Red wines and flavonoids diminish Staphylococcus aureus virulence with anti-biofilm and anti-hemolytic activities.

Cho, Hyun Seob,Lee, Jin-Hyung,Cho, Moo Hwan,Lee, Jintae Harwood Academic Publishers 2015 Biofouling Vol.31 No.1

<P>The emergence of antibiotic resistant Staphylococcus aureus presents a worldwide problem that requires non-antibiotic strategies. This study investigated the anti-biofilm and anti-hemolytic activities of four red wines and two white wines against three S. aureus strains. All red wines at 0.5-2% significantly inhibited S. aureus biofilm formation and hemolysis by S. aureus, whereas the two white wines had no effect. Furthermore, at these concentrations, red wines did not affect bacterial growth. Analyses of hemolysis and active component identification in red wines revealed that the anti-biofilm compounds and anti-hemolytic compounds largely responsible were tannic acid, trans-resveratrol, and several flavonoids. In addition, red wines attenuated S. aureus virulence in vivo in the nematode Caenorhabditis elegans, which is killed by S. aureus. These findings show that red wines and their compounds warrant further attention in antivirulence strategies against persistent S. aureus infection.</P>

Sulfate-conjugated methylprednisolone as a colon-targeted methylprednisolone prodrug with improved therapeutic properties against rat colitis.

Kong, Hyesik,Lee, Younghyun,Hong, Sungchae,Han, Jeongoh,Choi, Biom,Jung, Yunjin,Kim, Young Mi Harwood Academic Publishers 2009 JOURNAL OF DRUG TARGETING Vol.17 No.6

<P>Methylprednisolone (MP) is one of the most widely used corticosteroids for the treatment of inflammatory bowel disease (IBD). However, systemic adverse effects of MP limit its availability for the disease. In present study, sulfate-conjugated methylprednisolone (MPS) was evaluated in vivo as a colon-targeted prodrug of MP and its therapeutic properties against 2,4,6-trinitrobenzenesulfonic acid-induced rat colitis were investigated. Upon oral administration, a large fraction of MPS reached the large intestine, where MPS was converted to MP implying that MPS would deliver MP effectively to the large intestine. The fecal recovery of MP (after MPS administration) was much greater than that after MP administration and the urinary recovery of MP (after MPS administration) was much less than that after MP administration, suggesting that MPS should exhibit enhanced therapeutic activity and reduced systemic adverse effects. Consistent with this notion, MPS was more effective than MP in ameliorating rat colitis. Moreover, the adverse effects of MPS on adrenal function and thymus were much lower than those of MP. Taken together, MPS may be therapeutically superior to MP in IBD treatment.</P>

Dose-related cytoprotective effect of alpha-lipoic acid on hydrogen peroxide-induced oxidative stress to pancreatic beta cells.

Lee, Byung Wan,Kwon, Soo Jin,Chae, Hee Young,Kang, Jun Goo,Kim, Chul Sik,Lee, Seong Jin,Yoo, Hyung Joon,Kim, Jae Hyeon,Park, Kyong Soo,Ihm, Sung-Hee Harwood Academic ; Distributed by STBS Ltd 2009 Free radical research Vol.43 No.1

<P>alpha-Lipoic acid (alpha-LA), an antioxidant used for diabetic polyneuropathy, was reported to induce AMP-activated protein kinase activation and reductions in insulin secretion in pancreatic beta-cells at high concentrations (> or = 500 micromol/l). This study investigated whether alpha-LA has a protective role under oxidative stress in beta-cells and its effect is dose-related. In INS-1 cells treated with alpha-LA (150-1200 micromol/l) for 24 h, alpha-LA itself (> or = 300 micromol/l) induced apoptotic death dose-dependently. However, pre-treatment with 150 and 300 micromol/l alpha-LA reduced the hydrogen peroxide-induced apoptosis in INS-1 cells and isolated islets. alpha-LA alleviated hydrogen peroxide-induced reactive oxygen species production, mitochondrial membrane depolarization and c-JNK activation in beta-cells. alpha-LA induced phosphoinositide 3-kinase-dependent Akt phosphorylation in INS-1 cells. While alpha-LA is harmful to beta-cells at high concentrations in vitro, it has potential cytoprotective effects on beta-cells under oxidative stress as in diabetes by its antioxidant properties and possibly by Akt phosphorylation at clinically relevant concentrations.</P>

Inhibition of Rac and Rac-linked functions by 8-oxo-2'-deoxyguanosine in murine macrophages.

Lee, Sun-Hye,Taek Han, Sang,Choi, Seong-Won,Sung, Seung-Yong,You, Ho-Jin,Ye, Sang-Kyu,Chung, Myung-Hee Harwood Academic ; Distributed by STBS Ltd 2009 Free radical research Vol.43 No.1

<P>Rac is a protein involved in the various functions of macrophages (Mphi), including the production of reactive oxygen species (ROS), phagocytosis, chemotaxis and the secretion of cytokines (such as gamma-INF). This study tested the effects of nucleosides containing 8-oxoguanine(8-hydroxyguanine) such as 8-oxo-2'-guanosine (8-oxoG) or 8-oxo-2'-deoxyguanosine (8-oxodG), on Rac and the above-listed Rac-associated functions of Mphi using mouse peritoneal Mphi (MpMphi). It is reported that 8-oxodG was able to effectively inhibit Rac and the Rac-associated functions of MpMphi. Compared to 8-oxodG, 8-oxoG showed negligible effects. Furthermore, normal nucleosides such as deoxyguanosine (dG), guanosine (G) and adenosine (A) did not exert any effects. These results suggest that 8-oxodG could be used as a potential tool to modulate the functions of Mphi that are intimately related to various pathological processes.</P>

Enhanced protection of Ins-1 beta cells from apoptosis under hypoxia by delivery of DNA encoding secretion signal peptide-linked exendin-4.

Ah Kim, Hyun,Lee, Suyeon,Park, Jeong-Hyun,Lee, Sanghyun,Lee, Byung-Wan,Ihm, Sung Hee,Kim, Tae-il,Kim, Sung Wan,Ko, Kyung Soo,Lee, Minhyung Harwood Academic Publishers 2009 JOURNAL OF DRUG TARGETING Vol.17 No.3

<P>In this study, we developed an expression system of exendin-4, a glucagon-like peptide (GLP-1) analog, using a secretion signal peptide (SP) to facilitate exendin-4 secretion. For delivery of the exendin-4 expression system, high-molecular-weight polyethylenimine (25 kDa, PEI25k), low-molecular-weight polyethylenimine (2 kDa, PEI2k), and polyamidoamine (PAMAM) dendrimers were evaluated as gene carriers to Ins-1 beta cells. As a result, PEI25k showed the highest transfection efficiency. For the construction of the exendin-4 expression vector, DNA coding the SP sequence was inserted upstream of the exendin-4 cDNA, resulting in the construction of pbeta-SP-Ex-4. Transfection assay showed that the secretion level of exendin-4 increased in the pbeta-SP-Ex-4 transfected cells, compared with the pbeta-Ex-4 transfected cells. To identify the beta-cell protection effect of pbeta-SP-Ex-4 delivery, the Ins-1 beta cells were transfected with pbeta-SP-Ex-4 or pbeta-Ex-4 and incubated under normoxia or hypoxia. An MTT assay showed that the pbeta-SP-Ex-4 transfected cells had higher beta-cell viability than the pbeta-Ex-4 transfected cells under hypoxia. In addition, the pbeta-SP-Ex-4 transfected cells exhibited lower caspase-3 activity than the pbeta-Ex-4 transfected cells. Therefore, PEI25k/pbeta-SP-Ex-4 complex may be useful to protect isolated beta cells from apoptosis during transplantation.</P>

Protective mechanisms of NO preconditioning against NO-induced apoptosis in H9c2 cells: role of PKC and COX-2.

Kwak, Hyun-Jeong,Park, Kyoung Mi,Choi, Hye-Eun,Park, Hyun-Young Harwood Academic ; Distributed by STBS Ltd 2009 Free radical research Vol.43 No.8

<P>Cardiomyocyte apoptosis is involved in several cardiovascular diseases, including ischemia, hypertrophy and heart failure. Nitric oxide (NO) signalling is crucial in the regulation of cardiomyocyte apoptosis, capable of both inducing and preventing apoptosis depending upon the level of NO production. Growing evidence suggests that NO preconditioning has cardioprotective effects, but the mechanism remains unclear. The purpose of this study was to elucidate how NO preconditioning inhibits subsequent NO-induced apoptosis in H9c2 cells. According to the data, preconditioning with a low concentration of sodium nitroprusside (SNP, 0.3 mM) inhibited subsequent high-concentration-SNP (1.5 mM)-induced apoptosis and this effect was reversed by the protein kinase C (PKC) inhibitor chelerythrine and the cyclooxygenase-2 (COX-2) inhibitor rofecoxib. Low-concentration-SNP-mediated protection involved extracellular signal regulated kinase 1/2 (ERK1/2), a signal transducers and activators of transcription 1/3 (STAT1/3) activation and increased COX-2 expression. Activation of ERK1/2 and STAT1/3 was abolished by chelerythrine. However, COX-2 expression was not inhibited, implying that the COX-2-mediated protective effect occurred via a PKC-independent pathway. The results showed that low-concentration-SNP preconditioning suppresses subsequent high-concentration-SNP-induced apoptosis by ERK1/2-STAT 1/3 activation via PKC-dependent mechanisms in H9c2 cells. COX-2 also plays a role in NO-induced preconditioning, but is independent of PKC.</P>

[6]-Gingerol prevents UVB-induced ROS production and COX-2 expression in vitro and in vivo

Kim, Jin-Kyoung,Kim, Younghwa,Na, Kwang-Min,Surh, Young-Joon,Kim, Tae-Yoon Harwood Academic 2007 Free radical research Vol.41 No.5

<P> [6]-Gingerol, a naturally occurring plant phenol, is one of the major components of fresh ginger (Zingiber officinale Roscoe, Zingiberaceae) and has diverse pharmacologic effects. Here, we describe its novel anti-oxidant, anti-apoptotic, and anti-inflammatory activities in vitro and in vivo. In vitro, pre-treatment with [6]-gingerol reduced UVB-induced intracellular reactive oxygen species levels, activation of caspase-3, -8, -9, and Fas expression. It also reduced UVB-induced expression and transactivation of COX-2. Translocation of NF-&kgr;B from cytosol to nucleus in HaCaT cells was inhibited by [6]-gingerol via suppression of I&kgr;Bα phosphorylation (ser-32). Examination by EMSAs and immunohistochemistry showed that topical application of [6]-gingerol (30 μM) prior to UVB irradiation (5 kJ/m2) of hairless mice, also inhibited the induction of COX-2 mRNA and protein, as well as NF-&kgr;B translocation. These results suggest that [6]-gingerol could be an effective therapeutic agent providing protection against UVB-induced skin disorders.</P>

Preventive effect of 20(S)-ginsenoside Rg3 against lipopolysaccharide-induced hepatic and renal injury in rats

Kang, Ki Sung,Kim, Hyun Young,Yamabe, Noriko,Park, Jeong Hill,Yokozawa, Takako Harwood Academic 2007 Free radical research Vol.41 No.10

<P> The preventive effect of 20(S)-ginsenoside Rg3 (20(S)-Rg3) on lipopolysaccharide (LPS)-induced oxidative tissue injury in rats was investigated in this study. The elevated serum nitrite/nitrate, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and creatinine levels in LPS-treated control rats were significantly decreased following 15 consecutive days of 20(S)-Rg3 administration. In addition, thiobarbituric acid-reactive substance levels in the serum, liver and kidney were dose-dependently lower in 20(S)-Rg3-treated groups than in the LPS-treated control group. The nuclear factor-&kgr;B (NF-&kgr;B), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) protein expressions in the liver and kidney were significantly increased by LPS treatment. However, the 20(S)-Rg3 administrations significantly decreased these protein expressions except for HO-1 in the liver. On the other hand, in the kidney, oral administration of 20(S)-Rg3 showed a tendency to reduce NF-&kgr;B and iNOS protein expressions and also significantly reduced the elevated COX-2 and HO-1 protein expressions at a dose of 10 mg/kg body weight/day. All these results suggest the preventive effect of 20(S)-Rg3 against LPS-induced acute oxidative damage in the liver and kidney and the preventive effect of 20(S)-Rg3 administration against LPS toxicity was thought to be more predominant in the liver than kidney.</P>

8-Oxo-7,8-dihydroguanosine triphosphate(8-oxoGTP) down-regulates respiratory burst of neutrophils by antagonizing GTP toward Rac, a small GTP binding protein

Kim, Hee Joon,Yoon, Sun-Hee,Ryu, Hyun-Ok,Yoon, Byung-Hak,Choi, Seongwon,Ye, Sang-Kyu,Chung, Myung-Hee Harwood Academic 2007 Free radical research Vol.41 No.6

<P> 8-Oxo-7,8-dihydroguanosine triphosphate (8-oxoGTP) has been regarded simply as a oxidative mutagenic byproduct. The results obtained in this study imply that it may act as a down-regulator of respiratory burst of neutrophils. Human neutrophils treated with PMA produced superoxides and at the same time, the cytosol of these cells was intensely immunostained by 8-oxo-7,8-dihydroguanosine(8-oxoG) antibody, indicating that 8-oxoG-containing chemical species including 8-oxoGTP are produced. Human neutrophil lysates treated with PMA also produced superoxides, which was stimulated by GTP&ggr;S but inhibited by 8-oxoGTP&ggr;S. Moreover, 8-oxoGTP&ggr;S suppressed the stimulatory action of GTP&ggr;S. Likewise, GTP&ggr;S stimulated Rac activity in neutrophil lysates but 8-oxoGTP&ggr;S and GDP inhibited it. The inhibitory effect of GDP was one tenth that of 8-oxoGTP&ggr;S. Here again, 8-oxoGTP&ggr;S also suppressed the stimulatory action of GTP&ggr;S on Rac activity. These results imply the possibility that 8-oxoGTP is formed during respiratory burst of neutrophils and limits neutrophil production of superoxides by antagonizing GTP toward Rac.</P>

Down-regulation of aldose reductase renders J774A.1 cells more susceptible to acrolein- or hydrogen peroxide-induced cell death.

Kang, Eun Sil,Kim, Gil Hyeong,Woo, Im Sun,Kim, Hyo Jung,Eun, So Young,Ham, Sun Ah,Jin, Hana,Kim, Min Young,Park, Myung Hyun,Kim, Hye Jung,Chang, Ki Churl,Lee, Jae Heun,Kim, Jin-Hoi,Yabe-Nishimura, Chi Harwood Academic ; Distributed by STBS Ltd 2008 Free radical research Vol.42 No.11

<P>Aldose reductase (AR) is abundantly expressed in a variety of cell lineages and has been implicated in the cellular response against oxidative stress. However, the exact functional role of AR against oxidative stress remains relatively unclear. This study investigated the role of AR in acrolein- or hydrogen peroxide-induced apoptosis using the J774.A.1 macrophage cell line. Ablation of AR with a small interference RNA or inhibition of AR activity significantly enhanced the acrolein- or hydrogen peroxide-induced generation of reactive oxygen species and aldehydes, leading to increased apoptotic cell death. Blockade of AR activity in J774A.1 cells markedly augmented the acrolein- or hydrogen peroxide-induced translocation of Bax to mitochondria along with reduced Bcl-2 and increased release of cytochrome c from the mitochodria. Taken together, these findings indicate that AR plays an important role in the cellular response against oxidative stress, by sequestering the reactive molecules generated in cells exposed to toxic substances.</P>