Molecular exploration of age-related NF-κB/IKK downregulation by calorie restriction in rat kidney

Kim, Hyon Jeen; Yu, Byung Pal; Chung, Hae Young

doi:10.1016/s0891-5849(02)00798-0

Cited by 74 publications

(55 citation statements)

References 61 publications

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“…In our previous report, we presented evidence that increased NF-B binding activity during aging is elicited through the phosphorylation of IB kinase, causing a degradation of IB␣ and IB␤. We further showed CR inhibited IB kinase activation, down-regulating NFB activation as evidenced by increased bound IB␣ and IB␤ proteins in cytoplasm (Kim et al, 2002b) (Table 1). These observations led to the conclusions that the anti-oxidative action of CR is a major force responsible for the maintenance of properly functioning NFB/IKK/NIK and MAPKs, which might be associated with CR's life-prolonging action (Kim et al, 2002a,b).…”

Section: Nf-b and Agingmentioning

confidence: 76%

Molecular inflammation hypothesis of aging based on the anti‐aging mechanism of calorie restriction

Chung

Kim

et al. 2002

Microscopy Res & Technique

277

186

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Accumulating evidence strongly suggests that oxidative stress underlies aging processes. Research provides consistent evidence that calorie restriction (CR) reduces age-related oxidative stress and has anti-inflammatory properties. However, information is lacking on the molecular mechanism that would better define the interrelation of reactive oxygen species and nitrogen species and the pro-inflammatory states of the aging process. In this review, the biochemical and molecular bases of the inflammatory process in the aging process are analyzed to delineate the molecular inflammation hypothesis of aging. The key players involved in the proposed hypothesis are the age-related upregulation of NF-kappa B, IL-1 beta, IL-6, TNFalpha, cyclooxygenase-2, and inducible NO synthase, all of which are attenuated by CR. Furthermore, age-related NF kappa B activation is associated with phosphorylation by I kappa B kinase/NIK and MAPKs, while CR blocked these activation processes. The modulation of these factors provides molecular insights of the anti-inflammatory action of CR in relation to the aging process. Based on available finding and our recent supporting evidence, we prefer to use "molecular inflammation" to emphasize the importance of the molecular reaction mechanisms and their aberrance, predisposing to fully expressed chronic inflammatory phenomena. It was further proposed that CR's major force of the regulation of redox-sensitive inflammation may well be its life-prolonging action.

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Section: Nf-b and Agingmentioning

confidence: 76%

Molecular inflammation hypothesis of aging based on the anti‐aging mechanism of calorie restriction

Chung

Kim

et al. 2002

Microscopy Res & Technique

277

186

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“…Recent reports demonstrated the NF-jB-dependent induction of miR-146a expression by TLR signaling (Taganov et al, 2006;Cameron et al, 2008;Lukiw et al, 2008). Although details about the mechanisms of immunosenescence have yet to be elucidated, many studies have been conducted in aged humans to establish a clear correlation between an increase in the constitutive activation of NF-jB and chronic inflammation (Helenius et al, 1996;Spencer et al, 1997;Kim et al, 2002;Sarkar & Fisher, 2006). Our studies demonstrated that an appreciable rise in miR-146a expression was correlated with an age-dependent augmentation of the binding of NF-jB p65 to the miR-146a promoter in macrophages from aged mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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SummaryAge-associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR-146a, which negatively regulated the expression of IL-1b and IL-6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR-146a involving down-regulation of inflammation factors was interrupted in aged mice. Aberrant NF-jB binding to the miR-146a promoter was demonstrated to be associated with the abnormal expression of miR-146a in aged mice. The DNA methyltransferase inhibitor (5-aza-2-deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up-regulated miR-146a transcriptional activation by altering the DNA-binding activity of NF-jB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age-dependent miR-146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR-146a expression in LPS-stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS-induced inflammatory responses owing to up-regulation of miR-146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR-146a results in the age-associated dysfunction of macrophages, and miR-146a may be a good target for the treatment of age-related inflammatory diseases.

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“…Age-related oxidative stress regulates the dissociation of I-κB and nuclear translocation of NFκB. 158 Treatment of a human T cell line with hydrogen peroxide rapidly activates NFκB. 159 Stress response gene HO-1 exhibits several transcription factor binding sites including NFκB 160 and is elevated in brains of AD patients.…”

Section: Nfκb and Ap-1mentioning

confidence: 99%

Oxidative Stress and Transcriptional Regulation in Alzheimer Disease

Shi

Gibson

2007

Alzheimer Disease &Amp; Associated Disorders

145

107

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Alzheimer's disease (AD) is defined by progressive impairments in memory and cognition and by the presence of extra-cellular neuritic plaques and intracellular neurofibrillary tangles. However, oxidative stress and impaired mitochondrial function always accompany AD. Mitochondria are a major site of production of free radicals [i.e., reactive oxygen species (ROS)] and primary targets of ROS. ROS are cytotoxic, and evidence of ROS-induced damage to cell membranes, proteins and DNA in AD is overwhelming. Nevertheless, therapies based on antioxidants have been disappointing. Thus, alternative strategies are necessary. ROS also act as signaling molecules including for transcription. Thus, chronic exposure to ROS in AD could activate cascades of genes. Although initially protective, prolonged activation may be damaging. Thus, therapeutic approaches based on modulation of these gene cascades may lead to effective therapies. Genes involved in several pathways including antioxidant defense, detoxification, inflammation, etc. are induced in response to oxidative stress and in AD. However, genes that are associated with energy metabolism, which is necessary for normal brain function, are mostly down-regulated. Redox sensitive transcription factors such as activator protein-1 (AP-1), nuclear factor κB (NF-κB), specificity protein-1 and hypoxia-inducible factor (HIF) are important in redox-dependent gene regulation. PPARγ co-activator (PGC-1α) is a co-activator of several transcription factors and is a potent stimulator of mitochondrial biogenesis and respiration. Down-regulated expression of PGC-1α has been implicated in Huntington's disease (HD) and in several HD animal models. Its role in regulation of ROS metabolism makes it a potential candidate player between ROS, mitochondria and neurodegenerative diseases. This review summarizes the current progress on how oxidative stress regulates the expression of genes that might contribute to AD pathophysiology and the implications of the transcriptional modifications for AD. Finally, potential therapeutic strategies based on the updated understandings of redox state-dependent gene regulation in AD are proposed to overcome the lack of efficacy of antioxidant therapies. KeywordsOxidative stress; transcription factors; Kreb's cycle; redox; metabolism; Alzheimer's disease Oxidative stress and Alzheimer's diseaseAD is defined by progressive impairments in memory and cognition and by the presence of extracellular neuritic plaques and intracellular neurofibrillary tangles. β-amyloid peptide (Aβ) is the major component of the plaque, while the tangles are composed of hyperphosphorylated tau proteins. Since these three features define AD, any hypothesis Address correspondence to: Qingli Shi, Dept. of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, New York 10605, USA, Tel: 914-368-3129; Fax: 914-597-2757.cornell.edu. NIH Public Access Author ManuscriptAlzheimer Dis Assoc Disord. Author...

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Molecular exploration of age-related NF-κB/IKK downregulation by calorie restriction in rat kidney

Cited by 74 publications

References 61 publications

Molecular inflammation hypothesis of aging based on the anti‐aging mechanism of calorie restriction

Molecular inflammation hypothesis of aging based on the anti‐aging mechanism of calorie restriction

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Oxidative Stress and Transcriptional Regulation in Alzheimer Disease

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