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Prakasam A.,Medical University of South Carolina | Prakasam A.,UNC Nutrition Research Institute | Ghose S.,Medical University of South Carolina | Ghose S.,Jawaharlal Nehru University | And 7 more authors.
Cell Death and Disease | Year: 2014

BH3 interacting-domain death agonist (Bid) is a BH3-only pro-apoptotic member of the Bcl-2 family of proteins. Its function in apoptosis is associated with the proteolytic cleavage to the truncated form tBid, mainly by caspase-8. tBid translocates to mitochondria and assists Bax and Bak in induction of apoptosis. c-Jun N-terminal kinase (JNK)-dependent alternative processing of Bid to jBid was also reported. We have previously shown that the folate stress enzyme 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) activates JNK1 and JNK2 in cancer cells as a pro-apoptotic response. Here we report that in PC-3 prostate cancer cells, JNK1/2 phosphorylate Bid at Thr59 within the caspase cleavage site in response to ALDH1L1. In vitro, all three JNK isoforms, JNK 1-3, phosphorylated Thr59 of Bid with JNK1 being the least active. Thr59 phosphorylation protected Bid from cleavage by caspase-8, resulting in strong accumulation of the full-length protein and its translocation to mitochondria. Interestingly, although we did not observe jBid in response to ALDH1L1 in PC-3 cells, transient expression of Bid mutants lacking the caspase-8 cleavage site resulted in strong accumulation of jBid. Of note, a T59D mutant mimicking constitutive phosphorylation revealed more profound cleavage of Bid to jBid. JNK-driven Bid accumulation had a pro-apoptotic effect in our study: small interfering RNA silencing of either JNK1/2 or Bid prevented Bid phosphorylation and accumulation, and rescued ALDH1L1-expressing cells. As full-length Bid is a weaker apoptogen than tBid, we propose that the phosphorylation of Bid by JNKs, followed by the accumulation of the full-length protein, delays attainment of apoptosis, and allows the cell to evaluate the stress and make a decision regarding the response strategy. This mechanism perhaps can be modified by the alternative cleavage of phospho-T59 Bid to jBid at some conditions. © 2014 Macmillan Publishers Limited. Source

Nicuiescu M.D.,UNC Nutrition Research Institute | Nicuiescu M.D.,University of North Carolina at Chapel Hill | Lupu D.S.,UNC Nutrition Research Institute
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2011

Purpose of review: This review synthesizes recently published information regarding nutrition and its impact upon epigenetically mediated mechanisms involved in longevity and aging. Recent findings: Recent studies enriched considerably our understanding of the relationship between aging and gene-nutrient interactions that continuously shape our phenotype. Epigenetic mechanisms play an important role in mediating between the nutrient inputs and the ensuing phenotypic changes throughout our entire life and seem to be responsible, in part, for the biological changes that occur during aging. Less is known about the epigenetic role that nutrients have in directly influencing longevity and aging. However, recent studies clearly indicated that because nutrition modulates epigenetic events associated with various diseases (e.g., cancer, obesity, and diabetes), there is at least an indirect epigenetic link between nutrition and longevity and, therefore, biologic plausibility to hypothesize the epigenetic role of nutrition in altering longevity. Apart from limited human studies, promising animal studies brought us much closer to understanding how nutrition could have such an impact upon longevity and aging. Summary: Complex epigenetic mechanisms are involved in aging and longevity, directly or indirectly via disease mechanisms. Nutrition has a strong impact upon epigenetic processes and, therefore, holds promise in having important roles in regulating longevity and aging. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Niculescu M.D.,UNC Nutrition Research Institute | Niculescu M.D.,University of North Carolina at Chapel Hill | Lupu D.S.,UNC Nutrition Research Institute | Craciunescu C.N.,University of North Carolina at Chapel Hill
International Journal of Developmental Neuroscience | Year: 2011

The availability of ω-3 polyunsaturated fatty acids is essential for perinatal brain development. While the roles of docosahexaenoic acid (the most abundant ω-3 species) were extensively described, less is known about the role of α-linolenic acid (ALA), which is the initial molecular species undergoing elongation and desaturation within the ω-3 pathways. This study describes the association between maternal ALA availability during gestation and lactation, and alterations in hippocampal development (dentate gyrus) in the mouse male offspring, at the end of lactation (postnatal day 19, P19). Postnatal ALA supplementation increased cell proliferation (36% more proliferating cells compared to a control group) and early neuronal differentiation, while postnatal ALA deficiency increased cellular apoptosis within the dentate gyrus of suckling pups (61% more apoptotic cells compared to a control group). However, maternal ALA deficiency during gestation prevented the increased neurogenesis induced by postnatal supplementation. Fatty acid analysis revealed that ALA supplementation increased the concentration of the ω-3 species in the maternal liver and serum, but not in the brain of the offspring, excepting for ALA itself. Interestingly, ALA supplementation also increased the concentration of dihomo γ-linolenic acid (a ω-6 species) in the P19 brains, but not in maternal livers or serum. In conclusion, postnatal ALA supplementation enhances neurogenesis in the dentate gyrus of the offspring at postnatal day 19, but its beneficial effects are offset by maternal ALA deficiency during gestation. These results suggest that ALA is required in both fetal and postnatal stages of brain development. © 2011 ISDN. Source

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