Ceramide Activation of NFkB and Protection against Apoptosis

NF-kB is an inducible transcription factor classically implicated in the regulation of inflammatory response genes.106 NF-kB is activated by numerous stimuli including amyloid-beta peptides,107 reactive oxygen species,106,107 TNF,108 chemotherapeutic agents,20 NGF109 and ceramide.2,47,109 Intriguingly, the activation of NF-kB may elicit both apoptotic and antiapoptotic responses in neurons vs. glial cells.107,110-112 For example, activation of NF-kB in glial cells may be involved in apoptosis induced by amyloid-beta peptides, potentially through the activation of proinflammatory or cytotoxic genes such as nitric oxide synthase and interleukin-6.106,107 In contrast, activation of NF-kB in neurons may increase the expression of antioxidant genes and decrease neuronal apoptosis induced by amyloid-beta peptides44 or growth factor withdrawal.114 Moreover, previous studies had suggested that TNF could protect neurons from amyloid-beta-induced apoptosis by decreasing H2O2 production and activating NF-kB.115 Further, ceramide pretreatment mimicked the effect of TNF in protecting neurons from cell death induced by amyloid-beta peptides or glutamate.44 However, as previously discussed, ceramide can increase H2O2 production by directly inhibiting mitochondrial electron flow.65 These results raise the possibility that fundamental differences may exist in the effects of ceramide on mitochondria in different cell types. Alternatively, low levels of ceramide may induce sufficient generation of H2O2 to activate NF-kB and induce the expression of antioxidant genes but not be apoptotic. Indeed, recent data suggest that the production of H2O2 by low concentrations of Ap (0.1 pM) may induce a protective response in neurons through a transient activation of NF-kB.107 In contrast, doses of amyloid-beta peptides typically used to induce apoptosis (10 pM) generate significantly more H2O2 which inhibits NF-kB activation.107 Thus, depending upon the cell type and its genetic program, the nature of the specific activator, the magnitude and duration of the activation signal, as well an interaction with other signaling pathways, similar effector proteins may be involved in eliciting neurodegenerative or neuroprotective responses.

In summary, the dichotomous responses of neurons to ceramide are consistent with the hypothesis first put forth by Hannun and co-workers that ceramide may serve as a sensor of cellular stress involved in gauging the extent of cellular injury and initiating a response.19,36 If the stress is short term, transient ceramide production may promote an antiapoptotic response by affecting cell cycle progression and afford the cell an opportunity to recover from the stress. In contrast, if the stress endures, prolonged ceramide production in combination with other signals may initiate entry into apop-totic pathways. Understanding the circumstances and mechanisms whereby ceramide may activate antiapoptotic signals will undoubtedly provide basic insight into the relationships between lipid signaling pathways, cell cycle progression, and apoptosis. These efforts may provide novel approaches to regulating or slowing neurodegenerative processes.


This work was supported by grant MCB 9513596 from the National Science Foundation, a Career Development Award from the Juvenile Diabetes Foundation International, and by funds from the Higuchi Biosciences Center at the University of Kansas.


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Section B


Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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