A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington's disease

Alteration in neurotransmitters signaling in basal ganglia has been consistently shown to significantly contribute to the pathophysiological basis of Parkinson’s disease and Huntington’s disease. Dopamine is an important neurotransmitter which plays a critical role in coordinated body movements. Alteration in the level of brain dopamine and receptor radically contributes to irregular movements, glutamate mediated excitotoxic neuronal death and further leads to imbalance in the levels of other neurotransmitters viz. GABA, adenosine, acetylcholine and endocannabinoids. This review is based upon the data from clinical and preclinical studies to characterize the role of various striatal neurotransmitters in the pathogenesis of Parkinson’s disease and Huntington’s disease. Further, we have collected data of altered level of various neurotransmitters and their metabolites and receptor density in basal ganglia region. Although the exact mechanisms underlying neuropathology of movement disorders are not fully understood, but several mechanisms related to neurotransmitters alteration, excitotoxic neuronal death, oxidative stress, mitochondrial dysfunction, neuroinflammation are being put forward. Restoring neurotransmitters level and downstream signaling has been considered to be beneficial in the treatment of Parkinson’s disease and Huntington’s disease. Therefore, there is an urgent need to identify more specific drugs and drug targets that can restore the altered neurotransmitters level in brain and prevent/delay neurodegeneration.

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A critical role of TAK1 in B-cell receptor–mediated nuclear factor κB activation

Blood ◽

10.1182/blood-2008-08-176057 ◽

2009 ◽

Vol 113 (19) ◽

pp. 4566-4574 ◽

Cited By ~ 57

Author(s):

James Schuman ◽

Yuhong Chen ◽

Andrew Podd ◽

Mei Yu ◽

Hong-Hsing Liu ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Critical Role ◽

Cell Receptor ◽

Nuclear Factor Κb ◽

Cell Development ◽

B Cell Receptor ◽

Nuclear Factor

Abstract The kinase TAK1 is essential for T-cell receptor (TCR)–mediated nuclear factor κB (NF-κB) activation and T-cell development. However, the role of TAK1 in B-cell receptor (BCR)–mediated NF-κB activation and B-cell development is not clear. Here we show that B-cell–specific deletion of TAK1 impaired the transition from transitional type 2 to mature follicular (FO) B cells and caused a marked decrease of marginal zone (MZ) B cells. TAK1-deficient B cells exhibited an increase of BCR-induced apoptosis and impaired proliferation in response to BCR ligation. Importantly, TAK1-deficient B cells failed to activate NF-κB after BCR stimulation. Thus, TAK1 is critical for B-cell maturation and BCR-induced NF-κB activation.

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Anacardic acid (6-nonadecyl salicylic acid), an inhibitor of histone acetyltransferase, suppresses expression of nuclear factor-κB–regulated gene products involved in cell survival, proliferation, invasion, and inflammation through inhibition of the inhibitory subunit of nuclear factor-κBα kinase, leading to potentiation of apoptosis

Blood ◽

10.1182/blood-2007-10-117994 ◽

2008 ◽

Vol 111 (10) ◽

pp. 4880-4891 ◽

Cited By ~ 167

Author(s):

Bokyung Sung ◽

Manoj K. Pandey ◽

Kwang Seok Ahn ◽

Tingfang Yi ◽

Madan M. Chaturvedi ◽

...

Keyword(s):

Salicylic Acid ◽

Histone Acetyltransferase ◽

Critical Role ◽

Nuclear Factor Κb ◽

Chemotherapeutic Agents ◽

Anacardic Acid ◽

Nuclear Factor ◽

Gene Products ◽

Down Regulation

Abstract Anacardic acid (6-pentadecylsalicylic acid) is derived from traditional medicinal plants, such as cashew nuts, and has been linked to anticancer, anti-inflammatory, and radiosensitization activities through a mechanism that is not yet fully understood. Because of the role of nuclear factor-κB (NF-κB) activation in these cellular responses, we postulated that anacardic acid might interfere with this pathway. We found that this salicylic acid potentiated the apoptosis induced by cytokine and chemotherapeutic agents, which correlated with the down-regulation of various gene products that mediate proliferation (cyclin D1 and cyclooxygenase-2), survival (Bcl-2, Bcl-xL, cFLIP, cIAP-1, and survivin), invasion (matrix metalloproteinase-9 and intercellular adhesion molecule-1), and angiogenesis (vascular endothelial growth factor), all known to be regulated by the NF-κB. We found that anacardic acid inhibited both inducible and constitutive NF-κB activation; suppressed the activation of IκBα kinase that led to abrogation of phosphorylation and degradation of IκBα; inhibited acetylation and nuclear translocation of p65; and suppressed NF-κB–dependent reporter gene expression. Down-regulation of the p300 histone acetyltransferase gene by RNA interference abrogated the effect of anacardic acid on NF-κB suppression, suggesting the critical role of this enzyme. Overall, our results demonstrate a novel role for anacardic acid in potentially preventing or treating cancer through modulation of NF-κB signaling pathway.

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Cyclooxygenase-2 Regulated by the Nuclear Factor-κB Pathway Plays an Important Role in Endometrial Breakdown in a Female Mouse Menstrual-like Model

Endocrinology ◽

10.1210/en.2012-1993 ◽

2013 ◽

Vol 154 (8) ◽

pp. 2900-2911 ◽

Cited By ~ 11

Author(s):

Xiangbo Xu ◽

Xihua Chen ◽

Yunfeng Li ◽

Huizi Cao ◽

Cuige Shi ◽

...

Keyword(s):

Critical Role ◽

Nuclear Factor Κb ◽

Pcr Analysis ◽

Pyrrolidine Dithiocarbamate ◽

Nuclear Factor ◽

Cox Inhibitor ◽

Cox 2

Abstract The role of prostaglandins (PGs) in menstruation has long been proposed. Although evidence from studies on human and nonhuman primates supports the involvement of PGs in menstruation, whether PGs play an obligatory role in the process remains unclear. Although cyclooxygenase (COX) inhibitors have been used in the treatment of irregular uterine bleeding, the mechanism involved has not been elucidated. In this study, we used a recently established mouse menstrual-like model for investigating the role of COX in endometrial breakdown and its regulation. Administration of the nonspecific COX inhibitor indomethacin and the COX-2 selective inhibitor DuP-697 led to inhibition of the menstrual-like process. Furthermore, immunostaining analysis showed that the nuclear factor (NF)κB proteins P50, P65, and COX-2 colocalized in the outer decidual stroma at 12 to 16 hours after progesterone withdrawal. Chromatin immunoprecipitation analysis showed that NFκB binding to the Cox-2 promoter increased at 12 hours after progesterone withdrawal in vivo, and real-time PCR analysis showed that the NFκB inhibitors pyrrolidine dithiocarbamate and MG-132 inhibited Cox-2 mRNA expression in vivo and in vitro, respectively. Furthermore, COX-2 and NFκB inhibitors similarly reduced endometrial breakdown, suggesting that NFκB/COX-2-derived PGs play a critical role in this process. In addition, the CD45+ leukocyte numbers were sharply reduced following indomethacin (COX-1 and COX-2 inhibitor), DuP-697 (COX-2 inhibitor), and pyrrolidine dithiocarbamate (NFκB inhibitor) treatment. Collectively, these data indicate that NFκB/COX-2-induced PGs regulate leukocyte influx, leading to endometrial breakdown.

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Classical and/or alternative NF-κB pathway activation in multiple myeloma

Blood ◽

10.1182/blood-2009-09-243535 ◽

2010 ◽

Vol 115 (17) ◽

pp. 3541-3552 ◽

Cited By ~ 178

Author(s):

Yulia N. Demchenko ◽

Oleg K. Glebov ◽

Adriana Zingone ◽

Jonathan J. Keats ◽

P. Leif Bergsagel ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Alternative Pathway ◽

Critical Role ◽

Nuclear Factor Κb ◽

Alternative Activation ◽

Classical Pathway ◽

Nuclear Factor ◽

Pathway Activation

Abstract Mutations involving the nuclear factor-κB (NF-κB) pathway are present in at least 17% of multiple myeloma (MM) tumors and 40% of MM cell lines (MMCLs). These mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NF-κB. Studies on a panel of 51 MMCLs provide some clarification of the mechanisms through which these mutations act and the significance of classical versus alternative activation of NF-κB. First, only one mutation (NFKB2) selectively activates the alternative pathway, whereas several mutations (CYLD, NFKB1, and TACI) selectively activate the classical pathway. However, most mutations affecting NF-κB–inducing kinase (NIK) levels (NIK, TRAF2, TRAF3, cIAP1&2, and CD40) activate the alternative but often both pathways. Second, we confirm the critical role of TRAF2 in regulating NIK degradation, whereas TRAF3 enhances but is not essential for cIAP1/2-mediated proteasomal degradation of NIK in MM. Third, using transfection to selectively activate the classical or alternative NF-κB pathways, we show virtually identical changes in gene expression in one MMCL, whereas the changes are similar albeit nonidentical in a second MMCL. Our results suggest that MM tumors can achieve increased autonomy from the bone marrow microenvironment by mutations that activate either NF-κB pathway.

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Essential Role of Transcription Factor Nuclear Factor-κB in Regulation of Interleukin-8 Gene Expression by Nitrite Reductase from Pseudomonas aeruginosa in Respiratory Epithelial Cells

Infection and Immunity ◽

10.1128/iai.67.8.3872-3878.1999 ◽

1999 ◽

Vol 67 (8) ◽

pp. 3872-3878 ◽

Cited By ~ 30

Author(s):

Naoki Mori ◽

Kazunori Oishi ◽

Borann Sar ◽

Naofumi Mukaida ◽

Tsuyoshi Nagatake ◽

...

Keyword(s):

Gene Expression ◽

Pseudomonas Aeruginosa ◽

Epithelial Cells ◽

Nitrite Reductase ◽

Critical Role ◽

Nuclear Factor Κb ◽

Interleukin 8 ◽

Nuclear Factor ◽

Respiratory Cells

ABSTRACT Persistent infection with Pseudomonas aeruginosaincreases interleukin-8 (IL-8) levels and causes dense neutrophil infiltrations in the airways of patients with chronic airway diseases. Recently, we have reported that nitrite reductase from P. aeruginosa induces the production of IL-8 in respiratory cells, including bronchial epithelial cells. To determine the molecular mechanism(s) of nitrite reductase-induced IL-8 expression in respiratory cells, A549 epithelial cells were transfected with plasmids containing serial deletions of the 5′-flanking region of the IL-8 gene and then exposed to nitrite reductase. Nitrite reductase significantly enhanced IL-8 gene promoter-driven reporter activity. This increased IL-8 gene expression was inhibited by mutating the nuclear factor-κB (NF-κB) binding element. Nitrite reductase enhanced nuclear localization of the NF-κB binding complex. Furthermore, nitrite reductase induced the degradation of IκBα, the major cytoplasmic inhibitor of NF-κB, and the expression of IκBα mRNA. These data support the critical role of the activation of NF-κB in nitrite reductase-induced IL-8 gene expression in airway epithelium.

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