Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice.

Lee, Jae Woong,Lee, Yong Kyoung,Ban, Jung Ok,Ha, Tae Youl,Yun, Yeo Pyo,Han, Sang Bae,Oh, Ki Wan,Hong, Jin Tae Wistar Institute of Anatomy and Biology 2009 The Journal of nutrition Vol.139 No.10

<P>Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (Abeta) in cerebral plaques. Abeta is derived from the beta-amyloid precursor protein (APP) by the enzymes alpha-, beta- and gamma-secretase. Compounds that enhance alpha-secretase, but inhibit beta- or gamma-secretase activity, have therapeutic potential in the treatment of AD. Green tea, or its major polyphenolic compound, has been shown to have neuroprotective effects. In this study, we investigated the possible effects of (-)-epigallocatechin-3-gallate (EGCG) on memory dysfunction caused by Abeta through the change of Abeta-induced secretase activities. Mice were pretreated with EGCG (1.5 or 3 mg/kg body weight in drinking water) for 3 wk before intracerebroventricular administration of 0.5 microg Abeta(1-42). EGCG dose-dependently reduced the Abeta(1-42)-induced memory dysfunction, which was evaluated using passive avoidance and water maze tests. Abeta(1-42) induced a decrease in brain alpha-secretase and increases in both brain beta- and gamma-secretase activities, which were reduced by EGCG. In the cortex and the hippocampus, expression of the metabolic products of the beta- and gamma-secretases from APP, C99, and Abeta also were dose-dependently suppressed by EGCG. Paralleled with the suppression of beta- and gamma-secretases by EGCG, we found that EGCG inhibited the activation of extracellular signal-regulated kinase and nuclear transcription factor-kappaB in the Abeta(1-42)-injected mouse brains. In addition, EGCG inhibited Abeta(1-42)-induced apoptotic neuronal cell death in the brain. To further test the ability of EGCG to affect memory, EGCG (3 mg/kg body weight) was administered in drinking water for 1 wk to genetically developed preseniline 2 (PS2) mutant AD mice. Compared with untreated mutant PS2 AD mice, treatment with EGCG enhanced memory function and brain alpha-secretase activity but reduced brain beta- and gamma-secretase activities as well as Abeta levels. Moreover, EGCG inhibited the fibrillization of Abeta in vitro with a half maximal inhibitory concentration of 7.5 mg/L. These studies suggest that EGCG may be a beneficial agent in the prevention of development or progression of AD.</P>

Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells.

Lu, Xianghua,Jung, Jae in,Cho, Han Jin,Lim, Do Young,Lee, Hyun Sook,Chun, Hyang Sook,Kwon, Dae Young,Park, Jung Han Yoon Wistar Institute of Anatomy and Biology 2005 The Journal of nutrition Vol.135 No.12

<P>Fisetin, a natural flavonol present in edible vegetables, fruits, and wine, was reported to exert anticarcinogenic effects. The objective of the current study was to examine the effect of fisetin on the cell cycle progression of the human colon cancer cell line HT-29. HT-29 cells were cultured in serum-free medium with 0, 20, 40, or 60 micromol/L fisetin. Fisetin dose dependently inhibited both cell growth and DNA synthesis (P < 0.05), with a 79 +/- 1% decrease in cell number observed 72 h after the addition of 60 micromol/L fisetin. Perturbed cell cycle progression from the G(1) to S phase was observed at 8 h with 60 micromol/L fisetin treatment, whereas a G(2)/M phase arrest was observed after 24 h (P < 0.05). The phosphorylation state of the retinoblastoma proteins shifted from hyperphosphorylated to hypophosphorylated in cells treated with 40 micromol/L fisetin. (P < 0.05). Fisetin decreased the activities of cyclin-dependent kinases (CDK)2 and CDK4; these effects were likely attributable to decreases in the levels of cyclin E and D1 and an increase in p21(CIP1/WAF1) levels (P < 0.05). However, fisetin also inhibited CDk4 activity in a cell-free system (P < 0.05), indicating that it may directly inhibit CDk4 activity. The protein levels of cell division cycles (CDC)2 and CDC25C and the activity of CDC2 were also decreased in fisetin-treated cells (P < 0.05). These results indicate that inhibition of cell cycle progression in HT-29 cells after treatment with fisetin can be explained, at least in part, by modification of CDK activities.</P>

Dietary supplementation of L-arginine and conjugated linoleic acid reduces retroperitoneal fat mass and increases lean body mass in rats.

Nall, Jennifer L,Wu, Guoyao,Kim, Kyoung Hoon,Choi, Chang Weon,Smith, Stephen B Wistar Institute of Anatomy and Biology 2009 The Journal of nutrition Vol.139 No.7

<P>We hypothesized that l-arginine and conjugated linoleic acid (CLA) would have additive effects in decreasing adiposity. Sprague Dawley rats were assigned to the following dietary groups (n = 6/group; 5 wk total): 1) control (2.55% l-alanine plus 1.5% canola oil); 2) arginine (1.25% l-arginine plus 1.5% canola oil); 3) CLA (2.55% l-alanine plus 1.5% CLA); and 4) arginine plus CLA (1.25% l-arginine plus 1.5% CLA). Supplemental amino acids were provided in drinking water and CLA was incorporated into the food pellets. Daily weight gain, food intake, arginine intake, and final body and eviscerated body weights were greater in rats fed supplemental CLA then in rats fed canola oil. The retroperitoneal adipose tissue:body weight ratio was less in rats fed supplemental CLA than in rats fed canola oil, but epididymal adipose tissue, liver, and soleus and extensor digitorum longus muscle weights were unaffected by arginine or CLA. CLA decreased epididymal adipose tissue concentrations of palmitoleic, oleic, and cis-vaccenic acid. CLA and arginine increased palmitate oxidation to CO(2) in epididymal adipose tissue in vitro relative to control rats. Glucose and palmitate incorporation into total lipids in epididymal adipose tissue was lower in rats fed supplemental arginine than in alanine-fed rats. Arginine increased plasma glycerol relative to alanine-fed rats and CLA and arginine independently decreased most serum essential amino acids and alanine, glutamate, glutamine, and ornithine. We conclude that CLA and arginine modulated adipose tissue metabolism by separate, but not additive, effects. Also, CLA and arginine may have depressed muscle protein turnover.</P>

Synaptic connectivity of urinary bladder afferents in the rat superficial dorsal horn and spinal parasympathetic nucleus

Park, Sook Kyung,Devi, Angom Pushparani,Bae, Jin Young,Cho, Yi Sul,Ko, Hyoung‐,Gon,Kim, Duk Yoon,Bae, Yong Chul Wistar Institute of Anatomy and Biology 2019 Journal of comparative neurology Vol.527 No.18

<P><B>Abstract</B></P><P>That visceral sensory afferents are functionally distinct from their somatic analogues has been known for a long time but the detailed knowledge of their synaptic connections and neurotransmitters at the first relay nucleus in the spinal cord has been limited. To provide information on these topics, we investigated the synapses and neurotransmitters of identified afferents from the urinary bladder to the superficial laminae of the rat spinal dorsal horn (DH) and the spinal parasympathetic nucleus (SPN) by tracing with horseradish peroxidase, quantitative electron microscopical analysis, and immunogold staining for GABA and glycine. In the DH, most bladder afferent boutons formed synapses with 1–2 postsynaptic dendrites, whereas in the SPN, close to a half of them formed synapses with 3–8 postsynaptic dendrites. The number of postsynaptic dendrites and dendritic spines per bladder afferent bouton, both measures of synaptic divergence and of potential for synaptic plasticity at a single bouton level, were significantly higher in the SPN than in the DH. Bladder afferent boutons frequently received inhibitory axoaxonic synapses from presynaptic endings in the DH but rarely in the SPN. The presynaptic endings were GABA‐ and/or glycine‐immunopositive. The bouton volume, mitochondrial volume, and active zone area, all determinants of synaptic strength, of the bladder afferent boutons were positively correlated with the number of postsynaptic dendrites. These findings suggest that visceral sensory information conveyed via the urinary bladder afferents is processed differently in the DH than in the SPN, and differently from the way somatosensory information is processed in the spinal cord.</P>

Ajoene, a stable garlic by-product, has an antioxidant effect through Nrf2-mediated glutamate-cysteine ligase induction in HepG2 cells and primary hepatocytes.

Kay, Hee Yeon,Won Yang, Jin,Kim, Tae Hyun,Lee, Da Yeon,Kang, Bomi,Ryu, Jae-Ha,Jeon, Raok,Kim, Sang Geon Wistar Institute of Anatomy and Biology 2010 The Journal of nutrition Vol.140 No.7

<P>Cytoprotective effects of chemopreventive agents may be attributed to the induction of antioxidant enzymes. Among these, the induction of glutamate-cysteine ligase (GCL) protects cells from oxidative injury by increasing glutathione (GSH) content. Nuclear factor erythroid-2-related factor 2 (Nrf2) transcriptionally regulates the expression of genes encoding for GCL and other cysteine-metabolizing enzymes. Despite extensive studies on the components in garlic, little information is available on organosulfur by-products made from garlic. In this study, we investigated whether ajoene, a chemically stable garlic by-product, has the ability to activate Nrf2 and induce GCL, and, if so, what is the role of activating Nrf2 in cytoprotection against oxidative stress. Immunoblottings and reporter gene assays were performed in HepG2 cells. Ajoene treatment activated Nrf2, as indicated by increased phosphorylation and nuclear accumulation of Nrf2, decreased interaction with Kelch-like ECH-associated protein-1, and decreased Nrf2 ubiquitination. Consistently, treatment of ajoene increased antioxidant response element reporter gene activity and the mRNA and protein levels of GCL subunits. Ajoene activated protein kinase C-delta (PKCdelta). Inhibition of PKCdelta activation by rottlerin abrogated its ability to activate Nrf2 and induce GCL, suggesting that ajoene promotes the Nrf2-dependent antioxidant defense system via PKCdelta activation. Consequently, ajoene prevented cell death, GSH depletion, and hydrogen peroxide production elicited by tert-butylhydroperoxide. The important role of Nrf2 in cytoprotection was verified by the reversal of ajoene's ability to protect hepatocytes in Nrf2-knockout mice. Our results demonstrate that ajoene increases PKCdelta-dependent Nrf2 activation, GCL induction, and the cellular GSH concentration, which may contribute to protecting cells from oxidative stress.</P>