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Jin S.W.,Chungnam National University | Choi C.Y.,Jeollanamdo Institute of Natural Resources Research | Kim H.G.,Chungnam National University | Kim S.J.,Chungnam National University | And 4 more authors.
Journal of Agricultural and Food Chemistry | Year: 2016

Betulinic acid (BA) is a naturally occurring pentacyclic triterpene that attenuates vascular diseases and atherosclerosis, but the mechanism by which it stimulates endothelial nitric oxide synthase (eNOS) is unclear. eNOS is the key regulatory enzyme in the vascular endothelium. This study examined the intracellular pathways underlying the effects of BA on eNOS activity and endothelial nitric oxide (NO) production in endothelial cells. BA treatment induced both eNOS phosphorylation at Ser1177 and NO production. It also increased the level of intracellular Ca2+ and phosphorylation of Ca2+/calmodulin-dependent kinase IIα (CaMKIIα) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). Inhibition of the L-type Ca2+ channel (LTCC) and the ryanodine receptor (RyR) abolished BA-induced intracellular levels of Ca2+ and eNOS phosphorylation. Treatment with W7 (a CaM antagonist), KN-93 (a selective inhibitor of CaMKII), and STO 609 (a selective inhibitor of CaMKK) suppressed eNOS phosphorylation and NO production. Moreover, AMP-activated protein kinase (AMPK) was induced by BA, and BA-induced eNOS phosphorylation was inhibited by compound C, an AMPK inhibitor. Taken together, these results indicate that BA activates eNOS phosphorylation and NO synthesis via the Ca2+/CaMKII and Ca2+/CaMKK/AMPK pathways. These findings provide further insight into the eNOS signaling pathways involved in the antiatherosclerosis effects of BA. © 2016 American Chemical Society.


Kim S.,Jeollanamdo Institute of Natural Resources Research | Rhim H.,Korea Institute of Science and Technology
Molecules and Cells | Year: 2011

Overload of intracellular Ca 2+ has been implicated in the pathogenesis of neuronal disorders, such as Alzheimer's disease. Various mechanisms produce abnormalities in intracellular Ca 2+ homeostasis systems. L-type Ca 2+ channels have been known to be closely involved in the mechanisms underlying the neurodegenerative properties of amyloid-β (Aβ) peptides. However, most studies of L-type Ca 2+ channels in Aβ-related mechanisms have been limited to Ca v1.2, and surprisingly little is known about the involvement of Ca v1.3 in Aβ-induced neuronal toxicity. In the present study, we examined the expression patterns of Ca v1.3 after Aβ25-35 exposure for 24 h and compared them with the expression patterns of Ca v1.2. The expression levels of Ca v1.3 were not significantly changed by Aβ25-35 at both the mRNA levels and the total protein level in cultured hippocampal neurons. However, surface protein levels of Ca v1.3 were significantly increased by Aβ25-35, but not by Aβ35-25. We next found that acute treatment with Aβ25-35 increased Ca v1.3 channel activities in HEK293 cells using whole-cell patch-clamp recordings. Furthermore, using GTP pulldown and co-immunoprecipitation assays in HEK293 cell lysates, we found that amyloid precursor protein interacts with β 3 subunits of Ca 2+ channels instead of Ca v1.2 or Ca v1.3 a1 subunits. These results show that Aβ25-35 chronically or acutely upregulates Ca v1.3 in the rat hippocampal and human kidney cells (HEK293). This suggests that Ca v1.3 has a potential role along with Ca v1.2 in the pathogenesis of Alzheimer's disease. © 2011 KSMCB.


Lee Y.-H.,University of Suwon | Kwak J.,Korea University | Choi H.-K.,Yonsei University | Choi K.-C.,University of Seoul | And 5 more authors.
International Journal of Molecular Medicine | Year: 2012

Manipulating acetylation status of key gene targets is likely to be crucial for effective cancer therapy. In this study, we utilized green tea catechins, epicatechin (EC), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG) to examine the regulation of androgen receptor acetylation in androgen-dependent prostate cancer cells by histone acetyltransferase (HAT) activity. EC, EGC and EGCG induced prostate cancer cell death, suppressed agonist-dependent androgen receptor (AR) activation and AR-regulated gene transcription. These results demonstrated a similar tendency to HAT inhibitory activities; EGCG>EGC>EC. The strongest HAT inhibitor among them, EGCG (50 μM), downregulated AR acetylation and finally, AR protein translocation to nucleus from the cytoplasmic compartment was effectively inhibited in the presence of the agonist. These results suggest another mechanism to develop effective therapeutics based on green tea catechins.


Choi J.H.,Chungnam National University | Jin S.W.,Chungnam National University | Kim H.G.,Chungnam National University | Khanal T.,Chungnam National University | And 8 more authors.
Food and Chemical Toxicology | Year: 2013

The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. DMN treatment for 4. weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. © 2013 Elsevier Ltd.


Karki R.,Mokpo National University | Jung M.-A.,Mokpo National University | Jung M.-A.,Jeollanamdo Institute of Natural Resources Research | Kim K.-J.,Taekyeung College | Kim D.-W.,Mokpo National University
Evidence-based Complementary and Alternative Medicine | Year: 2012

Atopic dermatitis (AD) is a chronic inflammatory skin disease which has a complex etiology that encompasses immunologic responses. The study was carried out to examine the effect of Nelumbo nucifera (Gaertn.) leaf (NL) on the AD-like skin lesion induced by repeated epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) on the dorsal skin of NC/Nga mice. Three different doses of NL (5, 25, and 50mg/mice/day) were administered orally from the day of sensitization with DNCB for 4 weeks. The efficacy of NL was judged by histopathological examination, blood IgE level, measurement of transepidermal water loss (TEWL), scratching behavior, and skin severity score. NL resulted in the suppression of clinical severity score, TEWL, scratching behavior, and blood IgE level. Histopathologic analyses revealed that thickening of the epidermis and mast cell degranulation was significantly reduced in NL group. These results suggest that NL may be a useful natural resource for the management of AD. Copyright 2012 Rajendra Karki et al.

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