scholarly journals The contribution of N2O3 to the cytotoxicity of the nitric oxide donor DETA/NO: an emerging role for S-nitrosylation

2013 ◽  
Vol 33 (2) ◽  
Author(s):  
Ahlam A. Ali ◽  
Jonathan A. Coulter ◽  
Claire H. Ogle ◽  
Marie M. Migaud ◽  
David G. Hirst ◽  
...  
Keyword(s):  
Oxygen Tension ◽  
Hypoxia Inducible Factor ◽  
Tumour Microenvironment ◽  
Nitric Oxide Donor ◽  
Apoptotic Pathway ◽  
No Donor ◽  
Hypoxic Conditions ◽  
Fluorimetric Analysis ◽  
First Time ◽  
The Relationship

The relationship between the biological activity of NO and its chemistry is complex. The objectives of this study were to investigate the influence of oxygen tension on the cytotoxicity of the NO• donor DETA/NO and to determine the effects of oxygen tension on the key RNS (reactive nitrogen species) responsible for any subsequent toxicity. The findings presented in this study indicate that the DETA/NO-mediated cytotoxic effects were enhanced under hypoxic conditions. Further investigations revealed that neither ONOO− (peroxynitrite) nor nitroxyl was generated. Fluorimetric analysis in the presence of scavengers suggest for the first time that another RNS, dinitrogen trioxide may be responsible for the cytotoxicity with DETA/NO. Results showed destabilization of HIF (hypoxia inducible factor)-1α and depletion of GSH levels following the treatment with DETA/NO under hypoxia, which renders cells more susceptible to DETA/NO cytotoxicity, and could account for another mechanism of DETA/NO cytotoxicity under hypoxia. In addition, there was significant accumulation of nuclear p53, which showed that p53 itself might be a target for S-nitrosylation following the treatment with DETA/NO. Both the intrinsic apoptotic pathway and the Fas extrinsic apoptotic pathway were also activated. Finally, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) is another important S-nitrosylated protein that may possibly play a key role in DETA/NO-mediated apoptosis and cytotoxicity. Therefore this study elucidates further mechanisms of DETA/NO mediated cytotoxicity with respect to S-nitrosylation that is emerging as a key player in the signalling and detection of DETA/NO-modified proteins in the tumour microenvironment.

Role of N-acetyl-N-nitroso-tryptophan as nitric oxide donor in the modulation of HIF-1-dependent signaling

2010 ◽  
Vol 391 (5) ◽  
pp. 533-540 ◽  
Author(s):  
Utta Berchner-Pfannschmidt ◽  
Suzan Tug ◽  
Jun Hu ◽  
Buena Delos Reyes ◽  
Joachim Fandrey ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Animal Studies ◽  
Hypoxia Inducible Factor ◽  
Nitric Oxide Donor ◽  
Strong Increase ◽  
No Donor ◽  
No Donors ◽  
Hypoxic Conditions

Abstract N-Acetyl-N-nitroso-tryptophan (NANT) is well known for its capacity to generate nitric oxide (NO)-releasing compounds. It is unknown, however, whether NANT can be successfully applied as a precursor of NO in a complex biological environment such as a cell culture system. NO donors can be useful to induce the transcription factor hypoxia-inducible factor 1 (HIF-1) that coordinates the protection of cells and tissues from the lack of oxygen, termed hypoxia. HIF-1 degradation is controlled by prolyl hydroxylase 2 (PHD2) which needs to be inhibited for HIF-1 accumulation. Here, the effects of NANT in inhibiting recombinant PHD2 and up-regulating of HIF-1 and HIF-1-mediated carboanhydrase-9 (CA9) mRNA expression were compared in living cells with the NO donors N-nitrosomelatonin (NOMela) and S-nitrosoglutathione (GSNO) under normoxic and hypoxic conditions. In contrast to GSNO, NANT was similar to NOMela being highly effective in inhibiting recombinant PHD2. NANT-mediated activation of HIF-1 in oxygenated cells was comparable to hypoxic activation of HIF-1 in all cases. In contrast, under hypoxia NANT was able to boost hypoxic cellular HIF-1 levels by further reducing the activity of cellular PHD2. The strong increase of HIF-dependent CA9 mRNA expression demonstrated that NANT-induced HIF-1 was transcriptionally active. Finally, the efficacy of NANT to increase both HIF-1 and CA9 mRNA did not depend on the absolute conformation of the tryptophan moiety. In conclusion, NANT appears to be an excellent NO donor for cells in culture and l-NANT should be useful for in vivo animal studies.

370 Hypoxic Conditions and Hypoxia-Inducible Factor 1-Alpha are Critical in the Radioresistance of Meningioma

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 286-287
Author(s):  
Michael Karsy ◽  
David Gillespie ◽  
Randy L Jensen
Keyword(s):  
Cell Viability ◽  
Cell Density ◽  
Cell Lines ◽  
Oxygen Tension ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Fractionated Radiotherapy ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Meningioma Cell

Abstract INTRODUCTION Meningiomas are common benign intracranial neoplasms treated with a combination of surgical resection, radiotherapy, and chemotherapy. Hypoxia-inducible factor 1 alpha (HIF1A) can predict disease aggressiveness, response to oxygen tension and regulate meningioma pathogenesis. The role of HIF1A and hypoxia was explored in the radiation resistance of meningioma, hypothesizing that HIF1A confers resistance to radiotherapy in meningiomas and that oxygen tension is key to radiation responsiveness. METHODS Various primary meningioma cell lines were studied (IOMM-LE, JEN, GAR, SAM). GAR primary cell lines were utilized in addition to a shRNA-HIF1A knockdown (GAR1589). Cell proliferation, viability, and apoptosis were evaluated in response to radiation in both normoxia (21% O2) and hypoxia (1% O2). RESULTS >Doubling times of the various meningioma cell lines ranged from 19.5 to 213.2 hours. Cell density impacted responsiveness to radiation, with confluent cells showing greater dose tolerance before reduced proliferation. In normoxic environments, HIF1A knockout resulted in increased susceptibility to single radiation fractions of 2 Gy (P = 0.05) and 10 Gy (P = 0.02); however, both cells had strong susceptibility at 20 Gy. Hypoxic environments reduced the viability differences between GAR and GAR1589 cells and slightly increased GAR cell viability at 2 Gy (P < 0.05). Fractionated radiotherapy (2 Gy) daily showed reduced GAR and GAR1589 cell viability in normoxia and hypoxia. Cell viability for GAR1589 at 3 fractions of 2-Gy radiation was reduced, but this effect was eliminated in hypoxic environments. Apoptosis was increased in GAR1589 cells at baseline and with increased fractions of radiation; however, this effect was reduced in hypoxic conditions. CONCLUSION These results support important findings for meningioma response to radiation, including 1) importance of cell density, 2) dependence on HIF1A mutation, and 3) a critical role for oxygen tension. These results may be helpful in understanding the mechanisms of meningioma resistance to radiation and serve as a model to trial novel adjuvant therapies and treatment types.

scholarly journals Hypoxia Inducible Factor-1α Is a Regulator of Autophagy in Osteoarthritic Chondrocytes

Cartilage ◽  
2021 ◽  
pp. 194760352110354
Author(s):  
Junren Lu ◽  
Yi Peng ◽  
Jiapeng Zou ◽  
Jiayi Wang ◽  
Shunyi Lu ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α ◽  
Hypoxic Conditions ◽  
Osteoarthritic Chondrocytes ◽  
Species Production ◽  
Related Proteins ◽  
The Relationship ◽  
Inflammatory Insult

Objective To investigate the relationship between hypoxia inducible factor-1α (HIF-1α) and the autophagic response in osteoarthritic chondrocytes (OA), under inflammatory insult as represented by in vitro OA model. Methods Human chondrocyte cell line C28/I2 was cultured in both normoxic and hypoxic conditions and treated with interleukin-1β (IL1β) to emulate OA inflammatory insult in vitro. Cellular HIF-1α expression was silenced using siRNA transfection and cellular autophagic (P62/LC3II) response and OA chondrocyte damage (COL2A1/MMP13) related proteins were examined using western blotting. Cellular mitophagic (BNIP3/PINK1/Parkin) and apoptotic (Caspase/Cleaved Caspase 3) were also evaluated to assess mitophagy-mediated cell death due to HIF-1α silencing. Results Chondrocyte basal autophagy levels were higher in a HIF-1α elevated environment and was more resistant to IL1β-induced inflammatory insult. Increase in autophagic proteins showed better chondrocyte repair, which resulted a lower level of reactive oxygen species production, and lesser damage to chondrocyte integrity. Silencing HIF-1α activates cellular PINK1/Parkin and BNIP3 mitophagic proteins, which leads to the activation of Caspase/Cleaved Caspase 3 apoptotic cascade. Conclusion Our results show that chondrocyte autophagy is dependent on HIF-1α expression, showing the importance of HIF-1α in hypoxic chondrocyte function in OA. Dysregulation of HIF-1α expression results in the activation of mitophagy-mediated apoptosis.

Affirmative Action and Leadership Attitudes in Brazilian Women Managers

2011 ◽  
Vol 10 (3) ◽  
pp. 139-143 ◽  
Author(s):  
Gazi Islam ◽  
Sarah E. S. Zilenovsky
Keyword(s):  
Affirmative Action ◽  
Latin American ◽  
Women Managers ◽  
Psychological Effects ◽  
Preferential Selection ◽  
Justice Perceptions ◽  
First Time ◽  
The Relationship

This note examines the relationship between affirmative action (AA) program perceptions and women’s self-ascribed capacity and desire to become leaders. We propose that women who believe that their organization implements a program of preferential selection toward women will experience negative psychological effects leading to lowered self-expectations for leadership, but that this effect will be moderated by their justice perceptions of AA programs. We test this proposition empirically for the first time with a Latin American female sample. Among Brazilian women managers, desire but not self-ascribed capacity to lead was reduced when they believed an AA policy was in place. Both desire’s and capacity’s relationships with belief in an AA policy were moderated by justice perceptions.

ЗУБРЫ НА СЕВЕРЕ РОССИИ — НАСТОЯЩЕЕ И БУДУЩЕЕ

2019 ◽  
pp. 42-44
Author(s):  
I.V. GUSAROV ◽  
V.A. OSTAPENKO ◽  
T.V. NOVIKOVА
Keyword(s):  
Biological Diversity ◽  
Climatic Conditions ◽  
Economic Consequences ◽  
European Bison ◽  
Rare And Endangered Species ◽  
The North ◽  
Rare And Endangered ◽  
Relationship Of ◽  
First Time ◽  
The Relationship

Впервые в мире создана популяция зубров на территории 60 градусов северной широты. В новых климатических условиях разведения и сохранения зубров определены и проанализированы факторы существования вида на севере Европейской части РФ. Выявлены признаки, динамика численности, которые являются составной частью системы, предназначенной для управления биоразнообразием. Интродукция, являясь процессом введения в экосистему нехарактерных для нее видов, может усиливать изменения биоценозов как положительно, так и отрицательно. Насколько быстро и успешно проходит процесс адаптации заселенного вида, и усматривается его влияние на окружающую среду зависит дальнейшее существование зубров и в целом биоразнообразия. В статье обсуждаются вопросы взаимоотношения зубров с другими видами копытных и хозяйственной деятельностью человека, а также дальнейшим использованием зубров в сельскохозяйственном производстве. Пластичность зубров, выявление изменений и их анализ при вселении видов в новые условия обитания необходимы не только для определения развития или деградации биоценозов и в целом экосистемы, но и прогноза социально-экономических последствий интродукции как одного из методов сохранения редких и исчезающих видов фауны.For the first time in the world, a bison population has been created in an area of 60 degrees north latitude. In the new climatic conditions of breeding and preservation of bison, the factors of the species existence in the north of the European part of the Russian Federation are identified and analyzed. The signs, dynamics of abundance, which are an integral part of the system designed to manage biodiversity are identified, since the preservation of biological diversity on the planet is one of the main problems of our time. Introduction, being the process of introducing non-typical species into an ecosystem, can enhance changes in biocenoses, both positively and negatively. The question posing sounds especially when it comes to such a large hoofed animal as the European bison. How quickly and successfully the process of adaptation of the universe takes place and its environmental impact is seen depends on the continued existence of bison and biodiversity in general. The article discusses the relationship of bison with other types of ungulates and human activities, as well as the further use of bison in agricultural production. How these issues will be resolved positively depends on the future of these animals. Thus, the plasticity of bison, the identification of changes and their analysis, with the introduction of species into new habitat conditions is necessary not only to determine the development or degradation of biocenoses and the ecosystem as a whole, but also to predict the socio-economic consequences due to the introduction as one of the methods of preserving rare and endangered species of fauna.

A University Education

2017 ◽  
Author(s):  
David Willetts
Keyword(s):  
Higher Education ◽  
Modern Society ◽  
University Education ◽  
Modern World ◽  
Controversial Issues ◽  
The Us ◽  
The Individual ◽  
The University ◽  
First Time ◽  
The Relationship

Universities have a crucial role in the modern world. In England, entrance to universities is by nation-wide competition which means English universities have an exceptional influence on schools--a striking theme of the book. This important book first investigates the university as an institution and then tracks the individual on their journey to and through university. In A University Education, David Willetts presents a compelling case for the ongoing importance of the university, both as one of the great institutions of modern society and as a transformational experience for the individual. The book also makes illuminating comparisons with higher education in other countries, especially the US and Germany. Drawing on his experience as UK Minister for Universities and Science from 2010 to 2014, the author offers a powerful account of the value of higher education and the case for more expansion. He covers controversial issues in which he was involved from access for disadvantaged students to the introduction of L9,000 fees. The final section addresses some of the big questions for the future, such as the the relationship between universities and business, especially in promoting innovation.. He argues that the two great contemporary trends of globalisation and technological innovation will both change the university significantly. This is an authoritative account of English universities setting them for the first time in their new legal and regulatory framework.

scholarly journals Variation in VKORC1 Is Associated with Vascular Dementia

2021 ◽  
Vol 80 (3) ◽  
pp. 1329-1337
Author(s):  
Jure Mur ◽  
Daniel L. McCartney ◽  
Daniel I. Chasman ◽  
Peter M. Visscher ◽  
Graciela Muniz-Terrera ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vascular Dementia ◽  
Genetic Variant ◽  
Warfarin Dose ◽  
Uk Biobank ◽  
Parental History ◽  
Genome Wide ◽  
History Of ◽  
First Time ◽  
The Relationship

Background: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10–7), which was included in the genome-wide significant KAT8 locus. Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. Methods: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use. Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10–6). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele = –0.29, p < 2×10–16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.

scholarly journals ACE2 Is an Adjacent Element of Atherosclerosis and COVID-19 Pathogenesis

2021 ◽  
Vol 22 (9) ◽  
pp. 4691
Author(s):  
Anastasia V. Poznyak ◽  
Evgeny E. Bezsonov ◽  
Ali H. Eid ◽  
Tatyana V. Popkova ◽  
Ludmila V. Nedosugova ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Renin Angiotensin System ◽  
Myocardial Damage ◽  
Angiotensin Converting Enzyme 2 ◽  
Adjacent Element ◽  
Chinese Province ◽  
Coronavirus Infection ◽  
First Time ◽  
The Relationship ◽  
Interspecies Barrier

COVID-19 is a highly contagious new infection caused by the single-stranded RNA Sars-CoV-2 virus. For the first time, this infection was recorded in December 2019 in the Chinese province of Wuhan. The virus presumably crossed the interspecies barrier and passed to humans from a bat. Initially, the disease was considered exclusively in the context of damage to the respiratory system, but it quickly became clear that the disease also entails serious consequences from various systems, including the cardiovascular system. Among these consequences are myocarditis, myocardial damage, subsequent heart failure, myocardial infarction, and Takotsubo syndrome. On the other hand, clinical data indicate that the presence of chronic diseases in a patient aggravates the course and outcome of coronavirus infection. In this context, the relationship between COVID-19 and atherosclerosis, a condition preceding cardiovascular disease and other disorders of the heart and blood vessels, is particularly interesting. The renin-angiotensin system is essential for the pathogenesis of both coronavirus disease and atherosclerosis. In particular, it has been shown that ACE2, an angiotensin-converting enzyme 2, plays a key role in Sars-CoV-2 infection due to its receptor activity. It is noteworthy that this enzyme is important for the normal functioning of the cardiovascular system. Disruptions in its production and functioning can lead to various disorders, including atherosclerosis.

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