Understanding life and death decisions in human leukaemias

2014 ◽  
Vol 42 (4) ◽  
pp. 747-751
Author(s):  
David J. MacEwan ◽  
Lawrence N. Barrera ◽  
Sujitra Keadsanti ◽  
Stuart A. Rushworth ◽  
Niraj M. Shah ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Apoptotic Cell ◽  
Chemotherapy Resistance ◽  
Nuclear Factor Κb ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cellular Processes ◽  
Cell Death Mechanisms ◽  
Factor Α ◽  
Human Leukaemia

Human leukaemia cells have an often unique ability to either undergo apoptotic cell death mechanisms or, at other times, undergo proliferative expansion, sometimes to the same stimulus such as the pluripotent cytokine TNFα (tumour necrosis factor α). This potential for life/death switching helps us to understand the molecular signalling machinery that underlies these cellular processes. Furthermore, looking at the involvement of these switching signalling pathways that may be aberrant in leukaemia informs us of their importance in cancer tumorigenesis and how they may be targeted pharmacologically to treat various types of human leukaemias. Furthermore, these important pathways may play a crucial role in acquired chemotherapy resistance and should be studied further to overcome in the clinic many drug-resistant forms of blood cancers. In the present article, we uncover the relationship that exists in human leukaemia life/death switching between the anti-apoptotic pro-inflammatory transcription factor NF-κB (nuclear factor κB) and the cytoprotective antioxidant-responsive transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2). We also discuss recent findings that reveal a major role for Btk (Bruton's tyrosine kinase) in both lymphocytic and myeloid forms of human leukaemias and lymphomas.

6-Gingerol Ameliorates Sepsis Induced Acute Lung Injury by Regulating Nuclear Factor-κB and Nuclear-Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Signaling Pathways

2020 ◽  
Vol 19 (3) ◽  
pp. 255-260
Author(s):  
Fan Yang ◽  
Lu Deng ◽  
MuHu Chen ◽  
Ying Liu ◽  
Jianpeng Zheng
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Heme Oxygenase ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Alveolar Collapse ◽  
Factor Α

Acute lung injury initiated systemic inflammation leads to sepsis. Septic mice show a series of degenerative changes in lungs as demonstrated by pulmonary congestion, alveolar collapse, inflammatory cell infiltration, and increased wet-todry weight in lungs. 6-Gingerol ameliorates histopathological changes and clinical outcome of the sepsis. The increase in the levels of tumor necrosis factor-α, interleukin-1 beta, interleukin-6, and interleukin-18 in septic mice were reduced by administration with 6-Gingerol. Also, 6-Gingerol attenuates sepsis-induced increase of malonaldehyde and decrease of catalase, superoxide, and glutathione. Enhanced phospho-p65, reduced nuclear factor erythropoietin-2-related factor 2, and heme oxygenase 1 in septic mice were reversed by administration with 6-Gingerol. In conclusion, 6-Gingerol demonstrates anti-inflammatory and antioxidant effects against sepsis associated acute lung injury through inactivation of nuclear factor-kappa B and activation of nuclear-factor erythroid 2-related factor 2 pathways.

scholarly journals Amelioration of the Protein Expression of Cox2, NFκB, and STAT-3 by Some Antioxidants in the Liver of Sodium Fluoride–Intoxicated Rats

Dose-Response ◽  
2018 ◽  
Vol 16 (3) ◽  
pp. 155932581880015 ◽  
Author(s):  
Ahlam Alhusaini ◽  
Laila Faddaa ◽  
Hanaa M. Ali ◽  
Iman Hassan ◽  
Nagla F. El Orabi ◽  
...  
Keyword(s):  
Sodium Fluoride ◽  
Histopathological Examination ◽  
Nuclear Factor Κb ◽  
Related Factor ◽  
Nuclear Factor ◽  
Concurrent Treatment ◽  
Cellular Degeneration ◽  
Abnormal Cells ◽  
Factor Α ◽  
Transcription 3

The present study aimed to explore the efficiency of N-acetyl cysteine (NACC) or thymoquinone (TMQ) alone or in combination in the downregulation of inflammatory molecule expression and decreasing hepatic injury in response to sodium fluoride (SF). Sodium fluoride upregulated serum alanine and aspartate transferases activities, tumor necrosis factor α and hepatic malondialdehyde and nitric oxide levels, and the expression of cyclooxygenase 2, nuclear factor κB cell, and signal transducer and activator of transcription 3. In contrast, hepatic glutathione level, superoxide dismutase activity, and nuclear factor erythroid 2-related factor 2 expression were decreased. However, the concurrent treatment with antioxidants, alone or in combination, modulated the levels of these parameters. Histopathological examination revealed that SF treatment resulted in focal areas of massive hepatic degeneration and many degenerated hepatocytes, whereas the treatment with TMQ or NACC exhibited moderate improvement in cellular degeneration of the liver with many abnormal cells. Rats receiving a combination of TMQ and NACC showed marked improvement in cellular degeneration of liver with apparently normal hepatic architecture with very few degenerated hepatocytes. The results also revealed that the combination of TMQ and NACC is the most effective regimen in ameliorating SF toxicity, suggesting their efficacy against the toxicity of fluoride compounds. Their activities might be mediated via multiple molecular pathways.

scholarly journals Regulation of macrophage function in tumors: the multifaceted role of NF-κB

Blood ◽  
2009 ◽  
Vol 113 (14) ◽  
pp. 3139-3146 ◽  
Author(s):  
Thorsten Hagemann ◽  
Subhra K. Biswas ◽  
Toby Lawrence ◽  
Antonio Sica ◽  
Claire E. Lewis
Keyword(s):  
Transcription Factor ◽  
Tumor Cells ◽  
Tumor Development ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Invasion And Metastasis ◽  
Exact Role ◽  
Cellular Processes ◽  
Transcription Factor Nuclear Factor

Abstract The pivotal role of tumor-associated macrophages (TAMs) in tumor progression is now well established. TAMs have been shown to influence multiple steps in tumor development including the growth, survival, invasion, and metastasis of tumor cells as well as angiogenesis and lymphangiogenesis in tumors. The molecular circuits that polarize TAMs toward such a protumoral phenotype are now the focus of intense investigation. The transcription factor, nuclear factor–κB (NF-κB), is a master regulator of many cellular processes and been shown to regulate various pathways that impact on the function of TAMs. Much evidence for this has come from the use of elegant transgenic murine tumor models in which modification of single components of the NF-κB signaling pathway has been shown to regulate the pro-tumor repertoire of TAMs. Here, we outline this evidence and attempt to reconcile the various views that have emerged recently over the exact role of NF-κB in this phenomenon.

scholarly journals Osmoprotective Transcription Factor NFAT5/TonEBP Modulates Nuclear Factor-κB Activity

2010 ◽  
Vol 21 (19) ◽  
pp. 3459-3474 ◽  
Author(s):  
Isabelle Roth ◽  
Valérie Leroy ◽  
H. Moo Kwon ◽  
Pierre-Yves Martin ◽  
Eric Féraille ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Collecting Duct ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Transforming Growth Factor Α ◽  
Osmotic Response ◽  
Dependent Signal ◽  
Factor Α

Tonicity-responsive binding-protein (TonEBP or NFAT5) is a widely expressed transcription factor whose activity is regulated by extracellular tonicity. TonEBP plays a key role in osmoprotection by binding to osmotic response element/TonE elements of genes that counteract the deleterious effects of cell shrinkage. Here, we show that in addition to this “classical” stimulation, TonEBP protects cells against hypertonicity by enhancing nuclear factor-κB (NF-κB) activity. We show that hypertonicity enhances NF-κB stimulation by lipopolysaccharide but not tumor necrosis factor-α, and we demonstrate overlapping protein kinase B (Akt)-dependent signal transduction pathways elicited by hypertonicity and transforming growth factor-α. Activation of p38 kinase by hypertonicity and downstream activation of Akt play key roles in TonEBP activity, IκBα degradation, and p65 nuclear translocation. TonEBP affects neither of these latter events and is itself insensitive to NF-κB signaling. Rather, we reveal a tonicity-dependent interaction between TonEBP and p65 and show that NF-κB activity is considerably enhanced after binding of NF-κB-TonEBP complexes to κB elements of NF-κB–responsive genes. We demonstrate the key roles of TonEBP and Akt in renal collecting duct epithelial cells and in macrophages. These findings reveal a novel role for TonEBP and Akt in NF-κB activation on the onset of hypertonic challenge.

Haem oxygenase-1 in inflammation

2004 ◽  
Vol 32 (6) ◽  
pp. 1093-1094 ◽  
Author(s):  
S.A. Rushworth ◽  
M.A. O'Connell
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Nuclear Factor Κb ◽  
Protective Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Inflammatory Stimuli ◽  
Haem Oxygenase ◽  
Flanking Region

HO-1 (haem oxygenase-1) is a stress-inducible enzyme that plays a protective role in inflammation. Pro-inflammatory mediators, including lipopolysaccharide and cytokines, induce HO-1 expression. The 5′-flanking region of the HO-1 gene contains binding sites for the transcription factors that regulate inflammation, including nuclear factor-κB and activator protein 1. However, these do not appear to mediate lipopolysaccharide-induced HO-1 gene expression. In response to haem and antioxidants, murine HO-1 is regulated by the transcription factor Nrf2 (NF-E2-related factor 2). This transcription factor may also be important in the regulation of HO-1 by pro-inflammatory stimuli.

A direct requirement of nuclear factor-κB for suppression of apoptosis in ventricular myocytes

2000 ◽  
Vol 279 (3) ◽  
pp. H939-H945 ◽  
Author(s):  
Shareef Mustapha ◽  
Alla Kirshner ◽  
Danielle De Moissac ◽  
Lorrie A. Kirshenbaum
Keyword(s):  
Dna Binding ◽  
Gene Transcription ◽  
Ventricular Myocytes ◽  
Vital Staining ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Cytoplasmic Factor ◽  
Tnf Α ◽  
Factor Α

Nuclear factor-κB (NF-κB) is a ubiquitously expressed cellular factor regulated by the cytoplasmic factor inhibitor protein κBα (IκBα). Activation of NF-κB by cytokines, including tumor necrosis factor-α (TNF-α), requires the phosphorylation and degradation of IκBα. An anti-apoptotic role for NF-κB has recently been suggested. In the present study, we ascertained whether death-promoting signals and apoptosis mediated by TNF-α are suppressed by NF-κB in postnatal ventricular myocytes. Stimulation of myocytes with TNF-α resulted in a 12.1-fold increase ( P < 0.01) in NF-κB-dependent gene transcription and DNA binding compared with controls. This was accompanied by a corresponding increase in the NF-κB target protein A20 as determined by Western blot analysis. Vital staining revealed that TNF-α was not cytotoxic to myocytes and did not provoke apoptosis. Adenovirus-mediated delivery of a nonphosphorylatable form of IκBα to inactivate NF-κB prevented TNF-α-stimulated NF-κB-dependent gene transcription and nuclear NF-κB DNA binding. Importantly, myocytes stimulated with TNF-α and defective for NF-κB activation resulted in a 2.2-fold increase ( P < 0.001) in apoptosis. To our knowledge, the data provide the first indication that a functional NF-κB signaling pathway is crucial for suppressing death-promoting signals mediated by TNF-α in ventricular myocytes.

Localized pancreatic NF-κB activation and inflammatory response in taurocholate-induced pancreatitis

2001 ◽  
Vol 280 (6) ◽  
pp. G1197-G1208 ◽  
Author(s):  
Eva Vaquero ◽  
Ilya Gukovsky ◽  
Vjekoslav Zaninovic ◽  
Anna S. Gukovskaya ◽  
Stephen J. Pandol
Keyword(s):  
Transcription Factor ◽  
Inflammatory Response ◽  
Pancreatic Head ◽  
Pancreatic Injury ◽  
Nuclear Factor Κb ◽  
Saline Infusion ◽  
Activator Protein 1 ◽  
Local Inflammatory Response ◽  
Monocyte Chemoattractant Protein 1 ◽  
Factor Α

Transcription factor nuclear factor-κB (NF-κB) is activated in cerulein pancreatitis and mediates cytokine expression. The role of transcription factor activation in other models of pancreatitis has not been established. Here we report upregulation of NF-κB and inflammatory molecules, and their correlation with local pancreatic injury, in a model of severe pancreatitis. Rats received intraductal infusion of taurocholate or saline, and the pancreatic head and tail were analyzed separately. NF-κB and activator protein-1 (AP-1) activation were assessed by gel shift assay, and mRNA expression of interleukin-6, tumor necrosis factor-α, KC, monocyte chemoattractant protein-1, and inducible nitric oxide synthase was assessed by semiquantitative RT-PCR. Morphological damage and trypsin activation were much greater in the pancreatic head than tail, in parallel with a stronger activation of NF-κB and cytokine mRNA. Saline infusion mildly affected these parameters. AP-1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion. NF-κB inhibition with N-acetylcysteine ameliorated the local inflammatory response. Correlation between localized NF-κB activation, cytokine upregulation, and tissue damage suggests a key role for NF-κB in the development of the inflammatory response of acute pancreatitis.

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