Betaine is an important human nutrient obtained from various foods. In the present study, we assessed the anti-inflammatory effect of betaine on nuclear factor-kappaB (NF-kappaB) during aging. Sprague-Dawley (SD) rats, ages 7 and 21 months, were used in this study. The older rats were fed betaine. To elucidate the effect of betaine on oxidative stress-induced NF-kappaB and its signaling pathway at molecular levels, YPEN-1 cells were used. Results showed that betaine suppressed NF-kappaB and its related gene expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), and intracellular cell adhesion molecule-1 (ICAM-1) in aged kidney. Furthermore, betaine attenuated oxidative stress-induced NF-kappaB via nuclear factor-inducing kinase/IkappaB kinase (NIK/IKK) and mitogen-activated protein kinases (MAPKs) in the YPEN-1 cells. On the basis of these results, we concluded that betaine suppressed the age-related NF-kappaB activities associated with upregulated NIK/IKK and MAPKs that were induced by oxidative stress. Thus, betaine might be useful as a preventive agent against the activation of NF-kappaB induced during inflammation and aging.

4-Hydroxyhexenal (HHE) is known to affect redox balance during aging, included are vascular dysfunctions. To better understand vascular abnormality through the molecular alterations resulting from HHE accumulation in aging processes, we set out to determine whether up-regulation of mitogen-activated protein kinase (MAPK) by HHE is mediated through nuclear factor kappa B (NF-kappaB) activation in endothelial cells. HHE induced NF-kappaB activation by inhibitor of kappaB (IkappaB) phosphorylation via the IkappaB kinase (IKK)/NF-kappaB inducing kinase (NIK) pathway. HHE increased the activity of p38 MAPK and extracellular signal regulated kinase (ERK), but not c-jun NH(2)-terminal kinase, indicating that p38 MAPK and ERK are closely involved in HHE-induced NF-kappaB transactivation. Pretreatment with ERK inhibitor PD98059, and p38 MAPK inhibitor SB203580, attenuated the induction of p65 translocation, IkappaB phosphorylation, and NF-kappaB luciferase activity. These findings strongly suggest that HHE induces NF-kappaB activation through IKK/NIK pathway and/or p38 MAPK and ERK activation associated with oxidative stress in endothelial cells.

Oxidative stress is a condition where the reduction and oxidation (redox) balance between reactive species (RS) such as superoxide anion ( · O 2 Ϫ ), hydrogen peroxide (H 2 O 2 ), peroxynitrite (ONOO Ϫ ), and hydroxyl radical ( · OH) and antioxidant species such as glutathione (GSH) and thioredoxin (Trx) is disrupted. 1-3)Oxidant-related reactions and cellular redox imbalance are implicated in a number of human diseases and aging. 4,5) Further, biological systems are protected against oxidative stress by a diversity of mechanisms designed to suppress the pernicious oxidative pathway. Numerous antioxidants are known to forestall oxidative damage or to limit its propagation. GSH, is a most abundant and an important intracellular thiol redox regulator that plays a major role in both the maintenance of redox status and in the protection of cells from electrophilic and oxidative attacks. 6) Many researchers who are interested in studying changes in the redox status rely on GSH levels as a reliable indicator of an organism's redox status. GSH depletion causes various biochemical and pathological changes, including mitochondrial dysfunction and swelling. 7,8) GSH depletion also is linked to aging processes, cardiovascular and neurodegenerative diseases. [9][10][11] A gradual rise of oxidative stress due to disrupted redox regulation during aging can influence the gene transcription and signal transduction pathways. The gene response to oxidative stress is seen due to the redox-sensitive transcription factors that modulate gene regulation. NF-kB is among the most important transcription factors shown to be exquisitely sensitive to oxidative stress conditions. 12) NF-kB regulates the activity of many genes, such as cyclooxygenase-2 (COX-2), TNFa, inducible NO synthase, and adhesion molecules. 13,14) Most of genes activated by NF-kB transcription factor are shown to be pro-inflammatory and involved in inflammation processes. In aged organisms, inflammatory reactions lead to a chronic pro-inflammatory state as evidenced from the activation of pro-inflammatory gene expression. 15,16) Betaine was first discovered in the juice of sugar beets (Beta vulgaris) in the 19th century and now found widely in various microorganisms, plant, and animals. 17) In Southeast Asia, this water-soluble component of Lycium chinensis has been used in traditional oriental medicine for the treatment of hepatic disorders.18) The biological function of betaine is proposed to act as an osmolyte to protect cells under stress 19) as a catabolic source of methyl through transmethylation in many biochemical pathways.17) As a methyl donor, betaine participates in methionine metabolism by its ability to convert homocysteine (Hcy) to methionine. 17,20) Recently, our lab published a paper on betaine's ability to suppress NF-kB during aging.15) However, this paper did not fully address how betaine exerts its regulatory role in the suppression of NF-kB.In the present study, we attempt to document that betaine decreases NF-kB through modulation of the cellular ...

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