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Green Tea Polyphenols Control Dysregulated Glutamate Dehydrogenase In Transgenic Mice By Hijacking The ADP Activation Site

October 20, 2011 Comments off

Green Tea Polyphenols Control Dysregulated Glutamate Dehydrogenase In Transgenic Mice By Hijacking The ADP Activation Site (PDF)
Source: Journal of Biological Chemistry

Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate and, in animals, is extensively regulated by a number of metabolites. Gain of function mutations in GDH that abrogate GTP inhibition causes the hyperinsulinism/hyperammonemia syndrome (HHS), resulting in increased pancreatic β-cells responsiveness to leucine and susceptibility to hypoglycemia following high protein meals. We have previously shown that two of the polyphenols from green tea (EGCG and ECG) inhibit GDH in-vitro and that EGCG blocks GDH-mediated insulin secretion in wild type rat islets. Using structural and site-directed mutagenesis studies, we demonstrate that ECG binds to the same site as the allosteric regulator, ADP. Perifusion assays using pancreatic islets from transgenic mice expressing a human HHS form of GDH demonstrate that the hyper-response to glutamine caused by dysregulated GDH is blocked by the addition of EGCG. As observed in HHS patients, these transgenic mice are hypersensitive to amino acid feeding and this is abrogated by oral administration of EGCG prior to challenge. Finally, the low basal blood glucose level in the HHS mouse model is improved upon chronic administration of EGCG. These results suggest that this common natural product, or some derivative thereof, may prove useful in controlling this genetic disorder. Of broader clinical implication is that other groups have shown restriction of glutamine catabolism via these GDH inhibitors can be useful in treating various tumors. This HHS transgenic mouse model offers a highly useful means to test these agents in-vivo.

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Curcumin Modulates Nuclear Factor B (NF- B)-mediated Inflammation in Human Tenocytes in Vitro: ROLE OF THE PHOSPHATIDYLINOSITOL 3-KINASE/Akt PATHWAY

August 11, 2011 Comments off

Curcumin Modulates Nuclear Factor B (NF- B)-mediated Inflammation in Human Tenocytes in Vitro: ROLE OF THE PHOSPHATIDYLINOSITOL 3-KINASE/Akt PATHWAY
Source: Journal of Biological Chemistry

Inflammatory processes play essential roles in the pathogenesis of tendinitis and tendinopathy. These events are accompanied by catabolic processes initiated by pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Pharmacological treatments for tendinitis are restricted to the use of non-steroidal anti-inflammatory drugs. Recent studies in various cell models have demonstrated that curcumin targets the NF-κB signaling pathway. However, its potential for the treatment of tendinitis has not been explored. Herein, we used an in vitro model of human tenocytes to study the mechanism of curcumin action on IL-1β-mediated inflammatory signaling. Curcumin at concentrations of 5–20 μM inhibited IL-1β-induced inflammation and apoptosis in cultures of human tenocytes. The anti-inflammatory effects of curcumin included down-regulation of gene products that mediate matrix degradation (matrix metalloproteinase-1, -9, and -13), prostanoid production (cyclooxygenase-2), apoptosis (Bax and activated caspase-3), and stimulation of cell survival (Bcl-2), all known to be regulated by NF-κB. Furthermore, curcumin suppressed IL-1β-induced NF-κB activation via inhibition of phosphorylation and degradation of inhibitor of κBα, inhibition of inhibitor of κB-kinase activity, and inhibition of nuclear translocation of NF-κB. Furthermore, the effects of IL-1β were abrogated by wortmannin, suggesting a role for the phosphatidylinositol 3-kinase (PI-3K) pathway in IL-1β signaling. Curcumin suppressed IL-1β-induced PI-3K p85/Akt activation and its association with IKK. These results demonstrate, for the first time, a potential role for curcumin in treating tendon inflammation through modulation of NF-κB signaling, which involves PI-3K/Akt and the tendon-specific transcription factor scleraxis in tenocytes.

See: Curry Spice Could Offer Treatment Hope for Tendinitis (Science Daily)

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