa}B activation, neopterin formation and the degradation of trp in THP-1Blue cells, which represent the human myelomonocytic cell line THP-1 stably transfected with an NF-{kappa}B inducible reporter system. In cells stimulated with LPS, a significant induction of NF-{kappa}B was observed, and this was paralleled by an increase of kynureunine (kyn) and neopterin concentrations and a decline of trp. The increase of the kyn to trp quotient indicates accelerated IDO activity. Higher LPS concentrations and longer incubation of cells were associated with higher activities of all three biochemical pathways and significant correlations existed between NF-{kappa}B activation, neopterin release and trp degradation (all p < 0.001). We conclude that there is a parallel induction of NF-{kappa}B, neopterin

Sulforaphane attenuates microglia-mediated neuronal necroptosis through down-regulation of MAPK/NF-κB signaling pathways in LPS-activated BV-2 microglia.

PubMed

Qin, Sisi; Yang, Canhong; Huang, Weihua; Du, Shuhua; Mai, Hantao; Xiao, Jijie; Lü, Tianming

2018-01-31

Sulforaphane (SFN), a natural dietary isothiocyanate in cruciferous vegetables such as broccoli and cabbage, has very strong anti-inflammatory activity. Activation of microglia leads to overexpression of a series of pro-inflammatory mediators, which play a vital role in neuronal damage. SFN may have neuroprotective effects in different neurodegenerative diseases related to inflammation. However, the mechanisms underlying SFN's protection of neurons against microglia-mediated neuronal damage are not fully understood. Here, we investigated how SFN attenuated microglia-mediated neuronal damage. Our results showed that SFN could not directly protect the viability of neurons following pro-inflammatory mediators, but increased the viability of BV-2 microglia and down-regulated the mRNA and protein levels of pro-inflammatory mediators including TNF-α, IL-1β, IL-6 and iNOS in a concentration-dependent manner in BV-2 cells. SFN also significantly blocked the phosphorylation of MAPKs (p38, JNK, and ERK1/2) and NF-κB p65, both by itself and with MAPK inhibitors (SB203580, SP 600125, and U0126) or an NF-κB inhibitor (PDTC). The expression of pro-inflammatory proteins was also blocked by SFN with or without inhibitors. Further, SFN indirectly increased the viability and maintained the morphology of neurons, and the protein expression of RIPK3 and MLKL was significantly suppressed by SFN in neuronal necroptosis through p38, JNK, and NF-κB p65 but not ERK1/2 signaling pathways. Together, our results demonstrate that SFN attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-κB signaling pathway in BV-2 microglia and thus indirectly suppresses microglia-mediated neuronal damage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mitogen- and Stress-Activated Kinase 1 (MSK1) Regulates Cigarette Smoke-Induced Histone Modifications on NF-κB-dependent Genes

PubMed Central

Sundar, Isaac K.; Chung, Sangwoon; Hwang, Jae-woong; Lapek, John D.; Bulger, Michael; Friedman, Alan E.; Yao, Hongwei; Davie, James R.; Rahman, Irfan

2012-01-01

Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKα (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-κB RelA/p65 kinase, mediating transcriptional activation of NF-κB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-κB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-κB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-κB activation and chromatin modifications, which have implications in pathogenesis

Vinpocetine Ameliorates Acetic Acid-Induced Colitis by Inhibiting NF-κB Activation in Mice.

PubMed

Colombo, Bárbara B; Fattori, Victor; Guazelli, Carla F S; Zaninelli, Tiago H; Carvalho, Thacyana T; Ferraz, Camila R; Bussmann, Allan J C; Ruiz-Miyazawa, Kenji W; Baracat, Marcela M; Casagrande, Rúbia; Verri, Waldiceu A

2018-04-10

The idiopathic inflammatory bowel diseases (IBD) comprise two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. Recruited neutrophils and macrophages contribute to intestinal tissue damage via production of ROS and NF-κB-dependent pro-inflammatory cytokines. The introduction of anti-TNF-α therapies in the treatment of IBD patients was a seminal advance. This therapy is often limited by a loss of efficacy due to the development of adaptive immune response, underscoring the need for novel therapies targeting similar pathways. Vinpocetine is a nootropic drug and in addition to its antioxidant effect, it is known to have anti-inflammatory and analgesic properties, partly by inhibition of NF-κB and downstream cytokines. Therefore, the present study evaluated the effect of the vinpocetine in a model of acid acetic-induced colitis in mice. Treatment with vinpocetine reduced edema, MPO activity, microscopic score and macroscopic damage, and visceral mechanical hyperalgesia. Vinpocetine prevented the reduction of colonic levels of GSH, ABTS radical scavenging ability, and normalized levels of anti-inflammatory cytokine IL-10. Moreover, vinpocetine reduced NF-κB activation and thereby NF-κB-dependent pro-inflammatory cytokines IL-1β, TNF-α, and IL-33 in the colon. Thus, we demonstrate for the first time that vinpocetine has anti-inflammatory, antioxidant, and analgesic effects in a model of acid acetic-induced colitis in mice and deserves further screening to address its suitability as an approach for the treatment of IBD.

Design and feasibility of integrating personalized PRO dashboards into prostate cancer care

PubMed Central

Izard, Jason P; Dalkin, Bruce L; Mikles, Sean P; Gore, John L

2016-01-01

Objective Patient-reported outcomes (PROs) are a valued source of health information, but prior work focuses largely on data capture without guidance on visual displays that promote effective PRO use in patient-centered care. We engaged patients, providers, and design experts in human-centered design of “PRO dashboards” that illustrate trends in health-related quality of life (HRQOL) reported by patients following prostate cancer treatment. Materials and Methods We designed and assessed the feasibility of integrating dashboards into care in 3 steps: (1) capture PRO needs of patients and providers through focus groups and interviews; (2) iteratively build and refine a prototype dashboard; and (3) pilot test dashboards with patients and their provider during follow-up care. Results Focus groups (n = 60 patients) prioritized needs for dashboards that compared longitudinal trends in patients’ HRQOL with “men like me.” Of the candidate dashboard designs, 50 patients and 50 providers rated pictographs less helpful than bar charts, line graphs, or tables (P < .001) and preferred bar charts and line graphs most. Given these needs and the design recommendations from our Patient Advisory Board (n = 7) and design experts (n = 7), we built and refined a prototype that charts patients’ HRQOL compared with age- and treatment-matched patients in personalized dashboards. Pilot testing dashboard use (n = 12 patients) improved compliance with quality indicators for prostate cancer care (P < .01). Conclusion PRO dashboards are a promising approach for integrating patient-generated data into prostate cancer care. Informed by human-centered design principles, this work establishes guidance on dashboard content, tailoring, and clinical use that patients and providers find meaningful. PMID:26260247

Curcumin Modulates the Radiosensitivity of Colorectal Cancer Cells by Suppressing Constitutive and Inducible NF-{kappa}B Activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sandur, Santosh K.; Deorukhkar, Amit; Pandey, Manoj K.

2009-10-01

Purpose: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. Methods and Materials: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-{kappa}B (NF-{kappa}B)more » activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. Results: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-{kappa}B activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-{kappa}B activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of {kappa}B alpha, inhibition of inhibitor of {kappa}B kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-{kappa}B-regulated gene products (Bcl-2, Bcl-x{sub L}, inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). Conclusions: Our results suggest that transient inducible NF-{kappa}B activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.« less

Potent Anti-Inflammatory Activity of Ursolic Acid, a Triterpenoid Antioxidant, Is Mediated through Suppression of NF-κB, AP-1 and NF-AT

PubMed Central

Checker, Rahul; Sandur, Santosh K.; Sharma, Deepak; Patwardhan, Raghavendra S.; Jayakumar, S.; Kohli, Vineet; Sethi, Gautam; Aggarwal, Bharat B.; Sainis, Krishna B.

2012-01-01

Background Ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, is the major component of many plants including apples, basil, cranberries, peppermint, rosemary, oregano and prunes and has been reported to possess antioxidant and anti-tumor properties. These properties of UA have been attributed to its ability to suppress NF-κB (nuclear factor kappa B) activation. Since NF-κB, in co-ordination with NF-AT (nuclear factor of activated T cells) and AP-1(activator protein-1), is known to regulate inflammatory genes, we hypothesized that UA might exhibit potent anti-inflammatory effects. Methodology/Principal Findings The anti-inflammatory effects of UA were assessed in activated T cells, B cells and macrophages. Effects of UA on ERK, JNK, NF-κB, AP-1 and NF-AT were studied to elucidate its mechanism of action. In vivo efficacy of UA was studied using mouse model of graft-versus-host disease. UA inhibited activation, proliferation and cytokine secretion in T cells, B cells and macrophages. UA inhibited mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells. It inhibited mitogen-induced phosphorylation of ERK and JNK and suppressed the activation of immunoregulatory transcription factors NF-κB, NF-AT and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and also significantly reduced the serum levels of pro-inflammatory cytokines IL-6 and IFN-γ. UA treatment inhibited T cell activation even when added post-mitogenic stimulation demonstrating its therapeutic utility as an anti-inflammatory agent. Conclusions/Significance The present study describes the detailed mechanism of anti-inflammatory activity of UA. Further, UA may find application in the treatment of inflammatory disorders. PMID:22363615

Perineural Dexmedetomidine Attenuates Inflammation in Rat Sciatic Nerve via the NF-κB Pathway

PubMed Central

Huang, Yan; Lu, Yi; Zhang, Lei; Yan, Jia; Jiang, Jue; Jiang, Hong

2014-01-01

Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the pro-inflammatory cytokines IL-6 and TNF-α. In this study, we established a rat model that simulates a clinical surgical procedure to investigate the anti-inflammatory effect of perineural administration of dexmedetomidine and the underlying mechanism. Dexmedetomidine reduced the sciatic nerve levels of IL-6 and TNF-α at both the mRNA and protein level. Dexmedetomidine also inhibited the translocation of activated NF-κB to the nucleus and the binding activity of NF-κB. The anti-inflammatory effect is confirmed to be dose-dependent. Finally, pyrrolidine dithiocarbamate also reduced the levels of IL-6 and TNF-α and the activation of NF-κB. In conclusion, dexmedetomidine inhibited the nuclear translocation and binding activity of activated NF-κB, thus reducing inflammatory cytokines. PMID:24663080

Learn about NF

MedlinePlus

... Understanding NF Neurofibromatosis Intro to NF NF1 NF2 Schwannomatosis Genetics of NF Living with NF NF Registry ... of passing the condition on to their offspring. Schwannomatosis is less well understood, but the majority of ...

GeoProMT: A Collaborative Platform Supporting Natural Hazards Project Management From Assessment to Resilience

NASA Astrophysics Data System (ADS)

Renschler, C.; Sheridan, M. F.; Patra, A. K.

2008-05-01

The impact and consequences of extreme geophysical events (hurricanes, floods, wildfires, volcanic flows, mudflows, etc.) on properties and processes should be continuously assessed by a well-coordinated interdisciplinary research and outreach approach addressing risk assessment and resilience. Communication between various involved disciplines and stakeholders is the key to a successful implementation of an integrated risk management plan. These issues become apparent at the level of decision support tools for extreme events/disaster management in natural and managed environments. The Geospatial Project Management Tool (GeoProMT) is a collaborative platform for research and training to document and communicate the fundamental steps in transforming information for extreme events at various scales for analysis and management. GeoProMT is an internet-based interface for the management of shared geo-spatial and multi-temporal information such as measurements, remotely sensed images, and other GIS data. This tool enhances collaborative research activities and the ability to assimilate data from diverse sources by integrating information management. This facilitates a better understanding of natural processes and enhances the integrated assessment of resilience against both the slow and fast onset of hazard risks. Fundamental to understanding and communicating complex natural processes are: (a) representation of spatiotemporal variability, extremes, and uncertainty of environmental properties and processes in the digital domain, (b) transformation of their spatiotemporal representation across scales (e.g. interpolation, aggregation, disaggregation.) during data processing and modeling in the digital domain, and designing and developing tools for (c) geo-spatial data management, and (d) geo-spatial process modeling and effective implementation, and (e) supporting decision- and policy-making in natural resources and hazard management at various spatial and temporal scales

Anti-nociceptive effect of dexmedetomidine in a rat model of monoarthritis via suppression of the TLR4/NF-κB p65 pathway

PubMed Central

Ji, Dong; Zhou, Yalan; Li, Shuangshuang; Li, Dai; Chen, Hui; Xiong, Yuanchang; Zhang, Yuqiu; Xu, Hua

2017-01-01

As a therapeutic target for neuropathic pain, the anti-nociceptive effects of α 2-adrenoceptors (α2AR) have attracted attention. Dexmedetomidine (DEX), a potent and highly selective α2AR agonist, has exhibited significant analgesic effects in neuropathic pain, but the underlying mechanism has remained elusive. The present study investigated the effect of DEX on Toll-like receptor (TLR)4 and nuclear factor (NF)-κB p65 expression, as well as the production of pro-inflammatory cytokines. The rat monoarthritis (MA) model was induced by intra-articular injection of complete Freund's adjuvant (CFA) at the ankle joint. After induction of MA, the rats were intrathecally treated with normal saline or DEX (2.5 µg) for 3 consecutive days. The concentration of interleukin-1β and −6 as well as tumor necrosis factor-α was examined by ELISA. The expression levels of TLR4 and NF-κB p65 were determined by western blot analysis and immunohistochemistry. The results indicated that the pro-inflammatory cytokines TLR4 and NF-κB p65 were significantly upregulated in MA rats. DEX treatment markedly reduced mechanical and thermal hyperalgesia, suppressed MA-induced elevation of the pro-inflammatory cytokines and inhibited the TLR4/NF-κB p65 pathway, while these effects were blocked by pre-treatment with the selective α2AR antagonist BRL44408 (15 µg) at 30 min prior to CFA injection. These results suggested that DEX has an anti-nociceptive effect via suppressing the TLR4/NF-κB p65 pathway. PMID:29201195

The Handwriting Performance of Children with NF1

ERIC Educational Resources Information Center

Gilboa, Yafit; Josman, Naomi; Fattal-Valevski, Aviva; Toledano-Alhadef, Hagit; Rosenblum, Sara

2010-01-01

The objective of this study was to analyze the process and product of handwriting among children with Neurofibromatosis Type 1 (NF1) in comparison to those of Typically Developing (TD) children. Children with NF1 are at risk for some cognitive deficits, a wide range of deficits in perceptual skills and, motor and visual-motor integration skills…

Redox Regulation of NF-κB p50 and M1 Polarization in Microglia

PubMed Central

Taetzsch, Thomas; Levesque, Shannon; McGraw, Constance; Brookins, Savannah; Luqa, Rafy; Bonini, Marcelo G.; Mason, Ronald P.; Oh, Unsong; Block, Michelle L.

2014-01-01

Redox-signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF-κB p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro-inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H2O2 showed altered NF-κB p50 protein-protein interactions, decreased NF-κB p50 DNA binding, and augmented late-stage TNFα expression, indicating that H2O2 impairs NF-κB p50 function and prolongs amplified M1 activation. NF-κB p50−/− mice and cultures exhibited a disrupted M2 (alternative) response and impaired resolution of the M1 response. Persistent neuroinflammation continued 1 week after LPS (1mg/kg, IP) administration in the NF-κB p50−/− mice. However, peripheral inflammation had already resolved in both strains of mice. Treatment with the spin-trap DMPO mildly reduced LPS-induced 22 h TNFα in the brain in NF-κB p50+/+ mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFα production in NF-κB p50−/− mice, implicating a fundamental role for NF-κB p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-κB p50 as a key redox-signaling mechanism regulating the M1/M2 balance in microglia, where loss of function leads to a CNS-specific vulnerability to chronic inflammation. PMID:25331559

Building Excellence in Project Execution: Integrated Project Management

DTIC Science & Technology

2015-04-30

challenge by adopting and refining the CMMI Model and building the tenets of integrated project management (IPM) into project planning and execution...Systems Center Pacific (SSC Pacific) is addressing this challenge by adopting and refining the CMMI Model, and building the tenets of integrated project...successfully managing stakeholder expectations and meeting requirements. Under the Capability Maturity Model Integration ( CMMI ), IPM is defined as

Increased expression of NF-AT3 and NF-AT4 in the atria correlates with procollagen I carboxyl terminal peptide and TGF-β1 levels in serum of patients with atrial fibrillation.

PubMed

Zhao, Fei; Zhang, ShiJiang; Chen, YiJiang; Gu, WeiDong; Ni, BuQing; Shao, YongFeng; Wu, YanHu; Qin, JianWei

2014-11-25

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Unfortunately, the precise mechanisms and sensitive serum biomarkers of atrial remodeling in AF remain unclear. The aim of this study was to determine whether the expression of the transcription factors NF-AT3 and NF-AT4 correlate with atrial structural remodeling of atrial fibrillation and serum markers for collagen I and III synthesis. Right and left atrial specimens were obtained from 90 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (n = 30), paroxysmal atrial fibrillation (n = 30), and persistent atrial fibrillation (n = 30) groups. NF-AT3, NF-AT4, and collagen I and III mRNA and protein expression in atria were measured. We also tested the levels of the carboxyl-terminal peptide from pro-collagen I, the N-terminal type I procollagen propeptides, the N-terminal type III procollagen propeptides, and TGF-β1 in serum using an enzyme immunosorbent assay. NF-AT3 and NF-AT4 mRNA and protein expression were increased in the AF groups, especially in the left atrium. NF-AT3 and NF-AT4 expression in the right atrium was increased in the persistent atrial fibrillation group compared the sinus rhythm group with similar valvular disease. In patients with AF, the expression levels of nuclear NF-AT3 and NF-AT4 correlated with those of collagens I and III in the atria and with PICP and TGF-β1 in blood. These data support the hypothesis that nuclear NF-AT3 and NF-AT4 participates in atrial structural remodeling, and that PICP and TGF-β1 levels may be sensitive serum biomarkers to estimate atrial structural remodeling with atrial fibrillation.

Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis

PubMed Central

Kim, Ji H.; Gupta, Subash C.; Park, Byoungduck; Yadav, Vivek R.; Aggarwal, Bharat B.

2012-01-01

Scope The incidence of cancer is significantly lower in regions where turmeric is heavily consumed. Whether lower cancer incidence is due to turmeric was investigated by examining its effects on tumor cell proliferation, on pro-inflammatory transcription factors NF-κB and STAT3, and on associated gene products. Methods and results Cell proliferation and cell cytotoxicity were measured by the MTT method, NF-κB activity by EMSA, protein expression by Western blot analysis, ROS generation by FACS analysis, and osteoclastogenesis by TRAP assay. Turmeric inhibited NF-κB activation and down-regulated NF-κB-regulated gene products linked to survival (Bcl-2, cFLIP, XIAP, and cIAP1), proliferation (cyclin D1 and c-Myc), and metastasis (CXCR4) of cancer cells. The spice suppressed the activation of STAT3, and induced the death receptors (DR)4 and DR5. Turmeric enhanced the production of ROS, and suppressed the growth of tumor cell lines. Furthermore, turmeric sensitized the tumor cells to chemotherapeutic agents capecitabine and taxol. Turmeric was found to be more potent than pure curcumin for cell growth inhibition. Turmeric also inhibited NF-κB activation induced by RANKL that correlated with the suppression of osteoclastogenesis. Conclusion Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-κB and STAT3 pathways. PMID:22147524

Human T-Cell Lymphotropic Virus: A Model of NF-κB-Associated Tumorigenesis

PubMed Central

Qu, Zhaoxia; Xiao, Gutian

2011-01-01

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL), whereas the highly related HTLV-2 is not associated with ATL or other cancers. In addition to ATL leukemogenesis, studies of the HTLV viruses also provide an exceptional model for understanding basic pathogenic mechanisms of virus-host interactions and human oncogenesis. Accumulating evidence suggests that the viral regulatory protein Tax and host inflammatory transcription factor NF-κB are largely responsible for the different pathogenic potentials of HTLV-1 and HTLV-2. Here, we discuss the molecular mechanisms of HTLV-1 oncogenic pathogenesis with a focus on the interplay between the Tax oncoprotein and NF-κB pro-oncogenic signaling. We also outline some of the most intriguing and outstanding questions in the fields of HTLV and NF-κB. Answers to those questions will greatly advance our understanding of ATL leukemogenesis and other NF-κB-associated tumorigenesis and will help us design personalized cancer therapies. PMID:21743832

Meta-Analysis Identifies NF-κB as a Therapeutic Target in Renal Cancer

PubMed Central

Peri, Suraj; Devarajan, Karthik; Yang, Dong-Hua; Knudson, Alfred G.; Balachandran, Siddharth

2013-01-01

Objective To determine the expression patterns of NF-κB regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes. Methods Meta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-κB regulators and targets to determine the nature and extent of NF-κB deregulation in ccRCC. Results A highly-disproportionate fraction (~40%; p < 0.001) of NF-κB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-κB activity in this cancer. A subset of these genes, comprising a key NF-κB regulator (IKBKB) and established mediators of the NF-κB cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an ‘interferon signature’ may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-κB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-κB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-κB activity, and the appearance of an interferon signature during ccRCC tumorigenesis. Conclusions These findings identify NF-κB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-κB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-κB targets for potential therapeutic intervention in this currently

Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer's disease.

PubMed

Seo, Ean-Jeong; Fischer, Nicolas; Efferth, Thomas

2018-03-01

Alzheimer's disease (AD) is the most prevalent form of dementia. The exact pathophysiology of this disease remains incompletely understood and safe and effective therapies are required. AD is highly correlated with neuroinflammation and oxidative stress in brain causing neuronal loss. Nuclear factor of activated B-cells (NF-κB) is involved in physiological inflammatory processes and thus representing a promising target for inflammation-based AD therapy. Phytochemicals are able to interfere with the NF-κB pathway. They inhibit the phosphorylation or the ubiquitination of signaling molecules, and thus, inhibit the degradation of IκB. The translocation of NF-κB to the nucleus and subsequent transcription of pro-inflammatory cytokines are inhibited by the actions of phytochemicals. Additionally, natural compounds preventing the interaction of NF-κB can block NF-κB's transcriptional activity by inhibiting its binding to target DNA. Many polyphenols including curcumin, resveratrol, pterostilbene, punicalagin, macranthoin G, salidroside, 4-O-methylhonokiol, lycopene, genistein, obovatol and gallic acid were reported as potent NF-κB inhibitors for AD treatment. Several alkaloids such as galantamine, glaucocalyxin B, tetrandrine, berberine, oridonin, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in vivo. Besides, vitamins, tanshinone IIA, artemisinin, dihydroasparagusic acid, geniposide, xanthoceraside, l-theranine, 1,8-cineole and paeoniflorin were described as promising NF-κB inhibitors. In conclusion, natural products from plants represent interesting candidates for AD treatment. They may qualify as promising compounds for the development of derivatives providing enhanced pharmacological features. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ro52-mediated Monoubiquitination of IKKβ Down-regulates NF-κB Signalling

PubMed Central

Wada, Keiji; Niida, Motoko; Tanaka, Makoto; Kamitani, Tetsu

2009-01-01

Upon activation, NF-κB translocates into the nucleus and initiates biological events. This NF-κB signalling is mainly regulated by the protein kinase IKKβ. Early in this signalling pathway, IKKβ is phosphorylated for activation by several factors, such as pro-inflammatory cytokines and the Tax oncoprotein of HTLV-1. In cells infected by HTLV-1, IKKβ is persistently phosphorylated and conjugated with monoubiquitin due to Tax expression. Although this Tax-induced monoubiquitination appears to be an important regulation system for IKKβ, how the monoubiquitination occurs is unknown and its role in NF-κB signalling is still unclear. Here, we show that an E3-ubiquitin ligase Ro52 interacts weakly with wild-type IKKβ but strongly with a phosphomimetic mutant IKKβ to conjugate monoubiquitin in cooperation with an E2-ubiquitin-conjugating enzyme UbcH5B. These results suggest that the Tax-induced phosphorylation of IKKβ causes an interaction with Ro52 for the subsequent monoubiquitination. NF-κB reporter assays have shown that the IKKβ activity is suppressed by wild-type Ro52, but not by its inactive mutant. In addition, monoubiquitin fusion of IKKβ reduced its activity for NF-κB signalling. We also found that Ro52 dramatically reduces the level of Tax. These results suggest that Ro52 down-regulates Tax-induced NF-κB signalling by monoubiquitinating IKKβ and by reducing the level of Tax. PMID:19675099

Health-Related Quality of Life for Pediatric NF1 Patients

DTIC Science & Technology

2006-08-01

The objective of this project is to develop an NF1-specific health-related quality of life (HRQL) instrument for use with pediatric patients...parents will complete the NF1-specific measure, in addition to parent- and self-report measures of behavior, functioning, and generic health-related quality of life .

The excess health care costs of KardioPro, an integrated care program for coronary heart disease prevention.

PubMed

Becker, Christian; Holle, Rolf; Stollenwerk, Björn

2015-06-01

Coronary heart disease (CHD) is a major cause of death and important driver of health care costs. Recent German health care reforms have promoted integrated care contracts allowing statutory health insurance providers more room to organize health care provision. One provider offers KardioPro, an integrated primary care-based CHD prevention program. As insurance providers should be aware of the financial consequences when developing optional programs, this study aims to analyze the costs associated with KardioPro participation. 13,264 KardioPro participants were compared with a propensity score-matched control group. Post-enrollment health care costs were calculated based on routine data over a follow-up period of up to 4 years. For those people who incurred costs, KardioPro participation was significantly associated with increased physician costs (by 33%), reduced hospital costs (by 19%), and reduced pharmaceutical costs (by 16%). Overall costs were increased by 4%, but this was not significant. Total excess costs per observation year were €131 per person (95% confidence interval: [€-36.5; €296]). Overall, KardioPro likely affected treatment as the program increased costs of physician services and reduced costs of hospital services. Further effects of substituting potential inpatient care with increased outpatient care might become fully apparent only over a longer time horizon. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Investments on Pro-poor Development Projects on Goats: Ensuring Success for Improved Livelihoods.

PubMed

Devendra, C

2013-01-01

The elements that determine the success of development projects on goats and the prerequisites for ensuring this are discussed in the context of the bewildering diversity of goat genetic resources, production systems, multifunctionality, and opportunities for responding to constraints for productivity enhancement. Key determinants for the success of pro-poor projects are the imperatives of realistic project design, resolution of priorities and positive impacts to increase investments and spur agricultural growth, and appropriate policy. Throughout the developing world, there exist 97% of the total world population of 921 million goats across all agro-ecological zones (AEZs), including 570 breeds and 64% share of the breeds. They occupy a very important biological and socio-economic niche in farming systems making significant multifunctional contributions especially to food, nutrition and financial security, stability of farm households, and survival of the poor in the rural areas. Definitions are given of successful and failed projects. The analyses highlighted in successful projects the value of strong participatory efforts with farmers and climate change. Climate change effects on goats are inevitable and are mediated through heat stress, type of AEZ, water availability, quantity and quality of the available feed resources and type of production system. Within the prevailing production systems, improved integrated tree crops - ruminant systems are underestimated and are an important pathway to enhance C sequestration. Key development strategies and opportunities for research and development (R and D) are enormous, and include inter alia defining a policy framework, resolution of priority constraints using systems perspectives and community-based participatory activities, application of yield-enhancing technologies, intensification, scaling up, and impacts. The priority for development concerns the rainfed areas with large concentrations of ruminants in which

Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Sung-Dong; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749; Cheon, So Yeong

Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did notmore » inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration. - Highlights: • The nt-p65-TMD is intra-nuclear interactomic inhibitor of endogenous p65. • The nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines. • The excellent therapeutic potential of nt-p65-TMD was confirmed in sepsis model.« less

Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis.

PubMed

Kim, Ji H; Gupta, Subash C; Park, Byoungduck; Yadav, Vivek R; Aggarwal, Bharat B

2012-03-01

The incidence of cancer is significantly lower in regions where turmeric is heavily consumed. Whether lower cancer incidence is due to turmeric was investigated by examining its effects on tumor cell proliferation, on pro-inflammatory transcription factors NF-κB and STAT3, and on associated gene products. Cell proliferation and cell cytotoxicity were measured by the MTT method, NF-κB activity by EMSA, protein expression by Western blot analysis, ROS generation by FACS analysis, and osteoclastogenesis by TRAP assay. Turmeric inhibited NF-κB activation and down-regulated NF-κB-regulated gene products linked to survival (Bcl-2, cFLIP, XIAP, and cIAP1), proliferation (cyclin D1 and c-Myc), and metastasis (CXCR4) of cancer cells. The spice suppressed the activation of STAT3, and induced the death receptors (DR)4 and DR5. Turmeric enhanced the production of ROS, and suppressed the growth of tumor cell lines. Furthermore, turmeric sensitized the tumor cells to chemotherapeutic agents capecitabine and taxol. Turmeric was found to be more potent than pure curcumin for cell growth inhibition. Turmeric also inhibited NF-κB activation induced by RANKL that correlated with the suppression of osteoclastogenesis. Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-κB and STAT3 pathways. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Glucocorticoids and estrogens modulate the NF-κB pathway differently in the micro- and macrovasculature.

PubMed

Edgar, Abarca-Rojano; Judith, Pacheco-Yépez; Elisa, Drago-Serrano Maria; Rafael, Campos-Rodríguez

2013-12-01

Estrogens and glucocorticoids have synergistic effects in the micro and macrovasculature of endothelial cells (ECs), having pro-inflammatory effects in the former and inhibiting the expression of adhesion molecules in the latter. The molecular basis of these effects in the endothelium has not yet been clarified. We postulate that the ECs of the micro- and macrovasculature have different non-genomic mechanisms that regulate levels of preexisting complexes of glucocorticoids and estrogens with their respective receptors. Since these receptors are regulated by NF-κB, their expression could be critical to the activation of a pro- or anti-inflammatory response. In the macrovasculature the synergistic effects of estrogens and glucocorticoids on ECs may be through the inhibition of NF-κB, leading to the inhibition of the expression of inflammatory molecules. It seems likely that glucocorticoid-receptor and estrogen-receptor complexes directly bind to NF-κB proteins in the macrovasculature, resulting in the inhibition of an excessive proinflammatory response. Further insights into these processes may help clarify the role of the endothelial cells of different vascular beds during the inflammatory response and chronic inflammation, and thus contribute to the design of more effective therapeutic strategies for the prevention of diseases related to inflammation, including atherosclerosis, systemic lupus erythematosus and rheumatoid arthritis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Functional characterization of bovine TIRAP and MyD88 in mediating bacterial lipopolysaccharide-induced endothelial NF-kappaB activation and apoptosis.

PubMed

Cates, Elizabeth A; Connor, Erin E; Mosser, David M; Bannerman, Douglas D

2009-11-01

Mastitis is a prevalent disease in dairy cows. Gram-negative bacteria, which express the pro-inflammatory molecule lipopolysaccharide (LPS), are responsible for the majority of acute clinical cases of mastitis. Previous studies have identified differential susceptibility of human and bovine endothelial cells (EC) to the pro-inflammatory and injury-inducing effects of LPS. The Toll-like receptor (TLR)-4 signaling pathway, which is activated by LPS, has been well studied in humans, but not in ruminants. Human myeloid differentiation-factor 88 (MyD88) and TIR-domain containing adaptor protein (TIRAP) are critical proteins in the LPS-induced NF-kappaB and apoptotic signaling pathways. To assess the role of the bovine orthologs of these proteins in bovine TLR-4 signaling, dominant-negative constructs were expressed in bovine EC, and LPS-induced NF-kappaB activation and apoptosis evaluated. The results from this study indicate that bovine MyD88 and TIRAP play functional roles in transducing LPS signaling from TLR-4 to downstream effector molecules involved in NF-kappaB activation, and that TIRAP promotes apoptotic signaling.

42 CFR 483.132 - Evaluating the need for NF services and NF level of care (PASARR/NF).

Code of Federal Regulations, 2010 CFR

2010-10-01

... and 483.136, the State mental health or mental retardation authority must determine whether an NF... 42 Public Health 5 2010-10-01 2010-10-01 false Evaluating the need for NF services and NF level of care (PASARR/NF). 483.132 Section 483.132 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES...

Fisetin-treatment alleviates airway inflammation through inhbition of MyD88/NF-κB signaling pathway.

PubMed

Huang, Wei; Li, Ming-Li; Xia, Ming-Yue; Shao, Jian-Ying

2018-07-01

Asthma is a common chronic airway inflammation disease and is considered as a major public health problem. Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid abundantly found in different vegetables and fruits. Fisetin has been reported to exhibit various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. We evaluated the effects of fisetin on allergic asthma regulation in mice. Mice were first sensitized, then airway-challenged with ovalbumin (OVA). Whether fisetin treatment attenuated OVA-induced airway inflammation was examined via inflammation inhibition through MyD88-related NF-κB (p65) signaling pathway. Mice were divided into the control (Con), OVA-induced asthma (Mod), 40 (FL) and 50 (FH) mg/kg fisetin-treated OVA-induced asthma groups. Our results found that OVA-induced airway inflammation in mice caused a significant inflammatory response via the activation of MyD88 and NF-κB signaling pathways, leading to release of pro-inflammatory cytokines. In contrast, fisetin-treated mice after OVA induction inhibited activation of MyD88 and NF-κB signaling pathways, resulting in downregulation of pro-inflammatory cytokine secretion. Further, fisetin significantly ameliorated the airway hyperresponsiveness (AHR) towards methacholine (Mch). In addition, fisetin reduced the number of eosinophil, monocyte, neutrophil and total white blood cell in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. The serum and BALF samples obtained from the OVA-induced mice with fisetin showed lower levels of pro-inflammatory cytokines. The results of our study illustrated that fisetin may be a new promising candidate to inhibit airway inflammation response induced by OVA.

Fisetin-treatment alleviates airway inflammation through inhbition of MyD88/NF-κB signaling pathway

PubMed Central

Huang, Wei; Li, Ming-Li; Xia, Ming-Yue; Shao, Jian-Ying

2018-01-01

Asthma is a common chronic airway inflammation disease and is considered as a major public health problem. Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a naturally occurring flavonoid abundantly found in different vegetables and fruits. Fisetin has been reported to exhibit various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. We evaluated the effects of fisetin on allergic asthma regulation in mice. Mice were first sensi-tized, then airway-challenged with ovalbumin (OVA). Whether fisetin treatment attenuated OVA-induced airway inflammation was examined via inflammation inhibition through MyD88-related NF-κB (p65) signaling pathway. Mice were divided into the control (Con), OVA-induced asthma (Mod), 40 (FL) and 50 (FH) mg/kg fisetin-treated OVA-induced asthma groups. Our results found that OVA-induced airway inflammation in mice caused a significant inflammatory response via the activation of MyD88 and NF-κB signaling pathways, leading to release of pro-inflammatory cytokines. In contrast, fisetin-treated mice after OVA induction inhibited activation of MyD88 and NF-κB signaling pathways, resulting in downregulation of pro-inflammatory cytokine secretion. Further, fisetin significantly ameliorated the airway hyperresponsiveness (AHR) towards methacholine (Mch). In addition, fisetin reduced the number of eosinophil, monocyte, neutrophil and total white blood cell in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. The serum and BALF samples obtained from the OVA-induced mice with fisetin showed lower levels of pro-inflammatory cytokines. The results of our study illustrated that fisetin may be a new promising candidate to inhibit airway inflammation response induced by OVA. PMID:29568921

NF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise

PubMed Central

Wong, Victor C.; Bass, Victor L.; Bullock, M. Elise; Chavali, Arvind K.; Lee, Robin E.C.; Mothes, Walther; Gaudet, Suzanne; Miller-Jensen, Kathryn

2018-01-01

SUMMARY Noisy gene expression generates diverse phenotypes, but little is known about mechanisms that modulate noise. Combining experiments and modeling, we studied how tumor necrosis factor (TNF) initiates noisy expression of latent HIV via the transcription factor nuclear factor κB (NF-κB) and how the HIV genomic integration site modulates noise to generate divergent (low-versus-high) phenotypes of viral activation. We show that TNF-induced transcriptional noise varies more than mean transcript number and that amplification of this noise explains low-versus-high viral activation. For a given integration site, live-cell imaging shows that NF-κB activation correlates with viral activation, but across integration sites, NF-κB activation cannot account for differences in transcriptional noise and phenotypes. Instead, differences in transcriptional noise are associated with differences in chromatin state and RNA polymerase II regulation. We conclude that, whereas NF-κB regulates transcript abundance in each cell, the chromatin environment modulates noise in the population to support diverse HIV activation in response to TNF. PMID:29346759

Integrative Cardiac Health Project (ICHP)

DTIC Science & Technology

2017-04-01

AWARD NUMBER: W81XWH-16-2-0007 TITLE: Integrative Cardiac Health Project (ICHP) PRINCIPAL INVESTIGATOR: COL (Ret) Marina N. Vernalis, MC, USA...2017 4. TITLE AND SUBTITLE Integrative Cardiac Health Project (ICHP) 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-2-0007 5c. PROGRAM ELEMENT...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The Integrative Cardiac Health Project (ICHP) aims to lead the way in Cardiovascular Disease (CVD

Attenuation of liver pro-inflammatory responses by Zingiber officinale via inhibition of NF-kappa B activation in high-fat diet-fed rats.

PubMed

Li, Xiao-Hong; McGrath, Kristine C-Y; Nammi, Srinivas; Heather, Alison K; Roufogalis, Basil D

2012-03-01

The aim of this study was to investigate whether treatment with a ginger (Zingiber officinale) extract of high-fat diet (HFD)-fed rats suppresses Nuclear factor-kappa B (NF-κB)-driven hepatic inflammation and to subsequently explore the molecular mechanisms in vitro. Adult male Sprague-Dawley rats were treated with an ethanolic extract of Zingiber officinale (400 mg/kg) along with a HFD for 6 weeks. Hepatic cytokine mRNA levels, cytokine protein levels and NF-κB activation were measured by real-time PCR, Western blot and an NF-κB nuclear translocation assay, respectively. In vitro, cell culture studies were carried out in human hepatocyte (HuH-7) cells by treatment with Zingiber officinale (100 μg/mL) for 24 hr prior to interleukin-1β (IL-1β, 8 ng/mL)-induced inflammation. We showed that Zingiber officinale treatment decreased cytokine gene TNFα and IL-6 expression in HFD-fed rats, which was associated with suppression of NF-κB activation. In vitro, Zingiber officinale treatment decreased NF-κB-target inflammatory gene expression of IL-6, IL-8 and serum amyloid A1 (SAA1), while it suppressed NF-κB activity, IκBα degradation and IκB kinase (IKK) activity. In conclusion, Zingiber officinale suppressed markers of hepatic inflammation in HFD-fed rats, as demonstrated by decreased hepatic cytokine gene expression and decreased NF-κB activation. The study demonstrates that the anti-inflammatory effect of Zingiber officinale occurs at least in part through the NF-κB signalling pathway. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

Magnoflorine Enhances LPS-Activated Pro-Inflammatory Responses via MyD88-Dependent Pathways in U937 Macrophages.

PubMed

Haque, Md Areeful; Jantan, Ibrahim; Harikrishnan, Hemavathy; Abdul Wahab, Siti Mariam

2018-06-15

Magnoflorine, a major bioactive metabolite isolated from Tinospora crispa, has been reported for its diverse biochemical and pharmacological properties. However, there is little report on its underlying mechanisms of action on immune responses, particularly on macrophage activation. In this study, we aimed to investigate the effects of magnoflorine, isolated from T. crispa on the pro-inflammatory mediators generation induced by LPS and the concomitant NF- κ B, MAPKs, and PI3K-Akt signaling pathways in U937 macrophages. Differentiated U937 macrophages were treated with magnoflorine and the release of pro-inflammatory mediators was evaluated through ELISA, while the relative mRNA expression of the respective mediators was quantified through qRT-PCR. Correspondingly, western blotting was executed to observe the modulatory effects of magnoflorine on the expression of various markers related to NF- κ B, MAPK and PI3K-Akt signaling activation in LPS-primed U937 macrophages. Magnoflorine significantly enhanced the upregulation of TNF- α , IL-1 β , and PGE 2 production as well as COX-2 protein expression. Successively, magnoflorine prompted the mRNA transcription level of these pro-inflammatory mediators. Magnoflorine enhanced the NF- κ B activation by prompting p65, I κ B α , and IKK α / β phosphorylation as well as I κ B α degradation. Besides, magnoflorine treatments concentration-dependently augmented the phosphorylation of JNK, ERK, and p38 MAPKs as well as Akt. The immunoaugmenting effects were further confirmed by investigating the effects of magnoflorine on specific inhibitors, where the treatment with specific inhibitors of NF- κ B, MAPKs, and PI3K-Akt proficiently blocked the magnoflorine-triggered TNF- α release and COX-2 expression. Magnoflorine furthermore enhanced the MyD88 and TLR4 upregulation. The results suggest that magnoflorine has high potential on augmenting immune responses. Georg Thieme Verlag KG Stuttgart · New York.

Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-κB signaling pathway.

PubMed

Xu, Yiming; Liu, Ling

2017-09-01

Influenza A viruses (IAV) result in severe public health problems with worldwide each year. Overresponse of immune system to IAV infection leads to complications, and ultimately causing morbidity and mortality. Curcumin has been reported to have anti-inflammatory ability. However, its molecular mechanism in immune responses remains unclear. We detected the pro-inflammatory cytokine secretion and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-related protein expression in human macrophages or mice infected by IAV with or without curcumin treatment. We found that the IAV infection caused a dramatic enhancement of pro-inflammatory cytokine productions of human macrophages and mice immune cells. However, curcumin treatment after IAV infection downregulated these cytokines production in a dose-dependent manner. Moreover, the NF-κB has been activated in human macrophages after IAV infection, while administration of curcumin inhibited NF-κB signaling pathway via promoting the expression of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), and inhibiting the translocation of p65 from cytoplasm to nucleus. In summary, IAV infection could result in the inflammatory responses of immune cells, especially macrophages. Curcumin has the therapeutic potentials to relieve these inflammatory responses through inhibiting the NF-κB signaling pathway. © 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Macrophage Mitochondrial Oxidative Stress Promotes Atherosclerosis and NF-κB-Mediated Inflammation in Macrophages

PubMed Central

Wang, Ying; Wang, Gary Z.; Rabinovitch, Peter S.; Tabas, Ira

2014-01-01

Rationale Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell-type specific causation studies in vivo are lacking, and the molecular mechanisms of potential pro-atherogenic effects remain to be determined. Objective To assess the importance of macrophage mitoOS in atherogenesis and explore the underlying molecular mechanisms. Methods & Results We first validated Western-type diet-fed Ldlr-/- mice as a model of human mitoOS-atherosclerosis association by showing that a marker of mitoOS in lesional macrophages, non-nuclear oxidative DNA damage, correlates with aortic root lesion development. To investigate the importance of macrophage-mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6chi monocyte infiltration into lesions, and lower levels of the monocyte chemotactic protein-1 (MCP-1). The decrease in lesional MCP-1 was associated with suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the pro-inflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed MCP-1 expression by decreasing activation of the Iκ-kinase-RelA NF-κB pathway. Conclusions MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-κB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis. PMID:24297735

The Influenza A Virus Genotype Determines the Antiviral Function of NF-κB.

PubMed

Dam, Sharmistha; Kracht, Michael; Pleschka, Stephan; Schmitz, M Lienhard

2016-09-01

The role of NF-κB in influenza A virus (IAV) infection does not reveal a coherent picture, as pro- and also antiviral functions of this transcription factor have been described. To address this issue, we used clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9)-mediated genome engineering to generate murine MLE-15 cells lacking two essential components of the NF-κB pathway. Cells devoid of either the central NF-κB essential modulator (NEMO) scaffold protein and thus defective in IκB kinase (IKK) activation or cells not expressing the NF-κB DNA-binding and transactivation subunit p65 were tested for propagation of the SC35 virus, which has an avian host range, and its mouse-adapted variant, SC35M. While NF-κB was not relevant for replication of SC35M, the absence of NF-κB activity increased replication of the nonadapted SC35 virus. This antiviral effect of NF-κB was most prominent upon infection of cells with low virus titers as they usually occur during the initiation phase of IAV infection. The defect in NF-κB signaling resulted in diminished IAV-triggered phosphorylation of interferon regulatory factor 3 (IRF3) and expression of the antiviral beta interferon (IFN-β) gene. To identify the viral proteins responsible for NF-κB dependency, reassortant viruses were generated by reverse genetics. SC35 viruses containing the SC35M segment encoding neuraminidase (NA) were completely inert to the inhibitory effect of NF-κB, emphasizing the importance of the viral genotype for susceptibility to the antiviral functions of NF-κB. This study addresses two different issues. First, we investigated the role of the host cell transcription factor NF-κB in IAV replication by genetic manipulation of IAVs by reverse genetics combined with targeted genome engineering of host cells using CRISPR-Cas9. The analysis of these two highly defined genetic systems indicated that the IAV genotype can influence whether NF-κB displays an antiviral

The Influenza A Virus Genotype Determines the Antiviral Function of NF-κB

PubMed Central

Dam, Sharmistha; Kracht, Michael; Pleschka, Stephan

2016-01-01

ABSTRACT The role of NF-κB in influenza A virus (IAV) infection does not reveal a coherent picture, as pro- and also antiviral functions of this transcription factor have been described. To address this issue, we used clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9)-mediated genome engineering to generate murine MLE-15 cells lacking two essential components of the NF-κB pathway. Cells devoid of either the central NF-κB essential modulator (NEMO) scaffold protein and thus defective in IκB kinase (IKK) activation or cells not expressing the NF-κB DNA-binding and transactivation subunit p65 were tested for propagation of the SC35 virus, which has an avian host range, and its mouse-adapted variant, SC35M. While NF-κB was not relevant for replication of SC35M, the absence of NF-κB activity increased replication of the nonadapted SC35 virus. This antiviral effect of NF-κB was most prominent upon infection of cells with low virus titers as they usually occur during the initiation phase of IAV infection. The defect in NF-κB signaling resulted in diminished IAV-triggered phosphorylation of interferon regulatory factor 3 (IRF3) and expression of the antiviral beta interferon (IFN-β) gene. To identify the viral proteins responsible for NF-κB dependency, reassortant viruses were generated by reverse genetics. SC35 viruses containing the SC35M segment encoding neuraminidase (NA) were completely inert to the inhibitory effect of NF-κB, emphasizing the importance of the viral genotype for susceptibility to the antiviral functions of NF-κB. IMPORTANCE This study addresses two different issues. First, we investigated the role of the host cell transcription factor NF-κB in IAV replication by genetic manipulation of IAVs by reverse genetics combined with targeted genome engineering of host cells using CRISPR-Cas9. The analysis of these two highly defined genetic systems indicated that the IAV genotype can influence whether NF-κB displays

NF-κB expression and its association with nutritional status in hemodialysis patients.

PubMed

Farage, Najla E; Stockler-Pinto, Milena B; Leal, Viviane O; Cardozo, Ludmila Lmf; Carraro-Eduardo, José Carlos; Fouque, Denis; Mafra, Denise

2016-12-01

This study aimed to evaluate the association among the expressions of pro- and anti-inflammatory nuclear factors (nuclear factor-kappaB, NF-κB and nuclear erythroid 2-related factor 2, Nrf2) and nutritional status in HD patients. This cross-sectional study included eighty-three HD patients. The peripheral blood mononuclear cells were isolated and processed for the evaluation of NF-κB and Nrf2 RNAm expression by quantitative real-time polymerase chain reaction. Muscle mass was estimated by creatinine index (CI) and percentage of body fat (%BF) by anthropometry. Seven-point subjective global assessment was also used to evaluate the nutritional status. The NF-κB expression was negatively correlated with CI (r = -0.54, p = 0.0001), serum albumin (r = -0.32, p = 0.02) and %BF (r = -0.61, p = 0.001). Multiple linear regression analysis revealed that NF-κB expression was independently associated with CI (β: -0.8, p = 0.013) and %BF (β: -0.42, p = 0.04). There was no correlation among Nrf2 and anthropometric and biochemical variables. The classical NF-κB activation seems to be associated with poor nutritional status in HD patients; however, the exact underlying mechanisms deserve further studies.

Gelam Honey Attenuates Carrageenan-Induced Rat Paw Inflammation via NF-κB Pathway

PubMed Central

Hussein, Saba Zuhair; Mohd Yusoff, Kamaruddin; Makpol, Suzana; Mohd Yusof, Yasmin Anum

2013-01-01

The activation of nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of a number of inflammatory diseases. In this study, we investigated the anti-inflammatory mechanism of Gelam honey in inflammation induced rats via NF-κB signalling pathway. Rats paw edema was induced by subplantar injection of 1% carrageenan into the right hind paw. Rats were pre-treated with Gelam honey at different doses (1 or 2 g/kg, p.o.) and NSAID Indomethacin (10 mg/kg, p.o.), in two time points (1 and 7 days). Our results showed that Gelam honey at both concentrations suppressed the gene expressions of NF-κB (p65 & p50) and IκBα in inflamed rats paw tissues. In addition, Gelam honey inhibited the nuclear translocation and activation of NF-κB and decreased the cytosolic degradation of IκBα dose dependently in inflamed rats paw tissues. The immunohistochemical expressions of pro-inflammatory mediators COX-2 and TNF-α were also decreased in inflamed rats paw tissues when treated with Gelam honey. The results of our findings suggest that Gelam honey exhibits its inhibitory effects by attenuating NF-κB translocation to the nucleus and inhibiting IκBα degradation, with subsequent decrease of inflammatory mediators COX-2 and TNF-α. PMID:24015236

Fatigue and gene expression in human leukocytes: Increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue

PubMed Central

Bower, Julienne E.; Ganz, Patricia A.; Irwin, Michael R.; Arevalo, Jesusa M.G.; Cole, Steve W.

2013-01-01

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n = 11) and non-fatigued controls (n = 10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p < .05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors. PMID:20854893

Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue.

PubMed

Bower, Julienne E; Ganz, Patricia A; Irwin, Michael R; Arevalo, Jesusa M G; Cole, Steve W

2011-01-01

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n=11) and non-fatigued controls (n=10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p<.05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors. Copyright © 2010 Elsevier Inc. All rights reserved.

Effect of low extracellular pH on NF-κB activation in macrophages.

PubMed

Gerry, A B; Leake, D S

2014-04-01

Many diseases, including atherosclerosis, involve chronic inflammation. The master transcription factor for inflammation is NF-κB. Inflammatory sites have a low extracellular pH. Our objective was to demonstrate the effect of pH on NF-κB activation and cytokine secretion. Mouse J774 macrophages or human THP-1 or monocyte-derived macrophages were incubated at pH 7.0-7.4 and inflammatory cytokine secretion and NF-κB activity were measured. A pH of 7.0 greatly decreased pro-inflammatory cytokine secretion (TNF or IL-6) by J774 macrophages, but not THP-1 or human monocyte-derived macrophages. Upon stimulation of mouse macrophages, the levels of IκBα, which inhibits NF-κB, fell but low pH prevented its later increase, which normally restores the baseline activity of NF-κB, even though the levels of mRNA for IκBα were increased. pH 7.0 greatly increased and prolonged NF-κB binding to its consensus promoter sequence, especially the anti-inflammatory p50:p50 homodimers. Human p50 was overexpressed using adenovirus in THP-1 macrophages and monocyte-derived macrophages to see if it would confer pH sensitivity to NF-κB activity in human cells. Overexpression of p50 increased p50:p50 DNA-binding and in THP-1 macrophages inhibited considerably TNF and IL-6 secretion, but there was still no effect of pH on p50:p50 DNA binding or cytokine secretion. A modest decrease in pH can sometimes have marked effects on NF-κB activation and cytokine secretion and might be one reason to explain why mice normally develop less atherosclerosis than do humans. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Mindfulness-Based Stress Reduction Training Reduces Loneliness and Pro-Inflammatory Gene Expression in Older Adults: A Small Randomized Controlled Trial

PubMed Central

Creswell, J. David; Irwin, Michael R.; Burklund, Lisa J.; Lieberman, Matthew D.; Arevalo, Jesusa M. G.; Ma, Jeffrey; Breen, Elizabeth Crabb; Cole, Steven W.

2013-01-01

Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness-Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N=40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition × time interaction: F(1,35)=7.86, p=.008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF-κB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-κB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition × time interaction: (F(1,33)=3.39, p=.075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults. PMID:22820409

VaProS: a database-integration approach for protein/genome information retrieval.

PubMed

Gojobori, Takashi; Ikeo, Kazuho; Katayama, Yukie; Kawabata, Takeshi; Kinjo, Akira R; Kinoshita, Kengo; Kwon, Yeondae; Migita, Ohsuke; Mizutani, Hisashi; Muraoka, Masafumi; Nagata, Koji; Omori, Satoshi; Sugawara, Hideaki; Yamada, Daichi; Yura, Kei

2016-12-01

Life science research now heavily relies on all sorts of databases for genome sequences, transcription, protein three-dimensional (3D) structures, protein-protein interactions, phenotypes and so forth. The knowledge accumulated by all the omics research is so vast that a computer-aided search of data is now a prerequisite for starting a new study. In addition, a combinatory search throughout these databases has a chance to extract new ideas and new hypotheses that can be examined by wet-lab experiments. By virtually integrating the related databases on the Internet, we have built a new web application that facilitates life science researchers for retrieving experts' knowledge stored in the databases and for building a new hypothesis of the research target. This web application, named VaProS, puts stress on the interconnection between the functional information of genome sequences and protein 3D structures, such as structural effect of the gene mutation. In this manuscript, we present the notion of VaProS, the databases and tools that can be accessed without any knowledge of database locations and data formats, and the power of search exemplified in quest of the molecular mechanisms of lysosomal storage disease. VaProS can be freely accessed at http://p4d-info.nig.ac.jp/vapros/ .

Dark chocolate attenuates intracellular pro-inflammatory reactivity to acute psychosocial stress in men: A randomized controlled trial.

PubMed

Kuebler, Ulrike; Arpagaus, Angela; Meister, Rebecca E; von Känel, Roland; Huber, Susanne; Ehlert, Ulrike; Wirtz, Petra H

2016-10-01

Flavanol-rich dark chocolate consumption relates to lower risk of cardiovascular mortality, but underlying mechanisms are elusive. We investigated the effect of acute dark chocolate consumption on inflammatory measures before and after stress. Healthy men, aged 20-50years, were randomly assigned to a single intake of either 50g of flavanol-rich dark chocolate (n=31) or 50g of optically identical flavanol-free placebo-chocolate (n=34). Two hours after chocolate intake, both groups underwent the 15-min Trier Social Stress Test. We measured DNA-binding-activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, as well as plasma and whole blood mRNA levels of the pro-inflammatory cytokines IL-1β and IL-6, and the anti-inflammatory cytokine IL-10, prior to chocolate intake as well as before and several times after stress. We also repeatedly measured the flavanol epicatechin and the stress hormones epinephrine and cortisol in plasma and saliva, respectively. Compared to the placebo-chocolate-group, the dark-chocolate-group revealed a marginal increase in IL-10 mRNA prior to stress (p=0.065), and a significantly blunted stress reactivity of NF-κB-BA, IL-1β mRNA, and IL-6 mRNA (p's⩽0.036) with higher epicatechin levels relating to lower pro-inflammatory stress reactivity (p's⩽0.033). Stress hormone changes to stress were controlled. None of the other measures showed a significant chocolate effect (p's⩾0.19). Our findings indicate that acute flavanol-rich dark chocolate exerts anti-inflammatory effects both by increasing mRNA expression of the anti-inflammatory cytokine IL-10 and by attenuating the intracellular pro-inflammatory stress response. This mechanism may add to beneficial effects of dark chocolate on cardiovascular health. Copyright © 2016 Elsevier Inc. All rights reserved.

NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells.

PubMed

Kim, Ki-Hyung; Park, Seong-Hwan; Do, Kee Hun; Kim, Juil; Choi, Kyung Un; Moon, Yuseok

2016-11-01

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in developed countries. Chronic endogenous sterile pro-inflammatory responses are strongly linked to EOC progression and chemoresistance to anti-cancer therapeutics. In the present study, the activity of epithelial NF-κB, a key pro-inflammatory transcription factor, was enhanced with the progress of EOC. This result was mechanistically linked with an increased expression of NSAID-Activated Gene 1 (NAG-1) in MyD88-positive type I EOC stem-like cells, compared with that in MyD88-negative type II EOC cells. Elevated NAG-1 as a potent biomarker of poor prognosis in the ovarian cancer was positively associated with the levels of NF-κB activation, chemokines and stemness markers in type I EOC cells. In terms of signal transduction, NAG-1-activated SMAD-linked and non-canonical TGFβ-activated kinase 1 (TAK-1)-activated pathways contributed to NF-κB activation and the subsequent induction of some chemokines and cancer stemness markers. In addition to effects on NF-κB-dependent gene regulation, NAG-1 was involved in expression of EGF receptor and subsequent activation of EGF receptor-linked signaling. The present study also provided evidences for links between NAG-1-linked signaling and chemoresistance in ovarian cancer cells. NAG-1 and pro-inflammatory NF-κB were positively associated with resistance to paclitaxel in MyD88-positive type I EOC cells. Mechanistically, this chemoresistance occurred due to enhanced activation of the SMAD-4- and non-SMAD-TAK-1-linked pathways. All of the present data suggested NAG-1 protein as a crucial mediator of EOC progression and resistance to the standard first-line chemotherapy against EOC, particularly in MyD88-positive ovarian cancer stem-like cells.

Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammation

PubMed Central

Leus, Niek G.J.; Zwinderman, Martijn R.H.; Dekker, Frank J.

2016-01-01

Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications are lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor κB (NF-κB) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-κB interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-κB pathway is the development of highly potent small molecules that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-κB-mediated) inflammation and NF-κB lysine acetylation. In addition, we address the application of frequently used small molecule HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chemistry efforts aimed at HDAC 3-selective inhibitors are discussed. PMID:27371876

Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana

Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observedmore » link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.« less

Nickel(II) Complex of Polyhydroxybenzaldehyde N4-Thiosemicarbazone Exhibits Anti-Inflammatory Activity by Inhibiting NF-κB Transactivation

PubMed Central

Loh, Sheng Wei; Looi, Chung Yeng; Hassandarvish, Pouya; Phan, Alicia Yi Ling; Wong, Won Fen; Wang, Hao; Paterson, Ian C.; Ea, Chee Kwee; Mustafa, Mohd Rais; Maah, Mohd Jamil

2014-01-01

Background The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity. Methodology/Principal Findings Four ligands (1–4) and their respective nickel-containing complexes (5–8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis. Conclusions/Significance Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects. PMID:24977407

Investments on Pro-poor Development Projects on Goats: Ensuring Success for Improved Livelihoods*

PubMed Central

Devendra, C.

2013-01-01

The elements that determine the success of development projects on goats and the prerequisites for ensuring this are discussed in the context of the bewildering diversity of goat genetic resources, production systems, multifunctionality, and opportunities for responding to constraints for productivity enhancement. Key determinants for the success of pro-poor projects are the imperatives of realistic project design, resolution of priorities and positive impacts to increase investments and spur agricultural growth, and appropriate policy. Throughout the developing world, there exist 97% of the total world population of 921 million goats across all agro-ecological zones (AEZs), including 570 breeds and 64% share of the breeds. They occupy a very important biological and socio-economic niche in farming systems making significant multifunctional contributions especially to food, nutrition and financial security, stability of farm households, and survival of the poor in the rural areas. Definitions are given of successful and failed projects. The analyses highlighted in successful projects the value of strong participatory efforts with farmers and climate change. Climate change effects on goats are inevitable and are mediated through heat stress, type of AEZ, water availability, quantity and quality of the available feed resources and type of production system. Within the prevailing production systems, improved integrated tree crops - ruminant systems are underestimated and are an important pathway to enhance C sequestration. Key development strategies and opportunities for research and development (R and D) are enormous, and include inter alia defining a policy framework, resolution of priority constraints using systems perspectives and community-based participatory activities, application of yield-enhancing technologies, intensification, scaling up, and impacts. The priority for development concerns the rainfed areas with large concentrations of ruminants in which

ProSens: integrated production control by automated inspection planning and efficient multisensor metrology

NASA Astrophysics Data System (ADS)

Glaser, Ulf; Li, Zhichao; Bichmann, Stephan, II; Pfeifer, Tilo

2003-05-01

By China's entry into the WTO, Chinese as well as German companies are facing the question, how to minimize the risk of unfamiliar cooperation partners when developing products. The rise of customer demands concerning quality, product diversity and the reduction of expenses require flexibility and efficiency with reliable component suppliers. In order to build and strengthen sino-german cooperations, a manufacturing control using homogenized and efficient measures to assure high quality is of vital importance. Lack of unifications may cause identical measurements conducted at subcontractors or customers to be carried out with different measurement processes which leads to incomparable results. Rapidly growing company cooperations and simultaneously decreasing of manufacturing scope cause substantial difficulties when coordinating joint quality control activities. "ProSens," a sino-german project consortium consisting of industrial users, technology producers and research institutes, aims at improving selected production processes by: Creation of a homogeneous quality awareness in sino-german cooperations. Sensitization for process accompanying metrology at an early stage of product development. Increase of the process performance by the use of integrated metrology. Reduction of production time and cost. Unification of quality control of complex products by means of efficient measurement strategies and CAD-based inspection planning.

Spinal Neurofibromatosis without Café-au-Lait Macules in Two Families with Null Mutations of the NF1 Gene

PubMed Central

Kaufmann, Dieter; Müller, Ralf; Bartelt, Britta; Wolf, Michael; Kunzi-Rapp, Karin; Hanemann, Clemens Oliver; Fahsold, Raimund; Hein, Christian; Vogel, Walther; Assum, Günter

2001-01-01

Spinal neurofibromatosis (SNF) is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors and café-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstrated, by linkage analysis, for three families with SNF. In one of them, a cosegregating frameshift mutation in exon 46 of the NF1 gene was identified. In the present study, we report four individuals from two families who carry NF1 null mutations that would be expected to cause NF1. Three patients have multiple spinal tumors and no café-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation (IVS31-5A→G) enlarging exon 32 by 4 bp at the 5′ end was found. The latter mutation has also been observed in an unrelated patient with classical NF1. Both NF1 mutations cause a reduction in neurofibromin of ∼50%, with no truncated protein present in the cells. This demonstrates that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for SNF. We speculate that this phenotype is caused by an unknown modifying gene that compensates for some, but not all, of the effects caused by neurofibromin deficiency. PMID:11704931

Flavonoid Fraction of Bergamot Juice Reduces LPS-Induced Inflammatory Response through SIRT1-Mediated NF-κB Inhibition in THP-1 Monocytes

PubMed Central

Risitano, Roberto; Currò, Monica; Cirmi, Santa; Ferlazzo, Nadia; Campiglia, Pietro; Caccamo, Daniela; Ientile, Riccardo; Navarra, Michele

2014-01-01

Plant polyphenols exert anti-inflammatory activity through both anti-oxidant effects and modulation of pivotal pro-inflammatory genes. Recently, Citrus bergamia has been studied as a natural source of bioactive molecules with antioxidant activity, but few studies have focused on molecular mechanisms underlying their potential beneficial effects. Several findings have suggested that polyphenols could influence cellular function by acting as activators of SIRT1, a nuclear histone deacetylase, involved in the inhibition of NF-κB signaling. On the basis of these observations we studied the anti-inflammatory effects produced by the flavonoid fraction of the bergamot juice (BJe) in a model of LPS-stimulated THP-1 cell line, focusing on SIRT1-mediated NF-κB inhibition. We demonstrated that BJe inhibited both gene expression and secretion of LPS-induced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) by a mechanism involving the inhibition of NF-κB activation. In addition, we showed that BJe treatment reversed the LPS-enhanced acetylation of p65 in THP-1 cells. Interestingly, increasing concentrations of Sirtinol were able to suppress the inhibitory effect of BJe via p65 acetylation, underscoring that NF-κB–mediated inflammatory cytokine production may be directly linked to SIRT1 activity. These results suggest that BJe may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process. PMID:25260046

Flavonoid fraction of Bergamot juice reduces LPS-induced inflammatory response through SIRT1-mediated NF-κB inhibition in THP-1 monocytes.

PubMed

Risitano, Roberto; Currò, Monica; Cirmi, Santa; Ferlazzo, Nadia; Campiglia, Pietro; Caccamo, Daniela; Ientile, Riccardo; Navarra, Michele

2014-01-01

Plant polyphenols exert anti-inflammatory activity through both anti-oxidant effects and modulation of pivotal pro-inflammatory genes. Recently, Citrus bergamia has been studied as a natural source of bioactive molecules with antioxidant activity, but few studies have focused on molecular mechanisms underlying their potential beneficial effects. Several findings have suggested that polyphenols could influence cellular function by acting as activators of SIRT1, a nuclear histone deacetylase, involved in the inhibition of NF-κB signaling. On the basis of these observations we studied the anti-inflammatory effects produced by the flavonoid fraction of the bergamot juice (BJe) in a model of LPS-stimulated THP-1 cell line, focusing on SIRT1-mediated NF-κB inhibition. We demonstrated that BJe inhibited both gene expression and secretion of LPS-induced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) by a mechanism involving the inhibition of NF-κB activation. In addition, we showed that BJe treatment reversed the LPS-enhanced acetylation of p65 in THP-1 cells. Interestingly, increasing concentrations of Sirtinol were able to suppress the inhibitory effect of BJe via p65 acetylation, underscoring that NF-κB-mediated inflammatory cytokine production may be directly linked to SIRT1 activity. These results suggest that BJe may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process.

Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taylor, Cormac T.; Kent, Brian D.; Crinion, Sophie J.

Highlights: • Intermittent hypoxia (IH) leads to NF-κB activation in human primary adipocytes. • Adipocytes bear higher pro-inflammatory potential than other human primary cells. • IH leads to upregulation of multiple pro-inflammatory genes in human adipocytes. - Abstract: Introduction: Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmentedmore » inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. Methods and results: Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. Conclusion: Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may

Short communication: molecular characterization of dog and cat p65 subunits of NF-kappaB.

PubMed

Ishikawa, Shingo; Takemitsu, Hiroshi; Li, Gebin; Mori, Nobuko; Yamamoto, Ichiro; Arai, Toshiro

2015-04-01

Nuclear factor kappa B (NF-κB) plays an important role in the immune system. The p65 subunit is an important part of NF-κB unit, and studies of dog and cat p65 subunits of NF-κB (dp65 and cp65) are important in understanding their immune function. In this study, we described the molecular characterization of dp65 and cp65. The dp65 and cp65 complementary DNA encoded 542 and 555 amino acids, respectively, showing a high sequence homology with the mammalian p65 subunit (>87.5%). Quantitative polymerase chain reaction revealed that the p65 messenger RNA is highly expressed in the dog stomach and cat heart and adipose tissue. Functional NF-κB promoter-luciferase reporter vectors revealed that our isolated dp65 and cp65 cDNA encodes a functionally active protein. Transiently expressed dp65 and cp65 up-regulated pro-inflammatory cytokine expression levels in dog and cat, respectively. These findings suggest that dp65 and cp65 play important roles in regulating immune function. Copyright © 2015 Elsevier Ltd. All rights reserved.

Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain

PubMed Central

Lee, Won Hee; Sonntag, William E.; Mitschelen, Matthew; Yan, Han; Lee, Yong Woo

2010-01-01

Purpose Pro-inflammatory environments in the brain have been implicated in the onset and progression of neurological disorders. In the present study, we investigate the hypothesis that brain irradiation induces regionally specific alterations in cytokine gene and protein expression. Materials and methods Four month old F344 × BN rats received either whole brain irradiation with a single dose of 10 Gy γ-rays or sham-irradiation, and were maintained for 4, 8, and 24 h following irradiation. The mRNA and protein expression levels of pro-inflammatory mediators were analysed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. To elucidate the molecular mechanisms of irradiation-induced brain inflammation, effects of irradiation on the DNA-binding activity of pro-inflammatory transcription factors were also examined. Results A significant and marked up-regulation of mRNA and protein expression of pro-inflammatory mediators, including tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1), was observed in hippocampal and cortical regions isolated from irradiated brain. Cytokine expression was regionally specific since TNF-α levels were significantly elevated in cortex compared to hippocampus (57% greater) and IL-1β levels were elevated in hippocampus compared to cortical samples (126% greater). Increases in cytokine levels also were observed after irradiation of mouse BV-2 microglial cells. A series of electrophoretic mobility shift assays (EMSA) demonstrated that irradiation significantly increased activation of activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and cAMP response element-binding protein (CREB). Conclusion The present study demonstrated that whole brain irradiation induces regionally specific pro-inflammatory environments through activation of AP-1, NF-κB, and CREB and overexpression of TNF-α, IL

Mindfulness-Based Stress Reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial.

PubMed

Creswell, J David; Irwin, Michael R; Burklund, Lisa J; Lieberman, Matthew D; Arevalo, Jesusa M G; Ma, Jeffrey; Breen, Elizabeth Crabb; Cole, Steven W

2012-10-01

Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness-Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N = 40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition × time interaction: F(1,35) = 7.86, p = .008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF-κB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-κB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition × time interaction: (F(1,33) = 3.39, p = .075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults. Copyright © 2012 Elsevier Inc. All rights reserved.

Modifying pro-drug risk factors in adolescents: results from project ALERT.

PubMed

Ghosh-Dastidar, Bonnie; Longshore, Douglas L; Ellickson, Phyllis L; McCaffrey, Daniel F

2004-06-01

The objective of this study was to evaluate the impact of a revised state-of-the-art drug prevention program, Project ALERT, on risk factors for drug use in mostly rural midwestern schools and communities. Fifty-five middle schools from South Dakota were randomly assigned to treatment or control conditions. Treatment-group students received 11 lessons in Grade 7 and 3 more in Grade 8. Effects for 4276 eighth graders were assessed 18 months after baseline. Results indicate that Project ALERT had statistically significant effects on all the targeted risk factors associated with cigarette and marijuana use and more modest gains with the pro-alcohol risk factors. The program helped adolescents at low, moderate, and high risk for future use, with the effect sizes typically stronger for the low- and moderate-risk groups. Thus, school-based drug prevention programs can lower risk factors that correlate with drug use, help low- to high-risk adolescents, and be effective in diverse school environments.

PRO-140 (Progenics).

PubMed

Poli, G

2001-09-01

PRO-140, a monoclonal antibody against the HIV coreceptor CCR5, is under investigation by Progenics and the Aaron Diamond AIDS Research Center (ADARC) as a potential treatment for HIV infection [211441], [286246], [286247]. Phase I/II trials were expected to commence during 2001 [395621], [409142], despite being initially planned for 2000 [322637], [361819], [365216], [375598], [408483]. In January 1998, ADARC and Progenics reported that the HIV binding site on the CCR5 coreceptor is distinct from betachemokine binding domains, which they claimed may allow for the development of therapeutics with fewer side effects [273391], 421256]. In vitro studies have shown PRO-140 potently blocked all of 17 primary HIV isolates that use CCR5 as a fusion coreceptor [342173]. In October 2000, Progenics was awarded an SBIR grant to fund a 2-year project exploring the breadth, potency and durability of PRO-140 therapy in laboratory and animal models of HIV infection. This project was a collaboration between Progenics, Weill Medical College of Cornell University and the Scripps Research Institute [385982]. In May 1999, the company entered into an agreement with Protein Design Labs (PDL) for the humanization by PDL of PRO-140 [325445]. In November 1997, Progenics was awarded a 600,000 dollars grant from the NIAID for the examination of new approaches to HIV vaccine design based on CCR5 [268407].

Prevalence of mutations in hepatitis C virus core protein associated with alteration of NF-kappaB activation.

PubMed

Mann, Elizabeth A; Stanford, Sandra; Sherman, Kenneth E

2006-10-01

The hepatitis C virus (HCV) core protein is a key structural element of the virion but also affects a number of cellular pathways, including nuclear factor kappaB (NF-kappaB) signaling. NF-kappaB is a transcription factor that regulates both anti-apoptotic and pro-inflammatory genes and its activation may contribute to HCV-mediated pathogenesis. Amino acid sequence divergence in core is seen at the genotype level as well as within patient isolates. Recent work has implicated amino acids 9-11 of core in the modulation of NF-kappaB activation. We report that the sequence RKT is highly conserved (93%) at this position across all HCV genotypes, based on sequences collected in the Los Alamos HCV database. Of the 13 types of variants present in the database, the two most prevalent substitutions are RQT and RKP. We further show that core encoding RKP fails to activate NF-kappaB signaling in vitro while NF-kappaB activation by core encoding RQT does not differ from control RKT core. The effect of RKP core is specific to NF-kappaB signaling as activator protein 1 (AP-1) activity is not altered. Further studies are needed to assess potential associations between specific amino acid substitutions at positions 9-11 and liver disease progression and/or response to treatment in individual patients.

Interleukin-6 upregulates paraoxonase 1 gene expression via an AKT/NF-κB-dependent pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Chi-Chih; Hsueh, Chi-Mei; Chen, Chiu-Yuan

2013-07-19

Highlights: •IL-6 could induce PON1 gene expression. •IL-6 increased NF-κB protein expression and NF-κB-p50 and -p65 subunits nuclear translocation. •IL-6-induced PON1 up-regulation was through an AKT/NF-κB pathway. -- Abstract: The aim of this study is to investigate the relationship between paraoxonase 1 (PON1) and atherosclerosis-related inflammation. In this study, human hepatoma HepG2 cell line was used as a hepatocyte model to examine the effects of the pro-inflammatory cytokines on PON1 expression. The results showed that IL-6, but not TNF-α and IL-1β, significantly increased both the function and protein level of PON1; data from real-time RT-PCR analysis revealed that the IL-6-inducedmore » PON1 expression occurred at the transcriptional level. Increase of IκB kinase activity and IκB phosphorylation, and reduction of IκB protein level were also observed in IL-6-treated HepG2 cells compared with untreated culture. This event was accompanied by increase of NF-κB-p50 and -p65 nuclear translocation. Moreover, treatment with IL-6 augmented the DNA binding activity of NF-κB. Furthermore, pharmacological inhibition of NF-κB activation by PDTC and BAY 11-7082, markedly suppressed the IL-6-mediated PON1 expression. In addition, IL-6 increased the levels of phosphorylated protein kinase B (PKB, AKT). An AKT inhibitor LY294002 effectively suppressed IKK/IκB/NF-κB signaling and PON1 gene expression induced by IL-6. Our findings demonstrate that IL-6 upregulates PON1 gene expression through an AKT/NF-κB signaling axis in human hepatocyte-derived HepG2 cell line.« less

An investigation of desalination by nanofiltration, reverse osmosis and integrated (hybrid NF/RO) membranes employed in brackish water treatment.

PubMed

Talaeipour, M; Nouri, J; Hassani, A H; Mahvi, A H

2017-01-01

hybrid system of those parameters and ions included salinity 78.65, TDS 76.52, EC 76.42, Cl 63.95, and Na 70.91. Comparing rejection percent in three above-mentioned methods, it could be concluded that, in reverse osmosis process, ions and non-ion parameters rejection ability were rather better than nanofiltration process, and also better in hybrid compared to reverse osmosis process. The results reported in this paper indicate that the integration of membrane nanofiltration with reverse osmosis (hybrid NF/RO) can be completed by each other probably to remove salinity, TDS, EC, Cl, and Na.

Noncanonical NF-κB Signaling Is Limited by Classical NF-κB Activity

PubMed Central

Gray, Carolyn M.; Remouchamps, Caroline; McCorkell, Kelly A.; Solt, Laura A.; Dejardin, Emmanuel; Orange, Jordan S.; May, Michael J.

2014-01-01

Precise regulation of nuclear factor κB (NF-κB) signaling is crucial for normal immune responses, and defective NF-κB activity underlies a range of immunodeficiencies. NF-κB is activated through two signaling cascades: the classical and noncanonical pathways. The classical pathway requires inhibitor of κB kinase β (IKKβ) and NF-κB essential modulator (NEMO), and hypomorphic mutations in the gene encoding NEMO (ikbkg) lead to inherited immunodeficiencies, collectively termed NEMO-ID. Noncanonical NF-κB activation requires NF-κB–inducing kinase (NIK) and IKKα, but not NEMO. We found that noncanonical NF-κB was basally active in peripheral blood mononuclear cells from NEMO-ID patients, and that noncanonical NF-κB signaling was similarly enhanced in cell lines lacking functional NEMO. NIK, which normally undergoes constitutive degradation, was aberrantly present in resting NEMO-deficient cells, and regulation of its abundance was rescued by reconstitution with full-length NEMO, but not a mutant NEMO protein unable to physically associate with IKKα or IKKβ. Binding of NEMO to IKKα was not required for ligand-dependent stabilization of NIK or noncanonical NF-κB signaling. Rather, an intact and functional IKK complex was essential to suppress basal NIK activity in unstimulated cells. Despite interacting with IKKα and IKKβ to form an IKK complex, NEMO mutants associated with immunodeficiency failed to rescue classical NF-κB signaling or reverse the accumulation of NIK. Together, these findings identify a crucial role for classical NF-κB activity in the suppression of basal noncanonical NF-κB signaling. PMID:24497610

ESIF Call for High-Impact Integrated Projects | Energy Systems Integration

Science.gov Websites

Integrated Projects As a U.S. Department of Energy user facility, the Energy Systems Integration Facility concepts, tools, and technologies needed to measure, analyze, predict, protect, and control the grid of the Facility | NREL ESIF Call for High-Impact Integrated Projects ESIF Call for High-Impact

Constitutive NF-κB activation and tumor-growth promotion by Romo1-mediated reactive oxygen species production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chung, Jin Sil; Lee, Sora; Yoo, Young Do, E-mail: ydy1130@korea.ac.kr

2014-08-08

Highlights: • Romo1 expression is required for constitutive nuclear DNA-binding activity of NF-κB. • Romo1 depletion suppresses tumor growth in vivo. • Romo1 presents a potential therapeutic target for diseases. - Abstract: Deregulation of nuclear factor-κB (NF-κB) and related pathways contribute to tumor cell proliferation and invasion. Mechanisms for constitutive NF-κB activation are not fully explained; however, the underlying defects appear to generate and maintain pro-oxidative conditions. In hepatocellular carcinoma (HCC) tissues, up-regulation of reactive oxygen species modulator 1 (Romo1) correlates positively with tumor size. In the present study, we showed that Romo1 expression is required to maintain constitutive nuclearmore » DNA-binding activity of NF-κB and transcriptional activity through constitutive IκBα phosphorylation. Overexpression of Romo1 promoted p65 nuclear translocation and DNA-binding activity. We also show that Romo1 depletion suppressed anchorage-independent colony formation by HCC cells and suppressed tumor growth in vivo. Based on these findings, Romo1 may be a principal regulatory factor in the maintenance of constitutive NF-κB activation in tumor cells. In the interest of anti-proliferative treatments for cancer, Romo1 may also present a productive target for drug development.« less

Cyclo(His-Pro) promotes cytoprotection by activating Nrf2-mediated up-regulation of antioxidant defence

PubMed Central

Minelli, Alba; Conte, Carmela; Grottelli, Silvia; Bellezza, Maria; Cacciatore, Ivana; Bolaños, Juan P

2009-01-01

Hystidyl-proline [cyclo(His-Pro)] is an endogenous cyclic dipeptide produced by the cleavage of thyrotropin releasing hormone. Previous studies have shown that cyclo(His-Pro) protects against oxidative stress, although the underlying mechanism has remained elusive. Here, we addressed this issue and found that cyclo(His-Pro) triggered nuclear accumulation of NF-E2-related factor-2 (Nrf2), a transcription factor that up-regulates antioxidant-/electrophile-responsive element (ARE-EpRE)-related genes, in PC12 cells. Cyclo(His-Pro) attenuated reactive oxygen species production, and prevented glutathione depletion caused by glutamate, rotenone, paraquat and β-amyloid treatment. Moreover, real-time PCR analyses revealed that cyclo(His-Pro) induced the expression of a number of ARE-related genes and protected cells against hydrogen peroxide-mediated apoptotic death. Furthermore, these effects were abolished by RNA interference-mediated Nrf2 knockdown. Finally, pharmacological inhibition of p-38 MAPK partially prevented both cyclo(His-Pro)-mediated Nrf2 activation and cellular protection. These results suggest that the signalling mechanism responsible for the cytoprotective actions of cyclo(His-Pro) would involve p-38 MAPK activation leading to Nrf2-mediated up-regulation of antioxidant cellular defence. PMID:18373731

Eupatilin inhibits T-cell activation by modulation of intracellular calcium flux and NF-kappaB and NF-AT activity.

PubMed

Kim, Young-Dae; Choi, Suck-Chei; Oh, Tae-Young; Chun, Jang-Soo; Jun, Chang-Duk

2009-09-01

Eupatilin, one of the pharmacologically active ingredients of Artemisia princeps, exhibits a potent anti-ulcer activity, but its effects on T-cell immunity have not been investigated. Here, we show that eupatilin has a profound inhibitory effect on IL-2 production in Jurkat T cells as well as in human peripheral blood leukocytes. Eupatilin neither influenced clustering of CD3 and LFA-1 to the immunological synapse nor inhibited conjugate formation between T cells and B cells in the presence or absence of superantigen (SEE). Eupatilin also failed to inhibit T-cell receptor (TCR) internalization, thereby, suggesting that eupatilin does not interfere with TCR-mediated signals on the membrane proximal region. In unstimulated T cells, eupatilin significantly induced apoptotic cell death, as evidenced by an increased population of annexin V(+)/PI(+) cells and cleavage of caspase-3 and PARP. To our surprise, however, once cells were activated, eupatilin had little effect on apoptosis, and instead slightly protected cells from activation-induced cell death, suggesting that apoptosis also is not a mechanism for eupatilin-induced T-cell suppression. On the contrary, eupatilin dramatically inhibited I-kappaBalpha degradation and NF-AT dephosphorylation and, consequently, inhibited NF-kappaB and NF-AT promoter activities in PMA/A23187-stimulated T cells. Interestingly, intracellular calcium flux was significantly perturbed in cells pre-treated with eupatilin, suggesting that calcium-dependent cascades might be targets for eupatilin action. Collectively, our results provide evidence for dual regulatory functions of eupatilin: (1) a pro-apoptotic effect on resting T cells and (2) an immunosuppressive effect on activated T cells, presumably through modulation of Ca(2+) flux. (c) 2009 Wiley-Liss, Inc.

25-Hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ichikawa, Tomohiro; Sugiura, Hisatoshi, E-mail: sugiura@rm.med.tohoku.ac.jp; Koarai, Akira

2013-05-01

Abnormal structural alterations termed remodeling, including fibrosis and alveolar wall destruction, are important features of the pathophysiology of chronic airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase (CH25H) in macrophages and is reported to be involved in the formation of arteriosclerosis. We previously demonstrated that the expression of CH25H and production of 25HC were increased in the lungs of COPD. However, the role of 25-HC in lung tissue remodeling is unknown. In this study, we investigated the effect of 25-HC on fibroblast-mediated tissue remodeling using human fetal lung fibroblastsmore » (HFL-1) in vitro. 25-HC significantly augmented α-smooth muscle actin (SMA) (P<0.001) and collagen I (P<0.001) expression in HFL-1. 25-HC also significantly enhanced the release and activation of matrix metallaoproteinase (MMP)-2 (P<0.001) and MMP-9 (P<0.001) without any significant effect on the production of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. 25-HC stimulated transforming growth factor (TGF)-β{sub 1} production (P<0.01) and a neutralizing anti-TGF-β antibody restored these 25-HC-augmented pro-fibrotic responses. 25-HC significantly promoted the translocation of nuclear factor (NF)-κB p65 into the nuclei (P<0.01), but not phospholylated-c-jun, a complex of activator protein-1. Pharmacological inhibition of NF-κB restored the 25-HC-augmented pro-fibrotic responses and TGF-β{sub 1} release. These results suggest that 25-HC could contribute to fibroblast-mediated lung tissue remodeling by promoting myofibroblast differentiation and the excessive release of extracellular matrix protein and MMPs via an NF-κB-TGF-β dependent pathway.« less

NF-κB–YY1–miR-29 Regulatory Circuitry in Skeletal Myogenesis and Rhabdomyosarcoma

PubMed Central

Wang, Huating; Garzon, Ramiro; Sun, Hao; Ladner, Katherine J.; Singh, Ravi; Dahlman, Jason; Cheng, Alfred; Hall, Brett M.; Qualman, Stephen J.; Chandler, Dawn S.; Croce, Carlo M.; Guttridge, Denis C.

2008-01-01

SUMMARY Studies support the importance of microRNAs in physiological and pathological processes. Here we describe the regulation and function of miR-29 in myogenesis and Rhabdomyosarcoma (RMS). Results demonstrate that in myoblasts miR-29 is repressed by NF-κB acting through YY1 and the Polycomb. During myogenesis, NF-κB and YY1 downregulation causes derepression of miR-29, which in turn accelerates differentiation by targeting its repressor YY1. However, in RMS cells and primary tumors that possess impaired differentiation, miR-29 is epigenetically silenced by an activated NF-κB-YY1 pathway. Reconstitution of miR-29 in RMS in mice inhibits tumor growth and stimulates differentiation, suggesting that miR-29 acts as a tumor suppressor through its pro-myogenic function. Together, results identify a NF-κB–YY1–miR-29 regulatory circuit whose disruption may contribute to RMS. SIGNIFICANCE MicroRNAs regulate skeletal myogenesis, but their impact in muscle diseases is not well understood. Here we describe miR-29 as an enhancer of myogenic differentiation and a suppressor of RMS. We find that miR-29 exists in a regulatory circuit involving NF-κB and YY1. In myoblasts NF-B acts through YY1 to epigenetically suppress miR-29, while during differentiation miR-29 is induced to facilitate myogenesis by a negative feedback on YY1. Significantly, RMS tumors lose miR-29 due to an elevation in NF-B and YY1, and readjustment of miR-29 levels in RMS stimulates differentiation. Thus, myogenesis is dependent on NF-κB–YY1–miR-29 circuitry whose dysfunction may contribute to RMS pathogenesis. Such findings offer potential avenues for the diagnosis and treatment of muscle relevant cancers. PMID:18977326

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

PubMed Central

Mahapatra, Saugata; Gallaher, Brandi; Smith, Sydni Caet; Graham, Joseph G.; Voth, Daniel E.; Shaw, Edward I.

2016-01-01

Coxiella burnetii is the causative agent of Q fever and an obligate intracellular pathogen in nature that survives and grows in a parasitophorous vacuole (PV) within eukaryotic host cells. C. burnetii promotes intracellular survival by subverting apoptotic and pro-inflammatory signaling pathways that are typically regulated by nuclear transcription factor-κB (NF-κB). We and others have demonstrated that C. burnetii NMII proteins inhibit expression of pro-inflammatory cytokines and induce expression of anti-apoptotic genes during infection. Here, we demonstrate that C. burnetii promotes intracellular survival by modulating NF-κB subunit p65 (RelA) phosphorylation, and thus activation, in a Type Four B Secretion System (T4BSS)-dependent manner. Immunoblot analysis of RelA phosphorylated at serine-536 demonstrated that C. burnetii increases NF-κB activation via the canonical pathway. However, RelA phosphorylation levels were even higher in infected cells where bacterial protein or mRNA synthesis was inhibited. Importantly, we demonstrate that inhibition of RelA phosphorylation impairs PV formation and C. burnetii growth. We found that a T4BSS-defective mutant (CbΔdotA) elicited phosphorylated RelA levels similar to those of wild type C. burnetii infection treated with Chloramphenicol. Moreover, cells infected with CbΔdotA or wild type C. burnetii treated with Chloramphenicol showed similar levels of GFP-RelA nuclear localization, and significantly increased localization compared to wild type C. burnetii infection. These data indicate that without de novo protein synthesis and a functional T4BSS, C. burnetii is unable to modulate NF-κB activation, which is crucial for optimal intracellular growth. PMID:28066723

Ceftiofur impairs pro-inflammatory cytokine secretion through the inhibition of the activation of NF-{kappa}B and MAPK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ci Xinxin; Song Yu; Zeng Fanqin

2008-07-18

Ceftiofur is a new broad-spectrum, third-generation cephalosporin antibiotic for veterinary use. Immunopharmacological studies can provide new information on the immunomodulatory activities of some drugs, including their effect on cytokine productions. For this reason, we investigated the effect of ceftiofur on cytokine productions in vitro. We found that ceftiofur can downregulate tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-1{beta} (IL-1{beta}), and interleukin-6 (IL-6), but did not affect interleukin-10 (IL-10) production. We further investigated signal transduction mechanisms to determine how ceftiofur affects. RAW 264.7 cells were pretreated with 1, 5, or 10 mg/L of ceftiofur 1 h prior to treatment with 1 mg/L of LPS.more » Thirty minutes later, cells were harvested and mitogen activated protein kinases (MAPKs) activation was measured by Western blot. Alternatively, cells were fixed and nuclear factor-{kappa}B (NF-{kappa}B) activation was measured using immunocytochemical analysis. Signal transduction studies showed that ceftiofur significantly inhibited extracellular signal-regulated kinase (ERK), p38, and c-jun NH{sub 2}-terminal kinase (JNK) phosphorylation protein expression. Ceftiofur also inhibited p65-NF-{kappa}B translocation into the nucleus. Therefore, ceftiofur may inhibit LPS-induced production of inflammatory cytokines by blocking NF-{kappa}B and MAPKs signaling in RAW264.7 cells.« less

Captopril reduces cardiac inflammatory markers in spontaneously hypertensive rats by inactivation of NF-kB

PubMed Central

2010-01-01

Background Captopril is an angiotensin-converting enzyme (ACE) inhibitor widely used in the treatment of arterial hypertension and cardiovascular diseases. Our objective was to study whether captopril is able to attenuate the cardiac inflammatory process associated with arterial hypertension. Methods Left ventricle mRNA expression and plasma levels of pro-inflammatory (interleukin-1β (IL-1β) and IL-6) and anti-inflammatory (IL-10) cytokines, were measured in spontaneously hypertensive rats (SHR) and their control normotensive, Wistar-Kyoto (WKY) rats, with or without a 12-week treatment with captopril (80 mg/Kg/day; n = six animals per group). To understand the mechanisms involved in the effect of captopril, mRNA expression of ACE, angiotensin II type I receptor (AT1R) and p22phox (a subunit of NADPH oxidase), as well as NF-κB activation and expression, were measured in the left ventricle of these animals. Results In SHR, the observed increases in blood pressures, heart rate, left ventricle relative weight, plasma levels and cardiac mRNA expression of IL-1β and IL-6, as well as the reductions in the plasma levels and in the cardiac mRNA expression of IL-10, were reversed after the treatment with captopril. Moreover, the mRNA expressions of ACE, AT1R and p22phox, which were enhanced in the left ventricle of SHR, were reduced to normal values after captopril treatment. Finally, SHR presented an elevated cardiac mRNA expression and activation of the transcription nuclear factor, NF-κB, accompanied by a reduced expression of its inhibitor, IκB; captopril administration corrected the observed changes in all these parameters. Conclusion These findings show that captopril decreases the inflammation process in the left ventricle of hypertensive rats and suggest that NF-κB-driven inflammatory reactivity might be responsible for this effect through an inactivation of NF-κB-dependent pro-inflammatory factors. PMID:20462420

The 19th Project Integration Meeting

NASA Technical Reports Server (NTRS)

Mcdonald, R. R.

1981-01-01

The Flat-Plate Solar Array Project is described. Project analysis and integration is discussed. Technology research in silicon material, large-area silicon sheet and environmental isolation; cell and module formation; engineering sciences, and module performance and failure analysis. It includes a report on, and copies of visual presentations made at, the 19th Project Integration Meeting held at Pasadena, California, on November 11, 1981.

Human β-defensin 3 affects the activity of pro-inflammatory pathways associated with MyD88 and TRIF

PubMed Central

Semple, Fiona; MacPherson, Heather; Webb, Sheila; Cox, Sarah L; Mallin, Lucy J; Tyrrell, Christine; Grimes, Graeme R; Semple, Colin A; Nix, Matthew A; Millhauser, Glenn L; Dorin, Julia R

2011-01-01

β-Defensins are cationic host defense peptides that form an amphipathic structure stabilized by three intramolecular disulfide bonds. They are key players in innate and adaptive immunity and have recently been shown to limit the production of pro-inflammatory cytokines in TLR4-stimulated macrophages. In the present study, we investigate the mechanism underlying the anti-inflammatory effect of human β-defensin 3 (hBD3). We show that the canonical structure of hBD3 is required for this immunosuppressive effect and that hBD3 rapidly associates with and enters macrophages. Examination of the global effect of hBD3 on transcription in TLR4-stimulated macrophages shows that hBD3 inhibits the transcription of pro-inflammatory genes. Among the altered genes there is significant enrichment of groups involved in the positive regulation of NF-κB including components of Toll-like receptor signaling pathways. We confirm these observations by showing corresponding decreases in protein levels of pro-inflammatory cytokines and cell surface molecules. In addition, we show that hBD3 reduces NF-κB signaling in cells transfected with MyD88 or TRIF and that hBD3 inhibits the TLR4 response in both MyD88- and TRIF-deficient macrophages. Taken together these findings suggest that the mechanism of hBD3 anti-inflammatory activity involves specific targeting of TLR signaling pathways resulting in transcriptional repression of pro-inflammatory genes. PMID:21809339

Anti-inflammatory function of Withangulatin A by targeted inhibiting COX-2 expression via MAPK and NF-kappaB pathways.

PubMed

Sun, Lijuan; Liu, Jianwen; Cui, Daling; Li, Jiyu; Yu, Youjun; Ma, Lei; Hu, Lihong

2010-02-15

Withangulatin A (WA), an active component isolated from Physalis angulata L., has been reported to possess anti-tumor and trypanocidal activities in model systems via multiple biochemical mechanisms. The aim of this study is to investigate its anti-inflammatory potential and the possible underlying mechanisms. In the current study, WA significantly suppressed mice T lymphocytes proliferation stimulated with LPS in a dose- and time-dependent manner and inhibited pro-inflammation cytokines (IL-2, IFN-gamma, and IL-6) dramatically. Moreover, WA targeted inhibited COX-2 expression mediated by MAPKs and NF-kappaB nuclear translocation pathways in mice T lymphocytes, and this result was further confirmed by the COX-1/2 luciferase reporter assay. Intriguingly, administration of WA inhibited the extent of mice ear swelling and decreased pro-inflammatory cytokines production in mice blood serum. Based on these evidences, WA influences the mice T lymphocytes function through targeted inhibiting COX-2 expression via MAPKs and NF-kappaB nuclear translocation signaling pathways, and this would make WA a strong candidate for further study as an anti-inflammatory agent. (c) 2009 Wiley-Liss, Inc.

A Pro-Inflammatory Role for Nuclear Factor Kappa B in Childhood Obstructive Sleep Apnea Syndrome

PubMed Central

Israel, Lee P.; Benharoch, Daniel; Gopas, Jacob; Goldbart, Aviv D.

2013-01-01

Study Objectives: Childhood obstructive sleep apnea syndrome (OSAS) is associated with an elevation of inflammatory markers such as C-reactive protein (CRP) that correlates with specific morbidities and subsides following intervention. In adults, OSAS is associated with activation of the transcription factor nuclear factor kappa B (NF-kB). We explored the mechanisms underlying NF-kB activation, based on the hypothesis that specific NF-kB signaling is activated in children with OSAS. Design: Adenoid and tonsillar tissues from children with OSAS and matched controls were immunostained against NF-kB classical (p65 and p50) and alternative (RelB and p52) pathway subunits, and NF-kB-dependent cytokines: interleukin (IL)- 1α, IL-1β, tumor necrosis factor-α, and IL-8). Serum CRP levels were measured in all subjects. NF-kB induction was evaluated by a luciferase-NF-kB reporter assay in L428 cells constitutively expressing NF-kB and in Jurkat cells with inducible NF-kB expression. p65 translocation to the nucleus, reflecting NF-kB activation, was measured in cells expressing fluorescent NF-kB-p65-GFP (green fluorescent protein). Setting: Sleep research laboratory. Patients or Participants: Twenty-five children with OSAS and 24 without OSAS. Interventions: N/A. Measurements and Results: Higher expression of IL-1α and classical NF-kB subunits p65 and p50 was observed in adenoids and tonsils of children with OSAS. Patient serum induced NF-kB activity, as measured by a luciferase-NF-kB reporter assay and by induction of p65 nuclear translocation in cells permanently transfected with GFP-p65 plasmid. IL-1β showed increased epithelial expression in OSAS tissues. Conclusions: Nuclear factor kappa B is locally and systemically activated in children with obstructive sleep apnea syndrome. This observation may motivate the search for new anti-inflammatory strategies for controlling nuclear factor kappa B activation in obstructive sleep apnea syndrome. Citation: Israel LP

Suppression of NF-κB activation by PDLIM2 restrains hepatic lipogenesis and inflammation in high fat diet induced mice.

PubMed

Hao, Ya-Rong; Tang, Feng-Juan; Zhang, Xue; Wang, Hui

2018-05-28

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance, dyslipidemia and a systemic pro-inflammatory response, a leading cause of cirrhosis and hepatocellular carcinoma. Here, we showed that PDZ-LIM domain-containing protein 2 (PDLIM2) was an effective suppressor of steatohepatitis. After 16 weeks on a high fat diet (HFD), obesity, insulin resistance, hepatic dyslipidemia and inflammation were markedly aggravated in PDLIM2-knockout (KO) mice. PDLIM2 deletion resulted in lipid accumulation in liver tissue samples of HFD-induced mice, as evidenced by the significant increase of hepatic TG and TC through reducing the expression of lipogenesis- and transcriptional regulators of lipid metabolism-related genes and enhancing fatty acid oxidation-associated molecules. In addition, PDLIM2-ablation promoted the expression of pro-inflammatory cytokines by activating nuclear factor kappa-B (NF-κB) signaling pathway, as supported by the remarkable increase of phosphorylated IKKβ, IκBα and NF-κB expressions in liver of HFD-fed mice. Of note, the in vitro study demonstrated that PDLIM2 ablation-enhanced inflammatory response and disorder of lipid metabolism were abrogated by suppressing NF-κB activity. Collectively, the findings could lead to the development of potential therapeutic strategy to prevent NAFLD and associated metabolic disorders by targeting PDLIM2. Copyright © 2018. Published by Elsevier Inc.

Effect of Sulforaphane on NOD2 via NF-κB: implications for Crohn's disease.

PubMed

Folkard, Danielle L; Marlow, Gareth; Mithen, Richard F; Ferguson, Lynnette R

2015-01-01

Sulforaphane has well established anti-cancer properties and more recently anti-inflammatory properties have also been determined. Sulforaphane has been shown to inhibit PRR-mediated pro-inflammatory signalling by either directly targeting the receptor or their downstream signalling molecules such as the transcription factor, NF-κB. These results raise the possibility that PRR-mediated inflammation could be suppressed by specific dietary bioactives. We examined whether sulforaphane could suppress NF-κB via the NOD2 pathway. Human embryonic kidney 293T (HEK293T) cells were stably transfected with NOD2 variants and the NF-κB reporter, pNifty2-SEAP. The cells were co-treated with sulforaphane and MDP and secreted alkaline phosphatase (SEAP) production was determined. We found that sulforaphane was able to significantly suppress the ligand-induced NF-κB activity at physiologically relevant concentrations, achievable via the consumption of broccoli within the diet. These results demonstrate that the anti-inflammatory role of sulforaphane is not restricted to LPS-induced inflammatory signalling. These data add to the growing evidence that PRR activation can be inhibited by specific phytochemicals and thus suggests that diet could be a way of controlling inflammation. This is particularly important for a disease like Crohn's disease where diet can play a key role in relieving or exacerbating symptoms.

Chemopreventive effects of standardized ethanol extract from the aerial parts of Artemisia princeps Pampanini cv. Sajabal via NF-κB inactivation on colitis-associated colon tumorigenesis in mice.

PubMed

Chung, Kyung-Sook; Choi, Hye-Eun; Shin, Ji-Sun; Cho, Eu-Jin; Cho, Young-Wuk; Choi, Jung-Hye; Baek, Nam-In; Lee, Kyung-Tae

2015-01-01

Chronic inflammation is an underlying risk factor of colon cancer, and NF-κB plays a critical role in the development of inflammation-associated colon cancer in an AOM/DSS mouse model. The aim of this study was to determine whether the standardized ethanol extract obtained from the aerial parts of Artemisia princeps Pampanini cv. Sajabal (EAPP) is effective at preventing inflammation-associated colon cancer, and if so, to identify the signaling pathways involved. In the present study, protective efficacy of EAPP on tumor formation and the infiltrations of monocytes and macrophages in colons of an AOM/DSS mouse model were evaluated. It was found that colitis and tumor burdens showed statistically meaningful improvements after EAPP administration. Furthermore, these improvements were accompanied by a reduction in NF-κB activity and in the levels of NF-κB-dependent pro-survival proteins, that is, survivin, cFLIP, XIAP, and Bcl-2. In vitro, EAPP significantly reduced NF-κB activation and the levels of IL-1β and IL-8 mRNA and pro-survival proteins in HT-29 and HCT-116 colon cancer cells. Furthermore, EAPP caused caspase-dependent apoptosis. Based on these results, the authors suggest EAPP suppresses inflammatory responses and induces apoptosis partly via NF-κB inactivation, and that EAPP could be useful for the prevention of colitis-associated tumorigenesis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Joint-operation in water resources project in Indonesia: Integrated or non-integrated

NASA Astrophysics Data System (ADS)

Ophiyandri, Taufika; Istijono, Bambang; Hidayat, Benny

2017-11-01

The construction of large water resources infrastructure project often involved a joint-operation (JO) project between two or more construction companies. The form of JO can be grouped into two categories - an integrated type and a non-integrated type. This paper investigates the reason of forming a JO project made by companies. The specific advantages and problems of JO project is also analysed in this paper. In order to achieve the objectives, three water resources infrastructure projects were selected as case studies. Data was gathered by conducting 11 semi-structured interviews to project owners, contractor managers, and project staffs. Data was analysed by means of content analysis. It was found that the most fundamental factor to form a JO is to win a competition or tender. An integrated model is in favour because it can reduce overhead costs and has a simple management system, while a non-integrated model is selected because it can avoid a sleeping partner and make contractor more responsible for their own job.

The 17th Project Integration Meeting

NASA Technical Reports Server (NTRS)

Mcdonald, R. R.

1981-01-01

Progress made by the Low-Cost Solar Array Project during the period September 1980 to February 1981 is described. Included are reports on project analysis and integration; technology development in silicon material, large-area silicon sheet and encapsulation; production process and equipment development; engineering, and operations. A report on and copies of visual presentations made at the Project Integration Meeting held at Pasadena, California on February 4 and 5, 1981 are also included.

PRoViScout: a planetary scouting rover demonstrator

NASA Astrophysics Data System (ADS)

Paar, Gerhard; Woods, Mark; Gimkiewicz, Christiane; Labrosse, Frédéric; Medina, Alberto; Tyler, Laurence; Barnes, David P.; Fritz, Gerald; Kapellos, Konstantinos

2012-01-01

Mobile systems exploring Planetary surfaces in future will require more autonomy than today. The EU FP7-SPACE Project ProViScout (2010-2012) establishes the building blocks of such autonomous exploration systems in terms of robotics vision by a decision-based combination of navigation and scientific target selection, and integrates them into a framework ready for and exposed to field demonstration. The PRoViScout on-board system consists of mission management components such as an Executive, a Mars Mission On-Board Planner and Scheduler, a Science Assessment Module, and Navigation & Vision Processing modules. The platform hardware consists of the rover with the sensors and pointing devices. We report on the major building blocks and their functions & interfaces, emphasizing on the computer vision parts such as image acquisition (using a novel zoomed 3D-Time-of-Flight & RGB camera), mapping from 3D-TOF data, panoramic image & stereo reconstruction, hazard and slope maps, visual odometry and the recognition of potential scientifically interesting targets.

Noisy transcription factor NF-κB oscillations stabilize and sensitize cytokine signaling in space

NASA Astrophysics Data System (ADS)

Gangstad, Sirin W.; Feldager, Cilie W.; Juul, Jeppe; Trusina, Ala

2013-02-01

NF-κB is a major transcription factor mediating inflammatory response. In response to a pro-inflammatory stimulus, it exhibits a characteristic response—a pulse followed by noisy oscillations in concentrations of considerably smaller amplitude. NF-κB is an important mediator of cellular communication, as it is both activated by and upregulates production of cytokines, signals used by white blood cells to find the source of inflammation. While the oscillatory dynamics of NF-κB has been extensively investigated both experimentally and theoretically, the role of the noise and the lower secondary amplitude has not been addressed. We use a cellular automaton model to address these issues in the context of spatially distributed communicating cells. We find that noisy secondary oscillations stabilize concentric wave patterns, thus improving signal quality. Furthermore, both lower secondary amplitude as well as noise in the oscillation period might be working against chronic inflammation, the state of self-sustained and stimulus-independent excitations. Our findings suggest that the characteristic irregular secondary oscillations of lower amplitude are not accidental. On the contrary, they might have evolved to increase robustness of the inflammatory response and the system's ability to return to a pre-stimulated state.

OsNF-YC2 and OsNF-YC4 proteins inhibit flowering under long-day conditions in rice.

PubMed

Kim, Soon-Kap; Park, Hyo-Young; Jang, Yun Hee; Lee, Keh Chien; Chung, Young Soo; Lee, Jeong Hwan; Kim, Jeong-Kook

2016-03-01

OsNF-YC2 and OsNF-YC4 proteins regulate the photoperiodic flowering response through the modulation of three flowering-time genes ( Ehd1, Hd3a , and RFT1 ) in rice. Plant NUCLEAR FACTOR Y (NF-Y) transcription factors control numerous developmental processes by forming heterotrimeric complexes, but little is known about their roles in flowering in rice. In this study, it is shown that some subunits of OsNF-YB and OsNF-YC interact with each other, and among them, OsNF-YC2 and OsNF-YC4 proteins regulate the photoperiodic flowering response of rice. Protein interaction studies showed that the physical interactions occurred between the three OsNF-YC proteins (OsNF-YC2, OsNF-YC4 and OsNF-YC6) and three OsNF-YB proteins (OsNF-YB8, OsNF-YB10 and OsNF-YB11). Repression and overexpression of the OsNF-YC2 and OsNF-YC4 genes revealed that they act as inhibitors of flowering only under long-day (LD) conditions. Overexpression of OsNF-YC6, however, promoted flowering only under LD conditions, suggesting it could function as a flowering promoter. These phenotypes correlated with the changes in the expression of three rice flowering-time genes [Early heading date 1 (Ehd1), Heading date 3a (Hd3a) and RICE FLOWERING LOCUS T1 (RFT1)]. The diurnal and tissue-specific expression patterns of the subsets of OsNF-YB and OsNF-YC genes were similar to those of CCT domain encoding genes such as OsCO3, Heading date 1 (Hd1) and Ghd7. We propose that OsNF-YC2 and OsNF-YC4 proteins regulate the photoperiodic flowering response by interacting directly with OsNF-YB8, OsNF-YB10 or OsNF-YB11 proteins in rice.

Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-{kappa}B pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Zhiquan; Xue, Liqiong; Guo, Cuicui

Highlights: Black-Right-Pointing-Pointer Stevioside ameliorates high-fat diet-induced insulin resistance. Black-Right-Pointing-Pointer Stevioside alleviates the adipose tissue inflammation. Black-Right-Pointing-Pointer Stevioside reduces macrophages infiltration into the adipose tissue. Black-Right-Pointing-Pointer Stevioside suppresses the activation of NF-{kappa}B in the adipose tissue. -- Abstract: Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration ofmore » SVS for 1 month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-{alpha}, IL6, IL10, IL1{beta}, KC, MIP-1{alpha}, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-{kappa}B) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-{kappa}B pathway.« less

Anthocyanins Downregulate Lipopolysaccharide-Induced Inflammatory Responses in BV2 Microglial Cells by Suppressing the NF-κB and Akt/MAPKs Signaling Pathways

PubMed Central

Jeong, Jin-Woo; Lee, Won Sup; Shin, Sung Chul; Kim, Gi-Young; Choi, Byung Tae; Choi, Yung Hyun

2013-01-01

Anthocyanins are naturally occurring polyphenols that impart bright color to fruits, vegetables and plants and have a variety of protective properties, which have generally been attributed to their antioxidant capacity. However, little is known about the molecular mechanisms underlying anti-inflammatory effects of anthocyanins related to neurodegenerative diseases. Therefore, we determined whether anthocyanins isolated from black soybean seed coats would inhibit pro-inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated murine BV2 microglial cells. Our results showed that anthocyanins significantly inhibited LPS-induced pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2, and pro-inflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, without significant cytotoxicity. Anthocyanins also downregulated excessive expression of inducible NO synthase, cyclooxygenase-2, TNF-α, and IL-1β in LPS-stimulated BV2 cells. Moreover, anthocyanins inhibited nuclear translocation of nuclear factor-kappa B (NF-κB) by reducing inhibitor of NF-κB alpha degradation as well as phosphorylating extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and Akt. These findings suggest that anthocyanins may offer substantial therapeutic potential for treating inflammatory and neurodegenerative diseases accompanied by microglial activation. PMID:23344054

Mems: Platform for Large-Scale Integrated Vacuum Electronic Circuits

DTIC Science & Technology

2017-03-20

SECURITY CLASSIFICATION OF: The objective of the LIVEC advanced study project was to develop a platform for large-scale integrated vacuum electronic ...Distribution Unlimited UU UU UU UU 20-03-2017 1-Jul-2014 30-Jun-2015 Final Report: MEMS Platform for Large-Scale Integrated Vacuum Electronic ... Electronic Circuits (LIVEC) Contract No: W911NF-14-C-0093 COR Dr. James Harvey U.S. ARO RTP, NC 27709-2211 Phone: 702-696-2533 e-mail

Integrated Risk Management Within NASA Programs/Projects

NASA Technical Reports Server (NTRS)

Connley, Warren; Rad, Adrian; Botzum, Stephen

2004-01-01

As NASA Project Risk Management activities continue to evolve, the need to successfully integrate risk management processes across the life cycle, between functional disciplines, stakeholders, various management policies, and within cost, schedule and performance requirements/constraints become more evident and important. Today's programs and projects are complex undertakings that include a myriad of processes, tools, techniques, management arrangements and other variables all of which must function together in order to achieve mission success. The perception and impact of risk may vary significantly among stakeholders and may influence decisions that may have unintended consequences on the project during a future phase of the life cycle. In these cases, risks may be unintentionally and/or arbitrarily transferred to others without the benefit of a comprehensive systemic risk assessment. Integrating risk across people, processes, and project requirements/constraints serves to enhance decisions, strengthen communication pathways, and reinforce the ability of the project team to identify and manage risks across the broad spectrum of project management responsibilities. The ability to identify risks in all areas of project management increases the likelihood a project will identify significant issues before they become problems and allows projects to make effective and efficient use of shrinking resources. By getting a total team integrated risk effort, applying a disciplined and rigorous process, along with understanding project requirements/constraints provides the opportunity for more effective risk management. Applying an integrated approach to risk management makes it possible to do a better job at balancing safety, cost, schedule, operational performance and other elements of risk. This paper will examine how people, processes, and project requirements/constraints can be integrated across the project lifecycle for better risk management and ultimately improve the

Functional conservation of rice OsNF-YB/YC and Arabidopsis AtNF-YB/YC proteins in the regulation of flowering time.

PubMed

Hwang, Yoon-Hyung; Kim, Soon-Kap; Lee, Keh Chien; Chung, Young Soo; Lee, Jeong Hwan; Kim, Jeong-Kook

2016-04-01

Rice Os NF - YB and Os NF - YC complement the late flowering phenotype of Arabidopsis nf - yb double and nf - yc triple mutants, respectively. In addition, OsNF-YB and OsNF-YC interact with AtNF-YC and AtNF-YB, respectively. Plant NUCLEAR FACTOR Y (NF-Y) transcription factors play important roles in plant development and abiotic stress. In Arabidopsis thaliana, two NF-YB (AtNF-YB2 and AtNF-YB3) and five NF-YC (AtNF-YC1, AtNF-YC2, AtNF-YC3, AtNF-YC4, and AtNF-YC9) genes regulate photoperiodic flowering by interacting with other AtNF-Y subunit proteins. Three rice NF-YB (OsNF-YB8, OsNF-YB10, and OsNF-YB11) and five rice OsNF-YC (OsNF-YC1, OsNF-YC2, OsNF-YC4, OsNF-YC6, and OsNF-YC7) genes are clustered with two AtNF-YB and five AtNF-YC genes, respectively. To investigate the functional conservation of these NF-YB and NF-YC genes in rice and Arabidopsis, we analyzed the flowering phenotypes of transgenic plants overexpressing the respective OsNF-YB and OsNF-YC genes in Arabidopsis mutants. Overexpression of OsNF-YB8/10/11 and OsNF-YC2 complemented the late flowering phenotype of Arabidopsis nf-yb2 nf-yb3 and nf-yc3 nf-yc4 nf-yc9 mutants, respectively. The rescued phenotype of 35S::OsNF-YC2 nf-yc3 nf-yc4 nf-yc9 plants was attributed to the upregulation of FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1). In vitro and in planta protein-protein analyses revealed that OsNF-YB8/10/11 and OsNF-YC1/2/4/6/7 interact with AtNF-YC3/4/9 and AtNF-YB2/3, respectively. Our data indicate that some OsNF-YB and OsNF-YC genes are functional equivalents of AtNF-YB2/3 and AtNF-YC3/4/9 genes, respectively, and suggest functional conservation of Arabidopsis and rice NF-Y genes in the control of flowering time.

AnswerPro: Designing to Motivate Interaction

ERIC Educational Resources Information Center

AlSugair, Balsam; Hopkins, Gail; FitzGerald, Elizabeth; Brailsford, Tim

2014-01-01

This paper describes the design and initial testing of AnswerPro, a mobile academic peer support system for school pupils aged 11-16 years. AnswerPro is a mobile optimised web application that enables pupils to seek support with school work from knowledgeable peers on various subjects. This paper presents research findings from the project, and in…

Overexpression of cellular repressor of E1A-stimulated genes inhibits TNF-{alpha}-induced apoptosis via NF-{kappa}B in mesenchymal stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Cheng-Fei; Cardiovascular Research Institute and Department of Cardiology, Shenyang Northern Hospital, Shenyang; Han, Ya-Ling, E-mail: hanyaling53@gmail.com

2011-03-25

Research highlights: {yields} CREG protected MSCs from tumor necrosis factor-{alpha} (TNF-{alpha}) induced apoptosis. {yields} CREG inhibits the phosphorylation of I{kappa}B{alpha} and prevents the activation of NF-{kappa}B. {yields} CREG inhibits NF-{kappa}B nuclear translocation and pro-apoptosis protein transcription. {yields} CREG anti-apoptotic effect involves inhibition of the death receptor pathway. {yields} p53 is downregulated by CREG via NF-{kappa}B pathway under TNF-{alpha} stimulation. -- Abstract: Bone marrow-derived mesenchymal stem cells (MSCs) show great potential for therapeutic repair after myocardial infarction. However, poor viability of transplanted MSCs in the ischemic heart has limited their use. Cellular repressor of E1A-stimulated genes (CREG) has been identified asmore » a potent inhibitor of apoptosis. This study therefore aimed to determine if rat bone marrow MSCs transfected with CREG-were able to effectively resist apoptosis induced by inflammatory mediators, and to demonstrate the mechanism of CREG action. Apoptosis was determined by flow cytometric and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays. The pathways mediating these apoptotic effects were investigated by Western blotting. Overexpression of CREG markedly protected MSCs from tumor necrosis factor-{alpha} (TNF-{alpha}) induced apoptosis by 50% after 10 h, through inhibition of the death-receptor-mediated apoptotic pathway, leading to attenuation of caspase-8 and caspase-3. Moreover, CREG resisted the serine phosphorylation of I{kappa}B{alpha} and prevented the nuclear translocation of the transcription factor nuclear factor-{kappa}B (NF-{kappa}B) under TNF-{alpha} stimulation. Treatment of cells with the NF-{kappa}B inhibitor pyrrolidine dithiocarbamate (PDTC) significantly increased the transcription of pro-apoptosis proteins (p53 and Fas) by NF-{kappa}B, and attenuated the anti-apoptotic effects of CREG on MSCs. The results of this

Ocular Alterations in a Rare Case of Segmental Neurofibromatosis Type 1 with a Non-Classified Mutational Variant of the NF-1 Gene.

PubMed

Abdolrahimzadeh, Solmaz; Piraino, Domenica Carmen; Plateroti, Rocco; Scuderi, Gianluca; Recupero, Santi Maria

2016-06-01

Neurofibromatosis type 1 (NF-1) is an autsomal dominant disorder which can occasionally result from somatic mosaicism and manifest as segmental forms of the disease. A 37-year-old woman with ascertained NF-1, based on clinical diagnostic criteria and genetic analysis, was referred for ophthalmological evaluation. Genetic analysis, magnetic resonance imaging (MRI), complete ophthalmological examination, and near infrared reflectance (NIR) images at 815 nm of the retina were obtained. Genetic analysis revealed a non-classified mutational variant of the NF-1 gene identified as NM_000267.3:c2084T > C (p.Leu695Pro.T). MRI demonstrated non-symptomatic bilateral optic nerve gliomas. The only cutaneous sign was a subcutaneous neurofibroma of the posterior cervical region. Slit-lamp examination showed bilateral Lisch nodules. NIR images of the retina did not show any choroidal hamartomas. We report a rare case of segmental neurofibromatosis with a non-classified mutational variant of the NF-1 gene described in only one previous case in the literature. The patient presented with clinical features of NF-1 localized to the head and neck region, compatible with diagnosis of segmental NF-1. Interestingly, ocular manifestations included bilateral optic nerve gliomas and Lisch nodules, but no choroidal hamartomas.

Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated

PubMed Central

Wakamatsu, Takuya; Yamamoto, Suguru; Ito, Toru; Sato, Yoko; Matsuo, Koji; Takahashi, Yoshimitsu; Kaneko, Yoshikatsu; Goto, Shin; Kazama, Junichiro James; Gejyo, Fumitake; Narita, Ichiei

2018-01-01

In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1β mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1β production, which may explain sustained chronic inflammation in CKD patients. PMID:29543732

The Pro-Am Collaborative Astronomy (PACA) Project

NASA Astrophysics Data System (ADS)

Yanamandra-Fisher, Padma A.

2016-10-01

The PACA Project is an ecosystem of several social media platforms (Facebook, Pinterest, Twitter, Flickr, Vimeo) that takes connects professional and amateur astronomers in a common observing campaign. It takes advantage of immediate connectivity amongst amateur astronomers worldwide, that can be galvanized to participate in a given observing campaign and provide observations/data that helps provide a long temporal backdrop for professional data. To date, The PACA Project has participated in organized campaigns such as NASA Comet ISON Observing Campaign in 2013; NASA Comet Integrated Observations Campaign to observe Comet Siding Spring flyby of Mars on 19 October 2014, and currently is participating in the ESA/Rosetta mission's ground-based amateur observing campaign, soon to finish. With several bright comets well placed in the sky, the PACA Project has focused groups for each comet of interest to its members. The PACA Project is now extending its observing campaigns to include planets, namely, Jupiter, Saturn and Mars. The 2014 observing campaign of comet Siding Spring included both comet and Mars amateur astronomers. With Mars, just past its recent opposition and heading towards its perihelic opposition, when it will be its largest size as viewed from Earth, in 2018; with NASA's JUNO spacecraft arrival at Jupiter on 4 July 2016 and NASA/ESA Cassini mission ending its mission to Saturn in 2017, all three planets are targets of amateur observers. The synergy between The PACA Project goals, amateur and professional astronomers translates well into a cohesive paradigm to monitor and observe comets and planets to increase the data on these targets for crowdsourcing. I shall highlight the results from the various campaigns, including various comets, Jupiter, Saturn and Mars and propose various science observing campaigns, resulting in both scientific research and citizen science.

Human β-defensin 3 affects the activity of pro-inflammatory pathways associated with MyD88 and TRIF.

PubMed

Semple, Fiona; MacPherson, Heather; Webb, Sheila; Cox, Sarah L; Mallin, Lucy J; Tyrrell, Christine; Grimes, Graeme R; Semple, Colin A; Nix, Matthew A; Millhauser, Glenn L; Dorin, Julia R

2011-11-01

β-Defensins are cationic host defense peptides that form an amphipathic structure stabilized by three intramolecular disulfide bonds. They are key players in innate and adaptive immunity and have recently been shown to limit the production of pro-inflammatory cytokines in TLR4-stimulated macrophages. In the present study, we investigate the mechanism underlying the anti-inflammatory effect of human β-defensin 3 (hBD3). We show that the canonical structure of hBD3 is required for this immunosuppressive effect and that hBD3 rapidly associates with and enters macrophages. Examination of the global effect of hBD3 on transcription in TLR4-stimulated macrophages shows that hBD3 inhibits the transcription of pro-inflammatory genes. Among the altered genes there is significant enrichment of groups involved in the positive regulation of NF-κB including components of Toll-like receptor signaling pathways. We confirm these observations by showing corresponding decreases in protein levels of pro-inflammatory cytokines and cell surface molecules. In addition, we show that hBD3 reduces NF-κB signaling in cells transfected with MyD88 or TRIF and that hBD3 inhibits the TLR4 response in both MyD88- and TRIF-deficient macrophages. Taken together these findings suggest that the mechanism of hBD3 anti-inflammatory activity involves specific targeting of TLR signaling pathways resulting in transcriptional repression of pro-inflammatory genes. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells

PubMed Central

Faria, Márcia; Matos, Paulo; Pereira, Teresa; Cabrera, Rafael; Cardoso, Bruno A.; Bugalho, Maria João

2017-01-01

Overexpression of tumor-associated RAC1b has been recently highlighted as one of the most promising targets for therapeutic intervention in colon, breast, lung and pancreatic cancer. RAC1b is a hyperactive variant of the small GTPase RAC1 and has been recently shown to be overexpressed in a subset of papillary thyroid carcinomas associated with unfavorable outcome. Using the K1 PTC derived cell line as an in vitro model, we observed that both RAC1 and RAC1b were able to induce a significant increase on NF-kB and cyclin D1 reporter activity. A clear p65 nuclear localization was found in cells transfected with RAC1b-WT, confirming NF-kB canonical pathway activation. Consistently, we observed a RAC1b-mediated decrease in IκBα (NF-kB inhibitor) protein levels. Moreover, we show that RAC1b overexpression stimulates G1/S progression and protects thyroid cells against induced apoptosis, the latter through a process involving the NF-kB pathway. Present data support previous findings suggesting an important role for RAC1b in the development of follicular cell-derived thyroid malignancies and point out NF-kB activation as one of the molecular mechanisms associated with the pro-tumorigenic advantage of RAC1b overexpression in thyroid carcinomas. PMID:28234980

Olive oil polyphenols reduce oxysterols -induced redox imbalance and pro-inflammatory response in intestinal cells.

PubMed

Serra, Gessica; Incani, Alessandra; Serreli, Gabriele; Porru, Laura; Melis, M Paola; Tuberoso, Carlo I G; Rossin, Daniela; Biasi, Fiorella; Deiana, Monica

2018-05-16

Dietary habits may strongly influence intestinal homeostasis. Oxysterols, the oxidized products of cholesterol present in cholesterol-containing foodstuffs, have been shown to exert pro-oxidant and pro-inflammatory effects, altering intestinal epithelial layer and thus contributing to the pathogenesis of human inflammatory bowel diseases and colon cancer. Extra virgin olive oil polyphenols possess antioxidant and anti-inflammatory properties, and concentrate in the intestinal lumen, where may help in preventing intestinal diseases. In the present study we evaluated the ability of an extra virgin olive oil phenolic extract to counteract the pro-oxidant and pro-inflammatory action of a representative mixture of dietary oxysterols in the human colon adenocarcinoma cell line (Caco-2) undergoing full differentiation into enterocyte-like cells. Oxysterols treatment significantly altered differentiated Caco-2 cells redox status, leading to oxidant species production and a decrease of GSH levels, after 1 h exposure, followed by an increase of cytokines production, IL-6 and IL-8, after 24 h. Oxysterol cell treatment also induced after 48 h an increase of NO release, due to the induction of iNOS. Pretreatment with the phenolic extract counteracted oxysterols effects, at least in part by modulating one of the main pathways activated in the cellular response to the action of oxysterols, the MAPK-NF-kB pathway. We demonstrated the ability of the phenolic extract to directly modulate p38 and JNK1/2 phosphorylation and activation of NF-kB, following its inhibitor IkB phosphorylation. The phenolic extract also inhibited iNOS induction, keeping NO concentration at the control level. Our results suggest a protective effect at intestinal level of extra virgin olive oil polyphenols, able to prevent or limit redox unbalance and the onset and progression of chronic intestinal inflammation. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Blood-based NfL

PubMed Central

Janelidze, Shorena; Hall, Sara; Magdalinou, Nadia; Lees, Andrew J.; Andreasson, Ulf; Norgren, Niklas; Linder, Jan; Forsgren, Lars; Constantinescu, Radu; Zetterberg, Henrik; Blennow, Kaj

2017-01-01

Objective: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders. Methods: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated. Results: We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81). Conclusions: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics. Classification of evidence: This study provides Class III evidence that blood NfL levels discriminate between PD and APD. PMID:28179466

Double NF1 Inactivation Affects Adrenocortical Function in NF1Prx1 Mice and a Human Patient

PubMed Central

Kobus, Karolina; Hartl, Daniela; Ott, Claus Eric; Osswald, Monika; Huebner, Angela; von der Hagen, Maja; Emmerich, Denise; Kühnisch, Jirko; Morreau, Hans; Hes, Frederik J.; Mautner, Victor F.; Harder, Anja; Tinschert, Sigrid; Mundlos, Stefan; Kolanczyk, Mateusz

2015-01-01

Background Neurofibromatosis type I (NF1, MIM#162200) is a relatively frequent genetic condition, which predisposes to tumor formation. Apart from tumors, individuals with NF1 often exhibit endocrine abnormalities such as precocious puberty (2,5–5% of NF1 patients) and some cases of hypertension (16% of NF1 patients). Several cases of adrenal cortex adenomas have been described in NF1 individuals supporting the notion that neurofibromin might play a role in adrenal cortex homeostasis. However, no experimental data were available to prove this hypothesis. Materials and Methods We analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient. Results In Nf1Prx1 mice Nf1 is inactivated in the developing limbs, head mesenchyme as well as in the adrenal gland cortex, but not the adrenal medulla or brain. We show that adrenal gland size is increased in NF1Prx1 mice. Nf1Prx1 female mice showed corticosterone and aldosterone overproduction. Molecular analysis of Nf1 deficient adrenals revealed deregulation of multiple proteins, including steroidogenic acute regulatory protein (StAR), a vital mitochondrial factor promoting transfer of cholesterol into steroid making mitochondria. This was associated with a marked upregulation of MAPK pathway and a female specific increase of cAMP concentration in murine adrenal lysates. Complementarily, we characterized a patient with neurofibromatosis type I with macronodular adrenal hyperplasia with ACTH-independent cortisol overproduction. Comparison of normal control tissue- and adrenal hyperplasia- derived genomic DNA revealed loss of heterozygosity (LOH) of the wild type NF1 allele, showing that biallelic NF1 gene inactivation occurred in the hyperplastic adrenal gland. Conclusions Our data suggest that biallelic loss of Nf1 induces autonomous adrenal hyper-activity. We conclude that Nf1 is involved in the regulation of adrenal cortex function in mice and humans. PMID:25775093

Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, Stacey L.; Neuroscience Program, Loyola University Medical Center, Maywood, IL; Department of Anatomy and Cell Biology, University of Illinois Chicago, Chicago, IL

Schwann cells derived from peripheral nerve sheath tumors from individuals with Neurofibromatosis Type 1 (NF1) are deficient for the protein neurofibromin, which contains a GAP-related domain (NF1-GRD). Neurofibromin-deficient Schwann cells have increased Ras activation, increased proliferation in response to certain growth stimuli, increased angiogenic potential, and altered cell morphology. This study examined whether expression of functional NF1-GRD can reverse the transformed phenotype of neurofibromin-deficient Schwann cells from both benign and malignant peripheral nerve sheath tumors. We reconstituted the NF1-GRD using retroviral transduction and examined the effects on cell morphology, growth potential, and angiogenic potential. NF1-GRD reconstitution resulted in morphologic changes,more » a 16-33% reduction in Ras activation, and a 53% decrease in proliferation in neurofibromin-deficient Schwann cells. However, NF1-GRD reconstitution was not sufficient to decrease the in vitro angiogenic potential of the cells. This study demonstrates that reconstitution of the NF1-GRD can at least partially reverse the transformation of human NF1 tumor-derived Schwann cells.« less

DAPk1 inhibits NF-κB activation through TNF-α and INF-γ-induced apoptosis.

PubMed

Yoo, Heon Jong; Byun, Hyun-Jung; Kim, Boh-Ram; Lee, Ki Hwan; Park, Sang-Yoon; Rho, Seung Bae

2012-07-01

Recent studies have shown DAPk as a molecular modulator induced by the second messenger, responsible for controlling cell destiny decisions, but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood. In this present report, we attempted to characterize the effects of TNF-α and INF-γ on DAPk1 in human ovarian carcinoma cell lines, OVCAR-3. Both TNF-α and INF-γ significantly induce DAPk1 levels in a time-dependent manner. At the same time, they both arrested cell cycle progression in the G(0)-G(1) and G2/M phase, down-regulated cyclin D1, CDK4 and NF-κB expression, while also up-regulating p27 and p16 expression. Subsequently, the efficacy of the combined treatment with DAPk1 was investigated. In the presence of DAPk1, TNF-α or INF-γ-induced apoptosis was additively increased, while TNF-α or INF-γ-induced NF-κB activity was inhibited. Conversely, TNF-α or INF-γ-dependent NF-κB activity was further enhanced by the inhibition of DAPk1 with its specific siRNA. The activity of NF-κB was dependent on the level of DAPk1, indicating the requirement of DAPk1 for the activation of NF-κB. Low levels of DAPk1 expression were frequently observed in different human patient's tissue and cancer cell lines compared to normal samples. In addition, over-expression of DAPk1 from either TNF-α or INF-γ-treatment cells suppressed the anti-apoptosis protein XIAP as well as COX-2 and ICAM-1, more than control. Taken together, our data findings suggest that DAPk1 can mediate the pro-apoptotic activity of TNF-α and INF-γ via the NF-κB signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

NZ suppresses TLR4/NF-κB signalings and NLRP3 inflammasome activation in LPS-induced RAW264.7 macrophages.

PubMed

Xiang, Pengjun; Chen, Tong; Mou, Yi; Wu, Hui; Xie, Peng; Lu, Guo; Gong, Xiaojian; Hu, Qinghua; Zhang, Yihua; Ji, Hui

2015-10-01

The purpose of the present study was to evaluate the potential therapeutic effects of NZ on lipopolysaccharide (LPS)-induced RAW264.7 cells and explore its underlying mechanisms. The effect of NZ on NO generation in LPS-activated macrophage was measured by Griess assay. The concentrations of TNF-α, IL-18, IL-1β were analyzed with ELISA kits. The LPS-induced production of reactive oxygen species (ROS) was determined by flow cytometry. The protein expressions of TLR4, NF-κB and NLRP3 signaling pathway were investigated with Western blot analysis. It was shown that NZ significantly reduced the production of NO and the generation of pro-inflammatory cytokines in LPS-induced RAW264.7 cells. In addition, NZ markedly inhibited the up-regulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and the activation of nuclear factor kappa B (NF-κB) in LPS-stimulated RAW 264.7 macrophages. Of note, NZ suppressed the expression of the inflammasome component such as NOD-like receptor 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC), as well as the levels of cytokines including Interleukin-18(IL-18) and Interleukin-1β(IL-1β). These results indicated that NZ inhibited the generations of NO and pro-inflammatory cytokines by suppressing TLR4/MyD88/NF-κB pathway, suggesting that NZ could be an effective candidate for ameliorating LPS-induced inflammatory responses.

TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis.

PubMed

Hou, Jiwei; Ma, Tan; Cao, Honghui; Chen, Yabing; Wang, Cong; Chen, Xiang; Xiang, Zou; Han, Xiaodong

2018-03-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-α (TNF-α) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-α in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-α and the transcription factor nuclear factor kappa B (NF-κB) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-α promotes myofibroblast differentiation of LR-MSCs through activating NF-κB signaling. Interestingly, we also found that TNF-α promotes the expression of β-catenin. Moreover, we demonstrated that suppression of the NF-κB signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of β-catenin. Our data implicates that inhibition of the NF-κB signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches. © 2017 Wiley Periodicals, Inc.

Project management techniques for highly integrated programs

NASA Technical Reports Server (NTRS)

Stewart, J. F.; Bauer, C. A.

1983-01-01

The management and control of a representative, highly integrated high-technology project, in the X-29A aircraft flight test project is addressed. The X-29A research aircraft required the development and integration of eight distinct technologies in one aircraft. The project management system developed for the X-29A flight test program focuses on the dynamic interactions and the the intercommunication among components of the system. The insights gained from the new conceptual framework permitted subordination of departments to more functional units of decisionmaking, information processing, and communication networks. These processes were used to develop a project management system for the X-29A around the information flows that minimized the effects inherent in sampled-data systems and exploited the closed-loop multivariable nature of highly integrated projects.

Anti-neuroinflammatory effects of grossamide from hemp seed via suppression of TLR-4-mediated NF-κB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells.

PubMed

Luo, Qian; Yan, Xiaoli; Bobrovskaya, Larisa; Ji, Mei; Yuan, Huiqing; Lou, Hongxiang; Fan, Peihong

2017-04-01

Grossamide, a representative lignanamide in hemp seed, has been reported to possess potential anti-inflammatory effects. However, the potential anti-neuroinflammatory effects and underlying mechanisms of action of grossamide are still unclear. Therefore, the present study investigated the possible effects and underlying mechanisms of grossamide against lipopolysaccharide (LPS)-induced inflammatory response in BV2 microglia cells. BV2 microglia cells were pre-treated with various concentrations of grossamide before being stimulated with LPS to induce inflammation. The levels of pro-inflammatory cytokines were determined using the enzyme-linked immunoassay (ELISA) and mRNA expression levels were measured by real-time PCR. The translocation of nuclear factor-kappa B (NF-κB) and contribution of TLR4-mediated NF-κB activation on inflammatory effects were evaluated by immunostaining and Western blot analysis. This study demonstrated that grossamide significantly inhibited the secretion of pro-inflammatory mediators such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and decreased the level of LPS-mediated IL-6 and TNF-α mRNA. In addition, it significantly reduced the phosphorylation levels of NF-κB subunit p65 in a concentration-dependent manner and suppressed translocation of NF-κB p65 into the nucleus. Furthermore, grossamide markedly attenuated the LPS-induced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). Taken together, these data suggest that grossamide could be a potential therapeutic candidate for inhibiting neuroinflammation in neurodegenerative diseases.

Loss of neurofibromatosis type 1 (NF1) gene expression in pheochromocytomas from patients without NF1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geist, R.T.; Gutmann, D.H.; Moley, J.F.

The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, termed neurofibromin. Loss of NF1 gene expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 as well as malignant and neuroblastomas from patients without NF1. Previously, we demonstrated the lack of neurofibromin expression in six pheochromocytomas from patients with NF1, suggesting that neurofibromin loss is associated with the progression to neoplasia in pheochromocytomas in these patients. The lack of NF1 gene expression in NF1 patient pheochromocytomas supports the notion that neurofibromin might be an essential regulator of cell growth in these cells. To determine whethermore » NF1 gene expression is similarly altered in pheochromocytomas from patients without NF1, twenty pheochromocytomas were examined for the presence of NF1 RNA by reverse-transcribed PCR (RT-PCR). Lack of NF1 gene expression was documented in four of these twenty tumors (20%) which corresponds to previously reported numbers for malignant melanomas and neuroblastomas in non-NF1 patients. Of these twenty pheochromocytomas, one of four sporadic tumors, one of ten tumors from patients with MEN2A, one of four tumors from patients with MEN2B, and one of two tumors from patients with von Hippel-Lindau syndrome demonstrated loss of NF1 gene expression. In all cases, the quality and quantity of tumor RNA was determined by RT-PCR amplification using primers which amplify cyclophilin RNA. We previously demonstrated that these tumors do not harbor activating mutations of the N-ras, K-ras or H-ras proto-oncogenes. These results suggest that loss of NF1 gene expression is frequently associated with the progression to neoplasia in tumors derived from adrenal medullary tissue in patients without clinical manifestations of neurofibromatosis and supports the notion that neurofibromin is a tumor suppressor gene product involved in the pathogenesis of a wide variety of tumor types.« less

NASA UAS Integration into the NAS Project: Human Systems Integration

NASA Technical Reports Server (NTRS)

Shively, Jay

2016-01-01

This presentation provides an overview of the work the Human Systems Integration (HSI) sub-project has done on detect and avoid (DAA) displays while working on the UAS (Unmanned Aircraft System) Integration into the NAS project. The most recent simulation on DAA interoperability with Traffic Collision Avoidance System (TCAS) is discussed in the most detail. The relationship of the work to the larger UAS community and next steps are also detailed.

Pro-ELT; A Teacher Training Blended Approach

ERIC Educational Resources Information Center

Eshtehardi, Reza

2014-01-01

Pro-ELT is a blended teacher training course. The aim of Pro-ELT is to strengthen English teaching and learning through a blended training approach that includes; quality face to face delivery, supported distance learning and integrated proficiency and methodology training. It delivers quality language teaching and teacher development courses to…

Chronic Interpersonal Stress Predicts Activation of Pro- and Anti- Inflammatory Signaling Pathways Six Months Later

PubMed Central

Miller, Gregory; Rohleder, Nicolas; Cole, Steve W.

2009-01-01

OBJECTIVE Chronic interpersonal difficulties have a detrimental influence on mental and physical health, but little is known about the mechanisms underlying this phenomenon. METHODS 103 healthy young women (mean age = 17) were administered a structured interview to assess the degree of chronic interpersonal stress in their lives. At the same time blood was drawn to measure systemic inflammation, the expression of signaling molecules that regulate immune activation, and leukocyte production of the cytokine interleukin-6 following ex vivo stimulation with lipopolysaccharide. All of the immunologic assessments were repeated six months later. RESULTS To the extent subjects were high in chronic interpersonal stress at baseline, their leukocytes displayed greater increases in mRNA for the pro-inflammatory transcription factor nuclear factor-kappa B (NF-κB) over the next six months. They also showed larger increases in mRNA for inhibitor of kappaB, a molecule that sequesters NF-κB in the cytoplasm and minimizes its pro-inflammatory activities. Chronic interpersonal stress at baseline was unrelated to changes in biomarkers of systemic inflammation, but was associated with increasingly pronounced interleukin-6 responses to lipopolysaccharide. These associations were independent of demographics, lifestyle variables, and depressive symptoms. CONCLUSIONS These findings suggest that chronic interpersonal difficulties accentuate expression of pro- and anti-inflammatory signaling molecules. While this process does not result in systemic inflammation under quiescent conditions, it does accentuate leukocytes’ inflammatory response to microbial challenge. These dynamics may underlie the excess morbidity associated with social stress, particularly in inflammation-sensitive diseases like depression and atherosclerosis. PMID:19073750

Project Integration Architecture: Application Architecture

NASA Technical Reports Server (NTRS)

Jones, William Henry

2005-01-01

The Project Integration Architecture (PIA) implements a flexible, object-oriented, wrapping architecture which encapsulates all of the information associated with engineering applications. The architecture allows the progress of a project to be tracked and documented in its entirety. Additionally, by bringing all of the information sources and sinks of a project into a single architectural space, the ability to transport information between those applications is enabled.

A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF-κB activities in HT1080 cells.

PubMed

Lee, Seung-Hee; Lee, Jee Hyun; Kim, Eun-Ju; Kim, Won-Jung; Suk, Kyoungho; Kim, Joo-Hwan; Song, Gyu Yong; Lee, Won-Ha

2012-07-01

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. We have analysed a derivative of decursin (CSL-32) for activity against inflammatory activation of cancer cells, such as migration, invasion and expression of pro-inflammatory mediators. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumour necrosis factor α) in the presence or absence of CSL-32. The cellular responses and modification of signalling adapters were analysed with respect to the production of pro-inflammatory mediators, as also migration, adhesion and invasion. Treatment of HT1080 cells with CSL-32 inhibited their proliferation, without affecting cell viability, and TNFα-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8). CSL-32 also suppressed phosphorylation and degradation of IκB (inhibitory κB), phosphorylation of p65 subunit of NF-κB (nuclear factor-κB) and nuclear translocation of NF-κB, which are required for the expression of pro-inflammatory mediators. In addition, CSL-32 inhibited invasion and migration of HT1080 cells, as also cellular adhesion to fibronectin, an ECM (extracellular matrix) protein. CSL-32 treatment resulted in a dose-dependent inhibition of PI3K (phosphoinositide 3-kinase) activity, required for the cellular migration. The analyses show that CSL-32 inhibits processes associated with inflammation, such as the production of pro-inflammatory mediators, as well as adhesion, migration and invasion in HT1080 cells.

Plumbagin, a vitamin K3 analogue, abrogates lipopolysaccharide-induced oxidative stress, inflammation and endotoxic shock via NF-κB suppression.

PubMed

Checker, Rahul; Patwardhan, Raghavendra S; Sharma, Deepak; Menon, Jisha; Thoh, Maikho; Sandur, Santosh K; Sainis, Krishna B; Poduval, T B

2014-04-01

Plumbagin has been reported to modulate cellular redox status and suppress NF-κB. In the present study, we investigated the effect of plumbagin on lipopolysaccharide (LPS)-induced endotoxic shock, oxidative stress and inflammatory parameters in vitro and in vivo. Plumbagin inhibited LPS-induced nitric oxide, TNF-α, IL-6 and prostaglandin-E2 production in a concentration-dependent manner in RAW 264.7 cells without inducing any cell death. Plumbagin modulated cellular redox status in RAW cells. Plumbagin treatment significantly reduced MAPkinase and NF-κB activation in macrophages. Plumbagin prevented mice from endotoxic shock-associated mortality and decreased serum levels of pro-inflammatory markers. Plumbagin administration ameliorated LPS-induced oxidative stress in peritoneal macrophages and splenocytes. Plumbagin also attenuated endotoxic shock-associated changes in liver and lung histopathology and decreased the activation of ERK and NF-κB in liver. These findings demonstrate the efficacy of plumbagin in preventing LPS-induced endotoxemia and also provide mechanistic insights into the anti-inflammatory effects of plumbagin.

Regulation of LPS-induced mRNA expression of pro-inflammatory cytokines via alteration of NF-κB activity in mouse peritoneal macrophages exposed to fluoride.

PubMed

Tian, Yuhu; Huo, Meijun; Li, Guangsheng; Li, Yanyan; Wang, Jundong

2016-10-01

F toxicity to immune system, especially to macrophage, has been studied a lot recently. Nuclear factor-kappa B (NF-κB), as a transcription factor, plays a central role in immune and inflammatory responses via the regulation of downstream gene expression. Recent studies indicated that fluoride effect on inflammatory cytokine secretion, however, the molecular mechanism was less understood. In our study, peritoneal macrophages (PMs) were divided several groups and were administrated sodium fluoride (NaF, 50, 100, 200, 400, 800 μM) and/or lipopolysaccharide (LPS, 30 ng/mg). The mRNA expression of p65, inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in macrophages exposed to fluoride was determined by quantitative real-time RT-PCR respectively. The translocation of NF-κB from cytoplasm to nucleus, which in a way reflects NF-κB activity, was demonstrated by Immunofluorescence and ELISA. Our results showed that fluoride had a dose-dependent effect on NF-κB activity, which coincided with LPS-induced mRNA expression of its downstream genes, iNOS and IL-1β. Fluoride alone causes no effect on gene expression. However, the mRNA expression of TNF-α showed non-NF-κB-dependent manner. Therefore, we come to the conclusion that fluoride can regulate LPS-induced mRNA expression of iNOS and IL-1β via NF-κB pathway in mouse peritoneal macrophages. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quenching Rate Constants of NF(A1 Delta) by N2F4, NF3, NF(X), SiF4, HNCO and NCO at Room Temperature

DTIC Science & Technology

1993-01-01

F., ill; Helvajian . H .; Holloway. J. S.; Koffend, .3. J.1 base interaction between NF(aaA) and NF(X3Z-). Although the PAys. Chem. 1969, 93, 7818. 4...Since NF(a’&) possibly could be generated by the H + NF2 mis Metuho ieems reaction in practical laser devices. there is a need to know the reEimoM...and NF(b’Z+) are of a 30% CF4/Ar mixture together with additional A& tiahMb h • f also of practical interest. Since these reactions involve ground

Well Elderly Integrated Training Project. Final Report.

ERIC Educational Resources Information Center

Summit-Portage Area Health Education Network, Akron, OH.

The Well Elderly Integrated Training Project was conceptualized as a service-oriented endeavor with an evaluation component. The project required that a university medical school resource faculty develop an integrated training program and materials on health education (wellness) for trainers who were respected, healthy elderly high in the senior…

NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancer

PubMed Central

Kisseleva, Tatiana; Song, Li; Vorontchikhina, Marina; Feirt, Nikki; Kitajewski, Jan; Schindler, Christian

2006-01-01

The transcription factor NF-κB is an important regulator of homeostatic growth and inflammation. Although gene-targeting studies have revealed important roles for NF-κB, they have been complicated by component redundancy and lethal phenotypes. To examine the role of NF-κB in endothelial tissues, Tie2 promoter/enhancer–IκBαS32A/S36A transgenic mice were generated. These mice grew normally but exhibited enhanced sensitivity to LPS-induced toxemia, notable for an increase in vascular permeability and apoptosis. Moreover, B16-BL6 tumors grew significantly more aggressively in transgenic mice, underscoring a new role for NF-κB in the homeostatic response to cancer. Tumor vasculature in transgenic mice was extensive and disorganized. This correlated with a marked loss in tight junction formation and suggests that NF-κB plays an important role in the maintenance of vascular integrity and response to stress. PMID:17053836

Activation of the NF-κB pathway by the STAT3 inhibitor JSI-124 in human glioblastoma cells

PubMed Central

McFarland, Braden C.; Gray, G. Kenneth; Nozell, Susan E.; Hong, Suk W.; Benveniste, Etty N.

2013-01-01

Glioblastoma tumors are characterized by their invasiveness and resistance to therapies. The transcription factor STAT3 was recently identified as a master transcriptional regulator in the mesenchymal subtype of GBM, which has generated an increased interest in targeting STAT3. We have evaluated more closely the mechanism of action of one particular STAT3 inhibitor, JSI-124 (cucurbitacin I). In this study, we confirmed that JSI-124 inhibits both constitutive and stimulus-induced JAK2 and STAT3 phosphorylation, and decreases cell proliferation while inducing apoptosis in cultured GBM cells. However, we discovered that prior to the inhibition of STAT3, JSI-124 activates the NF-κB pathway, via NF-κB p65 phosphorylation and nuclear translocation. In addition, JSI-124 treatment induces the expression of IL-6, IL-8 and SOCS3 mRNA, which leads to a corresponding increase in IL-6, IL-8 and SOCS3 protein expression. Moreover, the NF-κB driven SOCS3 expression acts as a negative regulator of STAT3, abrogating any subsequent STAT3 activation and provides a mechanism of STAT3 inhibition following JSI-124 treatment. Chromatin immunoprecipitation analysis confirms that NF-κB p65 in addition to other activating co-factors are found at the promoters of IL-6, IL-8 and SOCS3, following JSI-124 treatment. Using pharmacological inhibition of NF-κB and inducible knockdown of NF-κB p65, we found that JSI-124-induced expression of IL-6, IL-8 and SOCS3 was significantly inhibited, demonstrating an NF-κB dependent mechanism. Our data indicate that although JSI-124 may demonstrate potential anti-tumor effects through inhibition of STAT3, other off-target pro-inflammatory pathways are activated, emphasizing that more careful and thorough pre-clinical investigations must be implemented to prevent potential harmful effects. PMID:23386688

Pro-lipogenic Action of Lysophosphatidic Acid in Ovarian Cancer

DTIC Science & Technology

2012-07-01

AD_________________ Award Number: W81XWH-11-1-0541 TITLE: Pro -lipogenic action of lysophosphatidic...DATE July 2012 2. REPORT TYPE Revised Annual 3. DATES COVERED 1 July 2011-30 June 2012 4. TITLE AND SUBTITLE Pro -lipogenic action of...cancer pilot research project titled “ Pro -lipogenic action of lysophosphatidic acid in ovarian cancer” is to determine the role of endogenous

Proceedings of the 13th Project integration meeting

NASA Technical Reports Server (NTRS)

Mcdonald, R. R.

1979-01-01

Progress made by the Low Cost Solar Array Project during the period April through August 1979 is presented. Reports are given on project analysis and integration; technology development in silicon material, large area sheet silicon, and encapsulation; production process and equipment development; engineering and operations, and a discussion of the steps taken to integrate these efforts. A report on, and copies of viewgraphs presented at the Project Integration Meeting held August 22-23, 1979 are presented.

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

PubMed Central

Liu, Ruozhou Tom; Wang, Aikun; To, Eleanor; Gao, Jiangyuan; Cao, Sijia; Cui, Jing Z.; Matsubara, Joanne A.

2015-01-01

Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κB. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Aβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use. PMID:25041941

Tunable UV Laser Photolysis of NF2: Quantum Yield for NF(a1 delta) Production.

DTIC Science & Technology

1988-05-25

UV Laser Photolysis of NF2: Quantum Yield for NF(a A) Production ’v0 LR. F. HEIDNER, H . HELVAJIAN , 4and J. B. KOFFEND Aerophysics Laboratory...experiments, the chemistry of NF2 with various hydrocarbons has been studied. It has also been shown that the addition-elimination reaction between H and NF2...COMPLI R LEN SP, 3 ,HAND L BE AM~ H O [ I , , i 1 CAIHOC IAM COOLED GaAs CAPACITANCE PHOTOTUIBE MANOMETER _ LENS /’~ ~L + . ANMEE _.... BANDPASS FILTER

Nuclear factor-κB is a common upstream signal for growth differentiation factor-5 expression in brown adipocytes exposed to pro-inflammatory cytokines and palmitate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinoi, Eiichi; Iezaki, Takashi; Ozaki, Kakeru

Highlights: • GDF5 expression is up-regulated by IL-1β, TNF-α and palmitate in brown pre-adipocytes. • NF-κB stimulates promoter activity and expression of GDF5 in brown pre-adipocytes. • Recruitment of NF-κB to the GDF5 promoter is facilitated in BAT from ob/ob mice. • An NF-κB inhibitor prevents upregulation of GDF5 expression in brown pre-adipocytes. - Abstract: We have previously demonstrated that genetic and acquired obesity similarly led to drastic upregulation in brown adipose tissue (BAT), rather than white adipose tissue, of expression of both mRNA and corresponding protein for the bone morphogenic protein/growth differentiation factor (GDF) member GDF5 capable of promotingmore » brown adipogenesis. In this study, we evaluated expression profiles of GDF5 in cultured murine brown pre-adipocytes exposed to pro-inflammatory cytokines and free fatty acids (FFAs), which are all shown to play a role in the pathogenesis of obesity. Both interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were effective in up-regulating GDF5 expression in a concentration-dependent manner, while similar upregulation was seen in cells exposed to the saturated FFA palmitate, but not to the unsaturated FFA oleate. In silico analysis revealed existence of the putative nuclear factor-κB (NF-κB) binding site in the 5′-flanking region of mouse GDF5, whereas introduction of NF-κB subunits drastically facilitated both promoter activity and expression of GDF5 in brown pre-adipocytes. Chromatin immunoprecipitation analysis confirmed significant facilitation of the recruitment of NF-κB to the GDF5 promoter in lysed extracts of BAT from leptin-deficient ob/ob obese mice. Upregulation o GDF5 expression was invariably inhibited by an NF-κB inhibitor in cultured brown pre-adipocytes exposed to IL-1β, TNF-α and palmitate. These results suggest that obesity leads to upregulation of GDF5 expression responsible for the promotion of brown adipogenesis through a

3,4,5-Tricaffeoylquinic acid inhibits tumor necrosis factor-α-stimulated production of inflammatory mediators in keratinocytes via suppression of Akt- and NF-κB-pathways.

PubMed

Lee, Chung Soo; Lee, Seon Ae; Kim, Yun Jeong; Seo, Seong Jun; Lee, Min Won

2011-11-01

Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Caffeoyl derivatives are demonstrated to have anti-inflammatory and anti-oxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid prepared from Aconium koreanum on the pro-inflammatory cytokine-stimulated keratinocyte responses remains uncertain. In human keratinocytes, we investigated the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB and cell signaling Akt, which regulates the transcription genes involved in immune and inflammatory responses. 3,4,5-Tricaffeoylquinic acid inhibited the TNF-α-stimulated production of cytokines (IL-1β and IL-8) and chemokine (CCL17 and CCL27) in keratinocytes. Bay 11-7085 (an inhibitor of NF-κB activation) and Akt inhibitor attenuated the TNF-α-induced formation of inflammatory mediators. 3,4,5-Tricaffeoylquinic acid, Bay 11-7085, Akt inhibitor and N-acetylcysteine inhibited the TNF-α-induced activation of NF-κB, activation of Akt, and formation of reactive oxygen and nitrogen species. The results show that 3,4,5-tricaffeoylquinic acid seems to attenuate the TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of Akt and NF-κB pathways which may be mediated by reactive oxygen species. The findings suggest that 3,4,5-tricaffeoylquinic acid may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Project management plan : Dallas Integrated Corridor Management (ICM) demonstration project.

DOT National Transportation Integrated Search

2010-12-01

The Dallas Integrated Corridor Management System Demonstration Project is a multi-agency, de-centralized operation which will utilize a set of regional systems to integrate the operations of the corridor. The purpose of the Dallas ICM System is to im...

Mangiferin inhibits mastitis induced by LPS via suppressing NF-ĸB and NLRP3 signaling pathways.

PubMed

Qu, Shihui; Wang, Wenqing; Li, Depeng; Li, Shumin; Zhang, Like; Fu, Yunhe; Zhang, Naisheng

2017-02-01

During the past era, small molecules derived from various plants have attracted extensive attention for their versatile medicinal benefits. Among these, one organic molecule called mangiferin from certain plant species including mangoes and honey bush tea is widely used in treating inflammation. In this study, a LPS-induced mastitis model in mouse is established to investigate the anti-inflammatory effects and mechanism of mangiferin. The result shows that mangiferin significantly alleviates LPS-induced histopathology, meanwhile, also decreases LPS-induced MPO activity. Furthermore, mangiferin treatment remarkably impeded the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. In addition, mangiferin was found to inhibit LPS-induced NF-ĸB and NLRP3 inflammasome activation. In conclusion, these results suggested that LPS-induced mastitis can be abated by mangiferin through inhibiting NF-ĸB and NLRP3 signaling pathways. Copyright © 2016 Elsevier B.V. All rights reserved.

Moringa fruit inhibits LPS-induced NO/iNOS expression through suppressing the NF-κ B activation in RAW264.7 cells.

PubMed

Lee, Hyo-Jin; Jeong, Yun-Jeong; Lee, Tae-Sung; Park, Yoon-Yub; Chae, Whi-Gun; Chung, Il-Kyung; Chang, Hyeun-Wook; Kim, Cheorl-Ho; Choi, Yung-Hyun; Kim, Wun-Jae; Moon, Sung-Kwon; Chang, Young-Chae

2013-01-01

In this study, we evaluated the anti-inflammatory effects of moringa (Moringa oleifera Lam.), a natural biologically active substance, by determining its inhibitory effects on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated macrophage RAW264.7 cells. Extracts from different parts of moringa (root, leaf, and fruit) reduced LPS-induced nitric oxide (NO) release in a dose-dependent manner. The moringa fruit extract most effectively inhibited LPS-induced NO production and levels of inducible nitric oxide synthase (iNOS). The moringa fruit extract also was shown to suppress the production of inflammatory cytokines including IL-1β, TNF-α, and IL-6. Furthermore, moringa fruit extract inhibited the cytoplasmic degradation of I κ B -α and the nuclear translocation of p65 proteins, resulting in lower levels of NF -κ B transactivation. Collectively, the results of this study demonstrate that moringa fruit extract reduces the levels of pro-inflammatory mediators including NO , IL-1β, TNF-α, and IL-6 via the inhibition of NF -κ B activation in RAW264.7 cells. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of moringa fruit extract.

Mycobacterium tuberculosis PE13 (Rv1195) manipulates the host cell fate via p38-ERK-NF-κB axis and apoptosis.

PubMed

Li, Hui; Li, Qiming; Yu, Zhaoxiao; Zhou, Mingliang; Xie, Jianping

2016-07-01

PE/PPE family proteins are mycobacteria unique molecules, named after their N-terminal conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains. Mycobacterium tuberculosis (Mtb) PE family gene encoded cell surface proteins are previously reported to be involved in virulence and interaction with host. To explore the role of a novel PE member (PE13, Rv1195), M. smegmatis was used as surrogate host. The study showed that Rv1195 was a cell wall associated protein. Rv1195 can enhance the survival of recombinants under stress conditions such as H2O2, SDS, low pH. This is largely due to the upregulated transcription of Rv1195, since diverse stresses can increase the promoter activity of Rv1195 gene, consistent with enhanced survival within macrophages. Ms_Rv1195 infection also increased the production of interlukin-6 (IL-6) and IL-1β from macrophages, while decreased the secretion of suppressor of cytokine signaling 3 (SOCS3) in comparison with the vector-only control. The cell death was also precipitated by the Ms_Rv1195 infection. Inhibitors treatment showed that the p38-ERK-NF-κB axis was involved in the Rv1195 triggered change of IL-6 and IL-1β expression. In summary, we showed that PE13 (Rv1195) is a new PE family member actively engaged in the interaction between Mycobacterium and host, signaling through p38-ERK-NF-κB axis and apoptosis.

Desktop Computing Integration Project

NASA Technical Reports Server (NTRS)

Tureman, Robert L., Jr.

1992-01-01

The Desktop Computing Integration Project for the Human Resources Management Division (HRMD) of LaRC was designed to help division personnel use personal computing resources to perform job tasks. The three goals of the project were to involve HRMD personnel in desktop computing, link mainframe data to desktop capabilities, and to estimate training needs for the division. The project resulted in increased usage of personal computers by Awards specialists, an increased awareness of LaRC resources to help perform tasks, and personal computer output that was used in presentation of information to center personnel. In addition, the necessary skills for HRMD personal computer users were identified. The Awards Office was chosen for the project because of the consistency of their data requests and the desire of employees in that area to use the personal computer.

Low-cost solar array project and Proceedings of the 14th Project Integration Meeting

NASA Technical Reports Server (NTRS)

Mcdonald, R. R.

1980-01-01

Activities are reported on the following areas: project analysis and integration; technology development in silicon material, large area sheet silicon, and encapsulation; production process and equipment development; and engineering and operations, and the steps taken to integrate these efforts. Visual materials presented at the project Integration Meeting are included.

The Neurofibromatoses. Part 1: NF1.

PubMed

Lu-Emerson, Christine; Plotkin, Scott R

2009-01-01

The neurofibromatoses, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, comprise a group of genetically distinct disorders of the nervous system unified by the predisposition to nerve sheath tumors. NF1 is the most common neurogenetic disorder, with a birth incidence of 1 in 3000. NF1 is inherited in auto-somal dominant fashion with full penetrance and variable expressivity. The hallmark lesion of NF1 is the neurofibroma, a benign tumor derived from the nerve sheath and composed of a mixture of proliferating Schwann cells, fibroblasts, mast cells, and pericytes. Other findings include gliomas, learning disability, vasculopathy, and bony abnormalities. Café au lait macules are typically the initial clinical manifestation of NF1 and tend to increase in size and number throughout childhood and puberty. Current treatment of patients with NF1 remains primarily surgical. Genetic counseling is essential for adult patients because molecular diagnostic testing can minimize the risk of transmission to children.

Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice

PubMed Central

Kishi, Noriyuki; MacDonald, Jessica L.; Ye, Julia; Molyneaux, Bradley J.; Azim, Eiman; Macklis, Jeffrey D.

2016-01-01

Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation. PMID:26821816

Segmental NF: A Guide for Patients

MedlinePlus

... for those in whom a diagnosis of segmental neurofibromatosis (NF) has been made or is being considered. ... have a child affected with NF. What is Neurofibromatosis (NF)? You may have heard of two different ...

NF-κB/Rel Proteins and the Humoral Immune Responses of Drosophila melanogaster

PubMed Central

Ganesan, Sandhya; Aggarwal, Kamna; Paquette, Nicholas; Silverman, Neal

2011-01-01

Nuclear Factor-κB (NF-κB)/Rel transcription factors form an integral part of innate immune defenses and are conserved throughout the animal kingdom. Studying the function, mechanism of activation and regulation of these factors is crucial for understanding host responses to microbial infections. The fruit fly Drosophila melanogaster has proved to be a valuable model system to study these evolutionarily conserved NF-κB mediated immune responses. Drosophila combats pathogens through humoral and cellular immune responses. These humoral responses are well characterized and are marked by the robust production of a battery of anti-microbial peptides. Two NF-κB signaling pathways, the Toll and the IMD pathways, are responsible for the induction of these antimicrobial peptides. Signal transduction in these pathways is strikingly similar to that in mammalian TLR pathways. In this chapter, we discuss in detail the molecular mechanisms of microbial recognition, signal transduction and NF-κB regulation, in both the Toll and the IMD pathways. Similarities and differences relative to their mammalian counterparts are discussed, and recent advances in our understanding of the intricate regulatory networks in these NF-κB signaling pathways are also highlighted. PMID:20852987

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells.

PubMed

Liu, Ruozhou Tom; Wang, Aikun; To, Eleanor; Gao, Jiangyuan; Cao, Sijia; Cui, Jing Z; Matsubara, Joanne A

2014-10-01

Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κΒ. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Αβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use. Copyright © 2014 Elsevier Ltd. All rights reserved.

[NF-κB signaling pathways and the future perspectives of bone disease therapy using selective inhibitors of NF-κB].

PubMed

Jimi, Eijiro; Fukushima, Hidefumi

2016-02-01

The transcriptional factor nuclear factor κB(NF-κB)regulates the expression of a wide variety of genes that are involved in immune and inflammatory responses, proliferation, and tumorigenesis. NF-κB consists of five members, such as p65(RelA), RelB, c-Rel, p50/p105(NF-κB1), and p52/p100(NF-κB2). There are two distinct NF-κB activation pathways, termed the classical and alternative NF-κB signaling pathways. Since mice lacking both p50 and p52 subunits developed typical osteopetrosis, due to total lack of osteoclasts, NF-κB is also important osteoclast differentiation. A selective NF-κB inhibitor blocked receptor activator of NF-κB ligand(RANKL)-induced osteoclastogenesis both in vitro and in vivo. Recent findings have shown that inactivation of NF-κB enhances osteoblast differentiation in vitro and bone formation in vivo. NF-κB is constitutively activated in many cancers including oral squamous cell carcinoma(OSCC), and is involved in the invasive characteristics of OSCC. A selective NF-κB inhibitor also prevented jaw bone destruction by OSCC by reduced osteoclast numbers in animal model. Thus the inhibition of NF-κB might useful for the treatment of bone diseases, such as arthritis, osteoporosis, periodontitis, and bone invasion by OSCC by inhibiting bone resorption and by stimulating bone formation.

Project for Integration of Pupils with Special Needs in Spain.

ERIC Educational Resources Information Center

Marchesi, Alvaro

1986-01-01

This paper analyzes a project approved by the Spanish government in 1985 to integrate special needs children into regular education. Outlined are characteristics of the Spanish educational system, parameters of practice in the integration project, and plans for the systematic evaluation of the integration project. (Author/JDD)

NF-κB in Hematological Malignancies

PubMed Central

Imbert, Véronique; Peyron, Jean-François

2017-01-01

NF-κB (Nuclear Factor Κ-light-chain-enhancer of activated B cells) transcription factors are critical regulators of immunity, stress response, apoptosis, and differentiation. Molecular defects promoting the constitutive activation of canonical and non-canonical NF-κB signaling pathways contribute to many diseases, including cancer, diabetes, chronic inflammation, and autoimmunity. In the present review, we focus our attention on the mechanisms of NF-κB deregulation in hematological malignancies. Key positive regulators of NF-κB signaling can act as oncogenes that are often prone to chromosomal translocation, amplifications, or activating mutations. Negative regulators of NF-κB have tumor suppressor functions, and are frequently inactivated either by genomic deletions or point mutations. NF-κB activation in tumoral cells is also driven by the microenvironment or chronic signaling that does not rely on genetic alterations. PMID:28561798

The SIMPSONS project: An integrated Mars transportation system

NASA Astrophysics Data System (ADS)

Kaplan, Matthew; Carlson, Eric; Bradfute, Sherie; Allen, Kent; Duvergne, Francois; Hernandez, Bert; Le, David; Nguyen, Quan; Thornhill, Brett

In response to the Request for Proposal (RFP) for an integrated transportation system network for an advanced Martian base, Frontier Transportation Systems (FTS) presents the results of the SIMPSONS project (Systems Integration for Mars Planetary Surface Operations Networks). The following topics are included: the project background, vehicle design, future work, conclusions, management status, and cost breakdown. The project focuses solely on the surface-to-surface transportation at an advanced Martian base.

The SIMPSONS project: An integrated Mars transportation system

NASA Technical Reports Server (NTRS)

Kaplan, Matthew; Carlson, Eric; Bradfute, Sherie; Allen, Kent; Duvergne, Francois; Hernandez, Bert; Le, David; Nguyen, Quan; Thornhill, Brett

1992-01-01

In response to the Request for Proposal (RFP) for an integrated transportation system network for an advanced Martian base, Frontier Transportation Systems (FTS) presents the results of the SIMPSONS project (Systems Integration for Mars Planetary Surface Operations Networks). The following topics are included: the project background, vehicle design, future work, conclusions, management status, and cost breakdown. The project focuses solely on the surface-to-surface transportation at an advanced Martian base.

Low NOx Fuel Flexible Combustor Integration Project Overview

NASA Technical Reports Server (NTRS)

Walton, Joanne C.; Chang, Clarence T.; Lee, Chi-Ming; Kramer, Stephen

2015-01-01

The Integrated Technology Demonstration (ITD) 40A Low NOx Fuel Flexible Combustor Integration development is being conducted as part of the NASA Environmentally Responsible Aviation (ERA) Project. Phase 2 of this effort began in 2012 and will end in 2015. This document describes the ERA goals, how the fuel flexible combustor integration development fulfills the ERA combustor goals, and outlines the work to be conducted during project execution.

Valsartan attenuates bleomycin-induced pulmonary fibrosis by inhibition of NF-κB expression and regulation of Th1/Th2 cytokines.

PubMed

Mojiri-Forushani, Hoda; Hemmati, Ali Asghar; Khodadadi, Ali; Rashno, Mohammad

2018-06-01

Pulmonary fibrosis (PF) is a chronic respiratory system disease. The role of inflammation and angiotensin in the development and progression of PF has previously been demonstrated. Alternation in antifibrotic/profibrotic mediators and NF-κB activation have important roles in PF development. NF-κB, a nuclear factor, induces the transcription of inflammatory and pro-inflammatory cytokines. The aim of this study was to evaluate the effect of valsartan as an angiotensin receptor blocker on IL-4, INF-γ, and NF-κB expression in the treatment of PF. Rats were divided into five groups: groups I (bleomycin) and II (control) received a single injection of bleomycin (7.5 IU/kg) or vehicle, respectively. Groups III-V received valsartan (20, 40, and 80 mg/kg, respectively) orally a week before and for 3 weeks after the bleomycin injection. Serum levels of IL-4 and INF- γ were then measured. Relative NF-κB expression was investigated by real-time PCR. Histopathological examination showed the anti-inflammation effect of valsartan. Bleomycin significantly increased IL-4 serum level and decreased that of INF-γ in the serum. Valsartan could restore their levels to normal. Valsartan raised the decreased ratio of INF-γ/IL-4. Exposure to bleomycin elevated NF-κB expression; and valsartan decreased the increased gene expression. Valsartan as an angiotensin receptor antagonist presumably by blocking angiotensin receptor causes to ameliorated PF, which was at least partly due to antifibrotic/profibrotic cytokine regulation and reduced NF-κB expression. Valsartan showed a significant protective effect against bleomycin-induced PF.

Flat-plate solar array project. Volume 8: Project analysis and integration

NASA Technical Reports Server (NTRS)

Mcguire, P.; Henry, P.

1986-01-01

Project Analysis and Integration (PA&I) performed planning and integration activities to support management of the various Flat-Plate Solar Array (FSA) Project R&D activities. Technical and economic goals were established by PA&I for each R&D task within the project to coordinate the thrust toward the National Photovoltaic Program goals. A sophisticated computer modeling capability was developed to assess technical progress toward meeting the economic goals. These models included a manufacturing facility simulation, a photovoltaic power station simulation and a decision aid model incorporating uncertainty. This family of analysis tools was used to track the progress of the technology and to explore the effects of alternative technical paths. Numerous studies conducted by PA&I signaled the achievement of milestones or were the foundation of major FSA project and national program decisions. The most important PA&I activities during the project history are summarized. The PA&I planning function is discussed and how it relates to project direction and important analytical models developed by PA&I for its analytical and assessment activities are reviewed.

Concurrent suppression of NF-κB, p38 MAPK and reactive oxygen species formation underlies the effect of a novel compound isolated from Curcuma comosa Roxb. in LPS-activated microglia.

PubMed

Jiamvoraphong, Nittaya; Jantaratnotai, Nattinee; Sanvarinda, Pantip; Tuchinda, Patoomratana; Piyachaturawat, Pawinee; Thampithak, Anusorn; Sanvarinda, Pimtip

2017-07-01

We investigated the molecular mechanisms underlying the effect of (3S)-1-(3,4-dihydroxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol, also known as compound 092, isolated from Curcuma comosa Roxb on the production of pro-inflammatory mediators and oxidative stress in lipopolysaccharide (LPS)-activated highly aggressive proliferating immortalized (HAPI) microglial cell lines. Nitric oxide (NO) production was determined using the Griess reaction, and reverse transcription polymerase chain reaction was used to measure the expression of inducible nitric oxide synthase (iNOS) mRNA. Western blotting was used to determine the levels of pro-inflammatory mediators and their related upstream proteins. Compound 092 suppressed NO production and iNOS expression in LPS-stimulated HAPI cells. These effects originated from the ability of compound 092 to attenuate the activation of nuclear factor (NF)-κB as determined by the reduction in p-NF-κB and p-IκB kinase (IKK) protein levels. Compound 092 also significantly lowered LPS-activated intracellular reactive oxygen species production and p38 mitogen-activated protein kinase (MAPK) activation. Compound 092 suppresses microglial activation through attenuation of p38 MAPK and NF-κB activation. Compound 092 thus holds the potential to treat neurodegenerative disorders associated with neuroinflammation and oxidative stress. © 2017 Royal Pharmaceutical Society.

Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway.

PubMed

Jia, Mengqi; Guo, Yanxia; Zhu, Deyu; Zhang, Nianzhao; Li, Lin; Jiang, Jin; Dong, Yiwen; Xu, Qingqing; Zhang, Xiulei; Wang, Meijuan; Yu, Haina; Wang, Fang; Tian, Keli; Zhang, Jinsan; Young, Charles Y F; Lou, Hongxiang; Yuan, Huiqing

2018-05-01

Anterior gradient 2 (AGR2), an endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI), is associated with cancer development and malignant progression. Here, we show that high level of AGR2 promotes the aggressive phenotype of prostate cancer (PCa) mouse models developed by either patient-derived xenografts or surgical intra-prostate implantation of PCa cells, associated with enrichment of the blood vessel network in tumor tissues. Angiogenesis markers VEGFR2 and CD34, accompanied with the invasive marker Vimentin, were predominantly stained in metastatic liver tissues. Secreted AGR2 was defined to enhance VEGFR2 activity as evidenced by physical interaction of purified recombinant human AGR2 (rhAGR2) with rhVEGFA through the formation of a disulfide bond. Mutant or deleted thioredoxin motif in rhAGR2 was also unable to bind to rhVEGFA that led to the significant abolishment in the vessel formation, but partially affecting the aggressive process, implicating alternative mechanisms are required for AGR2-conferring metastasis. Cytosolic AGR2 contributed to cell metastasis ascribed to its stabilizing effect on p65 protein, which subsequently activated the NF-κB and facilitated epithelial to mesenchymal transition (EMT). Importantly, GSH and cabozantinib, but not bevacizumab, effectively blocked the pro-angiogenic effect of rhAGR2 in vitro and in vivo, providing evidence that secreted AGR2 acts as a predictive biomarker for selection of angiogenesis-targeting therapeutic drugs based on its levels in the circular system. Copyright © 2018 Elsevier B.V. All rights reserved.

Current whole-body MRI applications in the neurofibromatoses: NF1, NF2, and schwannomatosis.

PubMed

Ahlawat, Shivani; Fayad, Laura M; Khan, Muhammad Shayan; Bredella, Miriam A; Harris, Gordon J; Evans, D Gareth; Farschtschi, Said; Jacobs, Michael A; Chhabra, Avneesh; Salamon, Johannes M; Wenzel, Ralph; Mautner, Victor F; Dombi, Eva; Cai, Wenli; Plotkin, Scott R; Blakeley, Jaishri O

2016-08-16

The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration Whole-Body MRI (WB-MRI) Working Group reviewed the existing literature on WB-MRI, an emerging technology for assessing disease in patients with neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN), to recommend optimal image acquisition and analysis methods to enable WB-MRI as an endpoint in NF clinical trials. A systematic process was used to review all published data about WB-MRI in NF syndromes to assess diagnostic accuracy, feasibility and reproducibility, and data about specific techniques for assessment of tumor burden, characterization of neoplasms, and response to therapy. WB-MRI at 1.5T or 3.0T is feasible for image acquisition. Short tau inversion recovery (STIR) sequence is used in all investigations to date, suggesting consensus about the utility of this sequence for detection of WB tumor burden in people with NF. There are insufficient data to support a consensus statement about the optimal imaging planes (axial vs coronal) or 2D vs 3D approaches. Functional imaging, although used in some NF studies, has not been systematically applied or evaluated. There are no comparative studies between regional vs WB-MRI or evaluations of WB-MRI reproducibility. WB-MRI is feasible for identifying tumors using both 1.5T and 3.0T systems. The STIR sequence is a core sequence. Additional investigation is needed to define the optimal approach for volumetric analysis, the reproducibility of WB-MRI in NF, and the diagnostic performance of WB-MRI vs regional MRI. © 2016 American Academy of Neurology.

Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers

PubMed Central

Todaka, Hiroshi; Higuchi, Takuma; Yagyu, Ken-ichi; Sugiyama, Yasunori; Yamaguchi, Fumika; Morisawa, Keiko; Ono, Masafumi; Fukushima, Atsuki; Tsuda, Masayuki; Taniguchi, Taketoshi

2015-01-01

MicroRNAs (miRNAs) are involved in the progression and suppression of various diseases through translational inhibition of target mRNAs. Therefore, the alteration of miRNA biogenesis induces several diseases. The nuclear factor 90 (NF90)-NF45 complex is known as a negative regulator in miRNA biogenesis. Here, we showed that NF90-NF45 double-transgenic (dbTg) mice develop skeletal muscle atrophy and centronuclear muscle fibers in adulthood. Subsequently, we found that the levels of myogenic miRNAs, including miRNA 133a (miR-133a), which promote muscle maturation, were significantly decreased in the skeletal muscle of NF90-NF45 dbTg mice compared with those in wild-type mice. However, levels of primary transcripts of the miRNAs (pri-miRNAs) were clearly elevated in NF90-NF45 dbTg mice. This result indicated that the NF90-NF45 complex suppressed miRNA production through inhibition of pri-miRNA processing. This finding was supported by the fact that processing of pri-miRNA 133a-1 (pri-miR-133a-1) was inhibited via binding of NF90-NF45 to the pri-miRNA. Finally, the level of dynamin 2, a causative gene of centronuclear myopathy and concomitantly a target of miR-133a, was elevated in the skeletal muscle of NF90-NF45 dbTg mice. Taken together, we conclude that the NF90-NF45 complex induces centronuclear myopathy through increased dynamin 2 expression by an NF90-NF45-induced reduction of miR-133a expression in vivo. PMID:25918244

Flavocoxid, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, blunts pro-inflammatory phenotype activation in endotoxin-stimulated macrophages.

PubMed

Altavilla, D; Squadrito, F; Bitto, A; Polito, F; Burnett, B P; Di Stefano, V; Minutoli, L

2009-08-01

The flavonoids, baicalin and catechin, from Scutellaria baicalensis and Acacia catechu, respectively, have been used for various clinical applications. Flavocoxid is a mixed extract containing baicalin and catechin, and acts as a dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (LOX) enzymes. The anti-inflammatory activity, measured by protein and gene expression of inflammatory markers, of flavocoxid in rat peritoneal macrophages stimulated with Salmonella enteritidis lipopolysaccharide (LPS) was investigated. LPS-stimulated (1 microg.mL(-1)) peritoneal rat macrophages were co-incubated with different concentrations of flavocoxid (32-128 microg.mL(-1)) or RPMI medium for different incubation times. Inducible COX-2, 5-LOX, inducible nitric oxide synthase (iNOS) and inhibitory protein kappaB-alpha (IkappaB-alpha) levels were evaluated by Western blot analysis. Nuclear factor kappaB (NF-kappaB) binding activity was investigated by electrophoretic mobility shift assay. Tumour necrosis factor-alpha (TNF-alpha) gene and protein expression were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay respectively. Finally, malondialdehyde (MDA) and nitrite levels in macrophage supernatants were evaluated. LPS stimulation induced a pro-inflammatory phenotype in rat peritoneal macrophages. Flavocoxid (128 microg.mL(-1)) significantly inhibited COX-2 (LPS = 18 +/- 2.1; flavocoxid = 3.8 +/- 0.9 integrated intensity), 5-LOX (LPS = 20 +/- 3.8; flavocoxid = 3.1 +/- 0.8 integrated intensity) and iNOS expression (LPS = 15 +/- 1.1; flavocoxid = 4.1 +/- 0.4 integrated intensity), but did not modify COX-1 expression. PGE(2) and LTB(4) levels in culture supernatants were consequently decreased. Flavocoxid also prevented the loss of IkappaB-alpha protein (LPS = 1.9 +/- 0.2; flavocoxid = 7.2 +/- 1.6 integrated intensity), blunted increased NF-kappaB binding activity (LPS = 9.2 +/- 2; flavocoxid = 2.4 +/- 0.7 integrated intensity) and the enhanced

The C-terminal domains of NF-H and NF-M subunits maintain axonal neurofilament content by blocking turnover of the stationary neurofilament network.

PubMed

Rao, Mala V; Yuan, Aidong; Campbell, Jabbar; Kumar, Asok; Nixon, Ralph A

2012-01-01

Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF) subunits have been proposed to contribute to this process and particularly to stability of this structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M)(tailΔ)] mice that the deletion of both of these domains selectively lowers NF levels 3-6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of disappearance of NF from the stationary NF network of optic axons in NF-(H/M)(tailΔ) mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF-(H/M)(tailΔ) axons. We conclude that NF-H and NF-M C-terminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons.

The C-Terminal Domains of NF-H and NF-M Subunits Maintain Axonal Neurofilament Content by Blocking Turnover of the Stationary Neurofilament Network

PubMed Central

Rao, Mala V.; Yuan, Aidong; Campbell, Jabbar; Kumar, Asok; Nixon, Ralph A.

2012-01-01

Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF) subunits have been proposed to contribute to this process and particularly to stability of this structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M)tailΔ] mice that the deletion of both of these domains selectively lowers NF levels 3–6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of disappearance of NF from the stationary NF network of optic axons in NF-(H/M)tailΔ mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF-(H/M)tailΔ axons. We conclude that NF-H and NF-M C-terminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons. PMID:23028520

Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Xiao-Jing; Zhang, Dong-Mei; Jia, Lin-Lin

We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocytemore » diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of

Branches of NF-κb signaling pathway regulate hepatocyte proliferation in rat liver regeneration.

PubMed

Chang, C F; Zhao, W M; Mei, J X; Zhou, Y; Pan, C Y; Xu, T T; Xu, C S

2015-07-13

Previous studies have demonstrated that the nuclear factor κB (NF-κB) pathway is involved in promoting cell proliferation. To further explore the regulatory branches and their sequence in the NF-κB pathway in the promotion of hepatocyte proliferation at the transcriptional level during rat liver regeneration, Rat Genome 230 2.0 array was used to detect the expression changes of the isolated hepatocytes. We found that many genes involved in the NF-κB pathway (including 73 known genes and 19 homologous genes) and cell proliferation (including 484 genes and 104 homologous genes) were associated with liver regeneration. Expression profile function (Ep) was used to analyze the biological processes. It was revealed that the NF-κB pathway promoted hepatocyte proliferation through three branches. Several methods of integrated statistics were applied to extract and screen key genes in liver regeneration, and it indicated that eight genes may play a vital role in rat liver regeneration. To confirm the above predicted results, Ccnd1, Jun and Myc were analyzed using qRT-PCR, and the results were generally consistent with that of microarray data. It is concluded that 3 branches and 8 key genes involved in the NF-κB pathway regulate hepatocyte proliferation during rat liver regeneration.

Screening for germline mutations in the neurofibromatosis type 2 (NF2) gene in NF2 patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andermann, A.A.; Ruttledge, M.H.; Rangaratnam, A.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease with over 95% penetrance which predisposes gene carriers to develop multiple tumors of the central nervous system. The NF2 gene is a putative tumor suppressor gene which was previously mapped to the long arm of chromosome 22, and has recently been identified, using positional cloning techniques. The gene encodes a protein, schwannomin (SCH), which is highly homologous to the band 4.1 protein family. In an attempt to identify and characterize mutations which lead to the manifestation of the disease, we have used single strand conformation analysis (SSCA) to screen for germlinemore » mutations in all 17 exons of the NF2 gene in 59 unrelated NF2 patients, representing both familial and new mutations. A total of 27 migration abnormalities was found in 26 patients. Using direct sequencing analysis, the majority of these variants were found to result in nonsense, splice-site or frameshift mutations. Mutations identified in familial NF2 patients segregate in the family, and may prove to be useful tools for a simple and direct SSCA-based technique of presymptomatic or prenatal diagnosis in relatives of patients with NF2. This may be of particular importance in children of patients who have new mutations in the NF2 gene, where linkage analysis may not be feasible.« less

Atg12 Maintains Skeletal Integrity by Modulating Pro-Osteoclastogenic Signals and Chondrocyte Differentiation

NASA Technical Reports Server (NTRS)

Tahimic, Candice; Bahl, Disha; Shirazi-Fard, Yasaman; Marsh, Timothy; Schreurs, Anne-Sofie; Rael, Victoria E.; Glikbarg, Chloe; Debnath, Jayantha; Globus, Ruth K.

2016-01-01

Weightlessness and radiation, two unique elements of space, profoundly decreases bone mass. This bone loss is attributed to increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. Our long-term goal is to identify signaling pathways that may be targeted to mitigate bone loss in scenarios of space exploration, radiotherapy and accidental radiation exposure. We have previously shown that exposure of MLO-Y4 osteocyte-like cells to simulated space radiation (56Fe) increased the expression of the pro-osteoclastogenic gene rankl and decreased protein levels of LC3B-II, a key player in autophagy. In this current study, we aimed to further elucidate the role of autophagy in maintaining structural integrity of the skeleton. We hypothesize that loss of autophagy in bone leads to an imbalance in pro-osteoclastogenic and pro-osteogenic signals, resulting in net bone loss. To test our hypothesis we performed global postnatal deletion of Atg12 using tamoxifeninducible Cre recombinase under the control of the CAG promoter. Six-week-old CAGCreERT2/ FloxAtg12 animals were treated daily with Tamoxifen or Vehicle (Control, oil only) for five days and euthanasia performed two weeks after the onset of treatment. Percent change in body weights (prior to treatment and at euthanasia) was not significantly different between treatment groups within the same gender. Compared to Vehicle (Control) groups, Tamoxifen (Atg12 iKO) groups showed decreased LC3B-I to II conversion and increased p62 protein levels, consistent with loss of autophagy. Quantitative PCR revealed increased expression of proosteoclastogenic cytokines mcp1 and rankl in bone and marrow respectively in male iKOs compared to male controls. Expression levels of these genes were not significantly altered in the Atg12 iKO females compared to females controls. Microcomputed tomography of tibiae revealed decreased cortical bone volume, cortical

Proceedings of the 22nd Project Integration Meeting

NASA Technical Reports Server (NTRS)

1983-01-01

This report describes progress made by the Flat-Plate Solar Array Project during the period January to September 1983. It includes reports on silicon sheet growth and characterization, module technology, silicon material, cell processing and high-efficiency cells, environmental isolation, engineering sciences, module performance and failure analysis and project analysis and integration. It includes a report on, and copies of visual presentations made at the 22nd Project Integration Meeting held at Pasadena, California, on September 28 and 29, 1983.

Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi

HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrolmore » induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction.« less

Amorfrutin A inhibits TNF-α-induced NF-κB activation and NF-κB-regulated target gene products.

PubMed

Shi, Hui; Ma, Juan; Mi, Chunliu; Li, Jing; Wang, Fei; Lee, Jung Joon; Jin, Xuejun

2014-07-01

The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified amorfrutin A as an inhibitor of NF-κB activation from the fruits of Amorpha fruticosa L. In present study, this compound significantly inhibited the TNF-α-induced expression of NF-κB reporter gene. Further analysis revealed that amorfrutin A was a potent inhibitor of NF-κB activation by the suppression of TNF-α-induced inhibitor of κBα (IκBα) degradation, p65 nuclear translocation, and DNA-binding activity of NF-κB. We also demonstrated that pretreatment of cells with this compound prevented the TNF-α-induced expression of NF-κB target genes, such as antiapoptosis (cIAP-1 and FLIP), proliferation (COX-2 and cyclinD1), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, IL-8, and MCP1). Furthermore, our results suggest that amorfrutin A potentiates TNF-α-induced apoptosis. Taken together, amorfrutin A could be a valuable candidate for the intervention of NF-κB-dependent pathological conditions such as inflammation. Copyright © 2014 Elsevier B.V. All rights reserved.

NF-κB Signalling in Glioblastoma

PubMed Central

Soubannier, Vincent; Stifani, Stefano

2017-01-01

Nuclear factor-κB (NF-κB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF-κB is a frequent event in numerous cancers, including glioblastoma, the most common and lethal form of brain tumours of glial cell origin (collectively termed gliomas). Glioblastoma is characterized by high cellular heterogeneity, resistance to therapy and almost inevitable recurrence after surgery and treatment. NF-κB is aberrantly activated in response to a variety of stimuli in glioblastoma, where its activity has been implicated in processes ranging from maintenance of cancer stem-like cells, stimulation of cancer cell invasion, promotion of mesenchymal identity, and resistance to radiotherapy. This review examines the mechanisms of NF-κB activation in glioblastoma, the involvement of NF-κB in several mechanisms underlying glioblastoma propagation, and discusses some of the important questions of future research into the roles of NF-κB in glioblastoma. PMID:28598356

Tesoro Los Angeles Refinery Integration and Compliance Project

EPA Pesticide Factsheets

EPA Region 9 has two announcements pertaining to the Los Angeles Refinery Integration and Compliance project (LARIC project): permit revisions meet all CAA requirements and federal PSD permitting provisions do not apply to this project.

Mast cells and histamine are triggering the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation

PubMed Central

Nizamutdinova, Irina Tsoy; Dusio, Giuseppina F.; Gasheva, Olga Yu.; Skoog, Hunter; Tobin, Richard; Peddaboina, Chander; Meininger, Cynthia J.; Zawieja, David C.; Newell-Rogers, M. Karen; Gashev, Anatoliy A.

2016-01-01

This study aimed to establish mechanistic links between the aging-associated changes in the functional status of mast cells and the altered responses of mesenteric tissue and mesenteric lymphatic vessels (MLVs) to acute inflammation. We used an in vivo model of acute peritoneal inflammation induced by lipopolysaccharide treatment of adult (9-month) and aged (24-month) F-344 rats. We analyzed contractility of isolated MLVs, mast cell activation, activation of nuclear factor-κB (NF-κB) without and with stabilization of mast cells by cromolyn or blockade of all types of histamine receptors and production of 27 major pro-inflammatory cytokines in adult and aged perilymphatic mesenteric tissues and blood. We found that the reactivity of aged contracting lymphatic vessels to LPS-induced acute inflammation was abolished and that activated mast cells trigger NF-κB signaling in the mesentery through release of histamine. The aging-associated basal activation of mesenteric mast cells limits acute inflammatory NF-κB activation in aged mesentery. We conclude that proper functioning of the mast cell/histamine/NF-κB axis is necessary for reactions of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and trafficking of immune cells near and within the collecting lymphatics. PMID:27875806

Analysis of IL-6, IL-10 and NF-κB Gene Polymorphisms in Aggressive and Chronic Periodontitis.

PubMed

Toker, Hülya; Görgün, Emine Pirim; Korkmaz, Ertan Mahir

2017-06-01

Pro-inflammatory cytokines, interleukin-6 (IL-6), demonstrated to be suppressed by interleukin-10 (IL-10) are known to be regulated by the transcription factor nuclear factor-κB(NF-κB). The aim of this study was to ascertain the association between genetic polymorphism of these genes (IL-6(-174), IL-10(-597) and NF-κB1-94ins/del)) and chronic/aggressive periodontitis. Forty-five patients with chronic periodontitis (CP), 58 patients with aggressive periodontitis (AP) and 38 periodontally healthy subjects were included in this study. Genomic DNA was isolated from whole blood samples. The NF-κB, IL-6, and IL-10 polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Among subjects for the ins/ins genotypes of NF-κB1 gene, the AA genotypes of IL-10 presented a higher frequency in chronic periodontitis group than in healthy controls (p=0.023). A statistically significant difference in genotyping frequencies between AP group and healthy controls was observed for the IL-6 gene. The AA genotype of IL-10 was overrepresented in CP and AP groups compared to healthy controls (OR=9.93, 95% CI: 2.11-46.7, OR=5.7, 95% CI: 1.22-26.89, respectively). Within the limits of this study, it can be concluded that the IL-10 (-597) AA genotype is associated with susceptibility to chronic/aggressive periodontitis and IL-6 (-174) GG genotypes and G allele seems to be associated with aggressive periodontitis. Clinical relevance: The results of the current study indicate that IL-6 and IL-10 genotypes seem to be associated with aggressive periodontitis. Also, the AA genotypes of IL-10 presented a higher frequency in chronic periodontitis subjects with carrying NF-κB1 ins/ins genotypes. Copyright© by the National Institute of Public Health, Prague 2017

Electroacupuncture ameliorates cognitive impairment through inhibition of NF-κB-mediated neuronal cell apoptosis in cerebral ischemia-reperfusion injured rats.

PubMed

Feng, Xiaodong; Yang, Shanli; Liu, Jiao; Huang, Jia; Peng, Jun; Lin, Jiumao; Tao, Jing; Chen, Lidian

2013-05-01

Cognitive impairment is a serious mental deficit following stroke that severely affects the quality of life of stroke survivors. Nuclear factor‑κB (NF-κB)-mediated neuronal cell apoptosis is involved in the development of post-stroke cognitive impairment; therefore, it has become a promising target for the treatment of impaired cognition. Acupuncture at the Baihui (DU20) and Shenting (DU24) acupoints is commonly used in China to clinically treat post‑stroke cognitive impairment; however, the precise mechanism of its action is largely unknown. In the present study, we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and investigated the underlying molecular mechanisms using a rat model of focal cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture at Baihui and Shenting was identified to significantly ameliorate neurological deficits and reduce cerebral infarct volume. Additionally, electroacupuncture improved learning and memory ability in cerebral I/R injured rats, demonstrating its therapeutic efficacy against post-stroke cognitive impairment. Furthermore, electroacupuncture significantly suppressed the I/R-induced activation of NF-κB signaling in ischemic cerebral tissues. The inhibitory effect of electroacupuncture on NF-κB activation led to the inhibition of cerebral cell apoptosis. Finally, electroacupuncture markedly downregulated the expression of pro-apoptotic Bax and Fas, two critical downstream target genes of the NF-κB pathway. Collectively, our findings suggest that inhibition of NF-κB‑mediated neuronal cell apoptosis may be one mechanism via which electroacupuncture at Baihui and Shenting exerts a therapeutic effect on post-stroke cognitive impairment.

24 CFR 266.608 - Mortgage insurance premium: Pro rata refund.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Mortgage insurance premium: Pro... PROJECT LOANS Contract Rights and Obligations Mortgage Insurance Premiums § 266.608 Mortgage insurance premium: Pro rata refund. If the Contract of Insurance is terminated by payment in full or is terminated...

24 CFR 266.608 - Mortgage insurance premium: Pro rata refund.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Mortgage insurance premium: Pro... PROJECT LOANS Contract Rights and Obligations Mortgage Insurance Premiums § 266.608 Mortgage insurance premium: Pro rata refund. If the Contract of Insurance is terminated by payment in full or is terminated...

CW deuterium fluoride chemical laser with reactant combination C2H4/NF3

NASA Astrophysics Data System (ADS)

Jiang, Zhongfu; Hua, Weihong

1998-05-01

The characters of combustion driven cw deuterium fluoride (DF) chemical laser with C2H4/NF3 reactant were numerically investigated. The numerical simulation was carried out using compressibility scaling method--a finite difference technique for the numerical integration of the steady and unsteady Navier-stokes equations for reactive flow. The small signal gain and the flow field were calculated. The numerical results shown that active zone length of the cw DF chemical laser with C2H4/NF3 is very long, which is about 6 cm, and the average cavity pressure is about 7 torr as the combustion pressure is about 1.5 atm. These results shown that the DF chemical laser with C2H4/NF3 is suitable for high cavity pressure performance.

A Policy Guide on Integrated Care (PGIC): Lessons Learned from EU Project INTEGRATE and Beyond

PubMed Central

Devroey, Dirk

2017-01-01

Efforts are underway in many European countries to channel efforts into creating improved integrated health and social care services. But most countries lack a strategic plan that is sustainable over time, and that reflects a comprehensive systems perspective. The Policy Guide on Integrated Care (PGIC) as presented in this paper resulted from experiences with the EU Project INTEGRATE and our own work with healthcare reform for patients with chronic conditions at the national and international level. This project is one of the largest EU funded projects on Integrated Care, conducted over a four-year period (2012–2016) and included partners from nine European countries. Project Integrate aimed to gain insights into the leadership, management and delivery of integrated care to support European care systems to respond to the challenges of ageing populations and the rise of people living with long-term conditions. The objective of this paper is to describe the PGIC as both a tool and a reasoning flow that aims at supporting policy makers at the national and international level with the development and implementation of integrated care. Any Policy Guide on Integrated should build upon three building blocks, being a mission, vision and a strategy that aim at capturing the large amount of factors that directly or indirectly influence the successful development of integrated care. PMID:29588631

A Policy Guide on Integrated Care (PGIC): Lessons Learned from EU Project INTEGRATE and Beyond.

PubMed

Borgermans, Liesbeth; Devroey, Dirk

2017-09-25

Efforts are underway in many European countries to channel efforts into creating improved integrated health and social care services. But most countries lack a strategic plan that is sustainable over time, and that reflects a comprehensive systems perspective. The Policy Guide on Integrated Care (PGIC) as presented in this paper resulted from experiences with the EU Project INTEGRATE and our own work with healthcare reform for patients with chronic conditions at the national and international level. This project is one of the largest EU funded projects on Integrated Care, conducted over a four-year period (2012-2016) and included partners from nine European countries. Project Integrate aimed to gain insights into the leadership, management and delivery of integrated care to support European care systems to respond to the challenges of ageing populations and the rise of people living with long-term conditions. The objective of this paper is to describe the PGIC as both a tool and a reasoning flow that aims at supporting policy makers at the national and international level with the development and implementation of integrated care. Any Policy Guide on Integrated should build upon three building blocks, being a mission, vision and a strategy that aim at capturing the large amount of factors that directly or indirectly influence the successful development of integrated care.

S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β.

PubMed

Deng, Hongbin; Zhang, Na; Wang, Yan; Chen, Jinjing; Shen, Jiajia; Wang, Zhen; Xu, Rong; Zhang, Jingpu; Song, Danqing; Li, Diandong

2012-12-10

Inflammatory mediators including inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) contribute to the course of a variety of inflammatory diseases. S632A3 is a new member of the glutarimide antibiotics isolated from a cultured broth of Streptomyces hygroscopicus S632 with a potent NF-κB inhibitory activity. In the present study, we investigated the anti-inflammatory effects and the underlying molecular mechanism of S632A3 on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. S632A3 concentration-dependently inhibited LPS-induced NO and prostaglandin E(2) (PGE(2)) production through the suppression of iNOS and COX-2 at gene transcription levels. In addition, S632A3 suppressed NF-κB-dependent inflammatory responses by inhibiting the activation of glycogen synthase kinase 3β (GSK-3β), while the activation of IκB kinase (IKK) complex was unaffected. S632A3 suppressed NF-κB activity by differentially affecting the CREB (cAMP response element-binding protein) and NF-κB p65 interacting with the coactivator CBP (CREB binding protein). S632A3 also inhibited GSK-3β-elicited iNOS and COX-2 expression. Moreover, S632A3 was shown to inhibit the activation of ASK1 (Apoptosis-signal regulating kinase 1) and p38 mitogen-activated protein kinase, therefore attenuated the LPS-induced NF-κB activity in macrophages. Furthermore, S632A3 significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 production while increased the anti-inflammatory cytokine IL-10 production in LPS-stimulated RAW264.7 cells. Our study thus provides a molecular mechanism by which S632A3 inhibited LPS-induced pro-inflammatory response in macrophages through interfering with the activation of GSK-3β and ASK1-p38 signaling. Copyright © 2012 Elsevier Inc. All rights reserved.

24 CFR 241.825 - Pro rata refund of insurance premium.

Code of Federal Regulations, 2010 CFR

2010-04-01

... AUTHORITIES SUPPLEMENTARY FINANCING FOR INSURED PROJECT MORTGAGES Contract Rights and Obligations-Multifamily Projects Without a HUD-Insured or HUD-Held Mortgage Premiums § 241.825 Pro rata refund of insurance premium...

Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling.

PubMed

Liu, Aiming; Tanaka, Naoki; Sun, Lu; Guo, Bin; Kim, Jung-Hwan; Krausz, Kristopher W; Fang, Zhongze; Jiang, Changtao; Yang, Julin; Gonzalez, Frank J

2014-11-05

Overdose of acetaminophen (APAP) can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. The traditional Chinese herb Bupleurum falcatum has been widely used for the treatment of several liver diseases in eastern Asian countries, and saikosaponin d (SSd) is one of its major pharmacologically-active components. However, the efficacy of Bupleurum falcatum or SSd on APAP toxicity remains unclear. C57/BL6 mice were administered SSd intraperitoneally once daily for 5days, followed by APAP challenge. Biochemical and pathological analysis revealed that mice treated with SSd were protected against APAP-induced hepatotoxicity. SSd markedly suppressed phosphorylation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and reversed the APAP-induced increases in the target genes of NF-κB, such as pro-inflammatory cytokine Il6 and Ccl2, and those of STAT3, such as Socs3, Fga, Fgb and Fgg. SSd also enhanced the expression of the anti-inflammatory cytokine Il10 mRNA. Collectively, these results demonstrate that SSd protects mice from APAP-induced hepatotoxicity mainly through down-regulating NF-κB- and STAT3-mediated inflammatory signaling. This study unveils one of the possible mechanisms of hepatoprotection caused by Bupleurum falcatum and/or SSd. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Vinpocetine reduces lipopolysaccharide-induced inflammatory pain and neutrophil recruitment in mice by targeting oxidative stress, cytokines and NF-κB.

PubMed

Ruiz-Miyazawa, Kenji W; Pinho-Ribeiro, Felipe A; Zarpelon, Ana C; Staurengo-Ferrari, Larissa; Silva, Rangel L; Alves-Filho, Jose C; Cunha, Thiago M; Cunha, Fernando Q; Casagrande, Rubia; Verri, Waldiceu A

2015-07-25

In response to lipopolysaccharide (LPS), tissue resident macrophages and recruited neutrophils produce inflammatory mediators through activation of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. These mediators include inflammatory cytokines and reactive oxygen species that, in turn, sensitize nociceptors and lead to inflammatory pain. Vinpocetine is a nootropic drug widely used to treat cognitive and neurovascular disorders, and more recently its anti-inflammatory properties through inhibition of NF-κB activation have been described. In the present study, we used the intraplantar and intraperitoneal LPS stimulus in mice to investigate the effects of vinpocetine pre-treatment (3, 10, or 30mg/kg by gavage) in hyperalgesia, leukocyte recruitment, oxidative stress, and pro-inflammatory cytokine production (TNF-α, IL-1β, and IL-33). LPS-induced NF-κB activation and cytokine production were investigated using RAW 264.7 macrophage cell in vitro. Vinpocetine (30mg/kg) significantly reduces hyperalgesia to mechanical and thermal stimuli, and myeloperoxidase (MPO) activity (a neutrophil marker) in the plantar paw skin, and also inhibits neutrophil and mononuclear cell recruitment, superoxide anion and nitric oxide production, oxidative stress, and cytokine production (TNF-α, IL-1β and IL-33) in the peritoneal cavity. At least in part, these effects seem to be mediated by direct effects of vinpocetine on macrophages, since it inhibited the production of the same cytokines (TNF-α, IL-1β and IL-33) and the NF-κB activation in LPS-stimulated RAW 264.7 macrophages. Our results suggest that vinpocetine represents an important therapeutic approach to treat inflammation and pain induced by a gram-negative bacterial component by targeting NF-κB activation and NF-κB-related cytokine production in macrophages. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Clinical and Molecular Consequences of NF1 Microdeletion

DTIC Science & Technology

2005-05-01

and Cell Biology of NFl, NF2 and Schwannomatosis , Aspen, June, 2005 "* Abstract: Shinohara MM, Kuechle MK, Graves J, Stephens K. Neurofibromin is a...caspase target. The CTF International Consortium for the Molecular and Cell Biology of NF1, NF2 and Schwannomatosis , Aspen, June, 2005. "* Abstract...Molecular and Cell Biology of NF1, NF2 and Schwannomatosis , Aspen, June, 2005 Abstract: Shinohara MM, Kuechle MK, Graves J, Stephens K. Neurofibromin is a

The CCCH-type zinc finger transcription factor Zc3h8 represses NF-κB-mediated inflammation in digestive organs in zebrafish.

PubMed

Zou, Qingliang; Gang, Kai; Yang, Qifen; Liu, Xiaolin; Tang, Xuemei; Lu, Huiqiang; He, Jianbo; Luo, Lingfei

2018-06-05

Degenerative diseases of organs lead to their impaired function. The cellular and molecular mechanisms underlying organ degeneration are therefore of great research and clinical interest but are currently incompletely characterized. Here, using a forward-genetic screen for genes regulating liver development and function in zebrafish, we identified a cq5 mutant that exhibited a liver-degeneration phenotype at 5 days post-fertilization, the developmental stage at which a functional liver develops. Positional cloning revealed that the liver degeneration was caused by a single point mutation in the gene zinc finger CCCH-type containing 8 (zc3h8), changing a highly conserved histidine to glutamine at position 353 of the Zc3h8 protein. The zc3h8 mutation-induced liver degeneration in the mutant was accompanied by reduced proliferation, increased apoptosis, and macrophage phagocytosis of hepatocytes. Transcriptional profile analyses revealed up-regulation and activation of both pro-inflammatory cytokines and the NF-κB signaling pathway in the zc3h8 mutant. Suppression of NF-κB signaling activity efficiently rescued the pro-inflammatory cytokine response as well as the inflammation-mediated liver degeneration phenotype of the mutant. Of note, the zc3h8 mutation induced degeneration of several other organs, including the gut and exocrine pancreas, indicating that Zc3h8 is a general repressor of inflammation in zebrafish. Collectively, our findings demonstrate that Zc3h8 maintains organ homeostasis by inhibiting the NF-κB-mediated inflammatory response in zebrafish and that Zc3h8 dysfunction causes degeneration of multiple organs, including the liver, gut, and pancreas. Copyright © 2018, The American Society for Biochemistry and Molecular Biology.

Maternal pomegranate juice attenuates maternal inflammation-induced fetal brain injury by inhibition of apoptosis, neural nitric oxide synthase and NF-κB in a rat model.

PubMed

Ginsberg, Yuval; Khatib, Nizar; Saadi, Noor; Ross, Michael G; Weinr, Zeev; Beloosesky, Ron

2018-04-27

Maternal inflammation is a risk factor for neonatal brain injury and future neurological deficits. Pomegranates have been shown to exhibit anti-inflammatory, anti-apoptotic and anti-oxidant activities. We hypothesized that pomegranate juice (POM) may attenuate fetal brain injury in a rat model of maternal inflammation. Pregnant rats (24 total) were randomized for i.p. LPS (100 ug/kg) or saline at time 0 at 18 days of gestation. From day 11 of gestation, 12 dams were provided ad libitum access to drinking water, and 12 dams were provided ad libitum access to drinking water with pomegranate juice (5cc per day), resulting in 4 groups of 6 dams (SAL/SAL, POM/SAL, SAL/LPS, POM/LPS). All dams were sacrificed 4 hours following the injection and maternal blood and fetal brains were collected from the 4 treatment groups. Maternal IL-6 serum levels and fetal brain caspase 3 active form (af), NF-kB p65, neuronal nitric oxide synthase (phospho-nNOS) and pro-inflammatory cytokine levels were determined by ELISA and western blot. Maternal LPS significantly increased maternal serum IL-6 levels (6039 ± 1039 vs 66 ± 46pg/ml; p < 0.05) and fetal brain caspase 3 af, NF-kB p65, phospho-nNOS and the pro-inflammatory cytokines compared to the control group (caspase 3 af 0.26 ± 0.01 vs. 0.20 ± 0.01 u; NF-κB p65 0.24 ± 0.01 vs. 0.1 ± 0.01 u; phospho-nNOS 0.23 ± 0.01 vs. 0.11 ± 0.01 u; IL-6 0.25 ± 0.01 vs. 0.09 ± 0.01 u; TNFα 0.26 ± 0.01 vs. 0.12 ± 0.01 u; CCL2 0.23 ± 0.01 vs. 0.1 ± 0.01 u). Maternal supplementation of POM to LPS exposed dams (POM/LPS) significantly reduced maternal serum IL-6 levels (3059± 1121pg/ml, fetal brain: caspase 3 af (0.2 ± 0.01 u), NF-κB p65 (0.22 ± 0.01 u), phospho-nNOS (0.19 ± 0.01 u) as well as the brain pro-inflammatory cytokines (IL-6, TNFα and CCL2) compared to LPS group. Maternal POM supplementation may attenuate maternal-inflammation-induced fetal brain injury. POM neuroprotective effects might be secondary to the suppression of

Kefir-isolated bacteria and yeasts inhibit Shigella flexneri invasion and modulate pro-inflammatory response on intestinal epithelial cells.

PubMed

Bolla, P A; Abraham, A G; Pérez, P F; de Los Angeles Serradell, M

2016-02-01

The aim of this work was to evaluate the ability of a kefir-isolated microbial mixture containing three bacterial and two yeast strains (MM) to protect intestinal epithelial cells against Shigella flexneri invasion, as well as to analyse the effect on pro-inflammatory response elicited by this pathogen. A significant decrease in S. flexneri strain 72 invasion was observed on both HT-29 and Caco-2 cells pre-incubated with MM. Pre-incubation with the individual strains Saccharomyces cerevisiae CIDCA 8112 or Lactococcus lactis subsp. lactis CIDCA 8221 also reduced the internalisation of S. flexneri into HT-29 cells although in a lesser extent than MM. Interestingly, Lactobacillus plantarum CIDCA 83114 exerted a protective effect on the invasion of Caco-2 and HT-29 cells by S. flexneri. Regarding the pro-inflammatory response on HT-29 cells, S. flexneri infection induced a significant activation of the expression of interleukin 8 (IL-8), chemokine (C-C motif) ligand 20 (CCL20) and tumour necrosis factor alpha (TNF-α) encoding genes (P<0.05), whereas incubation of cells with MM did not induce the expression of any of the mediators assessed. Interestingly, pre-incubation of HT-29 monolayer with MM produced an inhibition of S. flexneri-induced IL-8, CCL20 and TNF-α mRNA expression. In order to gain insight on the effect of MM (or the individual strains) on this pro-inflammatory response, a series of experiments using a HT-29-NF-κB-hrGFP reporter system were performed. Pre-incubation of HT-29-NF-κB-hrGFP cells with MM significantly dampened Shigella-induced activation. Our results showed that the contribution of yeast strain Kluyveromyces marxianus CIDCA 8154 seems to be crucial in the observed effect. In conclusion, results presented in this study demonstrate that pre-treatment with a microbial mixture containing bacteria and yeasts isolated from kefir, resulted in inhibition of S. flexneri internalisation into human intestinal epithelial cells, along with the

Project ASPIRE: Incorporating Integrative Medicine Into Residency Training

PubMed Central

Nawaz, Haq; Via, Christina M.; Ali, Ather; Rosenberger, Lisa D.

2016-01-01

Griffin Hospital, a community hospital affiliated with Yale School of Public Health and Yale School of Medicine, received Health Resources and Services Administration funding to strengthen and improve its combined internal medicine and general preventive medicine residency program by incorporating an integrative medicine curriculum. The purpose of project ASPIRE (Advancing Skills of Preventive medicine residents through Integrative medicine Education, Research and Evaluation) was to create, implement, and evaluate a needs-based, innovative training curriculum in integrative medicine. Through this robust new training, the authors aimed to produce preventive medicine-trained physicians with competencies in integrative medicine to collaboratively work with other integrative medicine practitioners in interdisciplinary teams to provide holistic, patient-centered care. The multifaceted collaborative curriculum was composed of didactics, grand rounds, journal club, objective structured clinical examinations, and two new practicum rotations in integrative medicine. The new practicum rotations included block rotations at the Integrative Medicine Center at Griffin Hospital and the Yale Stress Center. Between 2012 and 2014, three cohorts participated in the curriculum; two of these cohorts included three advanced preventive medicine residents each and the fourth included four residents. Project faculty conducted 14 lectures and journal clubs, and two grand rounds. Six of the ten participating residents (60%) completed integrative medicine clinical rotations. Residents’ attitudes toward integrative medicine were evaluated through self-assessment using the Complementary, Alternative, and Integrative Medicine Attitudes Questionnaire; data were analyzed in 2015. This article describes the results of this prospective observational study based on single-institution experience over the course of the 2-year project period. PMID:26477907

Performance and fate of organics in a pilot MBR-NF for treating antibiotic production wastewater with recycling NF concentrate.

PubMed

Wang, Jianxing; Li, Kun; Wei, Yuansong; Cheng, Yutao; Wei, Dongbin; Li, Mingyue

2015-02-01

A double membrane system comprising a membrane bioreactor (MBR) combined with a nanofiltration (NF) membrane was investigated on a pilot scale for the treatment of antibiotic production wastewater over a three-month period at a pharmaceutical company in Wuxi, China. By recycling the NF concentrate, the combined MBR-NF process was shown to be effective for the treatment of antibiotic production wastewater, resulting in excellent water quality and a high water yield of 92±5.6%. The water quality of the pilot-scale MBR-NF process was excellent; e.g., the concentrations of TOC, NH4(+)-N, TP were stable at 5.52, 0.68, 0.34 mg L(-1), respectively, and the values of turbidity and conductivity of the NF permeate were 0.15 NTU and 2.5 mS cm(-1), respectively; these values meet China's water quality standard requirements for industrial use (GB21903-2008). Not only were the antibiotic removal rates of spiramycin (SPM) and new spiramycin (NSPM) over 95%, the acute toxicity was also drastically reduced by the MBR-NF pilot system. The main organics in the MBR effluent were proteins, polysaccharides, and humic-like substances; they were almost completely retained by the NF membrane and further biodegraded in the MBR because the NF concentrate was recycled. The microbial community of the MBR did not significantly change with the recycling of the NF concentrate. Copyright © 2014 Elsevier Ltd. All rights reserved.

An ethyl acetate fraction derived from Houttuynia cordata extract inhibits the production of inflammatory markers by suppressing NF-кB and MAPK activation in lipopolysaccharide-stimulated RAW 264.7 macrophages.

PubMed

Chun, Jin Mi; Nho, Kyoung Jin; Kim, Hyo Seon; Lee, A Yeong; Moon, Byeong Cheol; Kim, Ho Kyoung

2014-07-10

Houttuynia cordata Thunb. (Saururaceae) has been used in traditional medicine for treatment of inflammatory diseases. This study evaluated the anti-inflammatory effects of an ethyl acetate fraction derived from a Houttuynia cordata extract (HCE-EA) on the production of inflammatory mediators and the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. To measure the effects of HCE-EA on pro-inflammatory cytokine and inflammatory mediator's expression in RAW 264.7 cells, we used the following methods: cell viability assay, Griess reagent assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting analysis. HCE-EA downregulated nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin (IL-6) production in the cells, as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Furthermore, HCE-EA suppressed nuclear translocation of the NF-κB p65 subunit, which correlated with an inhibitory effect on IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation. HCE-EA also attenuated the activation of MAPKs (p38 and JNK). Our results suggest that the anti-inflammatory properties of HCE-EA may stem from the inhibition of pro-inflammatory mediators via suppression of NF-κB and MAPK signaling pathways.

Project Integration Architecture: Architectural Overview

NASA Technical Reports Server (NTRS)

Jones, William Henry

2001-01-01

The Project Integration Architecture (PIA) implements a flexible, object-oriented, wrapping architecture which encapsulates all of the information associated with engineering applications. The architecture allows the progress of a project to be tracked and documented in its entirety. By being a single, self-revealing architecture, the ability to develop single tools, for example a single graphical user interface, to span all applications is enabled. Additionally, by bringing all of the information sources and sinks of a project into a single architectural space, the ability to transport information between those applications becomes possible, Object-encapsulation further allows information to become in a sense self-aware, knowing things such as its own dimensionality and providing functionality appropriate to its kind.

MCPIP1 contributes to the toxicity of proteasome inhibitor MG-132 in HeLa cells by the inhibition of NF-κB.

PubMed

Skalniak, Lukasz; Dziendziel, Monika; Jura, Jolanta

2014-10-01

Recently, we have shown that the treatment of cells with proteasome inhibitor MG-132 results in the induction of expression of monocyte chemotactic protein-1 induced protein 1 (MCPIP1). MCPIP1 is a ribonuclease, responsible for the degradation of transcripts encoding certain pro-inflammatory cytokines. The protein is also known as an inhibitor of NF-κB transcription factor. Thanks to its molecular properties, MCPIP1 is considered as a regulator of inflammation, differentiation, and survival. Using siRNA technology, we show here that MCPIP1 expression contributes to the toxic properties of MG-132 in HeLa cells. The inhibition of proteasome by MG-132 and epoxomicin markedly increased MCPIP1 expression. While MG-132 induces HeLa cell death, down-regulation of MCPIP1 expression by siRNA partially protects HeLa cells from MG-132 toxicity and restores Nuclear factor-κB (NF-κB) activity, inhibited by MG-132 treatment. Inversely, overexpression of MCPIP1 decreased constitutive activity of NF-κB and limited the survival of HeLa cells, as we have shown in the previous study. Interestingly, although MG-132 decreased the expression of IκBα and increased p65 phosphorylation, the inhibition of constitutive NF-κB activity was observed in MG-132-treated cells. Since the elevated constitutive activity of NF-κB is one of the mechanisms providing increased survival of cancer cells, including HeLa cells, we propose that death-promoting properties of MCPIP1 in MG-132-treated HeLa cells may, at least partially, derive from the negative effect on the constitutive NF-κB activity.

24 CFR 241.825 - Pro rata refund of insurance premium.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Projects Without a HUD-Insured or HUD-Held Mortgage Premiums § 241.825 Pro rata refund of insurance premium... of the current annual loan insurance premium theretofore paid which is applicable to the portion of... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Pro rata refund of insurance...

NF-κB signaling mechanisms in HTLV-1-induced adult T-cell leukemia/lymphoma.

PubMed

Harhaj, Edward William; Giam, Chou-Zen

2018-05-03

The human T-cell leukemia virus type 1 (HTLV-1) is a complex deltaretrovirus linked to adult T-cell leukemia/lymphoma (ATLL), a fatal CD4+ malignancy in 3-5% of infected individuals. The HTLV-1 Tax regulatory protein plays indispensable roles in regulating viral gene expression and activating cellular signaling pathways that drive the proliferation and clonal expansion of T cells bearing HTLV-1 proviral integrations. Tax is a potent activator of NF-κB, a key signaling pathway that is essential for the survival and proliferation of HTLV-1 infected T cells. However, constitutive NF-κB activation by Tax also triggers a senescence response, suggesting the possibility that only T cells capable of overcoming NF-κB-induced senescence can selectively undergo clonal expansion after HTLV-1 infection. Tax expression is often silenced in the majority of ATLL due to genetic alterations in the tax gene or DNA hypermethylation of the 5'-LTR. Despite the loss of Tax, NF-κB activation remains persistently activated in ATLL due to somatic mutations in genes in the T/B-cell receptor (T/BCR) and NF-κB signaling pathways. In this review, we focus on the key events driving Tax-dependent and independent mechanisms of NF-κB activation during the multi-step process leading to ATLL. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

UAS Integration into the NAS Project

NASA Technical Reports Server (NTRS)

Bauer, Jeff

2010-01-01

The goal of the UAS Integration in the NAS Project is to contribute capabilities that reduce technical barriers related to the safety and operational challenges associated with enabling routine UAS access to the NAS This goal will be accomplished through a two-phased approach of system-level integration of key concepts, technologies and/or procedures, and demonstrations of integrated capabilities in an operationally relevant environment. Technical objectives include: PHASE 1: a) Validating the key technical areas identified by this project. System-level analyses, a State of the Art Analysis (SOAA), and a ConOps will identify the challenges and barriers preventing routine UAS access to the NAS. b) Developing a national roadmap and gap analysis identifying specific deliverables in the area of operations, procedures, and technologies that will impact future policy decisions. PHASE 2: a) Provide regulators with a methodology for developing airworthiness requirements for UAS and data to support development of certifications standards and regulatory guidance. b) Provide systems-level integrated testing of concepts and/or capabilities that address barriers to routine access to the NAS. Through simulation and flight testing, address issues including separation assurance, communications requirements, and Pilot Aircraft Interfaces (PAIs) in operationally relevant environments

Rig-I regulates NF-κB activity through binding to Nf-κb1 3′-UTR mRNA

PubMed Central

Zhang, Hong-Xin; Liu, Zi-Xing; Sun, Yue-Ping; Lu, Shun-Yuan; Liu, Xue-Song; Huang, Qiu-Hua; Xie, Yin-Yin; Dang, Su-Ying; Zheng, Guang-Yong; Li, Yi-Xue; Kuang, Ying; Fei, Jian; Chen, Zhu; Wang, Zhu-Gang

2013-01-01

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κb1. Rig-I is required for NF-κB activity via regulating Nf-κb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3′-UTR of Nf-κb1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3′-UTR fragments can be recognized by Rig-I. The 3′-UTR binding with Rig-I plays a critical role in normal translation of Nf-κb1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-κb1 and 3′-UTR–mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-κB signaling and is involved in multiple biological processes in addition to host antivirus immunity. PMID:23553835

NF-κB signaling participates in both Receptor Activator of NF-κB Ligand- (RANKL) and interleukin-4- (IL-4) induced macrophage fusion: Receptor cross-talk leads to alterations in NF-κB pathways

PubMed Central

Yu, Minjun; Qi, Xiulan; Moreno, Jose L.; Farber, Donna L.; Keegan, Achsah D.

2011-01-01

NF-κB activation is essential for RANKL-induced osteoclast formation. IL-4 is known to inhibit the RANKL-induced osteoclast differentiation, while at the same time promote macrophage fusion to form multinucleated giant cells (MNG). Several groups have proposed that IL-4 inhibition of osteoclastogenesis is mediated by suppressing the RANKL-induced activation of NF-κB. However, we found that IL-4 did not block proximal, canonical NF-κB signaling. Instead, we found that IL-4 inhibited alternative NF-κB signaling and induced p105/50 expression. Interestingly, in nfκb1−/− bone marrow macrophages (BMM), the formation of both multinucleated osteoclast and MNG induced by RANKL or IL-4 respectively was impaired. This suggests that NF-κB signaling also plays an important role in IL-4-induced macrophage fusion. Indeed, we found that the RANKL-induced and IL-4-induced macrophage fusion were both inhibited by the NF-κB inhibitors IKK2 inhibitor, and NEMO inhibitory peptide. Furthermore, overexpression of p50, p65, p52 and RelB individually in nfκb1−/− or nfκb1+/+ BMM enhanced both giant osteoclast and MNG formation. Interestingly, knockdown of nfκb2 in wild type BMM dramatically enhanced both osteoclast and MNG formation. In addition, both RANKL- and IL-4-induced macrophage fusion were impaired in NIK−/− BMM. These results suggest IL-4 influences NF-κB pathways by increasing p105/p50 and suppressing RANKL-induced p52 translocation, and that NF-κB pathways participate in both RANKL- and IL-4- induced giant cell formation. PMID:21734075

ABCB5 promotes melanoma metastasis through enhancing NF-κB p65 protein stability.

PubMed

Wang, Shenghao; Tang, Li; Lin, Junyu; Shen, Zhongliang; Yao, Yikun; Wang, Wei; Tao, Shuai; Gu, Chenjian; Ma, Jie; Xie, Youhua; Liu, Yanfeng

2017-10-07

Melanoma is the most aggressive type of skin cancer. Melanoma has an extremely poor prognosis because of its high potential for vascular invasion, metastasis and recurrence. The mechanism of melanoma metastasis is not well understood. ATP-binding cassette sub-family B member 5 (ABCB5) plays a key role in melanoma growth. However, it is uncertain what function ABCB5 may exert in melanoma metastasis. In this report, we for the first time demonstrate ABCB5 as a crucial factor that promotes melanoma metastasis. ABCB5 positive (ABCB5 + ) malignant melanoma initiating cells (MMICs) display a higher metastatic potential compared with ABCB5 negative (ABCB5 - ) melanoma subpopulation. Knockdown of ABCB5 expression reduces melanoma cell migration and invasion in vitro and melanoma pulmonary metastasis in tumor xenograft mice. ABCB5 and NF-κB p65 expression levels are positively correlated in both melanoma tissues and cell lines. Consequently, ABCB5 activates the NF-κB pathway by inhibiting p65 ubiquitination to enhance p65 protein stability. Our finding highlights ABCB5 as a novel pro-metastasis factor and provides a potential therapeutic target for melanoma. Copyright © 2017 Elsevier Inc. All rights reserved.

NF-κB deregulation in Hodgkin lymphoma.

PubMed

Weniger, Marc A; Küppers, Ralf

2016-08-01

Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) show constitutive activity of both the canonical and non-canonical NF-κB signaling pathways. The central pathogenetic role of this activity is indicated from studies with HL cell lines, which undergo apoptosis upon NF-κB inhibition. Multiple factors contribute to the strong NF-κB activity of HRS cells. This includes interaction with other cells in the lymphoma microenvironment through CD30, CD40, BCMA and other receptors, but also recurrent somatic genetic lesions in various factors of the NF-κB pathway, including destructive mutations in negative regulators of NF-κB signaling (e.g. TNFAIP3, NFKBIA), and copy number gains of genes encoding positive regulators (e.g. REL, MAP3K14). In Epstein-Barr virus-positive cases of classical HL, the virus-encoded latent membrane protein 1 causes NF-κB activation by mimicking an active CD40 receptor. NF-κB activity is also seen in the tumor cells of the rare nodular lymphocyte predominant form of HL, but the causes for this activity are largely unclear. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sharing knowledge of Planetary Datasets through the Web-Based PRoGIS

NASA Astrophysics Data System (ADS)

Giordano, M. G.; Morley, J. M.; Muller, J. P. M.; Barnes, R. B.; Tao, Y. T.

2015-10-01

The large amount of raw and derived data available from various planetary surface missions (e.g. Mars and Moon in our case) has been integrated withco-registered and geocoded orbital image data to provide rover traverses and camera site locations in universal global co-ordinates [1]. This then allows an integrated GIS to use these geocoded products for scientific applications: we aim to create a web interface, PRoGIS, with minimal controls focusing on the usability and visualisation of the data, to allow planetary geologists to share annotated surface observations. These observations in a common context are shared between different tools and software (PRoGIS, Pro3D, 3D point cloud viewer). Our aim is to use only Open Source components that integrate Open Web Services for planetary data to make available an universal platform with a WebGIS interface, as well as a 3D point cloud and a Panorama viewer to explore derived data. On top of these tools we are building capabilities to make and share annotations amongst users. We use Python and Django for the server-side framework and Open Layers 3 for the WebGIS client. For good performance previewing 3D data (point clouds, pictures on the surface and panoramas) we employ ThreeJS, a WebGL Javascript library. Additionally, user and group controls allow scientists to store and share their observations. PRoGIS not only displays data but also launches sophisticated 3D vision reprocessing (PRoVIP) and an immersive 3D analysis environment (PRo3D).

NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion.

PubMed

Li, Liwen; Han, Lei; Sun, Fan; Zhou, Jingjiao; Ohaegbulam, Kim C; Tang, Xudong; Zang, Xingxing; Steinbrecher, Kris A; Qu, Zhaoxia; Xiao, Gutian

2018-01-01

Activation of the inflammatory transcription factor NF-κB in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-κB drives the antitumor macrophages to become pro-tumorigenic have not been determined in any cancer type yet. Similarly, how TAMs repress CD8 + cytotoxic T lymphocytes (CTLs) remains largely unknown, although their importance in regulatory T (Treg) cell regulation and tumor promotion has been well appreciated. Here, using an endogenous lung cancer model we uncover a direct crosstalk between TAMs and CTLs. TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner. Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs. Notably, one major role of cell-intrinsic NF-κB RelA is to drive TAMs to suppress CTLs for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes. These studies help understand how immunity is shaped in lung tumorigenesis, and suggest a RelA-targeted immunotherapy for this deadliest cancer.

ProFound: Source Extraction and Application to Modern Survey Data

NASA Astrophysics Data System (ADS)

Robotham, A. S. G.

2018-04-01

ProFound detects sources in noisy images, generates segmentation maps identifying the pixels belonging to each source, and measures statistics like flux, size, and ellipticity. These inputs are key requirements of ProFit (ascl:1612.004), our galaxy profiling package; these two packages used in unison semi-automatically profile large samples of galaxies. The key novel feature introduced in ProFound is that all photometry is executed on dilated segmentation maps that fully contain the identifiable flux, rather than using more traditional circular or ellipse-based photometry. Also, to be less sensitive to pathological segmentation issues, the de-blending is made across saddle points in flux. ProFound offers good initial parameter estimation for ProFit, and also segmentation maps that follow the sometimes complex geometry of resolved sources, whilst capturing nearly all of the flux. A number of bulge-disc decomposition projects are already making use of the ProFound and ProFit pipeline.

Found in Translation: Interdisciplinary Arts Integration in Project AIM

ERIC Educational Resources Information Center

Pruitt, Lara; Ingram, Debra; Weiss, Cynthia

2014-01-01

This paper will share the arts-integration methodology used in Project AIM and address the question; "How is translation evident in interdisciplinary arts instruction, and how does it affect students?" Methods: The staff and researchers from Project AIM, (an arts-integration program of the Center for Community Arts Partnerships at…

NF-κB Activation Protects Oligodendrocytes against Inflammation

PubMed Central

Stone, Sarrabeth; Jamison, Stephanie; Yue, Yuan; Durose, Wilaiwan

2017-01-01

NF-κB is a key player in inflammatory diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the effects of NF-κB activation on oligodendrocytes in MS and EAE remain unknown. We generated a mouse model that expresses IκBαΔN, a super-suppressor of NF-κB, specifically in oligodendrocytes and demonstrated that IκBαΔN expression had no effect on oligodendrocytes under normal conditions (both sexes). Interestingly, we showed that oligodendrocyte-specific expression of IκBαΔN blocked NF-κB activation in oligodendrocytes and resulted in exacerbated oligodendrocyte death and hypomyelination in young, developing mice that express IFN-γ ectopically in the CNS (both sexes). We also showed that NF-κB inactivation in oligodendrocytes aggravated IFN-γ-induced remyelinating oligodendrocyte death and remyelination failure in the cuprizone model (male mice). Moreover, we found that NF-κB inactivation in oligodendrocytes increased the susceptibility of mice to EAE (female mice). These findings imply the cytoprotective effects of NF-κB activation on oligodendrocytes in MS and EAE. SIGNIFICANCE STATEMENT Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. NF-κB is a major player in inflammatory diseases that acts by regulating inflammation and cell viability. Data indicate that NF-κB activation in inflammatory cells facilitates the development of MS. However, to date, attempts to understand the role of NF-κB activation in oligodendrocytes in MS have been unsuccessful. Herein, we generated a mouse model that allows for inactivation of NF-κB specifically in oligodendrocytes and then used this model to determine the precise role of NF-κB activation in oligodendrocytes in models of MS. The results presented in this study represent the first demonstration that NF-κB activation acts cell autonomously to protect oligodendrocytes against inflammation in animal models of MS

Blocking NF-κB: an inflammatory issue.

PubMed

Rahman, Arshad; Fazal, Fabeha

2011-11-01

The nuclear factor (NF)-κB is considered the master regulator of inflammatory responses. Studies in mouse models have established this transcription factor as an important mediator of many inflammatory disease states, including pulmonary diseases such as acute lung injury and acute respiratory distress syndrome. Endothelial cells provide the first barrier for leukocytes migrating to the inflamed sites and hence offer an attractive cellular context for targeting NF-κB for treatment of these diseases. However, recent studies showing that NF-κB also plays an important role in resolution phase of inflammation and in tissue repair and homeostasis have challenged the view of therapeutic inhibition of NF-κB. This article reviews the regulation of NF-κB in the context of endothelial cell signaling and provides a perspective on why "dampening" rather than "abolishing" NF-κB activation may be a safe and effective treatment strategy for inflammation-associated pulmonary and other inflammatory diseases.

Fisetin, a dietary flavonoid, ameliorates experimental colitis in mice: Relevance of NF-κB signaling.

PubMed

Sahu, Bidya Dhar; Kumar, Jerald Mahesh; Sistla, Ramakrishna

2016-02-01

Fisetin, a dietary flavonoid, is commonly found in many fruits and vegetables. Although studies indicate that fisetin has an anti-inflammatory property, little is known about its effects on intestinal inflammation. The present study investigated the effects of the fisetin on dextran sulphate sodium (DSS)-induced murine colitis, an animal model that resembles human inflammatory bowel disease. Fisetin treatment to DSS-exposed mice significantly reduced the severity of colitis and alleviated the macroscopic and microscopic signs of the disease. Moreover, fisetin reduced the levels of myeloperoxidase activity, the production of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) and the expressions of COX-2 and iNOS in the colon tissues. Further studies revealed that fisetin suppressed the activation of NF-κB (p65) by inhibiting IκBα phosphorylation and NF-κB (p65)-DNA binding activity and attenuated the phosphorylation of Akt and the p38, but not ERK and JNK MAPKs in the colon tissues of DSS-exposed mice. In addition, DSS-induced decline in reduced glutathione (GSH) and the increase in malondialdehyde (MDA) levels were significantly restored by oral fisetin. Furthermore, the results from in vitro studies showed that fisetin significantly reduced the pro-inflammatory cytokine and mediator release and suppressed the degradation and phosphorylation of IκBα with subsequent nuclear translocation of NF-κB (p65) in lipopolysaccharide (LPS)-stimulated mouse primary peritoneal macrophages. These results suggest that fisetin exerts anti-inflammatory activity via inhibition of Akt, p38 MAPK and NF-κB signaling in the colon tissues of DSS-exposed mice. Thus, fisetin may be a promising candidate as pharmaceuticals or nutraceuticals in the treatment of inflammatory bowel disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Photoprotective Potential of Penta-O-Galloyl-β-DGlucose by Targeting NF-κB and MAPK Signaling in UVB Radiation-Induced Human Dermal Fibroblasts and Mouse Skin.

PubMed

Kim, Byung-Hak; Choi, Mi Sun; Lee, Hyun Gyu; Lee, Song-Hee; Noh, Kum Hee; Kwon, Sunho; Jeong, Ae Jin; Lee, Haeri; Yi, Eun Hee; Park, Jung Youl; Lee, Jintae; Joo, Eun Young; Ye, Sang-Kyu

2015-11-01

Exposure of the skin to ultraviolet radiation can cause skin damage with various pathological changes including inflammation. In the present study, we identified the skin-protective activity of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (pentagalloyl glucose, PGG) in ultraviolet B (UVB) radiation-induced human dermal fibroblasts and mouse skin. PGG exhibited antioxidant activity with regard to intracellular reactive oxygen species (ROS) generation as well as ROS and reactive nitrogen species (RNS) scavenging. Furthermore, PGG exhibited anti-inflammatory activity, inhibiting the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, resulting in inhibition of the expression of pro-inflammatory mediators. Topical application of PGG followed by chronic exposure to UVB radiation in the dorsal skin of hairless mice resulted in a significant decrease in the progression of inflammatory skin damages, leading to inhibited activation of NF-κB signaling and expression of pro-inflammatory mediators. The present study demonstrated that PGG protected from skin damage induced by UVB radiation, and thus, may be a potential candidate for the prevention of environmental stimuli-induced inflammatory skin damage.

NF-κB Signaling in Gastric Cancer

PubMed Central

Sokolova, Olga; Naumann, Michael

2017-01-01

Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin-associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI-encoded products form a type 4 secretion system (T4SS), a pilus-like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF-κB, but CagA and VacA are dispensable for direct NF-κB activation. NF-κB-driven gene products include cytokines/chemokines, growth factors, anti-apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF-κB promote gastric carcinogenesis. Since it has been shown that chemotherapy-caused cellular stress could elicit activation of the survival factor NF-κB, which leads to acquisition of chemoresistance, the NF-κB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF-κB activation in gastric mucosa in order to understand the role of NF-κB in gastric carcinogenesis. PMID:28350359

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

PubMed Central

Murray, Megan Y; Zaitseva, Lyubov; Auger, Martin J; Craig, Jenny IO; MacEwan, David J; Rushworth, Stuart A; Bowles, Kristian M

2015-01-01

Multiple Myeloma (MM) is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last 10–15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. To model bortezomib-resistant MM we generated bortezomib-resistant MM cell lines (n = 4 ) and utilised primary malignant plasma cells from patients relapsing after bortezomib treatment (n = 6 ). We identified enhanced Bruton's tyrosine kinase (BTK) activity in bortezomib-resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib (0.5 μM) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5 nM). Further analysis of pro-survival signaling revealed a role for the NF-κB p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-κB p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-κB p65 interference, also restored sensitivity to bortezomib, significantly reducing cell viability (37.5 ± 6 .9 %, ANOVA P ≤ 0 .001). Accordingly, we propose the clinical evaluation of a bortezomib/ibrutinib combination therapy, including in patients resistant to single-agent bortezomib. PMID:25565020

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma.

PubMed

Murray, Megan Y; Zaitseva, Lyubov; Auger, Martin J; Craig, Jenny Io; MacEwan, David J; Rushworth, Stuart A; Bowles, Kristian M

2015-01-01

Multiple Myeloma (MM) is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last 10-15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. To model bortezomib-resistant MM we generated bortezomib-resistant MM cell lines (n = 4 ) and utilised primary malignant plasma cells from patients relapsing after bortezomib treatment (n = 6 ). We identified enhanced Bruton's tyrosine kinase (BTK) activity in bortezomib-resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib (0.5 μM) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5 nM). Further analysis of pro-survival signaling revealed a role for the NF-κB p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-κB p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-κB p65 interference, also restored sensitivity to bortezomib, significantly reducing cell viability (37.5 ± 6 .9 %, ANOVA P ≤ 0 .001). Accordingly, we propose the clinical evaluation of a bortezomib/ibrutinib combination therapy, including in patients resistant to single-agent bortezomib.

A Non-SUMOylated Tax Protein Is Still Functional for NF-κB Pathway Activation

PubMed Central

Pène, Sabrina; Waast, Laetitia; Bonnet, Amandine; Bénit, Laurence

2014-01-01

ABSTRACT Whether NF-κB promoter transactivation by the human T-cell leukemia virus type 1 (HTLV-1) Tax protein requires Tax SUMOylation is still a matter of debate. In this study, we revisited the role of Tax SUMOylation using a strategy based on the targeting of Ubc9, the unique E2 SUMO-conjugating enzyme. We show that either a catalytically inactive form of Ubc9 (Ubc9-C93S) or Ubc9 small interfering RNA (siRNA) dramatically reduces Tax conjugation to endogenous SUMO-1 or SUMO-2/3, demonstrating that as expected, Tax SUMOylation is under the control of the catalytic activity of Ubc9. We further report that a non-SUMOylated Tax protein produced in 293T cells is still able to activate either a transfected or an integrated NF-κB reporter promoter and to induce expression of an NF-κB-regulated endogenous gene. Importantly, blocking Ubc9 activity in T cells also results in the production of a non-SUMOylated Tax that is still fully functional for the activation of a NF-κB promoter. These results provide the definitive evidence that Tax SUMOylation is not required for NF-κB-driven gene induction. IMPORTANCE Human T-cell leukemia virus type 1 is able to transform CD4+ T lymphocytes. The viral oncoprotein Tax plays a key role in this process by promoting cell proliferation and survival, mainly through permanent activation of the NF-κB pathway. Elucidating the molecular mechanisms involved in NF-κB pathway activation by Tax is therefore a key issue to understand HTLV-1-mediated transformation. Tax SUMOylation was initially proposed to be critical for Tax-induced NF-κB promoter activation, which was challenged by our later observation that a low-level-SUMOylated Tax mutant was still functional for activation of NF-κB promoters. To clarify the role of Tax SUMOylation, we set up a new approach based on the inhibition of the SUMOylation machinery in Tax-expressing cells. We show that blocking the SUMO-conjugating enzyme Ubc9 abolishes Tax SUMOylation and that a non

A non-SUMOylated tax protein is still functional for NF-κB pathway activation.

PubMed

Pène, Sabrina; Waast, Laetitia; Bonnet, Amandine; Bénit, Laurence; Pique, Claudine

2014-09-01

Whether NF-κB promoter transactivation by the human T-cell leukemia virus type 1 (HTLV-1) Tax protein requires Tax SUMOylation is still a matter of debate. In this study, we revisited the role of Tax SUMOylation using a strategy based on the targeting of Ubc9, the unique E2 SUMO-conjugating enzyme. We show that either a catalytically inactive form of Ubc9 (Ubc9-C93S) or Ubc9 small interfering RNA (siRNA) dramatically reduces Tax conjugation to endogenous SUMO-1 or SUMO-2/3, demonstrating that as expected, Tax SUMOylation is under the control of the catalytic activity of Ubc9. We further report that a non-SUMOylated Tax protein produced in 293T cells is still able to activate either a transfected or an integrated NF-κB reporter promoter and to induce expression of an NF-κB-regulated endogenous gene. Importantly, blocking Ubc9 activity in T cells also results in the production of a non-SUMOylated Tax that is still fully functional for the activation of a NF-κB promoter. These results provide the definitive evidence that Tax SUMOylation is not required for NF-κB-driven gene induction. Human T-cell leukemia virus type 1 is able to transform CD4(+) T lymphocytes. The viral oncoprotein Tax plays a key role in this process by promoting cell proliferation and survival, mainly through permanent activation of the NF-κB pathway. Elucidating the molecular mechanisms involved in NF-κB pathway activation by Tax is therefore a key issue to understand HTLV-1-mediated transformation. Tax SUMOylation was initially proposed to be critical for Tax-induced NF-κB promoter activation, which was challenged by our later observation that a low-level-SUMOylated Tax mutant was still functional for activation of NF-κB promoters. To clarify the role of Tax SUMOylation, we set up a new approach based on the inhibition of the SUMOylation machinery in Tax-expressing cells. We show that blocking the SUMO-conjugating enzyme Ubc9 abolishes Tax SUMOylation and that a non-SUMOylated Tax still

Time-dependent modulation of thioredoxin reductase activity might contribute to sulforaphane-mediated inhibition of NF-kappaB binding to DNA.

PubMed

Heiss, Elke; Gerhäuser, Clarissa

2005-01-01

The chemopreventive agent sulforaphane (SFN) exerts anti-inflammatory activity by thiol-dependent inhibition of nuclear factor kappaB (NF-kappaB) DNA binding. To further analyze the underlying mechanisms, we focused on the thioredoxin/thioredoxin reductase (TrxR) system as a key redox mechanism regulating NF-kappaB DNA binding. Using cultured Raw 264.7 mouse macrophages as a model, 1-chloro-2,4-dinitrobenzene (CDNB), a known inhibitor of TrxR, was identified as an inhibitor of lipopolysaccharide (LPS)-mediated nitric oxide (NO) production and of NF-kappaB DNA binding. CDNB and SFN acted synergistically with respect to inhibition of LPS-induced NO release, and we consequently identified SFN as a novel inhibitor of TrxR enzymatic activity in vitro. Short-term treatment of Raw macrophages with SFN or CDNB resulted in the inhibition of TrxR activity in vivo with half-maximal inhibitory concentration of 25.0 +/- 3.5 microM and 9.4 +/- 3.7 microM, respectively, whereas after a 24-h treatment with 25 microM SFN, TrxR activity was >1.5-fold elevated. In additional experiments, we could exclude that inhibition of trans-activating activity of NF-kappaB contributed to the reduced expression of pro-inflammatory proteins by SFN, based on transient transfection experiments with a (kappaB)(2)- chloramphenicol acetyltransferase construct and a lack of inhibition of protein kinase A activity. These findings further emphasize the importance of redox modulation or thiol reactivity for the regulation of NF-kappaB-dependent transcription by SFN. Antioxid. Redox Signal. 7, 1601-1611. Antioxid. Redox Signal. 7, 1601-1611.

40 CFR Table 31 to Subpart G of... - Typical Number of Vacuum Breakers, NF6 and Roof Drains, a NF7

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 10 2013-07-01 2013-07-01 false Typical Number of Vacuum Breakers, NF6..., and Wastewater Pt. 63, Subpt. G, Table 31 Table 31 to Subpart G of Part 63—Typical Number of Vacuum Breakers, NF6 and Roof Drains, a NF7 Tank diameter D (feet) b No. of vacuum breakers, NF6 Pontoon roof...

Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer

PubMed Central

Marquardt, Jens U.; Gomez-Quiroz, Luis; Camacho, Lucrecia O. Arreguin; Pinna, Federico; Lee, Yun-Han; Kitade, Mitsuteru; Domínguez, Mayrel Palestino; Castven, Darko; Breuhahn, Kai; Conner, Elizabeth A.; Galle, Peter R.; Andersen, Jesper B.; Factor, Valentina M.; Thorgeirsson, Snorri S.

2015-01-01

Background & Aims The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-kB signaling. Methods We evaluated the CSCs-depleting potential of NF-kB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of Side Population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting. Results HCC cell lines exposed to curcumin exhibited differential responses to curcumin and were classified as sensitive and resistant. In sensitive lines, curcumin-mediated induction of cell death was directly related to the extent of NF-kB inhibition. The treatment also led to a selective CSC-depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-kB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth. In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, an important component of the CSC-depleting activity of curcumin could be attributed to a NF-kB-mediated HDAC inhibition. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitivity with human HCC database indicated that HCCs with poor prognosis and progenitor features are most likely to benefit from NF-kB inhibition. Conclusions These results demonstrate that blocking NF-kB can specifically target CSC populations and suggest a potential for combined inhibition of NF-kB and HDAC signaling for treatment of liver cancer patients with poor prognosis. PMID:25937435

Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer.

PubMed

Marquardt, Jens U; Gomez-Quiroz, Luis; Arreguin Camacho, Lucrecia O; Pinna, Federico; Lee, Yun-Han; Kitade, Mitsuteru; Domínguez, Mayrel Palestino; Castven, Darko; Breuhahn, Kai; Conner, Elizabeth A; Galle, Peter R; Andersen, Jesper B; Factor, Valentina M; Thorgeirsson, Snorri S

2015-09-01

The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-κB signaling. We evaluated the CSCs-depleting potential of NF-κB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of side population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting. HCC cell lines exposed to curcumin exhibited differential responses to curcumin and were classified as sensitive and resistant. In sensitive lines, curcumin-mediated induction of cell death was directly related to the extent of NF-κB inhibition. The treatment also led to a selective CSC-depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-κB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth. In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, an important component of the CSC-depleting activity of curcumin could be attributed to a NF-κB-mediated HDAC inhibition. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitivity with human HCC database indicated that HCCs with poor prognosis and progenitor features are most likely to benefit from NF-κB inhibition. These results demonstrate that blocking NF-κB can specifically target CSC populations and suggest a potential for combined inhibition of NF-κB and HDAC signaling for treatment of liver cancer patients with poor prognosis. Copyright © 2015 European Association for the Study of the Liver. All rights reserved.

MicroRNA-22 and microRNA-140 suppress NF-{kappa}B activity by regulating the expression of NF-{kappa}B coactivators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takata, Akemi; Otsuka, Motoyuki, E-mail: otsukamo-tky@umin.ac.jp; Kojima, Kentaro

2011-08-12

Highlights: {yields} miRNAs were screened for their ability to regulate NF-{kappa}B activity. {yields} miRNA-22 and miRNA-140-3p suppress NF-{kappa}B activity by regulating coactivators. {yields} miRNA-22 targets nuclear receptor coactivator 1 (NCOA1). {yields} miRNA-140-3p targets nuclear receptor-interacting protein 1 (NRIP1). -- Abstract: Nuclear factor {kappa}B (NF-{kappa}B) is a transcription factor that regulates a set of genes that are critical to many biological phenomena, including liver tumorigenesis. To identify microRNAs (miRNAs) that regulate NF-{kappa}B activity in the liver, we screened 60 miRNAs expressed in hepatocytes for their ability to modulate NF-{kappa}B activity. We found that miRNA-22 and miRNA-140-3p significantly suppressed NF-{kappa}B activity bymore » regulating the expression of nuclear receptor coactivator 1 (NCOA1) and nuclear receptor-interacting protein 1 (NRIP1), both of which are NF-{kappa}B coactivators. Our results provide new information about the roles of miRNAs in the regulation of NF-{kappa}B activity.« less

Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro-inflammatory cytokines induced in mice by LPS.

PubMed

Finkin-Groner, E; Moradov, D; Shifrin, H; Bejar, C; Nudelman, A; Weinstock, M

2015-02-01

In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. AN917 and AN680 (1-10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 μmol · kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%. Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression. © 2014 The British Pharmacological Society.

Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro-inflammatory cytokines induced in mice by LPS

PubMed Central

Finkin-Groner, E; Moradov, D; Shifrin, H; Bejar, C; Nudelman, A; Weinstock, M

2015-01-01

Background and Purpose In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. Experimental Approach Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. Key Results AN917 and AN680 (1–10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 μmol·kg−1) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%. Conclusion and Implications Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression. PMID:25322956

Analysis and Quantitation of NF-[kappa]B Nuclear Translocation in Tumor Necrosis Factor Alpha (TNF-[alpha]) Activated Vascular Endothelial Cells

NASA Astrophysics Data System (ADS)

Fuseler, John W.; Merrill, Dana M.; Rogers, Jennifer A.; Grisham, Matthew B.; Wolf, Robert E.

2006-07-01

Nuclear factor kappa B (NF-[kappa]B) is a heterodimeric transcription factor typically composed of p50 and p65 subunits and is a pleiotropic regulator of various inflammatory and immune responses. In quiescent cells, p50/p65 dimers are sequestered in the cytoplasm bound to its inhibitors, the I-[kappa]Bs, which prevent entry into the nucleus. Following cellular stimulation, the I-[kappa]Bs are rapidly degraded, activating NF-[kappa]B. The active form of NF-[kappa]B rapidly translocates into the nucleus, binding to consensus sequences in the promoter/enhancer region of various genes, promoting their transcription. In human vascular endothelial cells activated with tumor necrosis factor-alpha, the activation and translocation of NF-[kappa]B is rapid, reaching maximal nuclear localization by 30 min. In this study, the appearance of NF-[kappa]B (p65 subunit, p65-NF-[kappa]B) in the nucleus visualized by immunofluorescence and quantified by morphometric image analysis (integrated optical density, IOD) is compared to the appearance of activated p65-NF-[kappa]B protein in the nucleus determined biochemically. The appearance of p65-NF-[kappa]B in the nucleus measured by fluorescence image analysis and biochemically express a linear correlation (R2 = 0.9477). These data suggest that localization and relative protein concentrations of NF-[kappa]B can be reliably determined from IOD measurements of the immunofluorescent labeled protein.

The amelioration of phagocytic ability in microglial cells by curcumin through the inhibition of EMF-induced pro-inflammatory responses

PubMed Central

2014-01-01

Background Insufficient clearance by microglial cells, prevalent in several neurological conditions and diseases, is intricately intertwined with MFG-E8 expression and inflammatory responses. Electromagnetic field (EMF) exposure can elicit the pro-inflammatory activation and may also trigger an alteration of the clearance function in microglial cells. Curcumin has important roles in the anti-inflammatory and phagocytic process. Here, we evaluated the ability of curcumin to ameliorate the phagocytic ability of EMF-exposed microglial cells (N9 cells) and documented relative pathways. Methods N9 cells were pretreated with or without recombinant murine MFG-E8 (rmMFG-E8), curcumin and an antibody of toll-like receptor 4 (anti-TLR4), and subsequently treated with EMF or a sham exposure. Their phagocytic ability was evaluated using phosphatidylserine-containing fluorescent bioparticles. The pro-inflammatory activation of microglia was assessed via CD11b immunoreactivity and the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and nitric oxide (NO) via the enzyme-linked immunosorbent assay or the Griess test. We evaluated the ability of curcumin to ameliorate the phagocytic ability of EMF-exposed N9 cells, including checking the expression of MFG-E8, αvβ3 integrin, TLR4, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) using Western blotting. Results EMF exposure dramatically enhanced the expression of CD11b and depressed the phagocytic ability of N9 cells. rmMFG-E8 could clearly ameliorate the phagocytic ability of N9 cells after EMF exposure. We also found that EMF exposure significantly increased the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and the production of NO; however, these increases were efficiently chilled by the addition of curcumin to the culture medium. This reduction led to the amelioration of the phagocytic ability of EMF-exposed N9 cells

The integrated landscape assessment project

Treesearch

Miles A. Hemstrom; Janine Salwasser; Joshua Halofsky; Jimmy Kagan; Cyndi Comfort

2012-01-01

The Integrated Landscape Assessment Project (ILAP) is a three-year effort that produces information, models, data, and tools to help land managers, policymakers, and others examine mid- to broad-scale (e.g., watersheds to states and larger areas) prioritization of land management actions, perform landscape assessments, and estimate potential effects of management...

The role of NF-κB signaling pathway in polyhexamethylene guanidine phosphate induced inflammatory response in mouse macrophage RAW264.7 cells.

PubMed

Kim, Ha Ryong; Shin, Da Young; Chung, Kyu Hyuck

2015-03-04

Polyhexamethylene guanidine (PHMG) phosphate is a competitive disinfectant with strong antibacterial activity. However, epidemiologists revealed that inhaled PHMG-phosphate may increase the risk of pulmonary fibrosis associated with inflammation, resulting in the deaths of many people, including infants and pregnant women. In addition, in vitro and in vivo studies reported the inflammatory effects of PHMG-phosphate. Therefore, the aim of the present study was to clarify the inflammatory effects and its mechanism induced by PHMG-phosphate in murine RAW264.7 macrophages. Cell viability, inflammatory cytokine secretion, nuclear factor kappa B (NF-κB) activation, and reactive oxygen species (ROS) generation were investigated in macrophages exposed to PHMG-phosphate. PHMG-phosphate induced dose-dependent cytotoxicity, with LC50 values of 11.15-0.99mg/ml at 6 and 24h, respectively. PHMG-phosphate induced pro-inflammatory cytokines including IL-1β, IL-6, and IL-8. In particular, IL-8 expression was completely inhibited by the NF-κB inhibitor BAY11-7082. In addition, PHMG-phosphate decreased IκB-α protein expression and increased NF-κB-mediated luciferase activity, which was diminished by N-acetyl-l-cystein. However, abundant amounts of ROS were generated in the presence of PHMG-phosphate at high concentrations with a cytotoxic effect. Our results demonstrated that PHMG-phosphate triggered the activation of NF-κB signaling pathway by modulating the degradation of IκB-α. Furthermore, the NF-κB signaling pathway plays a critical role in the inflammatory responses induced by PHMG-phosphate. We assumed that ROS generated by PHMG-phosphate were associated with inflammatory responses as secondary mechanism. In conclusion, we suggest that PHMG-phosphate induces inflammatory responses via NF-κB signaling pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nivalenol induces oxidative stress and increases deoxynivalenol pro-oxidant effect in intestinal epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Del Regno, Marisanta; Adesso, Simona; Popolo, Ada

Mycotoxins are secondary fungal metabolites often found as contaminants in almost all agricultural commodities worldwide, and the consumption of food or feed contaminated by mycotoxins represents a major risk for human and animal health. Reactive oxygen species are normal products of cellular metabolism. However, disproportionate generation of reactive oxygen species poses a serious problem to bodily homeostasis and causes oxidative tissue damage. In this study we analyzed the effect of two trichothecenes mycotoxins: nivalenol and deoxynivalenol, alone and in combination, on oxidative stress in the non-tumorigenic intestinal epithelial cell line IEC-6. Our results indicate the pro-oxidant nivalenol effect in IEC-6,more » the stronger pro-oxidant effect of nivalenol when compared to deoxynivalenol and, interestingly, that nivalenol increases deoxynivalenol pro-oxidative effects. Mechanistic studies indicate that the observed effects were mediated by NADPH oxidase, calcium homeostasis alteration, NF-kB and Nrf2 pathways activation and by iNOS and nitrotyrosine formation. The toxicological interaction by nivalenol and deoxynivalenol reported in this study in IEC-6, points out the importance of the toxic effect of these mycotoxins, mostly in combination, further highlighting the risk assessment process of these toxins that are of growing concern. - Highlights: • Nivalenol induces oxidative stress in intestinal epithelial cells (IECs). • Nivalenol increases deoxynivalenol pro-oxidant effects in IECs. • Nivalenol and deoxynivalenol trigger antioxidant response IECs. • These results indicate the importance of mycotoxins co-contamination.« less

Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium

PubMed Central

Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

2016-01-01

Objective Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). Materials and Methods In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Results Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. Conclusion ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions. PMID:27540524

Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium.

PubMed

Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

2016-01-01

Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions.

Metabolic Networks Integrative Cardiac Health Project (ICHP) - Center of Excellence

DTIC Science & Technology

2016-08-01

Award Number: TITLE: Metabolic Networks Integrative Cardiac Health Project (ICHP) - Center of Excellence PRINCIPAL INVESTIGATOR: COL (Ret) Marina N...2016 2. REPORT TYPE FINAL 3. DATES COVERED (From - To) 29 Sep 2011 – 31 May 2016 4. TITLE AND SUBTITLE "Metabolic Networks Integrative Cardiac Health...ABSTRACT The Integrative Cardiac Health Project (ICHP) aims to lead the way in Cardiovascular Disease (CVD) Prevention by conducting novel research

Acetaminophen-induced hepatotoxicity is associated with early changes in NF-kB and NF-IL6 DNA binding activity.

PubMed

Blazka, M E; Germolec, D R; Simeonova, P; Bruccoleri, A; Pennypacker, K R; Luster, M I

Nuclear transcription factors, such as NF-kB and NF-IL6, are believed to play an important role in regulating the expression of genes that encode for products involved in tissue damage and inflammation and, thus, may represent early biomarkers for chemical toxicities. In the present study changes in DNA binding activity of these factors were examined in livers of mice administered hepatotoxic doses of acetaminophen (APAP). NF-kB and NF-IL6 DNA binding occurred constitutively in control mouse liver. However, within 4 hr following administration of hepatotoxic doses of APAP, their binding activities were transiently lost and is in contrast to AP-1 transcription factor where activation occurs under similar conditions. These changes corresponded with increased release of inflammatory mediators (IL-6, serum amyloid A) and increased levels of enzymatic markers of hepatocyte damage. Similarly, treatment of mice with gadolinium chloride, an inhibitor of Kupffer cell activation and known to protect against APAP-induced hepatotoxicity, reduced the observed pathophysiological response in the liver while altering the APAP-associated changes in NF-kB DNA binding activity. NF-kB was found predominantly in parenchymal and endothelial cells and was composed primarily of relatively inactive p50 homodimer subunits in control liver. Taken together, these studies suggest that hepatotoxicity is associated with early and complex changes in DNA binding activities of specific transcription factors. In particular, NF-kB and NF-IL6 may serve as negative regulators of hepatocyte-derived inflammatory mediators and is analogous to that previously observed in certain other cell systems such as B lymphocytes.

Technology evaluation: PRO-542, Progenics Pharmaceuticals inc.

PubMed

Mukhtar, M; Parveen, Z; Pomerantz, R J

2000-12-01

Progenics's rCD4-IgG2 (PRO-542) is a recombinant fusion protein, which has been developed using the company's Universal Antiviral Binding (UnAB) technology, and is in phase I/II clinical trials for the treatment of human immunodeficiency virus type I (HIV-1) infection [273391]. At the beginning of 1997, Progenics received a Phase II Small Business Innovation Research Program (SBIR) grant from the National Institute of Allergy and Infectious diseases (NIAID) to fund the development of PRO-542 [236048]. A further grant of $2.7 million was awarded in August 1998 for the clinical evaluation of PRO-542 and other anti-HIV therapies [294200]. Progenics is collaborating with the Aaron Diamond AIDS Research Center (ADARC) in New York and the Center for Disease Control and Prevention in Atlanta [178410]. In February 2000, Progenics and Genzyme Transgenics Corp signed an agreement to continue the development of a transgenic source of PRO-542. Genzyme will develop transgenic goats that produce PRO-542 in their milk in exchange for undisclosed fees and milestone payments. Genzyme will supply PRO-542 to Progenics for clinical trials with a possibility for eventual commercial supply [357291]. Following on from this, in October 2000, Progenics received an SBIR grant to fund a two-year project with Genzyme Transgenics into the development of cost-effective methods for the manufacture of PRO-542, by optimization of the production of the drug in the milk of transgenic dairy animals [385982]. In August 2000, Punk, Ziegel & Company predicted that Progenics Pharmaceuticals will become sustainably profitable in 2003 following the launch of PRO-542 and GMK (Progenics Pharmaceuticals) in 2002 [390063].

Quercetin ameliorates imiquimod-induced psoriasis-like skin inflammation in mice via the NF-κB pathway.

PubMed

Chen, Haiming; Lu, Chuanjian; Liu, Huazhen; Wang, Maojie; Zhao, Hui; Yan, Yuhong; Han, Ling

2017-07-01

Quercetin (QC) is a dietary flavonoid abundant in many natural plants. A series of studies have shown that it has been shown to exhibit several biological properties, including anti-inflammatory, anti-oxidant, cardio-protective, vasodilatory, liver-protective and anti-cancer activities. However, so far the possible therapeutic effect of QC on psoriasis has not been reported. The present study was undertaken to evaluate the potential beneficial effect of QC in psoriasis using a generated imiquimod (IMQ)-induced psoriasis-like mouse model, and to further elucidate its underlying mechanisms of action. Effects of QC on PASI scores, back temperature, histopathological changes, oxidative/anti-oxidative indexes, pro-inflammatory cytokines and NF-κB pathway in IMQ-induced mice were investigated. Our results showed that QC could significantly reduce the PASI scores, decrease the temperature of the psoriasis-like lesions, and ameliorate the deteriorating histopathology in IMQ-induced mice. Moreover, QC effectively attenuated levels of TNF-α, IL-6 and IL-17 in serum, increased activities of GSH, CAT and SOD, and decreased the accumulation of MDA in skin tissue induced by IMQ in mice. The mechanism may be associated with the down-regulation of NF-κB, IKKα, NIK and RelB expression and up-regulation of TRAF3, which were critically involved in the non-canonical NF-κB pathway. In conclusion, our present study demonstrated that QC had appreciable anti-psoriasis effects in IMQ-induced mice, and the underlying mechanism may involve the improvement of antioxidant and anti-inflammatory status and inhibition on the activation of the NF-κB signaling. Hence, QC, a naturally occurring flavone with potent anti-psoriatic effects, has the potential for further development as a candidate for psoriasis treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Decursinol angelate blocks transmigration and inflammatory activation of cancer cells through inhibition of PI3K, ERK and NF-kappaB activation.

PubMed

Kim, Won-Jung; Lee, Min-Young; Kim, Jung-Hee; Suk, Kyoungho; Lee, Won-Ha

2010-10-01

Inflammation is known to be closely associated with the development of cancer. Decursinol angelate (DA), a coumarin compound isolated from Angelica gigas and related compounds have been shown to possess potent anti-inflammatory activities. However, little is known about their effects on the inflammatory processes associated with cancer. In this study, the anti-inflammatory effect of DA was evaluated in cancer cell lines with respect to cellular invasion through the extracellular matrix (ECM) and the expression of pro-inflammatory mediators such as cytokine, cell adhesion molecules and matrix metalloproteinase (MMP)-9. DA inhibited the invasion of fibrosarcoma cell line, HT1080 and breast cancer cell line, MDA-MB-231 in the Matrigel invasion assay. DA-mediated suppression of cancer cell invasion was accomplished by suppression of PI3K activity known to be associated with cytoskeletal rearrangement related to cellular migration. DA also suppressed the adhesion of cancer cells to ECM mediated by down-regulation of beta(1)-integrin expression levels. Furthermore, DA inhibited the expression of pro-inflammatory cytokines and MMP-9 through suppression of PI3K, ERK and NF-kappaB activation. These results demonstrate that DA suppresses invasion and inflammatory activation of cancer cells through modulation of PI3K/AKT, ERK and NF-kappaB. These anti-inflammatory activities of DA may contribute to its anti-cancer activity. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Flavocoxid, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, blunts pro-inflammatory phenotype activation in endotoxin-stimulated macrophages

PubMed Central

Altavilla, D; Squadrito, F; Bitto, A; Polito, F; Burnett, BP; Di Stefano, V; Minutoli, L

2009-01-01

Background and purpose: The flavonoids, baicalin and catechin, from Scutellaria baicalensis and Acacia catechu, respectively, have been used for various clinical applications. Flavocoxid is a mixed extract containing baicalin and catechin, and acts as a dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (LOX) enzymes. The anti-inflammatory activity, measured by protein and gene expression of inflammatory markers, of flavocoxid in rat peritoneal macrophages stimulated with Salmonella enteritidis lipopolysaccharide (LPS) was investigated. Experimental approach: LPS-stimulated (1 µg·mL−1) peritoneal rat macrophages were co-incubated with different concentrations of flavocoxid (32–128 µg·mL−1) or RPMI medium for different incubation times. Inducible COX-2, 5-LOX, inducible nitric oxide synthase (iNOS) and inhibitory protein κB-α (IκB-α) levels were evaluated by Western blot analysis. Nuclear factor κB (NF-κB) binding activity was investigated by electrophoretic mobility shift assay. Tumour necrosis factor-α (TNF-α) gene and protein expression were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay respectively. Finally, malondialdehyde (MDA) and nitrite levels in macrophage supernatants were evaluated. Key results: LPS stimulation induced a pro-inflammatory phenotype in rat peritoneal macrophages. Flavocoxid (128 µg·mL−1) significantly inhibited COX-2 (LPS = 18 ± 2.1; flavocoxid = 3.8 ± 0.9 integrated intensity), 5-LOX (LPS = 20 ± 3.8; flavocoxid = 3.1 ± 0.8 integrated intensity) and iNOS expression (LPS = 15 ± 1.1; flavocoxid = 4.1 ± 0.4 integrated intensity), but did not modify COX-1 expression. PGE2 and LTB4 levels in culture supernatants were consequently decreased. Flavocoxid also prevented the loss of IκB-α protein (LPS = 1.9 ± 0.2; flavocoxid = 7.2 ± 1.6 integrated intensity), blunted increased NF-κB binding activity (LPS = 9.2 ± 2; flavocoxid = 2.4 ± 0.7 integrated intensity) and the

Functional Analysis of Human NF1 in Drosophila

DTIC Science & Technology

2008-12-01

also have learning problem. Such learning phenotypes have been recapitulated in animal models, including in mouse and Drosophila mutants. This proposal...by examining the phenotypes of mutated human genes expressed in Drosophila NF1 null mutants. We also propose that Gsα/NF1 activated AC pathway...in both Drosophila and mouse NF1 models. Our previous work has shown that defective cAMP signaling leads to the learning phenotype in Drosophila Nf1

Development of a Carbon Sequestration Visualization Tool using Google Earth Pro

NASA Astrophysics Data System (ADS)

Keating, G. N.; Greene, M. K.

2008-12-01

The Big Sky Carbon Sequestration Partnership seeks to prepare organizations throughout the western United States for a possible carbon-constrained economy. Through the development of CO2 capture and subsurface sequestration technology, the Partnership is working to enable the region to cleanly utilize its abundant fossil energy resources. The intent of the Los Alamos National Laboratory Big Sky Visualization tool is to allow geochemists, geologists, geophysicists, project managers, and other project members to view, identify, and query the data collected from CO2 injection tests using a single data source platform, a mission to which Google Earth Pro is uniquely and ideally suited . The visualization framework enables fusion of data from disparate sources and allows investigators to fully explore spatial and temporal trends in CO2 fate and transport within a reservoir. 3-D subsurface wells are projected above ground in Google Earth as the KML anchor points for the presentation of various surface subsurface data. This solution is the most integrative and cost-effective possible for the variety of users in the Big Sky community.

NF-κB as a target for oncogenic viruses

PubMed Central

Sun, Shao-Cong; Cesarman, Ethel

2013-01-01

NF-κB is a pivotal transcription factor that controls cell survival and proliferation in diverse physiological processes. The activity of NF-κB is tightly controlled through its cytoplasmic sequestration by specific inhibitors, IκBs. Various cellular stimuli induce the activation of an IκB kinase (IKK), which phosphorylates IκBs and triggers their proteasomal degradation, causing nuclear translocation of activated NF-κB. Under normal conditions, the activation of NF-κB occurs transiently, thus ensuring rapid but temporary induction of target genes. Deregulated NF-κB activation contributes to the development of various diseases, including cancers and immunological disorders. Accumulated studies demonstrate that the NF-κB signaling pathway is a target of several human oncogenic viruses, including the human T-cell leukemia virus type 1 (HTLV1), the Kaposi sarcoma-associated herpesvirus (KSHV), and the Epstein bar virus (EBV). These viruses encode specific oncoproteins that target different signaling components of the NF-κB pathway, leading to persistent activation of NF-κB. This chapter will discuss the molecular mechanisms by which NF-κB is activated by the viral oncoproteins. PMID:20845110

Optimization of Shipboard Manning Levels Using Imprint Pro Forces Module

DTIC Science & Technology

2015-09-01

NPS-OR-15-008 NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA OPTIMIZATION OF SHIPBOARD MANNING LEVELS USING IMPRINT PRO...Optimization of Shipboard Manning Levels Using IMPRINT Pro Forces Module 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER...ABSTRACT The Improved Performance Research Integration Tool ( IMPRINT ) is a dynamic, stochastic, discrete-event modeling tool used to develop a model

Blockade of nuclear factor-κB (NF-κB) pathway inhibits growth and induces apoptosis in chemoresistant ovarian carcinoma cells.

PubMed

Momeny, Majid; Yousefi, Hassan; Eyvani, Haniyeh; Moghaddaskho, Farima; Salehi, Ali; Esmaeili, Fatemeh; Alishahi, Zivar; Barghi, Farinaz; Vaezijoze, Somaye; Shamsaiegahkani, Sahar; Zarrinrad, Ghazaleh; Sankanian, Ghazaleh; Sabourinejad, Zahra; Hamzehlou, Sepideh; Bashash, Davood; Aboutorabi, Elaheh S; Ghaffari, Parisa; Dehpour, Ahmad R; Tavangar, Seyyed M; Tavakkoly-Bazzaz, Javad; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

2018-06-01

Epithelial ovarian cancer (EOC) has exhibited marginal improvement in survival rate, despite advances in surgical debulking and chemotherapy regimens. Although the majority of EOC patients achieve a clinical remission after induction therapy, over 80% relapse and succumb to chemoresistant disease. In this regard, it is of paramount importance to elucidate molecular mechanisms and signaling pathways which promote therapy resistance in EOC in order to devise novel and more effective treatment strategies. In this study, we showed that activation of nuclear factor-κB (NF-κB) is significantly higher in therapy-resistant EOC cells compared to chemosensitive counterparts, which was positively associated with resistance to cisplatin, carboplatin, paclitaxel and erlotinib. Bay 11-7082, a highly selective NF-κB inhibitor, reduced cell proliferation, clonogenicity and anoikis resistance in the therapy-resistant EOC cells and induced apoptotic cell death. Moreover, Bay 11-7082 decreased the expression of pro-survival, inflammatory and metastatic genes and synergistically increased anti-proliferative efficacy of cisplatin, carboplatin, paclitaxel and erlotinib. Altogether, these findings suggest that NF-κB is an attractive therapeutic target in EOC to be exploited in translational oncology and Bay 11-7082 is a potential anti-cancer drug to overcome chemoresistance and inhibit proliferation of the EOC cells. Copyright © 2018 Elsevier Ltd. All rights reserved.

HPV16 induces a wasting syndrome in transgenic mice: Amelioration by dietary polyphenols via NF-κB inhibition.

PubMed

Gil da Costa, Rui M; Aragão, Sofia; Moutinho, Magda; Alvarado, Antonieta; Carmo, Diogo; Casaca, Fátima; Silva, Sandra; Ribeiro, Joana; Sousa, Hugo; Ferreira, Rita; Nogueira-Ferreira, Rita; Pires, Maria João; Colaço, Bruno; Medeiros, Rui; Venâncio, Carlos; Oliveira, Maria Manuel; Bastos, Margarida M S M; Lopes, Carlos; Oliveira, Paula A

2017-01-15

Cancer patients often show a wasting syndrome for which there are little therapeutic options. Dietary polyphenols have been proposed for treating this syndrome, but their usefulness in cases associated with human papillomavirus (HPV)-induced cancers is unknown. We characterized HPV16-transgenic mice as a model of cancer cachexia and tested the efficacy of long-term oral supplementation with polyphenols curcumin and rutin. Both compounds were orally administered to six weeks-old HPV16-transgenic mice showing characteristic multi-step skin carcinogenesis, for 24weeks. Skin lesions and blood, liver and spleen inflammatory changes were characterized histologically and hematologically. Hepatic oxidative stress, skeletal muscle mass and the levels of muscle pro-inflammatory transcription factor NF-κB were also assessed. Skin carcinogenesis was associated with progressive, severe, systemic inflammation (leukocytosis, hepatitis, splenitis), significant mortality and cachexia. Curcumin and rutin totally suppressed mortality while reducing white blood cells and the incidence of splenitis and hepatitis. Rutin prevented muscle wasting more effectively than curcumin. Preservation of muscle mass and reduced hepatic inflammation were associated with down-regulation of the NF-κB canonical pathway and with reduced oxidative stress, respectively. These results point out HPV16-transgenic mice as a useful model for studying the wasting syndrome associated with HPV-induced cancers. Dietary NF-κB inhibitors may be useful resources for treating this syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Mn porphyrin-based SOD mimic, MnTnHex-2-PyP(5+), and non-SOD mimic, MnTBAP(3-), suppressed rat spinal cord ischemia/reperfusion injury via NF-κB pathways.

PubMed

Celic, T; Španjol, J; Bobinac, M; Tovmasyan, A; Vukelic, I; Reboucas, J S; Batinic-Haberle, I; Bobinac, D

2014-12-01

Herein we have demonstrated that both superoxide dismutase (SOD) mimic, cationic Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP(5+)), and non-SOD mimic, anionic Mn(III) meso-tetrakis(4-carboxylatophenyl)porphyrin (MnTBAP(3-)), protect against oxidative stress caused by spinal cord ischemia/reperfusion via suppression of nuclear factor kappa B (NF-κB) pro-inflammatory pathways. Earlier reports showed that Mn(III) N-alkylpyridylporphyrins were able to prevent the DNA binding of NF-κB in an aqueous system, whereas MnTBAP(3-) was not. Here, for the first time, in a complex in vivo system-animal model of spinal cord injury-a similar impact of MnTBAP(3-), at a dose identical to that of MnTnHex-2-PyP(5+), was demonstrated in NF-κB downregulation. Rats were treated subcutaneously at 1.5 mg/kg starting at 30 min before ischemia/reperfusion, and then every 12 h afterward for either 48 h or 7 days. The anti-inflammatory effects of both Mn porphyrins (MnPs) were demonstrated in the spinal cord tissue at both 48 h and 7 days. The downregulation of NF-κB, a major pro-inflammatory signaling protein regulating astrocyte activation, was detected and found to correlate well with the suppression of astrogliosis (as glial fibrillary acidic protein) by both MnPs. The markers of oxidative stress, lipid peroxidation and protein carbonyl formation, were significantly reduced by MnPs. The favorable impact of both MnPs on motor neurons (Tarlov score and inclined plane test) was assessed. No major changes in glutathione peroxidase- and SOD-like activities were demonstrated, which implies that none of the MnPs acted as SOD mimic. Increasing amount of data on the reactivity of MnTBAP(3-) with reactive nitrogen species (RNS) (.NO/HNO/ONOO(-)) suggests that RNS/MnTBAP(3-)-driven modification of NF-κB protein cysteines may be involved in its therapeutic effects. This differs from the therapeutic efficacy of MnTnHex-2-PyP(5+) which presumably occurs via reactive

An ethyl acetate fraction derived from Houttuynia cordata extract inhibits the production of inflammatory markers by suppressing NF-кB and MAPK activation in lipopolysaccharide-stimulated RAW 264.7 macrophages

PubMed Central

2014-01-01

Background Houttuynia cordata Thunb. (Saururaceae) has been used in traditional medicine for treatment of inflammatory diseases. This study evaluated the anti-inflammatory effects of an ethyl acetate fraction derived from a Houttuynia cordata extract (HCE-EA) on the production of inflammatory mediators and the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Methods To measure the effects of HCE-EA on pro-inflammatory cytokine and inflammatory mediator’s expression in RAW 264.7 cells, we used the following methods: cell viability assay, Griess reagent assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting analysis. Results HCE-EA downregulated nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin (IL-6) production in the cells, as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Furthermore, HCE-EA suppressed nuclear translocation of the NF-κB p65 subunit, which correlated with an inhibitory effect on IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation. HCE-EA also attenuated the activation of MAPKs (p38 and JNK). Conclusions Our results suggest that the anti-inflammatory properties of HCE-EA may stem from the inhibition of pro-inflammatory mediators via suppression of NF-κB and MAPK signaling pathways. PMID:25012519

Collaborative Teaching and Learning through Multi-Institutional Integrated Group Projects

ERIC Educational Resources Information Center

Long, Suzanna K.; Carlo, Héctor J.

2013-01-01

This teaching brief describes an innovative multi-institutional initiative through which integrated student groups from different courses collaborate on a common course project. In this integrated group project, students are asked to design a decentralized manufacturing organization for a company that will manufacture industrial Proton-Exchange…

Metabolic Networks Integrative Cardiac Health Project (ICHP) - Center of Excellence

DTIC Science & Technology

2016-04-01

2.6; P = 0.001) among all variables, as the most significant predictor of abnormal CIMT, thus increasing risk for CVD. Conclusions: The Integrative ...1 Award Number: W81XWH-11-2-0227 TITLE: "Metabolic Networks Integrative Cardiac Health Project (ICHP) - Center of Excellence." PRINCIPAL...April 2016 2. REPORT TYPE ANNUAL 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE "Metabolic Networks Integrative Cardiac Health Project (ICHP

The neurofibromatoses. Part 2: NF2 and schwannomatosis.

PubMed

Lu-Emerson, Christine; Plotkin, Scott R

2009-01-01

The neurofibromatoses, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, comprise a group of genetically distinct disorders of the nervous system that are unified by the predisposition to nerve sheath tumors. All 3 types of NF have tumor manifestations (consistent with tumor-suppressor status) and nontumor manifestations. In the second part of this 2-part series, the manifestations of NF2 and schwannomatosis are reviewed. NF2 is characterized by bilateral vestibular schwannomas, meningiomas, ependymomas, cataracts, and epiretinal membranes. The combination of complete hearing loss from vestibular schwannomas and blindness from bifacial weakness is a devastating potential outcome of NF2. Schwannomatosis is characterized by multiple nonvestibular, nonintradermal schwannomas and chronic pain. Recently, germline alterations in the SMARCB1/INI1 gene have been implicated in both familial and sporadic forms of this disorder. Neurologists play an important role in the diagnosis and management of the neurofibromatoses.

LincRNA-Gm4419 knockdown ameliorates NF-κB/NLRP3 inflammasome-mediated inflammation in diabetic nephropathy.

PubMed

Yi, Hong; Peng, Rui; Zhang, Lu-Yu; Sun, Yan; Peng, Hui-Min; Liu, Han-Deng; Yu, Li-Juan; Li, Ai-Ling; Zhang, Ya-Juan; Jiang, Wen-Hao; Zhang, Zheng

2017-02-02

Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. Recent researches have shown the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome are associated with inflammation in the progression of DN, but the exact mechanism is unclear. Long noncoding RNAs (lncRNAs) have roles in the development of many diseases including DN. However, the relationship between lncRNAs and inflammation in DN remains largely unknown. Our previous study has revealed that 14 lncRNAs are abnormally expressed in DN by RNA sequencing and real-time quantitative PCR (qRT-PCR) in the renal tissues of db/db DN mice. In this study, these lncRNAs were verified their expressions by qRT-PCR in mesangial cells (MCs) cultured under high- and low-glucose conditions. Twelve lncRNAs displayed the same expressional tendencies in both renal tissues and MCs. In particular, long intergenic noncoding RNA (lincRNA)-Gm4419 was the only one associating with NF-κB among these 12 lncRNAs by bioinformatics methods. Moreover, Gm4419 knockdown could obviously inhibit the expressions of pro-inflammatory cytokines and renal fibrosis biomarkers, and reduce cell proliferation in MCs under high-glucose condition, whereas overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in MCs under low-glucose condition. Interestingly, our results showed that Gm4419 could activate the NF-κB pathway by directly interacting with p50, the subunit of NF-κB. In addition, we found that p50 could interact with NLRP3 inflammasome in MCs. In conclusion, our findings suggest lincRNA-Gm4419 may participate in the inflammation, fibrosis and proliferation in MCs under high-glucose condition through NF-κB/NLRP3 inflammasome signaling pathway, and may provide new insights into the regulation of Gm4419 during the progression of DN.

CTF Meeting 2012: Translation of the Basic Understanding of the Biology and Genetics of NF1, NF2, and Schwannomatosis Toward the Development of Effective Therapies

PubMed Central

Widemann, Brigitte C.; Acosta, Maria T.; Ammoun, Sylvia; Belzberg, Allan J.; Bernards, Andre; Blakeley, Jaishri; Bretscher, Antony; Cichowski, Karen; Clapp, D. Wade; Dombi, Eva; Evans, Gareth D.; Ferner, Rosalie; Fernandez-Valle, Cristina; Fisher, Michael J.; Giovannini, Marco; Gutmann, David H.; Hanemann, C. Oliver; Hennigan, Robert; Huson, Susan; Ingram, David; Kissil, Joe; Korf, Bruce R.; Legius, Eric; Packer, Roger J.; McClatchey, Andrea I; McCormick, Frank; North, Kathryn; Pehrsson, Minja; Plotkin, Scott R.; Ramesh, Vijaya; Ratner, Nancy; Schirmer, Susann; Sherman, Larry; Schorry, Elizabeth; Stevenson, David; Stewart, Douglas R.; Ullrich, Nicole; Bakker, Annette C.; Morrison, Helen

2014-01-01

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a “state-of-the-field” for NF research in 2012. PMID:24443315

CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies.

PubMed

Widemann, Brigitte C; Acosta, Maria T; Ammoun, Sylvia; Belzberg, Allan J; Bernards, Andre; Blakeley, Jaishri; Bretscher, Antony; Cichowski, Karen; Clapp, D Wade; Dombi, Eva; Evans, Gareth D; Ferner, Rosalie; Fernandez-Valle, Cristina; Fisher, Michael J; Giovannini, Marco; Gutmann, David H; Hanemann, C Oliver; Hennigan, Robert; Huson, Susan; Ingram, David; Kissil, Joe; Korf, Bruce R; Legius, Eric; Packer, Roger J; McClatchey, Andrea I; McCormick, Frank; North, Kathryn; Pehrsson, Minja; Plotkin, Scott R; Ramesh, Vijaya; Ratner, Nancy; Schirmer, Susann; Sherman, Larry; Schorry, Elizabeth; Stevenson, David; Stewart, Douglas R; Ullrich, Nicole; Bakker, Annette C; Morrison, Helen

2014-03-01

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012. © 2014 Wiley Periodicals, Inc.

Manduca sexta proprophenoloxidase activating proteinase-3 (PAP3) stimulates melanization by activating proPAP3, proSPHs, and proPOs

PubMed Central

Wang, Yang; Lu, Zhiqiang; Jiang, Haobo

2014-01-01

Melanization participates in various insect physiological processes including antimicrobial immune responses. Phenoloxidase (PO), a critical component of the enzyme system catalyzing melanin formation, is produced as an inactive precursor prophenoloxidase (proPO) and becomes active via specific proteolytic cleavage by proPO activating proteinase (PAP). In Manduca sexta, three PAPs can activate proPOs in the presence of two serine proteinase homologs (SPH1 and SPH2). While the hemolymph proteinases (HPs) that generate the active PAPs are known, it is unclear how the proSPHs (especially proSPH1) are activated. In this study, we isolated from plasma of bar-stage M. sexta larvae an Ile-Glu-Ala-Arg-p-nitroanilide hydrolyzing enzyme that cleaved the proSPHs. This proteinase, PAP3, generated active SPH1 and SPH2, which function as cofactors for PAP3 in proPO activation. Cleavage of the purified recombinant proSPHs by PAP3 yielded 38 kDa bands similar in mobility to the SPHs formed in vivo. Surprisingly, PAP3 also can activate proPAP3 to stimulate melanization in a direct positive feedback loop. The enhanced proPO activation concurred with the cleavage activation of proHP6, proHP8, proPAP1, proPAP3, proSPH1, proSPH2, proPOs, but not proHP14 or proHP21. These results indicate that PAP3, like PAP1, is a key factor of the self-reinforcing mechanism in the proPO activation system, which is linked to other immune responses in M. sexta. PMID:24768974

Multiscale, Converging Defects of Macro-Porosity, Microstructure and Matrix Mineralization Impact Long Bone Fragility in NF1

PubMed Central

Kühnisch, Jirko; Seto, Jong; Lange, Claudia; Schrof, Susanne; Stumpp, Sabine; Kobus, Karolina; Grohmann, Julia; Kossler, Nadine; Varga, Peter; Osswald, Monika; Emmerich, Denise; Tinschert, Sigrid; Thielemann, Falk; Duda, Georg; Seifert, Wenke; el Khassawna, Thaqif; Stevenson, David A.; Elefteriou, Florent; Kornak, Uwe; Raum, Kay; Fratzl, Peter; Mundlos, Stefan; Kolanczyk, Mateusz

2014-01-01

Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions. PMID:24465906

Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB pathway.

PubMed

Jiang, Kang-Feng; Zhao, Gan; Deng, Gan-Zhen; Wu, Hai-Chong; Yin, Nan-Nan; Chen, Xiu-Ying; Qiu, Chang-Wei; Peng, Xiu-Li

2017-02-01

Recent studies show that Polydatin (PD) extracted from the roots of Polygonum cuspidatum Sieb, a widely used traditional Chinese remedies, possesses anti-inflammatory activity in several experimental models. In this study, we investigated the anti-inflammatory effects of PD on Staphylococcus aureus-induced mastitis in mice and elucidated the potential mechanisms. In mice with S aureus-induced mastitis, administration of PD (15, 30, 45 mg/kg, ip) or dexamethasone (Dex, 5 mg/kg, ip) significantly suppressed the infiltration of inflammatory cells, ameliorated the mammary structural damage, and inhibited the activity of myeloperoxidase, a biomarker of neutrophils accumulation. Furthermore, PD treatment dose-dependently decreased the levels of TNF-α, IL-1β, IL-6 and IL-8 in the mammary gland tissues. PD treatment also dose-dependently decreased the expression of TLR2, MyD88, IRAK1, IRAK4 and TRAF6 as well as the phosphorylation of TAK1, MKK3/6, p38 MAPK, IκB-α and NF-κB in the mammary gland tissues. In mouse mammary epithelial cells (mMECs) infected by S aureus in vitro, pretreatment with PD dose-dependently suppressed the upregulated pro-inflammatory cytokines and signaling proteins, and the nuclear translocation of NF-κB p65 and AP-1. A TLR2-neutralizing antibody mimicked PD in its suppression on S aureus-induced upregulation of MyD88, p-p38 and p-p65 levels in mMECs. PD (50, 100 μg/mL) affected neither the growth of S aureus in vitro, nor the viability of mMECs. In conclusion, PD does not exhibit antibacterial activity against S aureus, its therapeutic effects in mouse S aureus-induced mastitis depend on its ability to down-regulate pro-inflammatory cytokine levels via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB signaling pathway.

The CHPRC Groundwater and Technical Integration Support (Master Project) Quality Assurance Management Plan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fix, N. J.

The scope of the CH2M Hill Plateau Remediation Company, LLC (CHPRC) Groundwater and Technical Integration Support (Master Project) is for Pacific Northwest National Laboratory staff to provide technical and integration support to CHPRC. This work includes conducting investigations at the 300-FF-5 Operable Unit and other groundwater operable units, and providing strategic integration, technical integration and assessments, remediation decision support, and science and technology. The projects under this Master Project will be defined and included within the Master Project throughout the fiscal year, and will be incorporated into the Master Project Plan. This Quality Assurance Management Plan provides the quality assurancemore » requirements and processes that will be followed by the CHPRC Groundwater and Technical Integration Support (Master Project) and all releases associated with the CHPRC Soil and Groundwater Remediation Project. The plan is designed to be used exclusively by project staff.« less

Increased Resting Intracellular Calcium Modulates NF-κB-dependent Inducible Nitric-oxide Synthase Gene Expression in Dystrophic mdx Skeletal Myotubes*

PubMed Central

Altamirano, Francisco; López, Jose R.; Henríquez, Carlos; Molinski, Tadeusz; Allen, Paul D.; Jaimovich, Enrique

2012-01-01

Duchenne muscular dystrophy (DMD) is a genetic disorder caused by dystrophin mutations, characterized by chronic inflammation and severe muscle wasting. Dystrophic muscles exhibit activated immune cell infiltrates, up-regulated inflammatory gene expression, and increased NF-κB activity, but the contribution of the skeletal muscle cell to this process has been unclear. The aim of this work was to study the pathways that contribute to the increased resting calcium ([Ca2+]rest) observed in mdx myotubes and its possible link with up-regulation of NF-κB and pro-inflammatory gene expression in dystrophic muscle cells. [Ca2+]rest was higher in mdx than in WT myotubes (308 ± 6 versus 113 ± 2 nm, p < 0.001). In mdx myotubes, both the inhibition of Ca2+ entry (low Ca2+ solution, Ca2+-free solution, and Gd3+) and blockade of either ryanodine receptors or inositol 1,4,5-trisphosphate receptors reduced [Ca2+]rest. Basal activity of NF-κB was significantly up-regulated in mdx versus WT myotubes. There was an increased transcriptional activity and p65 nuclear localization, which could be reversed when [Ca2+]rest was reduced. Levels of mRNA for TNFα, IL-1β, and IL-6 were similar in WT and mdx myotubes, whereas inducible nitric-oxide synthase (iNOS) expression was increased 5-fold. Reducing [Ca2+]rest using different strategies reduced iNOS gene expression presumably as a result of decreased activation of NF-κB. We propose that NF-κB, modulated by increased [Ca2+]rest, is constitutively active in mdx myotubes, and this mechanism can account for iNOS overexpression and the increase in reactive nitrogen species that promote damage in dystrophic skeletal muscle cells. PMID:22549782

Lycopene Inhibits NF-kB-Mediated IL-8 Expression and Changes Redox and PPARγ Signalling in Cigarette Smoke–Stimulated Macrophages

PubMed Central

Simone, Rossella E.; Russo, Marco; Catalano, Assunta; Monego, Giovanni; Froehlich, Kati; Boehm, Volker; Palozza, Paola

2011-01-01

Increasing evidence suggests that lycopene, the major carotenoid present in tomato, may be preventive against smoke-induced cell damage. However, the mechanisms of such a prevention are still unclear. The aim of this study was to investigate the role of lycopene on the production of the pro-inflammatory cytokine IL-8 induced by cigarette smoke and the possible mechanisms implicated. Therefore, human THP-1 macrophages were exposed to cigarette smoke extract (CSE), alone and following a 6-h pre-treatment with lycopene (0.5–2 µM). CSE enhanced IL-8 production in a time- and a dose-dependent manner. Lycopene pre-treatment resulted in a significant inhibition of CSE-induced IL-8 expression at both mRNA and protein levels. NF-kB controlled the transcription of IL-8 induced by CSE, since PDTC prevented such a production. Lycopene suppressed CSE-induced NF-kB DNA binding, NF-kB/p65 nuclear translocation and phosphorylation of IKKα and IkBα. Such an inhibition was accompanied by a decrease in CSE-induced ROS production and NOX-4 expression. Lycopene further inhibited CSE-induced phosphorylation of the redox-sensitive ERK1/2, JNK and p38 MAPKs. Moreover, the carotenoid increased PPARγ levels which, in turn, enhanced PTEN expression and decreased pAKT levels in CSE-exposed cells. Such effects were abolished by the PPARγ inhibitor GW9662. Taken together, our data indicate that lycopene prevented CSE-induced IL-8 production through a mechanism involving an inactivation of NF-kB. NF-kB inactivation was accompanied by an inhibition of redox signalling and an activation of PPARγ signalling. The ability of lycopene in inhibiting IL-8 production, NF-kB/p65 nuclear translocation, and redox signalling and in increasing PPARγ expression was also found in isolated rat alveolar macrophages exposed to CSE. These findings provide novel data on new molecular mechanisms by which lycopene regulates cigarette smoke-driven inflammation in human macrophages. PMID:21625550

A successful integrated project.

PubMed

Zheng, P

1994-10-01

The experiences of the Juxian County Family Planning Committee of Shandong Province, China, were discussed in terms of the integration of family planning with income generation activities in rural areas. The integrated program was initiated in 1988 with pilot programs established by the Qiaoshan Family Planning Association to develop marketable skills in carpet weaving and grass braiding in Xiazhuang Town and Qiaoshan Township. The program gave priority of admission to women with only children and those who practiced family planning. 1400 women were recruited in these factories. Other income generation programs were developed for silkworm breeding and silk reeling, woolen embroidery, and printing. High ranking officials of the China Family Planning Association commended the work in income generation and family planning in Juxian County. This recognition spurred the second phase of development by the county family planning association: the establishment of village operated factories and mills for native products. By the end of 1991, there were 26 such projects in the county and per capita income to women increased by RMB 678 yuan. In the third stage of 1992, the number of association enterprises increased to 196 with recruitment of over 18,000 reproductive age women. The programs were initiated with collective funds from farmers and villages. The 170 projects in 1992 were developed with an investment of 9.6 million yuan, of which 2.26 million yuan was from individuals (23.5%). Emphasis was placed on self-reliance and recruitment of women with one child, women with 2 daughters and tubal ligations, and family planning motivators. The consequences of the integrated program were weakening traditional customs of marriage and childbearing, improvement in socioeconomic status of women, and effective service delivery of family planning and maternal and child health care services.

Tubular Epithelial NF-κB Activity Regulates Ischemic AKI

PubMed Central

Vigolo, Emilia; Hinze, Christian; Park, Joon-Keun; Roël, Giulietta; Balogh, András; Choi, Mira; Wübken, Anne; Cording, Jimmi; Blasig, Ingolf E.; Luft, Friedrich C.; Scheidereit, Claus; Schmidt-Ott, Kai M.; Schmidt-Ullrich, Ruth; Müller, Dominik N.

2016-01-01

NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type–specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)–induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed that IRI induced widespread NF-κB activation in renal tubular epithelia and in interstitial cells that peaked 2–3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBαΔN in renal proximal, distal, and collecting duct epithelial cells. Compared with control mice, these mice exhibited improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore, tubular NF-κB–dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBαΔN-expressing mice and exposed to hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed lower levels of chemokines than cells from control mice did. Our results indicate that postischemic NF-κB activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response. PMID:26823548

Branches of the NF-κB signaling pathway regulate proliferation of oval cells in rat liver regeneration.

PubMed

Zhao, W M; Qin, Y L; Niu, Z P; Chang, C F; Yang, J; Li, M H; Zhou, Y; Xu, C S

2016-03-24

The NF-kB (nuclear factor kB) pathway is involved in the proliferation of many cell types. To explore the mechanism of the NF-kB signaling pathway underlying the oval cell proliferation during rat liver regeneration, the Rat Genome 230 2.0 Array was used to detect expression changes of NF-kB signaling pathway-related genes in oval cells. The results revealed that the expression levels of many genes in the NF-kB pathway were significantly changed. This included 48 known genes and 16 homologous genes, as well as 370 genes and 85 homologous genes related to cell proliferation. To further understand the biological significance of these changes, an expression profile function was used to analyze the potential biological processes. The results showed that the NF-kB pathway promoted oval cell proliferation mainly through three signaling branches; the tumor necrosis factor alpha branch (TNF-a pathway), the growth factor branch, and the chemokine branch. An integrated statistics method was used to define the key genes in the NF-kB pathway. Seven genes were identified to play vital roles in the NF-kB pathway. To confirm these results, the protein content, including two key genes (TNF and FGF11) and two non-key genes (CCL2 and TNFRSF12A), were analyzed using two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrometry. The results were generally consistent with those of the array data. To conclude, three branches and seven key genes were involved in the NF-kB signaling pathway that regulates oval cell proliferation during rat liver regeneration.

The integrated project: a promising promotional strategy for primary health care.

PubMed

Daniel, C; Mora, B

1985-10-01

The integrated project using parasite control and nutrition as entry points for family planning practice has shown considerable success in promoting health consciousness among health workers and project beneficiaries. This progress is evident in the Family Planning, Parasite Control and Nutrition (FAPPCAN) areas. The project has also mobilized technical and financial support from the local government as well as from private and civic organizations. The need for integration is underscored by the following considerations: parasite control has proved to be effective for preventive health care; the integrated project uses indigenous community health workers to accomplish its objectives; the primary health care (PHC) movement depends primarily on voluntary community participation and the integrated project has shown that it can elicit this participation. The major health problems in the Philippines are: a prevalence of communicable and other infectious diseases; poor evironmental sanitation; malnutrition; and a rapid population growth rate. The integrated program utilizes the existing village health workers in identifying problems related to family planning, parasite control and nutrition and integrates these activities into the health delivery system; educates family members on how to detect health and health-related problems; works out linkages with government agencies and the local primary health care committee in defining the scope of health-related problems; mobilizes community members to initiate their own projects; gets the commitment of village officials and committe members. The integrated project operates within the PHC. A health van with a built-in video playback system provides educational and logistical support to the village worker. The primary detection and treatment of health problems are part of the village health workers' responsibilities. Research determines the project's capability to reactivate the village primary health care committees and sustain

Collaborative project-based learning: an integrative science and technological education project

NASA Astrophysics Data System (ADS)

Baser, Derya; Ozden, M. Yasar; Karaarslan, Hasan

2017-04-01

Background: Blending collaborative learning and project-based learning (PBL) based on Wolff (2003) design categories, students interacted in a learning environment where they developed their technology integration practices as well as their technological and collaborative skills.

Hydroquinone stimulates inflammatory functions in microvascular endothelial cells via NF-κB nuclear activation.

PubMed

Hebeda, Cristina Bichels; Pinedo, Fernanda Júdice; Vinolo, Marco Aurélio Ramirez; Curi, Rui; Farsky, Sandra Helena Poliselli

2011-11-01

Hydroquinone impairs several leucocyte cell functions, which alter the immune response. Although endothelial cell functions are important for the development of immune responses, hydroquinone actions on endothelial cell have not been shown. Therefore, the effect of hydroquinone exposure (10 or 100 μM for 2 hr) on primary culture of microvascular endothelial cells (PMECs) obtained from the cremaster muscle of Wistar rats incubated in the presence or absence of lipopolysaccharide (LPS, 2 μg/mL) was investigated. Hydroquinone treatment induced the membrane expression of cell adhesion molecules (CAMs) from the immunoglobulin superfamilies ICAM-1 (intercellular), VCAM-1(vascular) and PECAM-1 (platelet endothelial) and induced the secretion of cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α). The effects were dependent on transcriptional modifications because enhanced CAM mRNA expression as well as both cytokines and nuclear factor κB (NF-κB) nuclear activation was found. These effects may be due to the direct action of hydroquinone rather than its quinone metabolites, because endothelial cells do not present myeloperoxidase enzyme and hydroquinone incubation did not induce the expression of cytochrome P450 2E1 (CYP2E1) or prostaglandin H synthase 1. In addition, the incubation of endothelial cells with benzoquinone (10 μM, 2 hr) impaired PECAM-1 expression and did not modify NF-κB nuclear activation. Taken together, the data herein presented reveal that hydroquinone evokes pro-inflammatory properties in endothelial cells that are triggered by the enhancement of NF-κB nuclear translocation-dependent gene transcription. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

NF-κB and the link between inflammation and cancer.

PubMed

DiDonato, Joseph A; Mercurio, Frank; Karin, Michael

2012-03-01

The nuclear factor-κB (NF-κB) transcription factor family has been considered the central mediator of the inflammatory process and a key participant in innate and adaptive immune responses. Coincident with the molecular cloning of NF-κB/RelA and identification of its kinship to the v-Rel oncogene, it was anticipated that NF-κB itself would be involved in cancer development. Oncogenic activating mutations in NF-κB genes are rare and have been identified only in some lymphoid malignancies, while most NF-κB activating mutations in lymphoid malignancies occur in upstream signaling components that feed into NF-κB. NF-κB activation is also prevalent in carcinomas, in which NF-κB activation is mainly driven by inflammatory cytokines within the tumor microenvironment. Importantly, however, in all malignancies, NF-κB acts in a cell type-specific manner: activating survival genes within cancer cells and inflammation-promoting genes in components of the tumor microenvironment. Yet, the complex biological functions of NF-κB have made its therapeutic targeting a challenge. © 2012 John Wiley & Sons A/S.

Flat Plate Solar Array Project: Proceedings of the 20th Project Integration Meeting

NASA Technical Reports Server (NTRS)

Mcdonald, R. R.

1982-01-01

Progress made by the Flat-Plate Solar Array Project during the period November 1981 to April 1982 is reported. Project analysis and integration, technology research in silicon material, large-area silicon sheet and environmental isolation, cell and module formation, engineering sciences, and module performance and failure analysis are covered.

Inhibition of the NF-κB pathway as a candidate therapeutic strategy for cryopyrin-associated periodic syndrome.

PubMed

Shimogaki, Satoka; Ito, Sayaka; Komatsu, Sachiyo; Koike, Ryuji; Miyasaka, Nobuyuki; Umezawa, Kazuo; Kubota, Tetsuo

2014-05-01

Cryopyrin-associated periodic syndrome (CAPS) is caused by unrestricted IL-1β release due to mutation of the gene coding NLRP3. This study aimed to clarify whether NLRP3-related IL-1β release is dependent on the NF-κB pathway. Peripheral blood mononuclear cells (PBMCs) from healthy subjects or patients with Muckle-Wells syndrome were primed with LPS and subsequently stimulated by ATP. Human umbilical vein endothelial cells (HUVECs) were cultured with the supernatant obtained from LPS-plus ATP-stimulated PBMCs. Expression of proinflammatory molecules was estimated using RT-PCR, ELISA or immunochemical staining, in the presence or absence of an NF-κB inhibitor (-)-dehydroxymethylepoxyquinomicin (DHMEQ). DHMEQ inhibited expression of proIL-1β and NLRP3 by normal PBMCs primed with LPS, resulting in inhibition of caspase-1 activation and IL-1β secretion by the cells after subsequent stimulation with ATP. DHMEQ also inhibited expression of IL-1β, TNFα, IL-6 and VCAM-1 by HUVECs. Patient cells released IL-1β spontaneously or by ATP-stimulation even without LPS-priming. Both the spontaneous and stimulated IL-1β releases were inhibited by DHMEQ without affecting viability of the cells. These results clearly indicate that IL-1β production through the NLRP3 inflammasome is dependent on the NF-κB pathway, which could be a good target for the development of a novel therapeutic strategy for CAPS.

Protective activity of salidroside against ethanol-induced gastric ulcer via the MAPK/NF-κB pathway in vivo and in vitro.

PubMed

Chang, Xiayun; Luo, Fen; Jiang, Wenjiao; Zhu, Lingpeng; Gao, Jin; He, He; Wei, Tingting; Gong, Shilin; Yan, Tianhua

2015-09-01

Salidroside (Sal) is a traditional Chinese medicine with various pharmacological effects. The present study aimed to investigate the protective effect of Sal on ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage. 0.2 ml ethanol and 400 μM H2O2 were applied to establish a gastric ulcer model in vivo and in vitro respectively. The production of interleukin (IL)-6, interleukin (IL)-1β and tumor necrosis factor (TNF)-α was analyzed, as well as myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD). MTT assay was used to detect cell viability. In addition, MAPK/NF-κB signal pathway-related proteins p-ERK, p-JNK, p-p38, p-IκBα and p-NF-κBp65 were analyzed to determine the underlying protective mechanism. Downstream genes such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and leukotrienes B4 (LTB4) were also measured. Obtained data indicated that Sal inhibited the overproduction of pro-inflammatory cytokines and enhanced antioxidant activity. Collectively, it is assumed that Sal could alleviate ethanol-induced acute gastric ulcer and H2O2-induced gastric epithelial cell damage through the MAPK/NF-κB pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verhaak, Roel GW; Hoadley, Katherine A; Purdom, Elizabeth

The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefitmore » in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.« less

Selective Fluorination and Separation of Metals with NF3 for Mass Spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clark, Richard A.; Barinaga, Charles J.; McNamara, Bruce K.

2016-03-01

We report recent progress on the development of a new methodology based on the generation of volatile metal fluorides through the use of nitrogen trifluoride (NF3), and the separation and measurement of these metal fluorides by electron ionization mass spectrometry. Though unreactive under ambient conditions, NF3 reacts selectively at specified temperatures with various metal-containing species to form volatile metal fluorides. Utilizing these species-dependent traits, elements of a sample may be sequentially produced and thus separated on-line. Metals were reacted inside a thermogravimetric analyzer, the gas outlet of which was directly coupled to a quadrupole mass spectrometer with an electron impactmore » ionization source via a molecular leak valve. We present results of this project including the electron ionization mass spectrum of gaseous tellurium hexafluoride.« less

Proteomic Analyses of NF1-Interacting Proteins in Keratinocytes

DTIC Science & Technology

2015-04-01

and knockout mice further confirmed the interactions suggested by the proteomic analyses. In relation to the development of psoriasis -like symptoms...in the NF1 null epidermis, we analyzed NF1 expression in a mouse model of psoriasis (imiquimod-induced psoriasis -like skin inflammation) and...knockout of epidermal NF1 to elucidate the molecular underpinnings of psoriasis . 15. SUBJECT TERMS neurofibromin-1 (NF1), psoriasis , inflammation

Effects of Pro-Gly-Pro tripeptide on the dopamine system.

PubMed

Meshavkin, V K; Batishcheva, E Yu; Kost, N V; Sokolov, O Yu; Trufanova, A V; Samonina, G E

2011-08-01

Tripeptide Pro-Gly-Pro interacted with dopamine receptors in vitro and reduced behavioral manifestations of apomorphine-induced hyperfunction of the dopamine system in verticalization, stereotypy, and yawning tests. Presumably, the behavioral effects of Pro-Gly-Pro tripeptide were mediated through post- and presynaptic D(2)and D(3)receptors.

Effects of decoy molecules targeting NF-kappaB transcription factors in Cystic fibrosis IB3–1 cells

PubMed Central

Finotti, Alessia; Borgatti, Monica; Bezzerri, Valentino; Nicolis, Elena; Lampronti, Ilaria; Dechecchi, Maria; Mancini, Irene; Cabrini, Giulio; Saviano, Michele; Avitabile, Concetta; Romanelli, Alessandra; Gambari, Roberto

2012-01-01

One of the clinical features of cystic fibrosis (CF) is a deep inflammatory process, which is characterized by production and release of cytokines and chemokines, among which interleukin 8 (IL-8) represents one of the most important. Accordingly, there is a growing interest in developing therapies against CF to reduce the excessive inflammatory response in the airways of CF patients. Since transcription factor NF-kappaB plays a critical role in IL-8 expression, the transcription factor decoy (TFD) strategy might be of interest. In order to demonstrate that TFD against NF-kappaB interferes with the NF-kappaB pathway we proved, by chromatin immunoprecipitation (ChIP) that treatment with TFD oligodeoxyribonucleotides of cystic fibrosis IB3–1 cells infected with Pseudomonas aeruginosa leads to a decrease occupancy of the Il-8 gene promoter by NF-kappaB factors. In order to develop more stable therapeutic molecules, peptide nucleic acids (PNAs) based agents were considered. In this respect PNA-DNA-PNA (PDP) chimeras are molecules of great interest from several points of view: (1) they can be complexed with liposomes and microspheres; (2) they are resistant to DNases, serum and cytoplasmic extracts; (3) they are potent decoy molecules. By using electrophoretic mobility shift assay and RT-PCR analysis we have demonstrated that (1) the effects of PDP/PDP NF-kappaB decoy chimera on accumulation of pro-inflammatory mRNAs in P.aeruginosa infected IB3–1 cells reproduce that of decoy oligonucleotides; in particular (2) the PDP/PDP chimera is a strong inhibitor of IL-8 gene expression; (3) the effect of PDP/PDP chimeras, unlike those of ODN-based decoys, are observed even in the absence of protection with lipofectamine. These informations are of great impact, in our opinion, for the development of stable molecules to be used in non-viral gene therapy of cystic fibrosis. PMID:22772035

Proceedings of the 24th Project Integration Meeting

NASA Technical Reports Server (NTRS)

Tustin, D.

1984-01-01

Progress made by the Flat-Plate Solar Array Project is described. Reports on silicon sheet growth and characterization, silicon material, process development, high-efficiency cells, environmental isolation, engineering sciences, and reliability physics are presented along with copies of visual presentations made at the 24th Project Integration Meeting.

Enhancing Knowledge Integration: An Information System Capstone Project

ERIC Educational Resources Information Center

Steiger, David M.

2009-01-01

This database project focuses on learning through knowledge integration; i.e., sharing and applying specialized (database) knowledge within a group, and combining it with other business knowledge to create new knowledge. Specifically, the Tiny Tots, Inc. project described below requires students to design, build, and instantiate a database system…

Improving DOE Project Performance Using the DOD Integrated Master Plan - 12481

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alleman, Glen B.; Nosbisch, Michael R.

2012-07-01

DOE O 413 measures a project's progress to plan by the consumption of funding, the passage of time, and the meeting of milestones. In March of 2003, then Under Secretary, Energy, Science, Card received a memo directing the implementation of Project Management and the Project Management Manual, including the Integrated Master Plan and Integrated Master Schedule. This directive states 'the integrated master plan and schedule tie together all project tasks by showing their logical relationships and any constraints controlling the start or finish of each task. This process results in a hierarchy of related functional and layered schedules derived frommore » the Work Breakdown Structure that can be used for monitoring and controlling project progress'. This paper shows how restoring the IMP/IMS paradigm to DOE program management increases the probability of program success in ways not currently available using DOD O 413 processes alone. Using DOE O 413 series guidance, adding the Integrated Master Plan and Integrated Master Schedule paradigm would provide a hierarchical set of performance measures for each 'package of work,' that provides measurable visibility to the increasing maturity of the project. This measurable maturity provides the mechanism to forecast future performance of cost, schedule, and technical outcomes in ways not available using just the activities in DOE O 413. With this information project managers have another tool available to address the issues identified in GAO-07-336 and GAO-09-406. (authors)« less

Identification and characterization of NF-YB family genes in tung tree.

PubMed

Yang, Susu; Wang, Yangdong; Yin, Hengfu; Guo, Haobo; Gao, Ming; Zhu, Huiping; Chen, Yicun

2015-12-01

The NF-YB transcription factor gene family encodes a subunit of the CCAAT box-binding factor (CBF), a highly conserved trimeric activator that strongly binds to the CCAAT box promoter element. Studies on model plants have shown that NF-YB proteins participate in important developmental and physiological processes, but little is known about NF-YB proteins in trees. Here, we identified seven NF-YB transcription factor-encoding genes in Vernicia fordii, an important oilseed tree in China. A phylogenetic analysis separated the genes into two groups; non-LEC1 type (VfNF-YB1, 5, 7, 9, 11, 13) and LEC1-type (VfNF-YB 14). A gene structure analysis showed that VfNF-YB 5 has three introns and the other genes have no introns. The seven VfNF-YB sequences contain highly conserved domains, a disordered region at the N terminus, and two long helix structures at the C terminus. Phylogenetic analyses showed that VfNF-YB family genes are highly homologous to GmNF-YB genes, and many of them are closely related to functionally characterized NF-YBs. In expression analyses of various tissues (root, stem, leaf, and kernel) and the root during pathogen infection, VfNF-YB1, 5, and 11 were dominantly expressed in kernels, and VfNF-YB7 and 9 were expressed only in the root. Different VfNF-YB family genes showed different responses to pathogen infection, suggesting that they play different roles in the pathogen response. Together, these findings represent the first extensive evaluation of the NF-YB family in tung tree and provide a foundation for dissecting the functions of VfNF-YB genes in seed development, stress adaption, fatty acid synthesis, and pathogen response.

ANKRD1 modulates inflammatory responses in C2C12 myoblasts through feedback inhibition of NF-κB signaling activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xin-Hua; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Bauman, William A.

2015-08-14

Transcription factors of the nuclear factor-kappa B (NF-κB) family play a pivotal role in inflammation, immunity and cell survival responses. Recent studies revealed that NF-κB also regulates the processes of muscle atrophy. NF-κB activity is regulated by various factors, including ankyrin repeat domain 2 (AnkrD2), which belongs to the muscle ankyrin repeat protein family. Another member of this family, AnkrD1 is also a transcriptional effector. The expression levels of AnkrD1 are highly upregulated in denervated skeletal muscle, suggesting an involvement of AnkrD1 in NF-κB mediated cellular responses to paralysis. However, the molecular mechanism underlying the interactive role of AnkrD1 inmore » NF-κB mediated cellular responses is not well understood. In the current study, we examined the effect of AnkrD1 on NF-κB activity and determined the interactions between AnkrD1 expression and NF-κB signaling induced by TNFα in differentiating C2C12 myoblasts. TNFα upregulated AnkrD1 mRNA and protein levels. AnkrD1-siRNA significantly increased TNFα-induced transcriptional activation of NF-κB, whereas overexpression of AnkrD1 inhibited TNFα-induced NF-κB activity. Co-immunoprecipitation studies demonstrated that AnkrD1 was able to bind p50 subunit of NF-κB and vice versa. Finally, CHIP assays revealed that AnkrD1 bound chromatin at a NF-κB binding site in the AnrkD2 promoter and required NF-κB to do so. These results provide evidence of signaling integration between AnkrD1 and NF-κB pathways, and suggest a novel anti-inflammatory role of AnkrD1 through feedback inhibition of NF-κB transcriptional activity by which AnkrD1 modulates the balance between physiological and pathological inflammatory responses in skeletal muscle. - Highlights: • AnkrD1 is upregulated by TNFα and represses NF-κB-induced transcriptional activity. • AnkrD1 binds to p50 subunit of NF-κB and is recruited to NF-κB bound to chromatin. • AnkrD1 mediates a feed

Genomic organization of the neurofibromatosis 1 gene (NF1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Y.; O`Connell, P.; Huntsman Breidenbach, H.

Neurofibromatosis 1 maps to chromosome band 17q11.2, and the NF1 locus has been partially characterized. Even though the full-length NF1 cDNA has been sequenced, the complete genomic structure of the NF1 gene has not been elucidated. The 5{prime} end of NF1 is embedded in a CpG island containing a NotI restriction site, and the remainder of the gene lies in the adjacent 350-kb NotI fragment. In our efforts to develop a comprehensive screen for NF1 mutations, we have isolated genomic DNA clones that together harbor the entire NF1 cDNA sequence. We have identified all intron-exon boundaries of the coding regionmore » and established that it is composed of 59 exons. Furthermore, we have defined the 3{prime}-untranslated region (3{prime}-UTR) of the NF1 gene; it spans approximately 3.5 kb of genomic DNA sequence and is continuous with the stop codon. Oligonucleotide primer pairs synthesized from exon-flanking DNA sequences were used in the polymerase chain reaction with cloned, chromosome 17-specific genomic DNA as template to amplify NF1 exons 1 through 27b and the exon containing the 3{prime}-UTR separately. This information should be useful for implementing a comprehensive NF1 mutation screen using genomic DNA as template. 41 refs., 3 figs., 2 tabs.« less

NREL's EVI-Pro Lite Tool Paves the Way for Future Electric Vehicle

Science.gov Websites

Electric Vehicle Infrastructure Planning NREL's EVI-Pro Lite Tool Paves the Way for Future Electric Vehicle electric vehicle charging station To assist state and local governments anticipating this type of growth in simplified version of the Electric Vehicle Infrastructure Projection Tool (EVI-Pro) model. Combining a sleek

Cell-Specific Imd-NF-κB Responses Enable Simultaneous Antibacterial Immunity and Intestinal Epithelial Cell Shedding upon Bacterial Infection.

PubMed

Zhai, Zongzhao; Boquete, Jean-Philippe; Lemaitre, Bruno

2018-05-03

Intestinal infection triggers potent immune responses to combat pathogens and concomitantly drives epithelial renewal to maintain barrier integrity. Current models propose that epithelial renewal is primarily driven by damage caused by reactive oxygen species (ROS). Here we found that in Drosophila, the Imd-NF-κB pathway controlled enterocyte (EC) shedding upon infection, via a mechanism independent of ROS-associated apoptosis. Mechanistically, the Imd pathway synergized with JNK signaling to induce epithelial cell shedding specifically in the context of bacterial infection, requiring also the reduced expression of the transcription factor GATAe. Furthermore, cell-specific NF-κB responses enabled simultaneous production of antimicrobial peptides (AMPs) and epithelial shedding in different EC populations. Thus, the Imd-NF-κB pathway is central to the intestinal antibacterial response by mediating both AMP production and the maintenance of barrier integrity. Considering the similarities between Drosophila Imd signaling and mammalian TNFR pathway, our findings suggest the existence of an evolutionarily conserved genetic program in immunity-induced epithelial shedding. Copyright © 2018 Elsevier Inc. All rights reserved.

Steroid Hormones in NF1 Tumorigenesis

DTIC Science & Technology

2005-08-01

Schwannomatosis , in Aspen in June this year. Table 3. Summary of current xenograft proliferation/TUNEL (apoptosis) data. Culture I sex I Outlier? I PI/Al I...Biology of NF1, NF2, and schwannomatosis . Aspen, CO, June 2005, poster. CONCLUSIONS: In vitro data indicate that steroid hormone receptor levels in normal

Impact of Chronic Stress on the Spatial Learning and GR-PKAc-NF-κB Signaling in the Hippocampus and Cortex in Rats Following Cholinergic Depletion.

PubMed

Lee, Sun-Young; Cho, Woo-Hyun; Lee, Yo-Seob; Han, Jung-Soo

2018-05-01

Studies have shown that the removal of the cholinergic innervation to the hippocampus induces dysfunction of the hypothalamic-pituitary-adrenocortical axis and decreases the number of glucocorticoid receptors (GRs). Subsequent studies have revealed that the loss of cholinergic input to the hippocampus reduces the expression of GRs and activates nuclear factor-kappa B (NF-κB) signaling through interactions with the cytoplasmic catalytic subunit of protein kinase A (PKAc). We examined the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex. Male Sprague-Dawley rats received 192 IgG-saporin injections to selectively eliminate cholinergic neurons in their basal forebrain. Two weeks later, rats were subjected to 1 h of restraint stress per day for 14 days. Rats subjected to both chronic stress and cholinergic depletion showed more severe memory impairments compared to those that received either treatment alone. The reduction in nuclear GR levels induced by cholinergic depletion was unaffected by chronic stress. The activation of NF-κB signaling in the hippocampus and the cerebral cortex induced by cholinergic depletion was augmented by chronic stress, resulting in the increased expression of pro-inflammatory markers, such as inducible nitric oxide synthase and cyclooxygenase-2. The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer's disease to stress since activation of NF-κB is associated with stress.

NF90–NF45 is a selective RNA chaperone that rearranges viral and cellular riboswitches: biochemical analysis of a virus host factor activity

PubMed Central

Friedrich, Susann; Golbik, Ralph Peter

2017-01-01

Abstract The heterodimer NF90–NF45 is an RNA-binding protein complex that modulates the expression of various cellular mRNAs on the post-transcriptional level. Furthermore, it acts as a host factor that supports the replication of several RNA viruses. The molecular mechanisms underlying these activities have yet to be elucidated. Recently, we showed that the RNA-binding capabilities and binding specificity of NF90 considerably improves when it forms a complex with NF45. Here, we demonstrate that NF90 has a substrate-selective RNA chaperone activity (RCA) involving RNA annealing and strand displacement activities. The mechanism of the NF90-catalyzed RNA annealing was elucidated to comprise a combination of ‘matchmaking’ and compensation of repulsive charges, which finally results in the population of dsRNA products. Heterodimer formation with NF45 enhances ‘matchmaking’ of complementary ssRNAs and substantially increases the efficiency of NF90’s RCA. During investigations of the relevance of the NF90–NF45 RCA, the complex was shown to stimulate the first step in the RNA replication process of hepatitis C virus (HCV) in vitro and to stabilize a regulatory element within the mRNA of vascular endothelial growth factor (VEGF) by protein-guided changes of the RNAs’ structures. Thus, our study reveals how the intrinsic properties of an RNA-binding protein determine its biological activities. PMID:29040738

Pleiotropic Effects of Blastocystis spp. Subtypes 4 and 7 on Ligand-Specific Toll-Like Receptor Signaling and NF-κB Activation in a Human Monocyte Cell Line

PubMed Central

Teo, Joshua D. W.; MacAry, Paul A.; Tan, Kevin S. W.

2014-01-01

Blastocystis spp. is a common enteric stramenopile parasite that colonizes the colon of hosts of a diverse array of species, including humans. It has been shown to compromise intestinal epithelial cell barrier integrity and mediate the production of pro-inflammatory cytokines and chemokines. Mucosal epithelial surfaces, including the intestinal epithelium, are increasingly recognized to perform a vital surveillance role in the context of innate immunity, through the expression of pathogen recognition receptors, such as Toll-like receptors (TLRs). In this study, we use the human TLR reporter monocytic cell line, THP1-Blue, which expresses all human TLRs, to investigate effects of Blastocystis on TLR activation, more specifically the activation of TLR-2, -4 and -5. We have observed that live Blastocystis spp. parasites and whole cell lysate (WCL) alone do not activate TLRs in THP1-Blue. Live ST4-WR1 parasites inhibited LPS-mediated NF-κB activation in THP1-Blue. In contrast, ST7-B WCL and ST4-WR1 WCL induced pleiotropic modulation of ligand-specific TLR-2 and TLR-4 activation, with no significant effects on flagellin-mediated TLR-5 activation. Real time-qPCR analysis on SEAP reporter gene confirmed the augmenting effect of ST7-B on LPS-mediated NF-κB activation in THP1-Blue. Taken together, this is the first study to characterize interactions between Blastocystis spp. and host TLR activation using an in vitro reporter model. PMID:24551212

Flavonoids from sea buckthorn inhibit the lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages through the MAPK and NF-κB pathways.

PubMed

Jiang, Fan; Guan, Haining; Liu, Danyi; Wu, Xi; Fan, Mingcheng; Han, Jianchun

2017-03-22

Sea buckthorn has long been used as a functional food to regulate cholesterol, relieve angina, and diminish inflammation. Flavonoids are one of the main active components in sea buckthorn. We investigated the effects of sea buckthorn flavonoid (SF) treatment on two pathways that mediate inflammation, the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, to explore the anti-inflammatory activity of SFs in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The LPS-induced over-production of nitric oxide (NO) and prostaglandin E2 (PGE 2 ) was inhibited by SFs through a mechanism related to the modulatory effects of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes. Additionally, SFs downregulated the production and mRNA expression of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β. Moreover, SFs inhibited the phosphorylation of the p38 and stress-activated protein kinase/jun amino-terminal kinase (SAPK/JNK) MAPK pathways, and they reduced the nuclear translocation of NF-κB to prevent its activation by blocking the phosphorylation and degradation of inhibitor protein of NF-κB α (IκB-α). Based on these findings, SFs may exert their inhibitory effects on inflammation by regulating the release of inflammatory mediators through the MAPK and NF-κB pathways. SFs highlight the potential benefits of using functional foods with anti-inflammatory actions to combat inflammatory diseases.

Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

PubMed Central

Urbano, Paulo César Martins; Soccol, Vanete Thomaz; Azevedo, Valderilio Feijó

2014-01-01

Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α) raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products). This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation. PMID:25114503

Low-cost solar array project and Proceedings of the 15th Project Integration Meeting

NASA Technical Reports Server (NTRS)

1980-01-01

Progress made by the Low-Cost Solar Array Project during the period December 1979 to April 1980 is described. Project analysis and integration, technology development in silicon material, large area silicon sheet and encapsulation, production process and equipment development, engineering, and operation are included.

Special Project Examination in Integrated Science - Ordinary Level.

ERIC Educational Resources Information Center

Wimpenny, David

A science achievement test for the General Certificate of Education (GCE, England) was developed for students enrolled in the curriculum of the Schools Council Integrated Science Project. This document contains discussions of the testing program and a copy of the 1973 test. After an overview of the curriculum project and issues related to…

Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties

PubMed Central

Olivera, Anlys; Moore, Terry W.; Hu, Fang; Brown, Andrew P.; Sun, Aiming; Liotta, Dennis C.; Snyder, James P.; Yoon, Younghyoun; Shim, Hyunsuk; Marcus, Adam I.; Miller, Andrew H.; Pace, Thaddeus W. W.

2012-01-01

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogues with enhanced activity on the NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound termed 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analogue whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1–100µM) or vehicle (DMSO 1%) for 1 hour. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1µg/mL). EF31 (IC50 ~5µM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC50~35µM) and curcumin (IC50 >50µM). In addition, EF31 exhibited significantly greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB activity, EF31 (IC50~1.92µM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC50~131µM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analogue for further therapeutic development. PMID:22197802

Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties.

PubMed

Olivera, Anlys; Moore, Terry W; Hu, Fang; Brown, Andrew P; Sun, Aiming; Liotta, Dennis C; Snyder, James P; Yoon, Younghyoun; Shim, Hyunsuk; Marcus, Adam I; Miller, Andrew H; Pace, Thaddeus W W

2012-02-01

Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1-100 μM) or vehicle (DMSO 1%) for 1h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC(50)~5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC(50)~35 μM) and curcumin (IC(50) >50 μM). In addition, EF31 exhibited greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB, EF31 (IC(50)~1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC(50)~131 μM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development. Copyright © 2011 Elsevier B.V. All rights reserved.

Vaccinium bracteatum Thunb. Exerts Anti-Inflammatory Activity by Inhibiting NF-κB Activation in BV-2 Microglial Cells

PubMed Central

Kwon, Seung-Hwan; Ma, Shi-Xun; Ko, Yong-Hyun; Seo, Jee-Yeon; Lee, Bo-Ram; Lee, Taek Hwan; Kim, Sun Yeou; Lee, Seok-Yong; Jang, Choon-Gon

2016-01-01

This study was designed to evaluate the pharmacological effects of Vaccinium bracteatum Thunb. methanol extract (VBME) on microglial activation and to identify the underlying mechanisms of action of these effects. The anti-inflammatory properties of VBME were studied using lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We measured the production of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase (COX)-2, prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) as inflammatory parameters. We also examined the effect of VBME on intracellular reactive oxygen species (ROS) production and the activity of nuclear factor-kappa B p65 (NF-κB p65). VBME significantly inhibited LPS-induced production of NO and PGE2 and LPS-mediated upregulation of iNOS and COX-2 expression in a dose-dependent manner; importantly, VBME was not cytotoxic. VBME also significantly reduced the generation of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. In addition, VBME significantly dampened intracellular ROS production and suppressed NF-κB p65 translocation by blocking IκB-α phosphorylation and degradation in LPS-stimulated BV2 cells. Our findings indicate that VBME inhibits the production of inflammatory mediators in BV-2 microglial cells by suppressing NF-κB signaling. Thus, VBME may be useful in the treatment of neurodegenerative diseases due to its ability to inhibit inflammatory mediator production in activated BV-2 microglial cells. PMID:27169820

Vaccinium bracteatum Thunb. Exerts Anti-Inflammatory Activity by Inhibiting NF-κB Activation in BV-2 Microglial Cells.

PubMed

Kwon, Seung-Hwan; Ma, Shi-Xun; Ko, Yong-Hyun; Seo, Jee-Yeon; Lee, Bo-Ram; Lee, Taek Hwan; Kim, Sun Yeou; Lee, Seok-Yong; Jang, Choon-Gon

2016-09-01

This study was designed to evaluate the pharmacological effects of Vaccinium bracteatum Thunb. methanol extract (VBME) on microglial activation and to identify the underlying mechanisms of action of these effects. The anti-inflammatory properties of VBME were studied using lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We measured the production of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase (COX)-2, prostaglandin E₂ (PGE₂), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) as inflammatory parameters. We also examined the effect of VBME on intracellular reactive oxygen species (ROS) production and the activity of nuclear factor-kappa B p65 (NF-κB p65). VBME significantly inhibited LPS-induced production of NO and PGE2 and LPS-mediated upregulation of iNOS and COX-2 expression in a dose-dependent manner; importantly, VBME was not cytotoxic. VBME also significantly reduced the generation of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. In addition, VBME significantly dampened intracellular ROS production and suppressed NF-κB p65 translocation by blocking IκB-α phosphorylation and degradation in LPS-stimulated BV2 cells. Our findings indicate that VBME inhibits the production of inflammatory mediators in BV-2 microglial cells by suppressing NF-κB signaling. Thus, VBME may be useful in the treatment of neurodegenerative diseases due to its ability to inhibit inflammatory mediator production in activated BV-2 microglial cells.

Alternative Fuels Data Center: Electric Vehicle Infrastructure Projection

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Expression of NF-kappaB and IkappaB proteins in skeletal muscle of gastric cancer patients

PubMed Central

Rhoads, Mary G.; Kandarian, Susan C.; Pacelli, Fabio; Doglietto, Giovan Battista; Bossola, Maurizio

2011-01-01

The mechanisms eliciting cancer cachexia are not well understood. Wasting of skeletal muscle is problematic because it is responsible for the clinical deterioration in cancer patients and the ability to tolerate cancer treatment. Animal studies suggest that nuclear factor of kappa B (NF-κB) signaling is important in the progression of muscle wasting due to several types of tumors. However, there are no published studies in humans on a role for NF-κB in cancer cachexia. In this project we studied the rectus abdominis muscle from patients with gastric tumors (n=14) and age matched control subjects (n=10) for markers of NF-κB activation. Nuclear levels of p65, p50, and Bcl-3 were the same in both groups of subjects. However, phospho-p65 was elevated by 25% in muscles of cancer patients. In addition, expression of the inhibitor of kappa B alpha (IκBα), was decreased by 25% in cancer patients. Decreased expression of IκBα reflects its degradation by one of the IκBα kinases and is a marker of NF-κB activation. Interestingly, there was no correlation between the stage of cancer and the extent of IκBα decrease, nor was there a correlation between the degree of cachexia and decreased IκBα levels. This suggests that the activation of NF-κB is an early and sustained event in gastric cancer. The work implicates the NF-κB signaling in the initiation and progression of cancer cachexia in humans and demonstrates the need for additional study of this pathway; it also recommends NF-κB signaling as a therapeutic target for the amelioration of cachexia as has been suggested from rodent studies. PMID:19857958

Developing integrated parametric planning models for budgeting and managing complex projects

NASA Technical Reports Server (NTRS)

Etnyre, Vance A.; Black, Ken U.

1988-01-01

The applicability of integrated parametric models for the budgeting and management of complex projects is investigated. Methods for building a very flexible, interactive prototype for a project planning system, and software resources available for this purpose, are discussed and evaluated. The prototype is required to be sensitive to changing objectives, changing target dates, changing costs relationships, and changing budget constraints. To achieve the integration of costs and project and task durations, parametric cost functions are defined by a process of trapezoidal segmentation, where the total cost for the project is the sum of the various project cost segments, and each project cost segment is the integral of a linearly segmented cost loading function over a specific interval. The cost can thus be expressed algebraically. The prototype was designed using Lotus-123 as the primary software tool. This prototype implements a methodology for interactive project scheduling that provides a model of a system that meets most of the goals for the first phase of the study and some of the goals for the second phase.

Genome-wide characterization and expression analysis of citrus NUCLEAR FACTOR-Y (NF-Y) transcription factors identified a novel NF-YA gene involved in drought-stress response and tolerance.

PubMed

Pereira, Suzam L S; Martins, Cristina P S; Sousa, Aurizangela O; Camillo, Luciana R; Araújo, Caroline P; Alcantara, Grazielle M; Camargo, Danielle S; Cidade, Luciana C; de Almeida, Alex-Alan F; Costa, Marcio G C

2018-01-01

Nuclear factor Y (NF-Y) is a ubiquitous transcription factor found in eukaryotes. It is composed of three distinct subunits called NF-YA, NF-YB and NF-YC. NF-Ys have been identified as key regulators of multiple pathways in the control of development and tolerance to biotic and abiotic factors. The present study aimed to identify and characterize the complete repertoire of genes coding for NF-Y in citrus, as well as to perform the functional characterization of one of its members, namely CsNFYA5, in transgenic tobacco plants. A total of 22 genes coding for NF-Y were identified in the genomes of sweet orange (Citrus sinensis) and Clementine mandarin (C. clementina), including six CsNF-YAs, 11 CsNF-YBs and five CsNF-YCs. Phylogenetic analyses showed that there is a NF-Y orthologous in the Clementine genome for each sweet orange NF-Y gene; this was not observed when compared to Arabidopsis thaliana. CsNF-Y proteins shared the same conserved domains with their orthologous proteins in other organisms, including mouse. Analysis of gene expression by RNA-seq and EST data demonstrated that CsNF-Ys have a tissue-specific and stress inducible expression profile. qRT-PCR analysis revealed that CsNF-YA5 exhibits differential expression in response to water deficit in leaves and roots of citrus plants. Overexpression of CsNF-YA5 in transgenic tobacco plants contributed to the reduction of H2O2 production under dehydration conditions and increased plant growth and photosynthetic rate under normal conditions and drought stress. These biochemical and physiological responses to drought stress promoted by CsNF-YA5 may confer a productivity advantage in environments with frequent short-term soil water deficit.

Sirtuin 1 (Sirt1) Overexpression in BaF3 Cells Contributes to Cell Proliferation Promotion, Apoptosis Resistance and Pro-Inflammatory Cytokine Production.

PubMed

Wang, Qian; Yan, Chao; Xin, Miaomiao; Han, Li; Zhang, Yunqing; Sun, Mingshu

2017-03-27

BACKGROUND B lymphocyte hyperactivity is a main characteristic of systemic lupus erythematosus (SLE), and B lymphocytes play a prominent pathogenic role in the development and progression of SLE. The aim of this study was to investigate the role of Sirtuin 1 (Sirt1) in B lymphocytes. MATERIAL AND METHODS Mouse B lymphocytes BaF3 was transfected with Sirt1 vector or shRNA against Sirt1. Then the transfected cells viability and apoptosis were respectively determined by MTT assay and flow cytometry. In addition, the mRNA levels of three pro-inflammatory cytokines and p53 were detected by RT-PCR. Furthermore, the expression levels of nuclear factor-kappa B (NF-κB) pathway proteins were measured by Western blot. RESULTS Overexpression of Sirt1 significantly increased cell proliferation (p<0.05 or p<0.01) and significantly suppressed apoptosis (p<0.05). The mRNA level expressions of interleukin 1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) were significantly upregulated (p<0.05 or p<0.01), whereas p53 was significantly downregulated (p<0.05) by Sirt1 overexpression. In addition, the inhibitory subunit of NF-κB (IκBα) and p65 were significantly activated and phosphorylated (p<0.01 or p<0.001), and B-Cell CLL/Lymphoma 3 (Bcl-3) was significantly upregulated (p<0.05) by Sirt1 overexpression. CONCLUSIONS These results suggested that Sirt1 overexpression could promote BaF3 cell proliferation, inhibit apoptosis, and upregulate pro-inflammatory cytokines. The NF-κB pathway might be involved in these effects of Sirt1 on BaF3 cells, and Sirt1 might be a potential risk factor of SLE.

Electron transport parameters in NF3

NASA Astrophysics Data System (ADS)

Lisovskiy, V.; Yegorenkov, V.; Ogloblina, P.; Booth, J.-P.; Martins, S.; Landry, K.; Douai, D.; Cassagne, V.

2014-03-01

We present electron transport parameters (the first Townsend coefficient, the dissociative attachment coefficient, the fraction of electron energy lost by collisions with NF3 molecules, the average and characteristic electron energy, the electron mobility and the drift velocity) in NF3 gas calculated from published elastic and inelastic electron-NF3 collision cross-sections using the BOLSIG+ code. Calculations were performed for the combined RB (Rescigno 1995 Phys. Rev. E 52 329, Boesten et al 1996 J. Phys. B: At. Mol. Opt. Phys. 29 5475) momentum-transfer cross-section, as well as for the JB (Joucoski and Bettega 2002 J. Phys. B: At. Mol. Opt. Phys. 35 783) momentum-transfer cross-section. In addition, we have measured the radio frequency (rf) breakdown curves for various inter-electrode gaps and rfs, and from these we have determined the electron drift velocity in NF3 from the location of the turning point in these curves. These drift velocity values are in satisfactory agreement with those calculated by the BOLSIG+ code employing the JB momentum-transfer cross-section.

I-15 integrated corridor management system : project management plan.

DOT National Transportation Integrated Search

2011-06-01

The Project Management Plan (PMP) assists the San Diego ICM Team by defining a procedural framework for management and control of the I-15 Integrated Corridor Management Demonstration Project, and development and deployment of the ICM System. The PMP...

Collaborative Project-Based Learning: An Integrative Science and Technological Education Project

ERIC Educational Resources Information Center

Baser, Derya; Ozden, M. Yasar; Karaarslan, Hasan

2017-01-01

Background: Blending collaborative learning and project-based learning (PBL) based on Wolff (2003) design categories, students interacted in a learning environment where they developed their technology integration practices as well as their technological and collaborative skills. Purpose: The study aims to understand how seventh grade students…

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

PubMed

Koczkowska, Magdalena; Chen, Yunjia; Callens, Tom; Gomes, Alicia; Sharp, Angela; Johnson, Sherrell; Hsiao, Meng-Chang; Chen, Zhenbin; Balasubramanian, Meena; Barnett, Christopher P; Becker, Troy A; Ben-Shachar, Shay; Bertola, Debora R; Blakeley, Jaishri O; Burkitt-Wright, Emma M M; Callaway, Alison; Crenshaw, Melissa; Cunha, Karin S; Cunningham, Mitch; D'Agostino, Maria D; Dahan, Karin; De Luca, Alessandro; Destrée, Anne; Dhamija, Radhika; Eoli, Marica; Evans, D Gareth R; Galvin-Parton, Patricia; George-Abraham, Jaya K; Gripp, Karen W; Guevara-Campos, Jose; Hanchard, Neil A; Hernández-Chico, Concepcion; Immken, LaDonna; Janssens, Sandra; Jones, Kristi J; Keena, Beth A; Kochhar, Aaina; Liebelt, Jan; Martir-Negron, Arelis; Mahoney, Maurice J; Maystadt, Isabelle; McDougall, Carey; McEntagart, Meriel; Mendelsohn, Nancy; Miller, David T; Mortier, Geert; Morton, Jenny; Pappas, John; Plotkin, Scott R; Pond, Dinel; Rosenbaum, Kenneth; Rubin, Karol; Russell, Laura; Rutledge, Lane S; Saletti, Veronica; Schonberg, Rhonda; Schreiber, Allison; Seidel, Meredith; Siqveland, Elizabeth; Stockton, David W; Trevisson, Eva; Ullrich, Nicole J; Upadhyaya, Meena; van Minkelen, Rick; Verhelst, Helene; Wallace, Margaret R; Yap, Yoon-Sim; Zackai, Elaine; Zonana, Jonathan; Zurcher, Vickie; Claes, Kathleen; Martin, Yolanda; Korf, Bruce R; Legius, Eric; Messiaen, Ludwine M

2018-01-04

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of Embedded System Component Utilized in Delivery Integrated Design Project Course

NASA Astrophysics Data System (ADS)

Junid, Syed Abdul Mutalib Al; Hussaini, Yusnira; Nazmie Osman, Fairul; Razak, Abdul Hadi Abdul; Idros, Mohd Faizul Md; Karimi Halim, Abdul

2018-03-01

This paper reports the evaluation of the embedded system component utilized in delivering the integrated electronic engineering design project course. The evaluation is conducted based on the report project submitted as to fulfil the assessment criteria for the integrated electronic engineering design project course named; engineering system design. Six projects were assessed in this evaluation. The evaluation covers the type of controller, programming language and the number of embedded component utilization as well. From the evaluation, the C-programming based language is the best solution preferred by the students which provide them flexibility in the programming. Moreover, the Analog to Digital converter is intensively used in the projects which include sensors in their proposed design. As a conclusion, in delivering the integrated design project course, the knowledge over the embedded system solution is very important since the high density of the knowledge acquired in accomplishing the project assigned.

NF1 Signal Transduction and Vascular Dysfunction

DTIC Science & Technology

2014-05-01

presence of the Cad5:ERT allele, the Rosa26 LSL- tomato reporter, a floxed NF1 allele and the presence of a NF1 mutant (deletion) allele. Green arrows indicate mouse pups positive for all 4 selected alleles. 23

NF-kappa B activation correlates with disease phenotype in Crohn’s disease

PubMed Central

Han, Yoo Min; Koh, Jaemoon; Lee, Changhyun; Koh, Seong-Joon; Kim, ByeongGwan; Lee, Kook Lae; Im, Jong Pil; Kim, Joo Sung

2017-01-01

Background/Aims Unregulated activation of nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of Crohn’s disease. In this study, we investigated the clinical characteristics and disease outcome of Crohn’s disease patients with varying levels of the NF-κB activation. Methods Crohn’s disease patients who underwent surgical bowel resection were divided into two groups, based on the activation status of NF-κB. NF-κB activation was assessed by the immunoreactivity of nuclear NF-κB during immunohistochemical staining of bowel resection specimens. We compared the demographic, clinical and histologic characteristics between groups. Furthermore, the occurrence of reoperation, readmission, and medication change due to disease flare-up were investigated according to NF-κB activation status. Results Among 83 Crohn’s disease patients, 47 (56%) showed high NF-κB activity and 36 (44%) showed low NF-κB activity. Patients with high NF-κB activity had higher frequency of ileocolonic involvement (P = 0.028) and lower frequency of perianal involvement (P = 0.042) relative to those with low NF-κB activity. Total histologic scores were significantly higher in patients with high NF-κB activity than those with low NF-κB activity (P = 0.044). There was no significant difference in the frequency of reoperation, readmission, and medication change in relation to NF-κB activation status. Conclusions Crohn’s disease patients with high NF-κB activation showed specific clinical manifestations of higher frequency of ileocolonic involvement and lower frequency of perianal involvement relative to those with low NF-κB activation. High NF-κB activity was associated with higher histologic scores. However, the NF-κB activity did not affect the outcome and disease course after surgery. PMID:28753650

deepNF: Deep network fusion for protein function prediction.

PubMed

Gligorijevic, Vladimir; Barot, Meet; Bonneau, Richard

2018-06-01

The prevalence of high-throughput experimental methods has resulted in an abundance of large-scale molecular and functional interaction networks. The connectivity of these networks provides a rich source of information for inferring functional annotations for genes and proteins. An important challenge has been to develop methods for combining these heterogeneous networks to extract useful protein feature representations for function prediction. Most of the existing approaches for network integration use shallow models that encounter difficulty in capturing complex and highly-nonlinear network structures. Thus, we propose deepNF, a network fusion method based on Multimodal Deep Autoencoders to extract high-level features of proteins from multiple heterogeneous interaction networks. We apply this method to combine STRING networks to construct a common low-dimensional representation containing high-level protein features. We use separate layers for different network types in the early stages of the multimodal autoencoder, later connecting all the layers into a single bottleneck layer from which we extract features to predict protein function. We compare the cross-validation and temporal holdout predictive performance of our method with state-of-the-art methods, including the recently proposed method Mashup. Our results show that our method outperforms previous methods for both human and yeast STRING networks. We also show substantial improvement in the performance of our method in predicting GO terms of varying type and specificity. deepNF is freely available at: https://github.com/VGligorijevic/deepNF. vgligorijevic@flatironinstitute.org, rb133@nyu.edu. Supplementary data are available at Bioinformatics online.

Cryogenic system for BERLinPro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anders, W.; Hellwig, A.; Knobloch, J.

2014-01-29

In 2010 Helmholtz-Zentrum Berlin (HZB) received funding to design and build the Berlin Energy Recovery Linac Project BERLinPro. The goal of this compact Energy recovery linac (ERL) is to develop the accelerator physics and technology required to generate and accelerate a 100-mA, 1-mm mrad emittance electron beam. The BERLinPro know-how can then be transferred to various ERL-based applications. All accelerating RF cavities including the electron source are based on superconducting technology operated at 1.8 K. A Linde L700 helium liquefier is supplying 4.5 K helium. The subatmospheric pressure of 16 mbar of the helium bath of the cavities will bemore » achieved by pumping with a set of cold compressors and warm vacuum pumps. While the L700 is already in operating, the 1.8 K system and the helium transfer system are in design phase.« less

Integrating Engineering Data Systems for NASA Spaceflight Projects

NASA Technical Reports Server (NTRS)

Carvalho, Robert E.; Tollinger, Irene; Bell, David G.; Berrios, Daniel C.

2012-01-01

NASA has a large range of custom-built and commercial data systems to support spaceflight programs. Some of the systems are re-used by many programs and projects over time. Management and systems engineering processes require integration of data across many of these systems, a difficult problem given the widely diverse nature of system interfaces and data models. This paper describes an ongoing project to use a central data model with a web services architecture to support the integration and access of linked data across engineering functions for multiple NASA programs. The work involves the implementation of a web service-based middleware system called Data Aggregator to bring together data from a variety of systems to support space exploration. Data Aggregator includes a central data model registry for storing and managing links between the data in disparate systems. Initially developed for NASA's Constellation Program needs, Data Aggregator is currently being repurposed to support the International Space Station Program and new NASA projects with processes that involve significant aggregating and linking of data. This change in user needs led to development of a more streamlined data model registry for Data Aggregator in order to simplify adding new project application data as well as standardization of the Data Aggregator query syntax to facilitate cross-application querying by client applications. This paper documents the approach from a set of stand-alone engineering systems from which data are manually retrieved and integrated, to a web of engineering data systems from which the latest data are automatically retrieved and more quickly and accurately integrated. This paper includes the lessons learned through these efforts, including the design and development of a service-oriented architecture and the evolution of the data model registry approaches as the effort continues to evolve and adapt to support multiple NASA programs and priorities.

NF45 inhibits cardiomyocyte apoptosis following myocardial ischemia-reperfusion injury.

PubMed

Liu, Xiaojuan; Zhang, Chi; Qian, Long; Zhang, Chao; Wu, Kunpeng; Yang, Chen; Yan, Daliang; Wu, Xiang; Shi, Jiahai

2015-12-01

Cardiomyocyte apoptosis, which occurs during ischemia and reperfusion injury, can cause irreversible damage to cardiac function. There is accumulating evidence that nuclear factor 45 (NF45) and regulatory pathways are important in understanding reparative processes in the myocardium. NF45 is a multifunctional regulator of gene expression that participates in the regulation of DNA break repair. Recently, NF45 has been proved to be associated with tumor cell apoptosis in various human malignancies. However, the underlying mechanism of NF45 regulating myocardial ischemia-reperfusion (I/R) injury remains unclear. In this study, western blot showed that NF45 expression decreased after myocardial I/R in vivo. Double immunofluorescent staining revealed that NF45, located in the nucleus of cardiomyocyes, was correlated with cardiomyocyte apoptosis. Furthermore, NF45 expression decreased in H9c2 cells after hypoxia-reoxygenation (H/R) treatment in vitro, which was in line with the results in vivo. Overexpression of NF45 in H9c2 cells reduced cell apoptosis, as evidenced by increased Bcl-2 level, as well as decreased cleaved caspase-3, p53 and p21 expression. The expression of NF45 was reduced by LY294002 (a PI3K/Akt inhibitor), but not SB203580 (a p38 inhibitor), suggesting that NF45 prevented H/R-induced H9c2 cell apoptosis via PI3K/Akt pathway. Our data may supply a novel molecular target for acute myocardial infarction (AMI) therapy. Copyright © 2015 Elsevier GmbH. All rights reserved.

Aurantiamide acetate from baphicacanthus cusia root exhibits anti-inflammatory and anti-viral effects via inhibition of the NF-κB signaling pathway in Influenza A virus-infected cells.

PubMed

Zhou, Beixian; Yang, Zifeng; Feng, Qitong; Liang, Xiaoli; Li, Jing; Zanin, Mark; Jiang, Zhihong; Zhong, Nanshan

2017-03-06

Baphicacanthus cusia root also names "Nan Ban Lan Gen" has been traditionally used to prevent and treat influenza A virus infections. Here, we identified a peptide derivative, aurantiamide acetate (compound E17), as an active compound in extracts of B. cusia root. Although studies have shown that aurantiamide acetate possesses antioxidant and anti-inflammatory properties, the effects and mechanism by which it functions as an anti-viral or as an anti-inflammatory during influenza virus infection are poorly defined. Here we investigated the anti-viral activity and possible mechanism of compound E17 against influenza virus infection. The anti-viral activity of compound E17 against Influenza A virus (IAV) was determined using the cytopathic effect (CPE) inhibition assay. Viruses were titrated on Madin-Darby canine kidney (MDCK) cells by plaque assays. Ribonucleoprotein (RNP) luciferase reporter assay was further conducted to investigate the effect of compound E17 on the activity of the viral polymerase complex. HEK293T cells with a stably transfected NF-κB luciferase reporter plasmid were employed to examine the activity of compound E17 on NF-κB activation. Activation of the host signaling pathway induced by IAV infection in the absence or presence of compound E17 was assessed by western blotting. The effect of compound E17 on IAV-induced expression of pro-inflammatory cytokines was measured by real-time quantitative PCR and Luminex assays. Compound E17 exerted an inhibitory effect on IAV replication in MDCK cells but had no effect on avian IAV and influenza B virus. Treatment with compound E17 resulted in a reduction of RNP activity and virus titers. Compound E17 treatment inhibited the transcriptional activity of NF-κB in a NF-κB luciferase reporter stable HEK293 cell after stimulation with TNF-α. Furthermore, compound E17 blocked the activation of the NF-κB signaling pathway and decreased mRNA expression levels of pro-inflammatory genes in infected cells

The Role of NF1 in Memory Retrieval

DTIC Science & Technology

2014-09-01

ABSTRACT This
three‐year
grant
supports
our
efforts
in
studying
a
role
of
the
 neurofibromatosis 
type
 1
(NF1)
gene
in
mediating
retrieval
of
long‐term...year extension. The proposed research investigates involvement of neurofibromatosis type 1 gene-encoded neurofibromin (NF1) in retrieval of long...mutations of this gene lead to the most common monogenic disorder, neurofibromatosis type 1. The critical role of NF1 in learning and memory has been

Lactobacillus johnsonii HY7042 ameliorates Gardnerella vaginalis-induced vaginosis by killing Gardnerella vaginalis and inhibiting NF-κB activation.

PubMed

Joo, Hyun-Min; Hyun, Yang-Jin; Myoung, Kil-Sun; Ahn, Young-Tae; Lee, Jung-Hee; Huh, Chul-Sung; Han, Myung Joo; Kim, Dong-Hyun

2011-11-01

Hydrogen peroxide-producing lactic acid bacteria (LAB) were isolated from women's vaginas and their anti-inflammatory effects against Gardnerella vaginalis-induced vaginosis were examined in β-estradiol-immunosuppressed mice. Oral and intravaginal treatment with five LABs significantly decreased viable G. vaginalis numbers in vaginal cavities and myeloperoxidase activity in mouse vaginal tissues. Of the LABs examined, Lactobacillus johnsonii HY7042 (LJ) most potently inhibited G. vaginalis-induced vaginosis. This LAB also inhibited the expressions of IL-1β, IL-6, TNF-α, COX-2, and iNOS, and the activation of NF-κB in vaginal tissues, but increased IL-10 expression. Orally administered LJ (0.2×10(8) CFU/mouse) also inhibited the expression of TNF-α by 91.7% in β-estradiol-immunosuppressed mice intraperitoneally injected with LPS. However, it increased IL-10 expression by 63.3% in these mice. Furthermore, LJ inhibited the expressions of the pro-inflammatory cytokines, TNF-α and IL-1β, and the activation of NF-κB in lipopolysaccharide-stimulated peritoneal macrophages. LJ also killed G. vaginalis attached with and without HeLa cells. These findings suggest that LJ inhibits bacterial vaginosis by inhibiting the expressions of COX-2, iNOS, IL-1β, and TNF-α by regulating NF-κB activation and by killing G. vaginalis, and that LJ could ameliorate bacterial vaginosis. Copyright © 2011 Elsevier B.V. All rights reserved.

Spilanthol Inhibits COX-2 and ICAM-1 Expression via Suppression of NF-κB and MAPK Signaling in Interleukin-1β-Stimulated Human Lung Epithelial Cells.

PubMed

Huang, Wen-Chung; Wu, Ling-Yu; Hu, Sindy; Wu, Shu-Ju

2018-06-30

Spilanthol a phytochemical derived from the Spilanthes acmella plant has antimicrobial, antioxidant, and anti-inflammatory properties. This study evaluated its effects on the expression of intercellular adhesion molecule 1 (ICAM-1) and inflammation-related mediators in IL-1β-stimulated human lung epithelial A549 cells. Human lung epithelial A549 cells were pretreated with various concentrations of spilanthol (3-100 μM) followed by treatment with IL-1β to induce inflammation. The protein levels of pro-inflammatory cytokines, chemokines, and prostaglandin E2 (PGE2) were measured using ELISA. Cyclooxygenase-2 (COX-2), heme oxygenase (HO-1), nuclear transcription factor kappa-B (NF-κB), and mitogen-activated protein kinase (MAPK) were measured by immunoblotting. The mRNA expression levels of ICAM-1 and MUC5AC were determined by real-time polymerase chain reaction. Spilanthol decreased the expression of PGE 2 , COX-2, TNF-α, and MCP-1. It also decreased ICAM-1 expression and suppressed monocyte adhesion to IL-1β-stimulated A549 cells. Spilanthol also significantly inhibited the phosphorylation of MAPK and I-κB. These results suggest that spilanthol exerts anti-inflammatory effects by inhibiting the expression of the pro-inflammatory cytokines, COX-2, and ICAM-1 by inhibiting the NF-κB and MAPK signaling pathways. Graphical Abstract ᅟ.

Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/NF-κB-mediated inflammatory responses.

PubMed

Guo, Ruo-Bing; Wang, Guo-Feng; Zhao, An-Peng; Gu, Jun; Sun, Xiu-Lan; Hu, Gang

2012-01-01

Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2) and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.

Exposure to PM2.5 induces aberrant activation of NF-κB in human airway epithelial cells by downregulating miR-331 expression.

PubMed

Song, Lei; Li, Dan; Li, Xiaoping; Ma, Lianjun; Bai, Xiaoxue; Wen, Zhongmei; Zhang, Xiufang; Chen, Dong; Peng, Liping

2017-03-01

Exposure to particulate matter (PM) with an aerodynamic diameter≤2.5μm (PM2.5) induces reactive oxygen species (ROS) and pro-inflammatory cytokine production, leading to airway epithelial injury. However, the mechanisms underlying the toxicity of PM2.5 have not been clarified. Here, we show that exposure to PM2.5 induces sustained activation of the nuclear factor kappa B (NF-κB) signaling in human airway epithelial Beas-2B (B2B) cells. In addition, PM2.5 exposure significantly decreased miR-331 expression in B2B cells, which was abrogated by inhibition of ROS or phosphoinositide 3-kinase (PI3K)/Akt pathway. Induction of miR-331 overexpression attenuated the PM2.5 exposure-induced NF-kBp65 nuclear translocation, IL-6 and IL-8 expression in B2B cells. Furthermore, miR-331 targeted the inhibitor of NF-κB kinase beta (IKK-β) by down-regulating the IKK-β-regulated luciferase activity in HEK293 cells. Moreover, induction of miR-331 over-expression inhibited IKK-β expression while induction of IKK-β over-expression prevented the inhibition of miR-331 on the PM2.5 exposure-induced NF-kBp65 nuclear translocation, IL-6 and IL-8 expression in B2B cells. Therefore, PM2.5 exposure decreased miR-331 expression via the ROS/PI3K/Akt pathway, resulting in an increase in the IKK-β expression and sustained NF-κB activation in human airway epithelial cells. Our findings may provide new insights into the molecular mechanisms underlying the toxicity of PM2.5 exposure and aid in design of new therapeutic strategies to prevent PM2.5-induced toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

MASH Suite Pro: A Comprehensive Software Tool for Top-Down Proteomics*

PubMed Central

Cai, Wenxuan; Guner, Huseyin; Gregorich, Zachery R.; Chen, Albert J.; Ayaz-Guner, Serife; Peng, Ying; Valeja, Santosh G.; Liu, Xiaowen; Ge, Ying

2016-01-01

Top-down mass spectrometry (MS)-based proteomics is arguably a disruptive technology for the comprehensive analysis of all proteoforms arising from genetic variation, alternative splicing, and posttranslational modifications (PTMs). However, the complexity of top-down high-resolution mass spectra presents a significant challenge for data analysis. In contrast to the well-developed software packages available for data analysis in bottom-up proteomics, the data analysis tools in top-down proteomics remain underdeveloped. Moreover, despite recent efforts to develop algorithms and tools for the deconvolution of top-down high-resolution mass spectra and the identification of proteins from complex mixtures, a multifunctional software platform, which allows for the identification, quantitation, and characterization of proteoforms with visual validation, is still lacking. Herein, we have developed MASH Suite Pro, a comprehensive software tool for top-down proteomics with multifaceted functionality. MASH Suite Pro is capable of processing high-resolution MS and tandem MS (MS/MS) data using two deconvolution algorithms to optimize protein identification results. In addition, MASH Suite Pro allows for the characterization of PTMs and sequence variations, as well as the relative quantitation of multiple proteoforms in different experimental conditions. The program also provides visualization components for validation and correction of the computational outputs. Furthermore, MASH Suite Pro facilitates data reporting and presentation via direct output of the graphics. Thus, MASH Suite Pro significantly simplifies and speeds up the interpretation of high-resolution top-down proteomics data by integrating tools for protein identification, quantitation, characterization, and visual validation into a customizable and user-friendly interface. We envision that MASH Suite Pro will play an integral role in advancing the burgeoning field of top-down proteomics. PMID:26598644

Rosuvastatin Attenuates CD40L-Induced Downregulation of Extracellular Matrix Production in Human Aortic Smooth Muscle Cells via TRAF6-JNK-NF-κB Pathway

PubMed Central

Wang, Xiao-Lin; Zhou, Yuan-Li; Sun, Wei; Li, Li

2016-01-01

CD40L and statins exhibit pro-inflammatory and anti-inflammatory effects, respectively. They are both pleiotropic and can regulate extracellular matrix (ECM) degeneration in an atherosclerotic plaque. Statins can decrease both the CD40 expression and the resulting inflammation. However, the effects of CD40L and stains on atherosclerotic plaque ECM production and the underlying mechanisms are not well established. Moreover, prolyl-4-hydroxylase α1 (P4Hα1) is involved in collagen synthesis but its correlations with CD40L and statins are unknown. In the present study, CD40L suppressed P4Hα1 expression in human aortic smooth muscle cells (HASMCs) in a dose- and time-dependent manner, with insignificant changes in MMP2 expression and negative enzymatic activity of MMP9. CD40L increased TRAF6 expression, JNK phosphorylation, NF-κB nuclear translocation as well as DNA binding. Furthermore, silencing TRAF6, JNK or NF-κB genes abolished CD40L-induced suppression of P4Hα1. Lower NF-κB nuclear import rates were observed when JNK or TRAF6 silenced HASMCs were stimulated with CD40L compared to HASMCs with active JNK or TRAF6. Together, these results indicate that CD40L suppresses P4Hα1 expression in HASMCs by activating the TRAF6-JNK- NF-κB pathway. We also found that rosuvastatin inhibits CD40L-induced activation of the TRAF6-JNK- NF-κB pathway, thereby significantly rescuing the CD40L stimulated P4Hα1 inhibition. The results from this study will help find potential targets for stabilizing vulnerable atherosclerotic plaques. PMID:27120457

R1: Platelets and Megakaryocytes contain functional NF-κB

PubMed Central

Spinelli, Sherry L.; Casey, Ann E.; Pollock, Stephen J.; Gertz, Jacqueline M.; McMillan, David H.; Narasipura, Srinivasa D.; Mody, Nipa A.; King, Michael R.; Maggirwar, Sanjay B.; Francis, Charles W.; Taubman, Mark B.; Blumberg, Neil; Phipps, Richard P.

2010-01-01

The Nuclear Factor (NF)-κB transcription factor family is well-known for their role in eliciting inflammation and promoting cell survival. We discovered that human megakaryocytes and platelets express the majority of NF-κB family members including the regulatory Inhibitor (I)-κB and Inhibitor Kappa Kinase (IKK) molecules. Objective Investigate the presence and role of NF-κB proteins in megakaryocytes and platelets. Methods and Results Anucleate platelets exposed to NF-κB inhibitors demonstrated impaired fundamental functions involved in repairing vascular injury and thrombus formation. Specifically, NF-κB inhibition diminished lamellapodia formation, decreased clot retraction times and reduced thrombus stability. Moreover, inhibition of I-κB-α phosphorylation (BAY-11-7082) reverts fully spread platelets back to a spheroid morphology. Addition of recombinant IKK-β or I-κB-α protein to BAY inhibitor-treated platelets partially restore platelet spreading in I-κB-α inhibited platelets, and addition of active IKK-β increased endogenous I-κB-α phosphorylation levels. Conclusions These novel findings support a crucial and non-classical role for the NF-κB family in modulating platelet function and reveal that platelets are sensitive to NF-κB inhibitors. As NF-κB inhibitors are being developed as anti-inflammatory and anti-cancer agents, they may have unintended effects on platelets. Based on these data, NF-κB is also identified as a new target to dampen unwanted platelet activation. PMID:20042710

HIV-1 Nef Induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors

NASA Astrophysics Data System (ADS)

Liu, Xun; Shah, Ankit; Gangwani, Mohitkumar R.; Silverstein, Peter S.; Fu, Mingui; Kumar, Anil

2014-03-01

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients infected with HIV-1. The production of pro-inflammatory cytokines by astrocytes/microglia exposed to viral proteins is thought to be one of the mechanisms leading to HIV-1- mediated neurotoxicity. In the present study we examined the effects of Nef on CCL5 induction in astrocytes. The results demonstrate that CCL5 is significantly induced in Nef-transfected SVGA astrocytes. To determine the mechanisms responsible for the increased CCL5 caused by Nef, we employed siRNA and chemical antagonists. Antagonists of NF-κB, PI3K, and p38 significantly reduced the expression levels of CCL5 induced by Nef transfection. Furthermore, specific siRNAs demonstrated that the Akt, p38MAPK, NF-κB, CEBP, and AP-1 pathways play a role in Nef-mediated CCL5 expression. The results demonstrated that the PI3K/Akt and p38 MAPK pathways, along with the transcription factors NF-κB, CEBP, and AP-1, are involved in Nef-induced CCL5 production in astrocytes.

42 CFR 483.114 - Annual review of NF residents.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Annual review of NF residents. 483.114 Section 483... Screening and Annual Review of Mentally Ill and Mentally Retarded Individuals § 483.114 Annual review of NF... physical and mental condition, the resident requires— (1) The level of services provided by— (i) A NF; (ii...

NF-kappaB modulators from Valeriana officinalis.

PubMed

Jacobo-Herrera, Nadia J; Vartiainen, Nina; Bremner, Paul; Gibbons, Simon; Koistinaho, Jari; Heinrich, Michael

2006-10-01

Valeriana officinalis (Valerianaceae) has been of great interest for its therapeutic uses for treating mild nervous tension and temporary sleeping problems. In traditional European medicine it has been also reported as an antiinflammatory remedy. This study reports that the EtOAc extract of the underground parts of V. officinalis showed inhibitory activity against NF-kappaB at 100 microg/mL in the IL-6/Luc assay on HeLa cells and provided protection against excitotoxicity in primary brain cell cultures at micromolar concentrations. Bioassay-guided fractionation of the EtOAc extract led to the isolation of three known sesquiterpenes: acetylvalerenolic acid (1), valerenal (2) and valerenic acid (3), 1 and 3 were active as inhibitors of NF-kappaB at a concentration of 100 microg/mL. Acetylvalerenolic acid (1) reduced NF-kappaB activity to 4%, whereas valerenic acid (3) reduced NF-kappaB activity to 25%. Copyright 2006 John Wiley & Sons, Ltd.

NF-{kappa}B regulates Lef1 gene expression in chondrocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yun, Kangsun; Choi, Yoo Duk; Nam, Jong Hee

The relation of Wnt/{beta}-catenin signaling to osteoarthritis progression has been revealed with little information on the underlying molecular mechanism. In this study we found overexpression of Lef1 in cartilage tissue of osteoarthritic patients and elucidated molecular mechanism of NF-{kappa}B-mediated Lef1 gene regulation in chondrocytes. Treatment of IL-1{beta} augmented Lef1 upregulation and nuclear translocation of NF-{kappa}B in chondrocytes. Under IL-1{beta} signaling, treatment of NF-{kappa}B nuclear translocation inhibitor SN-50 reduced Lef1 expression. A conserved NF-{kappa}B-binding site between mouse and human was selected through bioinformatic analysis and mapped at the 14 kb upstream of Lef1 transcription initiation site. NF-{kappa}B binding to the sitemore » was confirmed by chromatin immunoprecipitation assay. Lef1 expression was synergistically upregulated by interactions of NF-{kappa}B with Lef1/{beta}-catenin in chondrocytes. Our results suggest a pivotal role of NF-{kappa}B in Lef1 expression in arthritic chondrocytes or cartilage degeneration.« less

Neu1 sialidase and matrix metalloproteinase-9 cross-talk regulates nucleic acid-induced endosomal TOLL-like receptor-7 and -9 activation, cellular signaling and pro-inflammatory responses.

PubMed

Abdulkhalek, Samar; Szewczuk, Myron R

2013-11-01

The precise mechanism(s) by which intracellular TOLL-like receptors (TLRs) become activated by their ligands remains unclear. Here, we report a molecular organizational G-protein coupled receptor (GPCR) signaling platform to potentiate a novel mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B GPCR, all of which form a tripartite complex with TLR-7 and -9. siRNA silencing Neu1, MMP-9 and neuromedin-B GPCR in RAW-blue macrophage cells significantly reduced TLR7 imiquimod- and TLR9 ODN1826-induced NF-κB (NF-κB-pSer(536)) activity. Tamiflu, specific MMP-9 inhibitor, neuromedin B receptor specific antagonist BIM23127, and the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 significantly block nucleic acid-induced TLR-7 and -9 MyD88 recruitment, NF-κB activation and proinflammatory TNFα and MCP-1 cytokine responses. For the first time, Neu1 clearly plays a central role in mediating nucleic acid-induced intracellular TLR activation, and the interactions involving NMBR-MMP9-Neu1 cross-talk constitute a novel intracellular TLR signaling platform that is essential for NF-κB activation and pro-inflammatory responses. © 2013. Published by Elsevier Inc. All rights reserved.

Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines

PubMed Central

Xu, Ning; An, Jun

2017-01-01

Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-κB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 µM) suppressed histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-κB activation and upstream IκKα phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell-mediated allergic inflammation. PMID:29250144

Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines.

PubMed

Xu, Ning; An, Jun

2017-12-01

Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-κB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 µM) suppressed histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-κB activation and upstream IκKα phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell-mediated allergic inflammation.

Toward a pro-active scientific advice on global volcanic activity within the multi-hazard framework of the EU Aristotle project

NASA Astrophysics Data System (ADS)

Barsotti, Sara; Duncan, Melanie; Loughlin, Susan; Gísladóttir, Bryndis; Roberts, Matthew; Karlsdóttir, Sigrún; Scollo, Simona; Salerno, Giuseppe; Corsaro, Rosa Anna; Charalampakis, Marinos; Papadopoulos, Gerassimos

2017-04-01

The demand for timely analysis and advice on global volcanic activity from scientists is growing. At the same time, decision-makers require more than an understanding of hazards; they need to know what impacts to expect from ongoing and future events. ARISTOTLE (All Risk Integrated System TOwards Trans-boundary hoListic Early-warning) is a two-year EC funded pilot project designed to do just that. The Emergency Response Coordination Centre (ERCC) works to support and coordinate response to disasters both inside and outside Europe using resources from the countries participating in the European Union Civil Protection Mechanism. Led by INGV and ZAMG, the ARISTOTLE consortium comprises 15 institutions across Europe and aims to deliver multi-hazard advice on natural events, including their potential interactions and impact, both inside and outside of Europe to the ERCC. Where possible, the ERCC would like a pro-active provision of scientific advice by the scientific group. Iceland Met Office leads the volcanic hazards work, with BGS, INGV and NOA comprising the volcano observatory team. At this stage, the volcanology component of the project comprises mainly volcanic ash and gas dispersal and potential impact on population and ground-based critical infrastructures. We approach it by relying upon available and official volcano monitoring institutions' reporting of activity, existing assessments and global databases of past events, modelling tools, remote-sensing observational systems and official VAAC advisories. We also make use of global assessments of volcanic hazards, country profiles, exposure and proxy indicators of threat to livelihoods, infrastructure and economic assets (e.g. Global Volcano Model outputs). Volcanic ash fall remains the only hazard modelled at the global scale. Volcanic risk assessments remain in their infancy, owing to challenges related to the multitude of hazards, data availability and model representation. We therefore face a number of

Pro-anorexia and pro-recovery photo sharing: a tale of two warring tribes.

PubMed

Yom-Tov, Elad; Fernandez-Luque, Luis; Weber, Ingmar; Crain, Steven P

2012-11-07

There is widespread use of the Internet to promote anorexia as a lifestyle choice. Pro-anorexia content can be harmful for people affected or at risk of having anorexia. That movement is actively engaged in sharing photos on social networks such as Flickr. To study the characteristics of the online communities engaged in disseminating content that encourages eating disorders (known as "pro-anorexia") and to investigate if the posting of such content is discouraged by the posting of recovery-oriented content. The extraction of pro-anorexia and pro-recovery photographs from the photo sharing site Flickr pertaining to 242,710 photos from 491 users and analyzing four separate social networks therein. Pro-anorexia and pro-recovery communities interact to a much higher degree among themselves than what is expected from the distribution of contacts (only 59-72% of contacts but 74-83% of comments are made to members inside the community). Pro-recovery users employ similar words to those used by pro-anorexia users to describe their photographs, possibly in order to ensure that their content appears when pro-anorexia users search for images. Pro-anorexia users who are exposed to comments from the opposite camp are less likely to cease posting pro-anorexia photographs than those who do not receive such comments (46% versus 61%), and if they cease, they do so approximately three months later. Our observations show two highly active communities, where most interaction is within each community. However, the pro-recovery community takes steps to ensure that their content is visible to the pro-anorexia community, both by using textual descriptions of their photographs that are similar to those used by the pro-anorexia group and by commenting to pro-anorexia content. The latter activity is, however, counterproductive, as it entrenches pro-anorexia users in their stance. Our results highlight the nature of pro-anorexia and pro-recovery photo sharing and accentuate the need for

Pro-Anorexia and Pro-Recovery Photo Sharing: A Tale of Two Warring Tribes

PubMed Central

Yom-Tov, Elad; Weber, Ingmar; Crain, Steven P

2012-01-01

Background There is widespread use of the Internet to promote anorexia as a lifestyle choice. Pro-anorexia content can be harmful for people affected or at risk of having anorexia. That movement is actively engaged in sharing photos on social networks such as Flickr. Objective To study the characteristics of the online communities engaged in disseminating content that encourages eating disorders (known as “pro-anorexia”) and to investigate if the posting of such content is discouraged by the posting of recovery-oriented content. Methods The extraction of pro-anorexia and pro-recovery photographs from the photo sharing site Flickr pertaining to 242,710 photos from 491 users and analyzing four separate social networks therein. Results Pro-anorexia and pro-recovery communities interact to a much higher degree among themselves than what is expected from the distribution of contacts (only 59-72% of contacts but 74-83% of comments are made to members inside the community). Pro-recovery users employ similar words to those used by pro-anorexia users to describe their photographs, possibly in order to ensure that their content appears when pro-anorexia users search for images. Pro-anorexia users who are exposed to comments from the opposite camp are less likely to cease posting pro-anorexia photographs than those who do not receive such comments (46% versus 61%), and if they cease, they do so approximately three months later. Our observations show two highly active communities, where most interaction is within each community. However, the pro-recovery community takes steps to ensure that their content is visible to the pro-anorexia community, both by using textual descriptions of their photographs that are similar to those used by the pro-anorexia group and by commenting to pro-anorexia content. The latter activity is, however, counterproductive, as it entrenches pro-anorexia users in their stance. Conclusions Our results highlight the nature of pro-anorexia and pro

Acrylamide-induced oxidative stress and inflammatory response are alleviated by N-acetylcysteine in PC12 cells: Involvement of the crosstalk between Nrf2 and NF-κB pathways regulated by MAPKs.

PubMed

Pan, Xiaoqi; Wu, Xu; Yan, Dandan; Peng, Cheng; Rao, Chaolong; Yan, Hong

2018-05-15

Acrylamide (ACR) is a classic neurotoxin in animals and humans. However, the mechanism underlying ACR neurotoxicity remains controversial, and effective prevention and treatment measures against this condition are scarce. This study focused on clarifying the crosstalk between the involved signaling pathways in ACR-induced oxidative stress and inflammatory response and investigating the protective effect of antioxidant N-acetylcysteine (NAC) against ACR in PC12 cells. Results revealed that ACR exposure led to oxidative stress characterized by significant increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels and glutathione (GSH) consumption. Inflammatory response was observed based on the dose-dependently increased levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). NAC attenuated ACR-induced enhancement of MDA and ROS levels and TNF-α generation. In addition, ACR activated nuclear transcription factor E2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) signaling pathways. Knockdown of Nrf2 by siRNA significantly blocked the increased NF-κB p65 protein expression in ACR-treated PC12 cells. Down-regulation of NF-κB by specific inhibitor BAY11-7082 similarly reduced ACR-induced increase in Nrf2 protein expression. NAC treatment increased Nrf2 expression and suppressed NF-κB p65 expression to ameliorate oxidative stress and inflammatory response caused by ACR. Further results showed that mitogen-activated protein kinases (MAPKs) pathway was activated prior to the activation of Nrf2 and NF-κB pathways. Inhibition of MAPKs blocked Nrf2 and NF-κB pathways. Collectively, ACR activated Nrf2 and NF-κB pathways which were regulated by MAPKs. A crosstalk between Nrf2 and NF-κB pathways existed in ACR-induced cell damage. NAC protected against oxidative damage and inflammatory response induced by ACR by activating Nrf2 and inhibiting NF-κB pathways in PC12 cells. Copyright © 2018 Elsevier B

Proceedings of the 21st Project Integration Meeting

NASA Technical Reports Server (NTRS)

1983-01-01

Progress made by the Flat Plate Solar Array Project during the period April 1982 to January 1983 is described. Reports on polysilicon refining, thin film solar cell and module technology development, central station electric utility activities, silicon sheet growth and characteristics, advanced photovoltaic materials, cell and processes research, module technology, environmental isolation, engineering sciences, module performance and failure analysis and project analysis and integration are included.

The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

PubMed Central

van den Bosch, Thea; Boichenko, Alexander; Leus, Niek G. J.; Eleni Ourailidou, Maria; Wapenaar, Hannah; Rotili, Dante; Mai, Antonello; Imhof, Axel; Bischoff, Rainer; Haisma, Hidde J.; Dekker, Frank J.

2016-01-01

Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as erasers. Because of their role in signal transduction cascades, these enzymes are important players in inflammation. Therefore, applications of histone acetyltransferase inhibitors to reduce inflammatory responses are interesting. Among the few histone acetyltransferase inhibitors described, C646 is one of the most potent (Ki of 0.4 μM for histone acetyltransferase p300). C646 was described to regulate the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. Interestingly, this pathway has been implicated in asthma and COPD. Therefore we hypothesized that via regulation of the NF-κB signaling pathway, C646 can inhibit pro-inflammatory gene expression, and have potential for the treatment of inflammatory lung diseases. In line with this, here we demonstrate that C646 reduces pro-inflammatory gene expression in RAW264.7 murine macrophages and murine precision-cut lung slices. To unravel its effects on cellular substrates we applied mass spectrometry and found, counterintuitively, a slight increase in acetylation of histone H3. Based on this finding, and structural features of C646, we presumed inhibitory activity of C646 on histone deacetylases, and indeed found inhibition of histone deacetylases from 7 μM and higher concentrations. This indicates that C646 has potential for further development towards applications in the treatment of inflammation, however, its newly discovered lack of selectivity at higher concentrations needs to be taken into account. PMID:26718586

Silencing of FKBP51 alleviates the mechanical pain threshold, inhibits DRG inflammatory factors and pain mediators through the NF-kappaB signaling pathway.

PubMed

Yu, Hong-Mei; Wang, Qi; Sun, Wen-Bo

2017-09-05

Neuropathic pain is chronic pain caused by lesions or diseases of the somatosensory system, currently available analgesics provide only temporal relief. The precise role of FK506 binding protein 51 (FKBP51) in neuropathic pain induced by chronic constriction injury (CCI) is not clear. The purpose of the present study was to investigate the effects and possible mechanisms of FKBP51 in neuropathic pain in the rat model of CCI. Our results showed that FKBP51 was obviously upregulated in a time-dependent manner in the dorsal root ganglion (DRG) of CCI rats. Additionally, silencing of FKBP51 remarkably attenuated mechanical allodynia and thermal hyperalgesia as reflected by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in CCI rats. Moreover, knockdown of FKBP51 reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG of CCI rats. Furthermore, we revealed that inhibition of FKBP51 greatly suppressed the activation of the NF-kappaB (NF-κB) signaling in the DRG of CCI rats. Interestingly, similar to the FKBP51 siRNA (si-FKBP51), ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF-κB) also alleviated neuropathic pain and neuro-inflammation, indicating that knockdown of FKBP51 alleviated neuropathic pain development of CCI rats by inhibiting the activation of NF-κB signaling pathway. Taken together, our findings indicate that FKBP51 may serve as a novel therapeutic target for neuropathic pain. Copyright © 2017. Published by Elsevier B.V.

Mechanisms of NF-κB deregulation in lymphoid malignancies.

PubMed

Krappmann, Daniel; Vincendeau, Michelle

2016-08-01

Deregulations promoting constitutive activation of canonical and non-canonical NF-κB signaling are a common feature of many lymphoid malignancies. Due to their cellular origin and the pivotal role of NF-κB for the normal function of B lymphocytes, B-cell malignancies are particularly prone to genetic aberrations that affect the pathway. Key positive regulators of NF-κB signaling can act as oncogenes that are often prone to chromosomal translocation, amplifications or activating mutations. Negative regulators of NF-κB have tumor suppressor functions and are frequently inactivated either by genomic deletions or point mutations. Whereas some aberrations are found in a variety of different lymphoid malignancies, some oncogenic alterations are very restricted to distinct lymphoma subsets, reflecting the clonal and cellular origin of specific lymphoma entities. NF-κB activation in many lymphoma cells is also driven by the microenvironment or chronic signaling that does not rely on genetic alterations. A number of drugs that target the NF-κB pathway are in preclinical or clinical development, revealing that there will be new options for therapies in the future. Since each lymphoma entity utilizes distinct mechanisms to activate NF-κB, a major challenge is to elucidate the exact pathological processes in order to faithfully predict clinical responses to the different therapeutic approaches. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation on Collaborative Satisfaction for Project Management Team in Integrated Project Delivery Mode

NASA Astrophysics Data System (ADS)

Zhang, L.; Li, Y.; Wu, Q.

2013-05-01

Integrated Project Delivery (IPD) is a newly-developed project delivery approach for construction projects, and the level of collaboration of project management team is crucial to the success of its implementation. Existing research has shown that collaborative satisfaction is one of the key indicators of team collaboration. By reviewing the literature on team collaborative satisfaction and taking into consideration the characteristics of IPD projects, this paper summarizes the factors that influence collaborative satisfaction of IPD project management team. Based on these factors, this research develops a fuzzy linguistic method to effectively evaluate the level of team collaborative satisfaction, in which the authors adopted the 2-tuple linguistic variables and 2-tuple linguistic hybrid average operators to enhance the objectivity and accuracy of the evaluation. The paper demonstrates the practicality and effectiveness of the method through carrying out a case study with the method.

Integrated learning of mathematics, science and technology concepts through LEGO/Logo projects

NASA Astrophysics Data System (ADS)

Wu, Lina

This dissertation examined integrated learning in the domains of mathematics, science and technology based on Piaget's constructivism, Papert's constructionism, and project-based approach to education. Ten fifth grade students were involved in a two-month long after school program where they designed and built their own computer-controlled LEGO/Logo projects that required the use of gears, ratios and motion concepts. The design of this study centered on three notions of integrated learning: (1) integration in terms of what educational materials/settings provide, (2) integration in terms of students' use of those materials, and (3) integration in the psychological sense. In terms of the first notion, the results generally showed that the LEGO/Logo environment supported the integrated learning of math, science and technology concepts. Regarding the second notion, the students all completed impressive projects of their own design. They successfully combined gears, motors, and LEGO parts together to create motion and writing control commands to manipulate the motion. But contrary to my initial expectations, their successful designs did not require numerical reasoning about ratios in designing effective gear systems. When they did reason about gear relationships, they worked with "qualitative" ratios, e.g., "a larger driver gear with a smaller driven gear increases the speed." In terms of the third notion of integrated learning, there was evidence in all four case study students of the psychological processes involved in linking mathematical, scientific, and/or technological concepts together to achieve new conceptual units. The students not only made connections between ideas and experiences, but also recognized decisive patterns and relationships in their project work. The students with stronger overall project performances showed more evidence of synthesis than the students with relatively weaker performances did. The findings support the conclusion that all three

Project Integration Architecture: Inter-Application Propagation of Information

NASA Technical Reports Server (NTRS)

Jones, William Henry

2005-01-01

A principal goal of the Project Integration Architecture (PIA) is to facilitate the meaningful inter-application transfer of application-value-added information. Such exchanging applications may be largely unrelated to each other except through their applicability to an overall project; however, the PIA effort recognizes as fundamental the need to make such applications cooperate despite wide disparaties either in the fidelity of the analyses carried out, or even the disciplines of the analysis. This paper discusses the approach and techniques applied and anticipated by the PIA project in treating this need.

Withaferin A Inhibits Nuclear Factor-κB-Dependent Pro-Inflammatory and Stress Response Pathways in the Astrocytes.

PubMed

Martorana, Francesca; Guidotti, Giulia; Brambilla, Liliana; Rossi, Daniela

2015-01-01

Several lines of evidence suggest that astrocytes play a key role in modulating the immune responses of the central nervous system (CNS) to infections, injuries, or pathologies. Yet, their contribution to these processes remains mostly elusive. Astroglia are endowed with a wide range of toll-like receptors (TLR) by which they can sense infectious agents as well as endogenous danger signals released by damaged cells. Here we demonstrate that the activation of astrocytic TLR4 by bacterial lipopolysaccharide (LPS) challenge can promote nuclear factor κB (NF-κB)-dependent induction of pro-inflammatory and stress response mediators, particularly Tumor Necrosis Factor α (TNFα), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). Since the steroid lactone Withaferin A was described to inhibit NF-κB activity in different cell types, we next determined the impact of this natural compound towards the identified astrocytic signalling pathway. Innate immune activation was induced by stimulation of the LPS/TLR4 axis in spinal cord astrocytes. We provide evidence that both pre-treating and post-treating the cells with Withaferin A attenuate astrocytic NF-κB activity as well as the consequent production of TNFα, COX-2, and iNOS induced by stimulation of the LPS/TLR4 pathway. This study suggests that Withaferin A may be an eligible candidate for the treatment of neuroinflammatory and stress conditions characterized by an important astrocytic input.

Withaferin A Inhibits Nuclear Factor-κB-Dependent Pro-Inflammatory and Stress Response Pathways in the Astrocytes

PubMed Central

Martorana, Francesca; Guidotti, Giulia; Brambilla, Liliana; Rossi, Daniela

2015-01-01

Several lines of evidence suggest that astrocytes play a key role in modulating the immune responses of the central nervous system (CNS) to infections, injuries, or pathologies. Yet, their contribution to these processes remains mostly elusive. Astroglia are endowed with a wide range of toll-like receptors (TLR) by which they can sense infectious agents as well as endogenous danger signals released by damaged cells. Here we demonstrate that the activation of astrocytic TLR4 by bacterial lipopolysaccharide (LPS) challenge can promote nuclear factor κB (NF-κB)-dependent induction of pro-inflammatory and stress response mediators, particularly Tumor Necrosis Factor α (TNFα), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). Since the steroid lactone Withaferin A was described to inhibit NF-κB activity in different cell types, we next determined the impact of this natural compound towards the identified astrocytic signalling pathway. Innate immune activation was induced by stimulation of the LPS/TLR4 axis in spinal cord astrocytes. We provide evidence that both pre-treating and post-treating the cells with Withaferin A attenuate astrocytic NF-κB activity as well as the consequent production of TNFα, COX-2, and iNOS induced by stimulation of the LPS/TLR4 pathway. This study suggests that Withaferin A may be an eligible candidate for the treatment of neuroinflammatory and stress conditions characterized by an important astrocytic input. PMID:26266054

Inoculating against Pro-Plagiarism Justifications: Rational and Affective Strategies

ERIC Educational Resources Information Center

Compton, Josh; Pfau, Michael

2008-01-01

Student plagiarism continues to threaten academic integrity. This investigation assessed whether an inoculation message strategy could combat university plagiarism by protecting student attitudes against pro-plagiarism justification arguments. Additionally, we sought theoretical confirmation of previous findings on involvement and accessibility in…

UAS Integration in the NAS Project: Integrated Test and LVC Infrastructure

NASA Technical Reports Server (NTRS)

Murphy, Jim; Hoang, Ty

2015-01-01

Overview presentation of the Integrated Test and Evaluation sub-project of the Unmanned Aircraft System (UAS) in the National Airspace System (NAS). The emphasis of the presentation is the Live, Virtual, and Constructive (LVC) system (a broadly used name for classifying modeling and simulation) infrastructure and use of external assets and connection.

Nestin is highly expressed in fetal spinal cord isolated from placenta previa patients and promotes inflammation by enhancing NF-κB activity.

PubMed

Li, Ling; Zhang, Jing; Gao, Huahe; Ma, Yuyan

2018-04-26

Purpose Nestin is expressed in various tissues of the embryo in patients with placenta previa, while the regulatory mechanism still unknown. Materials and methods All participants terminated pregnancy. Among them, 75 patients with placenta previa were assigned to the case group and 80 healthy pregnant women with normal placenta were assigned to the control group. Expression of nestin and CDK5 in fetal spinal cord tissues was detected by Western Blot and RT-qPCR methods. The enzyme-linked immunosorbent assay (ELISA) was used to determine the serum expression of some pro-inflammatory cytokines in placenta previa patients. The interaction between nestin and CDK5 was evaluated by immunoprecipitation and siRNA inhibition of nestin was performed to estimate its effect on NF-κB activity in fetal spinal cord tissues. Results Along with increased expression of nestin and CDK5 in fetal spinal cord tissues in the case group, IL-1β, IL-6, TNF-α, and IFN-γ were increased in the serum of placenta previa patients. siRNA inhibition analysis indicated that nestin interacted with CDK5 and regulated NF-κB activity in fetal spinal cord tissues. Conclusions Nestin is highly expressed and the interaction between nestin and CDK5 might lead to the progress of placenta previa through its regulation on NF-κB.

NF-E2 Overexpression Delays Erythroid Maturation and Increases Erythrocyte Production

PubMed Central

Mutschler, Manuel; Magin, Angela S.; Buerge, Martina; Roelz, Roland; Schanne, Daniel H.; Will, Britta; Pilz, Ingo H.; Migliaccio, Anna Rita; Pahl, Heike L.

2009-01-01

Summary The transcription factor Nuclear Factor-Erythroid 2 (NF-E2) is overexpressed in the vast majority of patients with polycythaemia vera (PV). In murine models, NF-E2 overexpression increases proliferation and promotes cellular viability in the absence of erythropoietin (EPO). EPO-independent growth is a hallmark of PV. We therefore hypothesized that NF-E2 overexpression contributes to erythrocytosis, the pathognomonic feature of PV. Consequently, we investigated the effect of NF-E2 overexpression in healthy CD34+ cells. NF-E2 overexpression led to a delay in erythroid maturation, manifested by a belated appearance of glycophorin A-positive erythroid precursors. Maturation delay was similarly observed in primary PV patient erythroid cultures compared to healthy controls. Protracted maturation led to a significant increase in the accumulated number of erythroid cells both in PV cultures and in CD34+ cells overexpressing NF-E2. Similarly, NF-E2 overexpression altered erythroid colony formation, leading to an increase in BFU-E formation. These data indicate that NF-E2 overexpression delays the early phase of erythroid maturation, resulting in an expansion of erythroid progenitors, thereby increasing the number of erythrocytes derived from one CD34+ cell. These data propose a role for NF-E2 in mediating the erythrocytosis of PV. PMID:19466964

Bone marrow stromal-B cell interactions in polycyclic aromatic hydrocarbon-induced pro/pre-B cell apoptosis.

PubMed

Allan, Lenka L; Mann, Koren K; Matulka, Raymond A; Ryu, Heui-Young; Schlezinger, Jennifer J; Sherr, David H

2003-12-01

Environmental polycyclic aromatic hydrocarbons (PAH) and related halogenated hydrocarbons are immunotoxic in a variety of systems. In a model system of B lymphopoiesis, PAH exposure rapidly induces apoptosis in CD43- pre-B and CD43+ pro/pre-B cells. Apoptosis induction by 7,12-dimethylbenzo[a]anthracene (DMBA) is dependent upon AhR+ bone marrow stromal cells and likely involves DMBA metabolism within the stromal cell. However, it is not known if PAH-treated stromal cells release free metabolites or soluble factors that may directly induce B cell death or if the effector death signal is delivered by stromal cell-B cell contact. Here, we demonstrate that supernatants from DMBA-treated bone marrow stromal cells contain an activity capable of inducing apoptosis in pro/pre-B cells cocultured with stromal cells. This activity (1) is not produced when stromal cells are cotreated with DMBA and alpha-naphthoflavone (alpha-NF), an aryl hydrocarbon receptor (AhR) and cytochrome P-450 inhibitor, (2) is > or = 50 kDa, (3) is trypsin and heat sensitive, and (4) is dependent on AhR+ stromal cells, which in turn deliver the effector death signal to pro/pre-B cells. The results (1) argue against a role for a soluble, stromal cell-derived cytokine as the effector of PAH-induced pro/pre-B cell death, (2) exclude the possibility of a free metabolite acting directly on AhR- pro/pre-B cell targets, and (3) suggest the elaboration by stromal cells of a relatively stable, DMBA metabolite-protein complex capable of acting on other stromal cells at some distance. Collectively, these studies suggest that, while stromal cell products, e.g., metabolite-protein complexes, may affect the function of distant stromal cells, the effector death signal delivered by stromal cells to bone marrow B cells is mediated by cell-cell contact.

Aeronautics Research Mission Directorate Integrated Systems Research Program (ISRP) and UAS Integration in the NAS Project

NASA Technical Reports Server (NTRS)

Wolfe, Jean

2010-01-01

Program Goal: Conduct research at an integrated system-level on promising concepts and technologies and explore, assess, or demonstrate the benefits in a relevant environment.Criteria for selection of projects for Integrated Systems Research: a) Technology has attained enough maturity in the foundational research program that they merit more in-depth evaluation at an integrated system level in a relevant environment. b) Technologies which systems analysis indicates have the most potential for contributing to the simultaneous attainment of goals. c) Technologies identified through stakeholder input as having potential for simultaneous attainment of goals. d) Research not being done by other government agencies and appropriate for NASA to conduct. e) Budget augmentation. Environmentally Responsible Aviation (ERA) Project Explore and assess new vehicle concepts and enabling technologies through system-level experimentation to simultaneously reduce fuel burn, noise, and emissions Unmanned Aircraft Systems (UAS) Integration in the National Airspace System (NAS) Project Contribute capabilities that reduce technical barriers related to the safety and operational challenges associated with enabling routine UAS access to the NAS Innovative Concepts for Green Aviation (ICGA) Project Spur innovation by offering research opportunities to the broader aeronautics community through peer-reviewed proposals, with a focus on making aviation more eco-friendly. Establish incentive prizes similar to the Centennial Challenges and sponsor innovation demonstrations of selected technologies that show promise of reducing aviation s impact on the environment

Proceedings of the 26th Project Integration Meeting

NASA Technical Reports Server (NTRS)

1986-01-01

Progress made by the Flat-plate Solar Array (FSA) Project is described for the period July 1985 to April 1986. Included are reports on silicon sheet growth and characterization, silicon material, process development, high-efficienty cells, environmental isolation, engineering sciences, and reliability physics. Also included are technical and plenary presentations made at the 26th Project Integration Meeting (PIM) held on April 29 to 30 and May 1, 1986.

Incorporating variability in simulations of seasonally forced phenology using integral projection models

DOE PAGES

Goodsman, Devin W.; Aukema, Brian H.; McDowell, Nate G.; ...

2017-11-26

Phenology models are becoming increasingly important tools to accurately predict how climate change will impact the life histories of organisms. We propose a class of integral projection phenology models derived from stochastic individual-based models of insect development and demography. Our derivation, which is based on the rate summation concept, produces integral projection models that capture the effect of phenotypic rate variability on insect phenology, but which are typically more computationally frugal than equivalent individual-based phenology models. We demonstrate our approach using a temperature-dependent model of the demography of the mountain pine beetle (Dendroctonus ponderosae Hopkins), an insect that kills maturemore » pine trees. This work illustrates how a wide range of stochastic phenology models can be reformulated as integral projection models. Due to their computational efficiency, these integral projection models are suitable for deployment in large-scale simulations, such as studies of altered pest distributions under climate change.« less

Incorporating variability in simulations of seasonally forced phenology using integral projection models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goodsman, Devin W.; Aukema, Brian H.; McDowell, Nate G.

Phenology models are becoming increasingly important tools to accurately predict how climate change will impact the life histories of organisms. We propose a class of integral projection phenology models derived from stochastic individual-based models of insect development and demography. Our derivation, which is based on the rate summation concept, produces integral projection models that capture the effect of phenotypic rate variability on insect phenology, but which are typically more computationally frugal than equivalent individual-based phenology models. We demonstrate our approach using a temperature-dependent model of the demography of the mountain pine beetle (Dendroctonus ponderosae Hopkins), an insect that kills maturemore » pine trees. This work illustrates how a wide range of stochastic phenology models can be reformulated as integral projection models. Due to their computational efficiency, these integral projection models are suitable for deployment in large-scale simulations, such as studies of altered pest distributions under climate change.« less

Incorporating variability in simulations of seasonally forced phenology using integral projection models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goodsman, Devin W.; Aukema, Brian H.; McDowell, Nate G.

Phenology models are becoming increasingly important tools to accurately predict how climate change will impact the life histories of organisms. We propose a class of integral projection phenology models derived from stochastic individual-based models of insect development and demography.Our derivation, which is based on the rate-summation concept, produces integral projection models that capture the effect of phenotypic rate variability on insect phenology, but which are typically more computationally frugal than equivalent individual-based phenology models. We demonstrate our approach using a temperature-dependent model of the demography of the mountain pine beetle (Dendroctonus ponderosae Hopkins), an insect that kills mature pine trees.more » This work illustrates how a wide range of stochastic phenology models can be reformulated as integral projection models. Due to their computational efficiency, these integral projection models are suitable for deployment in large-scale simulations, such as studies of altered pest distributions under climate change.« less

Direct non transcriptional role of NF-Y in DNA replication.

PubMed

Benatti, Paolo; Belluti, Silvia; Miotto, Benoit; Neusiedler, Julia; Dolfini, Diletta; Drac, Marjorie; Basile, Valentina; Schwob, Etienne; Mantovani, Roberto; Blow, J Julian; Imbriano, Carol

2016-04-01

NF-Y is a heterotrimeric transcription factor, which plays a pioneer role in the transcriptional control of promoters containing the CCAAT-box, among which genes involved in cell cycle regulation, apoptosis and DNA damage response. The knock-down of the sequence-specific subunit NF-YA triggers defects in S-phase progression, which lead to apoptotic cell death. Here, we report that NF-Y has a critical function in DNA replication progression, independent from its transcriptional activity. NF-YA colocalizes with early DNA replication factories, its depletion affects the loading of replisome proteins to DNA, among which Cdc45, and delays the passage from early to middle-late S phase. Molecular combing experiments are consistent with a role for NF-Y in the control of fork progression. Finally, we unambiguously demonstrate a direct non-transcriptional role of NF-Y in the overall efficiency of DNA replication, specifically in the DNA elongation process, using a Xenopus cell-free system. Our findings broaden the activity of NF-Y on a DNA metabolism other than transcription, supporting the existence of specific TFs required for proper and efficient DNA replication. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Mangiferin attenuates the symptoms of dextran sulfate sodium-induced colitis in mice via NF-κB and MAPK signaling inactivation

PubMed Central

Dou, Wei; Zhang, Jingjing; Ren, Gaiyan; Ding, Lili; Sun, Aning; Deng, Chao; Wu, Xiaojun; Wei, Xiaohui; Mani, Sridhar; Wang, Zhengtao

2015-01-01

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal (GI) tract, and currently no curative treatment available. Mangiferin, a natural glucosylxanthone mainly from the fruit, leaves and stem bark of the mango tree, has strong anti-inflammatory activity. We sought to investigate whether mangiferin attenuates inflammation in a mouse model of chemically induced IBD. Pre-administration of mangiferin significantly attenuated dextran sulfate sodium (DSS)-induced body weight loss, diarrhea, colon shortening and histological injury, which correlated with the decline in the activity of myeloperoxidase (MPO) and the level of tumor necrosis factor-α (TNF-α) in the colon. DSS-induced degradation of inhibitory κBα (IκBα) and the phosphorylation of nuclear factor-kappa B (NF-κB) p65 as well as the mRNA expression of pro-inflammatory mediators (inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), TNF-α, interleukin-1β (IL-1β) and IL-6) in the colon were also downregulated by mangiferin treatment. Additionally, the phosphorylation/activation of DSS-induced mitogen-activated protein kinase (MAPK) proteins was also inhibited by mangiferin treatment. In accordance with the in vivo results, mangiferin exposure blocked TNF-α-stimulated nuclear translocation of NF-κB in RAW264.7 mouse macrophage cells. Transient transfection gene reporter assay performed in TNF-α-stimulated HT-29 human colorectal adenocarcinoma cells indicated that mangiferin inhibits NF-κB transcriptional activity in a dose-dependent manner. The current study clearly demonstrates a protective role for mangiferin in experimental IBD through NF-κB and MAPK signaling inhibition. Since mangiferin is a natural compound with little toxicity, the results may contribute to the effective utilization of mangiferin in the treatment of human IBD. PMID:25194678

Mangiferin attenuates the symptoms of dextran sulfate sodium-induced colitis in mice via NF-κB and MAPK signaling inactivation.

PubMed

Dou, Wei; Zhang, Jingjing; Ren, Gaiyan; Ding, Lili; Sun, Aning; Deng, Chao; Wu, Xiaojun; Wei, Xiaohui; Mani, Sridhar; Wang, Zhengtao

2014-11-01

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal (GI) tract, and currently no curative treatment is available. Mangiferin, a natural glucosylxanthone mainly from the fruit, leaves and stem bark of a mango tree, has a strong anti-inflammatory activity. We sought to investigate whether mangiferin attenuates inflammation in a mouse model of chemically induced IBD. Pre-administration of mangiferin significantly attenuated dextran sulfate sodium (DSS)-induced body weight loss, diarrhea, colon shortening and histological injury, which correlated with the decline in the activity of myeloperoxidase (MPO) and the level of tumor necrosis factor-α (TNF-α) in the colon. DSS-induced degradation of inhibitory κBα (IκBα) and the phosphorylation of nuclear factor-kappa B (NF-κB) p65 as well as the mRNA expression of pro-inflammatory mediators (inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), TNF-α, interleukin-1β (IL-1β) and IL-6) in the colon were also downregulated by mangiferin treatment. Additionally, the phosphorylation/activation of DSS-induced mitogen-activated protein kinase (MAPK) proteins was also inhibited by mangiferin treatment. In accordance with the in vivo results, mangiferin exposure blocked TNF-α-stimulated nuclear translocation of NF-κB in RAW264.7 mouse macrophage cells. Transient transfection gene reporter assay performed in TNF-α-stimulated HT-29 human colorectal adenocarcinoma cells indicated that mangiferin inhibits NF-κB transcriptional activity in a dose-dependent manner. The current study clearly demonstrates a protective role for mangiferin in experimental IBD through NF-κB and MAPK signaling inhibition. Since mangiferin is a natural compound with little toxicity, the results may contribute to the effective utilization of mangiferin in the treatment of human IBD. Copyright © 2014 Elsevier B.V. All rights reserved.

The PACA Project: Convergence of Scientific Research, Social Media and Citizen Science in the Era of Astronomical Big Data

NASA Astrophysics Data System (ADS)

Yanamandra-Fisher, Padma A.

2015-08-01

The Pro-Am Collaborative Astronomy (PACA) project promotes and supports the professional-amateur astronomer collaboration in scientific research via social media and has been implemented in several comet observing campaigns. In 2014, two comet observing campaigns involving pro-am collaborations were initiated: (1) C/2013 A1 (C/SidingSpring) and (2) 67P/Churyumov-Gerasimenko (CG), target for ESA/Rosetta mission. The evolving need for individual customized observing campaigns has been incorporated into the evolution of The PACA Project that currently is focused on comets: from supporting observing campaigns of current comets, legacy data, historical comets; interconnected with social media and a set of shareable documents addressing observational strategies; consistent standards for data; data access, use, and storage, to align with the needs of professional observers in the era of astronmical big data. The empowerment of amateur astronomers vis-à-vis their partnerships with the professional scientists creates a new demographic of data scientists, enabling citizen science of the integrated data from both the professional and amateur communities.While PACA identifies a consistent collaborative approach to pro-am collaborations, given the volume of data generated for each campaign, new ways of rapid data analysis, mining access and storage are needed. Several interesting results emerged from the synergistic inclusion of both social media and amateur astronomers. The PACA Project is expanding to include pro-am collaborations on other solar system objects; allow for immersive outreach and include various types of astronomical communities, ranging from individuals, to astronmical societies and telescopic networks. Enabling citizen science research in the era of astronomical big data is a challenge which requires innovative approaches and integration of professional and amateur astronomers with data scientists and some examples of recent projects will be highlighted.

The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen.

PubMed

Abdul-Sada, Hussein; Müller, Marietta; Mehta, Rajni; Toth, Rachel; Arthur, J Simon C; Whitehouse, Adrian; Macdonald, Andrew

2017-04-11

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with a high metastatic potential. The majority of MCC cases are caused by the Merkel cell polyomavirus (MCPyV), through expression of the virus-encoded tumour antigens. Whilst mechanisms attributing tumour antigen expression to transformation are being uncovered, little is known of the mechanisms by which MCPyV persists in the host. We previously identified the MCPyV small T antigen (tAg) as a novel inhibitor of nuclear factor kappa B (NF-kB) signalling and a modulator of the host anti-viral response. Here we demonstrate that regulation of NF-kB activation involves a previously undocumented interaction between tAg and regulatory sub-unit 1 of protein phosphatase 4 (PP4R1). Formation of a complex with PP4R1 and PP4c is required to bridge MCPyV tAg to the NEMO adaptor protein, allowing deactivation of the NF-kB pathway. Mutations in MCPyV tAg that fail to interact with components of this complex, or siRNA depletion of PP4R1, prevents tAg-mediated inhibition of NF-kB and pro-inflammatory cytokine production. Comparison of tAg binding partners from other human polyomavirus demonstrates that interactions with NEMO and PP4R1 are unique to MCPyV. Collectively, these data identify PP4R1 as a novel target for virus subversion of the host anti-viral response.

Simultaneous imaging of temporal changes of NF-κB activity and viable tumor cells in Huh7/NF-κB-tk-luc2/rfp tumor-bearing mice.

PubMed

Wang, Wei-Hsun; Chiang, I-Tsang; Liu, Yu-Chang; Hsu, Fei-Ting; Chen, Hong-Wen; Chen, Chuan-Lin; Lee, Yi-Jang; Lin, Wuu-Jyh; Hwang, Jeng-Jong

2013-01-01

Few studies have reported that the effect of sorafenib on advanced human hepatocellular carcinoma (HCC) is taking place via the inhibition of NF-κB signal transduction. Here we constructed a human HCC Huh7 stable clone with NF-κB-responsive element to drive dual reporter genes, herpes simplex virus thymidine kinase (tk) and firefly luciferase (luc2), and co-transfected with a third red fluorescent protein (rfp) gene, renamed as Huh7/NF-κB-tk-luc2/rfp cells, and combined with bioluminescent imaging (BLI) and red fluorescent protein imaging (RFPI) to monitor the effect of sorafenib on NF-κB activation and tumor inhibition. The results show that sorafenib could suppress the NF-κB-DNA binding activity, and the expression of downstream effector proteins. Notably, the relative photon fluxes obtained from RFPI and BLI, which represent the viable tumor cells and cells with NF-κB activation, decreased after sorafenib treatment by 50 to 65%, and 87.5 to >90%, respectively, suggesting that NF-κB activation is suppressed in viable HCC cells by sorafenib. Simultaneous molecular imaging of the temporal change of NF-κB activity and of viable cells in the same Huh7/NF-κB-tk-luc2/rfp tumors of the animal may reflect the real status of NF-κB activity and the viable tumor cells at the time of imaging.

Zebrafish as a Model to Study NF1-Associated Learning Deficits

DTIC Science & Technology

2016-07-01

characterized by attention deficit and learning disabilities . The NF1 protein govern distinct aspects of cognitive behavior: the NF1- GRD attenuates Ras...most prominently scholastic under-performance characterized by attention deficit and learning disabilities . The NF1 protein govern distinct...disorder associated with attention deficits and learning disabilities . The primary known function of neurofibromin, encoded by the NF1 gene, is to

Language Integrated Technology Project Final Evaluation Report.

ERIC Educational Resources Information Center

Stiegemeier, Lois

The goal of the Language Integrated Technology Grant Project (LIT) consortium was to help provide critical components of successful reading programs through a combination of proven computer/print programs and teacher training. Through leadership provided by the Educational Service District 113 (Olympia, Washington), the LIT consortium of schools…

The PRO-AM Lunar Impact project Exoss

NASA Astrophysics Data System (ADS)

De Cicco, Marcelo

2016-04-01

In order to attain its goals, the Exoss project is now launching the lunar impact project - monitoring meteoroids impacts, using telescope observations of the non-illuminated side of the moon, looking for flashes that could be meteoroids striking the lunar surface, through a remote observatory.

Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells (NF-κB) - a Friend, a Foe, or a Bystander - in the Neurodegenerative Cascade and Pathogenesis of Alzheimer's Disease.

PubMed

Marwarha, Gurdeep; Ghribi, Othman

2017-01-01

NF-κB is a ubiquitous transcription factor that was discovered three decades ago. Since its discovery, this protein complex has been implicated in numerous physiological and pathophysiological processes such as synaptic plasticity, learning and memory, inflammation, insulin resistance, and oxidative stress among other factors that are intricately involved and dysregulated in Alzheimer's disease (AD). We embarked on a methodical and an objective review of contemporary literature to integrate the indispensable physiological functions of NF-κB in neuronal phsyiology with the undesirable pathophysiological attributes of NF-κB in the etiopathogenesis of Alzheimer's disease. In our approach, we first introduced Alzheimer's disease and subsequently highlighted the multifaceted roles of NF-κB in the biological processes altered in the progression of Alzheimer's disease including synaptic transmission, synaptic plasticity, learning, and memory, neuronal survival and apoptosis, adult neurogenesis, regulation of neural processes and structural plasticity, inflammation, and Amyloid-β production and toxicity. Our comprehensive review highlights and dissects the physiological role of NF-κB from its pathological role in the brain and delineates both, its beneficial as well as deleterious, role in the etiopathogenesis of Alzheimer's disease. In light of our understanding of the duality of the role of NF-κB in the pathogenesis of Alzheimer's disease, further studies are warranted to dissect and understand the basis of the dichotomous effects of NF-κB, so that certain selective benevolent and benign attributes of NF-κB can be spared while targeting its deleterious attributes and facets that are integral in the pathogenesis of Alzheimer's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

NF45/ILF2 tissue expression, promoter analysis, and interleukin-2 transactivating function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao Guohua; Shi Lingfang; Qiu Daoming

2005-05-01

NF45/ILF2 associates with NF90/ILF3 in the nucleus and regulates IL-2 gene transcription at the antigen receptor response element (ARRE)/NF-AT DNA target sequence (P.N. Kao, L. Chen, G. Brock, J. Ng, A.J. Smith, B. Corthesy, J. Biol. Chem. 269 (1994) 20691-20699). NF45 is widely expressed in normal tissues, especially testis, brain, and kidney, with a predominantly nuclear distribution. NF45 mRNA expression is increased in lymphoma and leukemia cell lines. The human and murine NF45 proteins differ only by substitution of valine by isoleucine at amino acid 142. Fluorescence in situ hybridization localized the human NF45 gene to chromosome 1q21.3, and mousemore » NF45 gene to chromosome 3F1. Promoter analysis of 2.5 kB of the murine NF45 gene reveals that significant activation is conferred by factors, possible including NF-Y, that bind to the CCAAT-box sequence. The function of human NF45 in regulating IL-2 gene expression was characterized in Jurkat T-cells stably transfected with plasmids directing expression of NF45 cDNA in sense or antisense orientations. NF45 sense expression increased IL-2 luciferase reporter gene activity 120-fold, and IL-2 protein expression 2-fold compared to control cells. NF45 is a highly conserved, regulated transcriptional activator, and one target gene is IL-2.« less

Contextualising and Analysing Planetary Rover Image Products through the Web-Based PRoGIS

NASA Astrophysics Data System (ADS)

Morley, Jeremy; Sprinks, James; Muller, Jan-Peter; Tao, Yu; Paar, Gerhard; Huber, Ben; Bauer, Arnold; Willner, Konrad; Traxler, Christoph; Garov, Andrey; Karachevtseva, Irina

2014-05-01

The international planetary science community has launched, landed and operated dozens of human and robotic missions to the planets and the Moon. They have collected various surface imagery that has only been partially utilized for further scientific purposes. The FP7 project PRoViDE (Planetary Robotics Vision Data Exploitation) is assembling a major portion of the imaging data gathered so far from planetary surface missions into a unique database, bringing them into a spatial context and providing access to a complete set of 3D vision products. Processing is complemented by a multi-resolution visualization engine that combines various levels of detail for a seamless and immersive real-time access to dynamically rendered 3D scenes. PRoViDE aims to (1) complete relevant 3D vision processing of planetary surface missions, such as Surveyor, Viking, Pathfinder, MER, MSL, Phoenix, Huygens, and Lunar ground-level imagery from Apollo, Russian Lunokhod and selected Luna missions, (2) provide highest resolution & accuracy remote sensing (orbital) vision data processing results for these sites to embed the robotic imagery and its products into spatial planetary context, (3) collect 3D Vision processing and remote sensing products within a single coherent spatial data base, (4) realise seamless fusion between orbital and ground vision data, (5) demonstrate the potential of planetary surface vision data by maximising image quality visualisation in 3D publishing platform, (6) collect and formulate use cases for novel scientific application scenarios exploiting the newly introduced spatial relationships and presentation, (7) demonstrate the concepts for MSL, (9) realize on-line dissemination of key data & its presentation by a web-based GIS and rendering tool named PRoGIS (Planetary Robotics GIS). PRoGIS is designed to give access to rover image archives in geographical context, using projected image view cones, obtained from existing meta-data and updated according to

Foot-and-mouth disease virus infection suppresses autophagy and NF-кB antiviral responses via degradation of ATG5-ATG12 by 3Cpro.

PubMed

Fan, Xuxu; Han, Shichong; Yan, Dan; Gao, Yuan; Wei, Yanquan; Liu, Xiangtao; Liao, Ying; Guo, Huichen; Sun, Shiqi

2017-01-19

Autophagy-related protein ATG5-ATG12 is an essential complex for the autophagophore elongation in autophagy, which has been reported to be involved in foot-and-mouth disease virus (FMDV) replication. Previous reports show that ATG5-ATG12 positively or negatively regulates type I interferon (IFN-α/β) pathway during virus infection. In this study, we found that FMDV infection rapidly induced LC3 lipidation and GFP-LC3 subcellular redistribution at the early infection stage in PK-15 cells. Along with infection time course to 2-5 h.p.i., the levels of LC3II and ATG5-ATG12 were gradually reduced. Further study showed that ATG5-ATG12 was degraded by viral protein 3C pro , demonstrating that FMDV suppresses autophagy along with viral protein production. Depletion of ATG5-ATG12 by siRNA knock down significantly increased the FMDV yields, whereas overexpression of ATG5-ATG12 had the opposite effects, suggesting that degradation of ATG5-ATG12 benefits virus growth. Further experiment showed that overexpression of ATG5-ATG12 positively regulated NF-кB pathway during FMDV infection, marked with promotion of IKKα/β phosphorylation and IκBα degradation, inhibition of p65 degradation, and facilitation of p65 nuclear translocation. Meanwhile, ATG5-ATG12 also promoted the phosphorylation of TBK1 and activation of IRF3 via preventing TRAF3 degradation. The positive regulation of NF-кB and IRF3 pathway by ATG5-ATG12 resulted in enhanced expression of IFN-β, chemokines/cytokines, and IFN stimulated genes, including anti-viral protein PKR. Altogether, above findings suggest that ATG5-ATG12 positively regulate anti-viral NF-κB and IRF3 signaling during FMDV infection, thereby limiting FMDV proliferation. FMDV has evolved mechanisms to counteract the antiviral function of ATG5-ATG12, via degradation of them by viral protein 3C pro .

Texas' Project RIO (Re-Integration of Offenders): Program Focus.

ERIC Educational Resources Information Center

Finn, Peter

Texas's Project RIO (Re-Integration of Offenders), which was developed in cooperation with the National Institute of Justice, National Institute of Corrections, and U.S. Department of Education's Office of Correctional Education, began in 1985 as a two-city pilot program to place parolees in jobs. Project RIO has since expanded steadily and now…

Calibration of a COTS Integration Cost Model Using Local Project Data

NASA Technical Reports Server (NTRS)

Boland, Dillard; Coon, Richard; Byers, Kathryn; Levitt, David

1997-01-01

The software measures and estimation techniques appropriate to a Commercial Off the Shelf (COTS) integration project differ from those commonly used for custom software development. Labor and schedule estimation tools that model COTS integration are available. Like all estimation tools, they must be calibrated with the organization's local project data. This paper describes the calibration of a commercial model using data collected by the Flight Dynamics Division (FDD) of the NASA Goddard Spaceflight Center (GSFC). The model calibrated is SLIM Release 4.0 from Quantitative Software Management (QSM). By adopting the SLIM reuse model and by treating configuration parameters as lines of code, we were able to establish a consistent calibration for COTS integration projects. The paper summarizes the metrics, the calibration process and results, and the validation of the calibration.

Progress of the Enhanced Hanford Single Shell Tank (SST) Integrity Project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venetz, Theodore J.; Washenfelder, Dennis J.; Boomer, Kayle D.

2015-01-07

To improve the understanding of the single-shell tanks (SSTs) integrity, Washington River Protection Solutions, LLC (WRPS), the USDOE Hanford Site tank contractor, developed an enhanced Single-Shell Tank Integrity Project (SSTIP) in 2009. An expert panel on SST integrity, consisting of various subject matters experts in industry and academia, was created to provide recommendations supporting the development of the project. This panel developed 33 recommendations in four main areas of interest: structural integrity, liner degradation, leak integrity and prevention, and mitigation of contamination migration. In late 2010, seventeen of these recommendations were used to develop the basis for the M-45-10-1 Changemore » Package for the Hanford Federal Agreement and Compliance Order, which is also known as the Tri-Party Agreement.« less

Theory, modeling, and integrated studies in the Arase (ERG) project

NASA Astrophysics Data System (ADS)

Seki, Kanako; Miyoshi, Yoshizumi; Ebihara, Yusuke; Katoh, Yuto; Amano, Takanobu; Saito, Shinji; Shoji, Masafumi; Nakamizo, Aoi; Keika, Kunihiro; Hori, Tomoaki; Nakano, Shin'ya; Watanabe, Shigeto; Kamiya, Kei; Takahashi, Naoko; Omura, Yoshiharu; Nose, Masahito; Fok, Mei-Ching; Tanaka, Takashi; Ieda, Akimasa; Yoshikawa, Akimasa

2018-02-01

Understanding of underlying mechanisms of drastic variations of the near-Earth space (geospace) is one of the current focuses of the magnetospheric physics. The science target of the geospace research project Exploration of energization and Radiation in Geospace (ERG) is to understand the geospace variations with a focus on the relativistic electron acceleration and loss processes. In order to achieve the goal, the ERG project consists of the three parts: the Arase (ERG) satellite, ground-based observations, and theory/modeling/integrated studies. The role of theory/modeling/integrated studies part is to promote relevant theoretical and simulation studies as well as integrated data analysis to combine different kinds of observations and modeling. Here we provide technical reports on simulation and empirical models related to the ERG project together with their roles in the integrated studies of dynamic geospace variations. The simulation and empirical models covered include the radial diffusion model of the radiation belt electrons, GEMSIS-RB and RBW models, CIMI model with global MHD simulation REPPU, GEMSIS-RC model, plasmasphere thermosphere model, self-consistent wave-particle interaction simulations (electron hybrid code and ion hybrid code), the ionospheric electric potential (GEMSIS-POT) model, and SuperDARN electric field models with data assimilation. ERG (Arase) science center tools to support integrated studies with various kinds of data are also briefly introduced.[Figure not available: see fulltext.

Channelling urban modernity to sustainable pro-poor tourism development in Indonesia

NASA Astrophysics Data System (ADS)

Prasetyanti, R.

2017-06-01

Sustainable urban planning and development requires not only a fast-growing economic growth and modernity, but also social equity and environmental sustainability. Meanwhile, the global goals of sustainable development have fascinatingly set a promising urban development future by enhancing ecology based pro-poor policy program. Apparently, pro-poor development agenda has led to the notion of pro-poor tourism as part of urban development strategies on poverty alleviation. This research presents Jakarta Hidden Tour and Kampung Warna-warni as certain cases of pro-poor tourism in Indonesia. By the emergence of criticism on “pro-growth” paradigm, the critical analysis of this research focuses on the scenario of sustainable pro-poor tourism through eco-cultural based Kampung-Tour development. In accordance, debates and dilemma have been continuously arising as pros and cons regarding the ethical issues of poverty alleviation based Kampung-Tour development. Nevertheless, this paper tries to redefine Slum Kampung as potential; the writer wildly offers a concept of poverty alleviation by reinventing pro-poor tourism strategy; revitalizing slum site to eco-cultural based pro-poor tourism development as an embodiment of a sustainable urban development. By holding system thinking analysis as research method, sustainable pro-poor tourism highlights the urgency community based tourism and eco-tourism so that poverty alleviation based tourism can be tangibly perceived by the poor. In this sense, good local governance and public private partnership must be enhanced, it is due to, like any other development projects; sustainable pro-poor tourism needs a strong political commitment to alleviate urban poverty, as well as to pursue a better future of sustainable nation.

Anti-inflammatory effects of ethanolic extract from Sargassum horneri (Turner) C. Agardh on lipopolysaccharide-stimulated macrophage activation via NF-κB pathway regulation.

PubMed

Kim, Mi Eun; Jung, Yun Chan; Jung, Inae; Lee, Hee-Woo; Youn, Hwa-Young; Lee, Jun Sik

2015-01-01

Inflammation is major symptom of the innate immune response by infection of microbes. Macrophages, one of immune response related cells, play a role in inflammatory response. Recent studies reported that various natural products can regulate the activation of immune cells such as macrophage. Sargassum horneri (Turner) C. Agardh is one of brown algae. Recently, various seaweeds including brown algae have antioxidant and anti-inflammatory effects. However, anti-inflammatory effects of Sargassum horneri (Turner) C. Agardh are still unknown. In this study, we investigated anti-inflammatory effects of ethanolic extract of Sargassum horneri (Turner) C. Agardh (ESH) on RAW 264.7 murine macrophage cell line. The ESH was extracted from dried Sargassum horneri (Turner) C. Agardh with 70% ethanol and then lyophilized at -40 °C. ESH was not cytotoxic to RAW 264.7, and nitric oxide (NO) production induced by LPS-stimulated macrophage activation was significantly decreased by the addition of 200 μg/mL of ESH. Moreover, ESH treatment reduced mRNA level of cytokines, including IL-1β, and pro-inflammatory genes such as iNOS and COX-2 in LPS-stimulated macrophage activation in a dose-dependent manner. ESH was found to elicit anti-inflammatory effects by inhibiting ERK, p-p38 and NF-κB phosphorylation. In addition, ESH inhibited the release of IL-1β in LPS-stimulated macrophages. These results suggest that ESH elicits anti-inflammatory effects on LPS-stimulated macrophage activation via the inhibition of ERK, p-p38, NF-κB, and pro-inflammatory gene expression.

Interdependence and Integration Learning in Student Project Teams: Do Team Project Assignments Achieve What We Want Them to?

ERIC Educational Resources Information Center

Skilton, Paul F.; Forsyth, David; White, Otis J.

2008-01-01

Building from research on learning in workplace project teams, the authors work forward from the idea that the principal condition enabling integration learning in student team projects is project complexity. Recognizing the challenges of developing and running complex student projects, the authors extend theory to propose that the experience of…

Research a Novel Integrated and Dynamic Multi-object Trade-Off Mechanism in Software Project

NASA Astrophysics Data System (ADS)

Jiang, Weijin; Xu, Yuhui

Aiming at practical requirements of present software project management and control, the paper presented to construct integrated multi-object trade-off model based on software project process management, so as to actualize integrated and dynamic trade-oil of the multi-object system of project. Based on analyzing basic principle of dynamic controlling and integrated multi-object trade-off system process, the paper integrated method of cybernetics and network technology, through monitoring on some critical reference points according to the control objects, emphatically discussed the integrated and dynamic multi- object trade-off model and corresponding rules and mechanism in order to realize integration of process management and trade-off of multi-object system.

Evaluation of Supported Placements in Integrated Community Environments Project (SPICE). Final Report.

ERIC Educational Resources Information Center

Wilson, Leslie; And Others

This evaluation project was designed to assess 37 persons (ages 21-72) who had moved from intermediate care facilities or skilled nursing facilities into innovative one-person or two-person community integrated living arrangements as a result of the Supported Placements in Integrated Community Environments project. The 37 persons had severe or…

Smoothing single-crystalline SiC surfaces by reactive ion etching using pure NF{sub 3} and NF{sub 3}/Ar mixture gas plasmas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tasaka, Akimasa, E-mail: aki-tasaka-load@yahoo.co.jp; Kotaka, Yuki; Oda, Atsushi

2014-09-01

In pure NF{sub 3} plasma, the etching rates of four kinds of single-crystalline SiC wafer etched at NF{sub 3} pressure of 2 Pa were the highest and it decreased with an increase in NF{sub 3} pressure. On the other hand, they increased with an increase in radio frequency (RF) power and were the highest at RF power of 200 W. A smooth surface was obtained on the single-crystalline 4H-SiC after reactive ion etching at NF{sub 3}/Ar gas pressure of 2 Pa and addition of Ar to NF{sub 3} plasma increased the smoothness of SiC surface. Scanning electron microscopy observation revealed that the numbermore » of pillars decreased with an increase in the Ar-concentration in the NF{sub 3}/Ar mixture gas. The roughness factor (R{sub a}) values were decreased from 51.5 nm to 25.5 nm for the As-cut SiC, from 0.25 nm to 0.20 nm for the Epi-SiC, from 5.0 nm to 0.7 nm for the Si-face mirror-polished SiC, and from 0.20 nm to 0.16 nm for the C-face mirror-polished SiC by adding 60% Ar to the NF{sub 3} gas. Both the R{sub a} values of the Epi- and the C-face mirror-polished wafer surfaces etched using the NF{sub 3}/Ar (40:60) plasma were similar to that treated with mirror polishing, so-called the Catalyst-Referred Etching (CARE) method, with which the lowest roughness of surface was obtained among the chemical mirror polishing methods. Etching duration for smoothing the single-crystalline SiC surface using its treatment was one third of that with the CARE method.« less

Ras-Independent Function of NF1

DTIC Science & Technology

2013-05-01

required to fulfill this process. Moreover, the skin disease we observed in those mice is psoriasis . 15. SUBJECT TERMS Neurofibromin (NF1), Ras...factor such as age contributes to the process. 3d. Proposed work: Determine the relation between NF1 and psoriasis (months 13-24). We will collect...several psoriasis related genes, such as Th17, IL22, IL23, CD68, CXCL8, CCL2, defensin-2 by quantitative PCR in the skin samples from the lesions

Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-κB signaling pathway.

PubMed

Zhou, Chen-hui; Wang, Chun-xi; Xie, Guang-bin; Wu, Ling-yun; Wei, Yong-xiang; Wang, Qiang; Zhang, Hua-sheng; Hang, Chun-hua; Zhou, Meng-liang; Shi, Ji-xin

2015-12-10

Early brain injury (EBI) determines the unfavorable outcomes after subarachnoid hemorrhage (SAH). Fisetin, a natural flavonoid, has anti-inflammatory and neuroprotection properties in several brain injury models, but the role of fisetin on EBI following SAH remains unknown. Our study aimed to explore the effects of fisetin on EBI after SAH in rats. Adult male Sprague-Dawley rats were randomly divided into the sham and SAH groups, fisetin (25mg/kg or 50mg/kg) or equal volume of vehicle was given at 30min after SAH. Neurological scores and brain edema were assayed. The protein expression of toll-like receptor 4 (TLR 4), p65, ZO-1 and bcl-2 was examined by Western blot. TLR 4 and p65 were also assessed by immunohistochemistry (IHC). Enzyme-linked immunosorbent assay (ELISA) was performed to detect the production of pro-inflammatory cytokines. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) was perform to assess neural cell apoptosis. High-dose (50mg/kg) fisetin significantly improved neurological function and reduced brain edema at both 24h and 72h after SAH. Remarkable reductions of TLR 4 expression and nuclear factor κB (NF-κB) translocation to nucleus were detected after fisetin treatment. In addition, fisetin significantly reduced the productions of pro-inflammatory cytokines, decreased neural cell apoptosis and increased the protein expression of ZO-1 and bcl-2. Our data provides the evidence for the first time that fisetin plays a protective role in EBI following SAH possibly by suppressing TLR 4/NF-κB mediated inflammatory pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes.

PubMed

Yuan, YiFeng; Das, Sushant K; Li, MaoQuan

2018-04-27

Diabetic wounds are characterized by delayed wound healing due to persistent inflammation and excessive production of reactive oxygen species. Vitamin D, which is well acknowledged to enhance intestinal calcium absorption and increase in plasma calcium level, has recently been shown to display beneficial effects in various vascular diseases by promoting angiogenesis and inhibiting inflammatory responses. However, the role of Vitamin D in diabetic wound healing is still unclear. In the present study, we investigated the role of Vitamin D in cutaneous wound healing in streptozotocin (STZ)-induced diabetic mice. Four weeks after injection of STZ, a full thickness excisional wound was created with a 6-mm diameter sterile biopsy punch on the dorsum of the mice. Vitamin D was given consecutively for 14 days by intraperitoneal injection. Vitamin D supplementation significantly accelerated wound healing in diabetic mice and improved the healing quality as assessed by measuring the wound closure rate and histomorphometric analyses. By monitoring the level of pro-inflammatory cytokines tumor necrosis factor-α ( TNF-α ), interleukin (IL) 6 ( IL-6 ), IL-1β ) in the wounds, reduced inflammatory response was found in VD treatment group. Furthermore, nuclear factor κB (NF-κB) pathway was found to be involved in the process of diabetic wound healing by assessing the relative proteins in diabetic wounds. Vitamin D supplementation obviously suppressed NF-κB pathway activation. These results demonstrated that Vitamin D improves impaired wound healing in STZ-induced diabetic mice through suppressing NF-κB-mediated inflammatory gene expression. © 2018 The Author(s).

Inter-organizational collaboration projects in the public sector: a balance between integration and demarcation.

PubMed

Löfström, Mikael

2010-01-01

For several years, the development of the Swedish public sector has been accompanied by a discussion about inter-organizational collaboration, which has been examined in several national experiments. The experience, however, indicates significant difficulties in implementing collaboration in local authorities' regular activities. This article argues that organizing inter-organizational collaboration in projects tends to be counterproductive, since the purpose of this collaboration is to increase the integration of local authorities. This article is based on case studies of three different collaboration projects. Each project is analyzed in relation to the way collaboration is organized within the project and how the relationship to the local authorities' activities is designed. The outcome of these studies shows that while collaboration projects increase integration between the responsible authorities, the integration stays within the projects. This is due to the fact that the projects were designed as units separate from the responsible authorities. As a result, the collaboration that occurs in the projects is not implemented in the local authorities' activities, and the viability of the increased integration of different responsible authorities does not extend beyond the projects. Copyright (c) 2009 John Wiley & Sons, Ltd.