Suppression of chronic inflammation with engineered nanomaterials delivering nuclear factor κB transcription factor decoy oligodeoxynucleotides

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

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Immunolocalization and Activation of Transcription Factor Nuclear Factor κB in Dysimmune Neuropathies and Familial Amyloidotic Polyneuropathy

Archives of Neurology ◽

10.1001/archneur.61.7.1097 ◽

2004 ◽

Vol 61 (7) ◽

Cited By ~ 16

Author(s):

Anna Mazzeo ◽

Mohammed Aguennouz ◽

Corrado Messina ◽

Giuseppe Vita

Keyword(s):

Transcription Factor ◽

Nuclear Factor Κb ◽

Familial Amyloidotic Polyneuropathy ◽

Nuclear Factor ◽

Activation Of Transcription ◽

Dysimmune Neuropathies ◽

Transcription Factor Nuclear Factor

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Nuclear factor-κB: a transcription factor for all seasons

Expert Opinion on Therapeutic Targets ◽

10.1517/14728222.11.2.109 ◽

2007 ◽

Vol 11 (2) ◽

pp. 109-110 ◽

Cited By ~ 8

Author(s):

Bharat B Aggarwal

Keyword(s):

Transcription Factor ◽

Nuclear Factor Κb ◽

Nuclear Factor

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Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor κB to modulate tumour necrosis factor-induced apoptosis: evidence from mitochondria-targeted antioxidants

Biochemical Journal ◽

10.1042/bj20050078 ◽

2005 ◽

Vol 389 (1) ◽

pp. 83-89 ◽

Cited By ~ 102

Author(s):

Gillian HUGHES ◽

Michael P. MURPHY ◽

Elizabeth C. LEDGERWOOD

Keyword(s):

Reactive Oxygen Species ◽

Transcription Factor ◽

Tumour Necrosis ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Oxygen Species ◽

Mitochondrial Matrix ◽

Mitochondrial Ros ◽

Induced Apoptosis ◽

Necrosis Factor

ROS (reactive oxygen species) from mitochondrial and non-mitochondrial sources have been implicated in TNFα (tumour necrosis factor α)-mediated signalling. In the present study, a new class of specific mitochondria-targeted antioxidants were used to explore directly the role of mitochondrial ROS in TNF-induced apoptosis. MitoVit E {[2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethyl]triphenylphosphonium bromide} (vitamin E attached to a lipophilic cation that facilitates accumulation of the antioxidant in the mitochondrial matrix) enhanced TNF-induced apoptosis of U937 cells. In time course analyses, cleavage and activation of caspase 8 in response to TNF were not affected by MitoVit E, whereas the activation of caspase 3 was significantly increased. Furthermore, there was an increased cleavage of the proapoptotic Bcl-2 family member Bid and an increased release of cytochrome c from mitochondria, in cells treated with TNF in the presence of MitoVit E. We considered several mechanisms by which MitoVit E might accelerate TNF-induced apoptosis including mitochondrial integrity (ATP/ADP levels and permeability transition), alterations in calcium homoeostasis and transcription factor activation. Of these, only the transcription factor NF-κB (nuclear factor κB) was implicated. TNF caused maximal nuclear translocation of NF-κB within 15 min, compared with 1 h in cells pretreated with MitoVit E. Thus the accumulation of an antioxidant within the mitochondrial matrix enhances TNF-induced apoptosis by decreasing or delaying the expression of the protective antiapoptotic proteins. These results demonstrate that mitochondrial ROS production is a physiologically relevant component of the TNF signal-transduction pathway during apoptosis, and reveal a novel functional role for mitochondrial ROS as a temporal regulator of NF-κB activation and NF-κB-dependent antiapoptotic signalling.

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Upregulated Signaling Pathways in Ruptured Human Saccular Intracranial Aneurysm Wall: An Emerging Regulative Role of Toll-Like Receptor Signaling and Nuclear Factor-κB, Hypoxia-Inducible Factor-1A, and ETS Transcription Factors

Neurosurgery ◽

10.1227/neu.0b013e318210f001 ◽

2011 ◽

Vol 68 (6) ◽

pp. 1667-1676 ◽

Cited By ~ 59

Author(s):

Mitja I. Kurki ◽

Sanna-Kaisa Häkkinen ◽

Juhana Frösen ◽

Riikka Tulamo ◽

Mikael von und zu Fraunberg ◽

...

Keyword(s):

Transcription Factor ◽

Intracranial Aneurysm ◽

Signaling Pathways ◽

Binding Sites ◽

Hypoxia Inducible Factor ◽

Transcription Factor Binding Sites ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Factor Binding

Abstract BACKGROUND: Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a devastating form of stroke that affects the working-age population. Cellular and molecular mechanisms predisposing to the rupture of the sIA wall are largely unknown. This knowledge would facilitate the design of novel diagnostic tools and therapies for the sIA disease. OBJECTIVE: To investigate gene expression patterns distinguishing ruptured and unruptured sIA. METHODS: We compared the whole-genome expression profile of 11 ruptured sIA wall samples with that of 8 unruptured ones using oligonucleotide microarrays. Signaling pathways enriched in the ruptured sIA walls were identified with bioinformatic analyses. Their transcriptional control was predicted in silico by seeking the enrichment of conserved transcription factor binding sites in the promoter regions of differentially expressed genes. RESULTS: Overall, 686 genes were significantly upregulated and 740 were downregulated in the ruptured sIA walls. Significantly upregulated biological processes included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling; and extracellular matrix degradation. Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factor binding sites were significantly enriched among the upregulated genes. CONCLUSION: We identified pathways and candidate genes associated with the rupture of human sIA wall. Our results may provide clues to the molecular mechanism in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture.

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Macrophages in pancreatic cancer: Starting things off on the wrong track

The Journal of Cell Biology ◽

10.1083/jcb.201307066 ◽

2013 ◽

Vol 202 (3) ◽

pp. 403-405

Author(s):

Xavier Deschênes-Simard ◽

Yusuke Mizukami ◽

Nabeel Bardeesy

Keyword(s):

Pancreatic Cancer ◽

Chronic Inflammation ◽

Acinar Cells ◽

Nuclear Factor Κb ◽

Pancreatic Acinar Cells ◽

Nuclear Factor ◽

Oncogenic Transformation ◽

Transcriptional Program ◽

Cell Biol ◽

Inflammatory Macrophages

Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor κB transcriptional program in normal pancreatic acinar cells, resulting in acinar–ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation.

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