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Ginseng (Panax ginseng Meyer) has been used in East Asian traditional medicine for a long time. Korean red ginseng (KRG) is effective against several disorders, including cancer. The cytotoxic effects of KRG extract in terms of autophagy- and apoptosis-mediated cell death and its mechanisms were investigated using human colorectal cancer lines. KRG induced autophagy-mediated cell death with enhanced expression of Atg5, Beclin-1, and LC3, and formed characteristic vacuoles in HCT-116 and SNU-1033 cells. An autophagy inhibitor prevented cell death induced by KRG. KRG generated mitochondrial reactive oxygen species (ROS); antioxidant countered this effect and decreased autophagy. KRG caused apoptotic cell death by increasing apoptotic cells and sub-G1 cells, and by activating caspases. A caspase inhibitor suppressed cell death induced by KRG. KRG increased phospho-Bcl-2 expression, but decreased Bcl-2 expression. Moreover, interaction of Bcl-2 with Beclin-1 was attenuated by KRG. Ginsenoside Rg2 was the most effective ginsenoside responsible for KRG-induced autophagy- and apoptosis-mediated cell death. KRG induced autophagy- and apoptosis-mediated cell death via mitochondrial ROS generation, and thus its administration may inhibit colon carcinogenesis.

Excessive ultraviolet (UV) radiation, a constituent of sunlight, can induce multiple types of skin damage. We recently demonstrated that americanin B, a lignin compound, protected cells against hydrogen peroxide (H2O2)-induced damage by exerting antioxidant effects and inhibiting apoptosis. In this study, we investigated the ability of americanin B to protect against cell injury induced by UVB (280-320nm), the most harmful UV wavelengths, in human HaCaT keratinocytes. Americanin B absorbed UVB, eliminated UVB-induced intracellular reactive oxygen species (ROS), and decreased the extent of UVB-induced oxidative modification of lipids, proteins, and DNA. In addition, americanin B inhibited UVB-induced apoptosis, as indicated by reductions in apoptotic body formation and DNA fragmentation. Furthermore, americanin B reversed the depolarization of the mitochondrial membrane induced by UVB exposure. These protective activities were associated with down-regulation of apoptosis-promoting proteins, Bax, caspase-9, and caspase-3 and up-regulation of an apoptosis inhibitor, Bcl-2. These results suggest that americanin B can protect human keratinocytes against UVB-induced cell damage.

Fucoxanthin, a natural carotenoid, is abundant in seaweed with antioxidant properties. This study investigated the role of fucoxanthin in the induction of antioxidant enzymes involved in the synthesis of reduced glutathione (GSH), synthesized by glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS), via Akt/nuclear factor-erythroid 2-related (Nrf2) pathway in human keratinocytes (HaCaT) and elucidated the underlying mechanism. Fucoxanthin treatment increased the mRNA and protein levels of GCLC and GSS in HaCaT cells. In addition, fucoxanthin treatment promoted the nuclear translocation and phosphorylation of Nrf2, a transcription factor for the genes encoding GCLC and GSS. Chromatin immune-precipitation and luciferase reporter gene assays revealed that fucoxanthin treatment increased the binding of Nrf2 to the antioxidant response element (ARE) sequence and transcriptional activity of Nrf2. Fucoxanthin treatment increased phosphorylation of Akt (active form), an up-regulator of Nrf2 and exposure to LY294002, a phosphoinositide 3-kinase (PI3K)/Akt inhibitor, suppressed the fucoxanthin-induced activation of Akt, Nrf2, resulting in decreased GCLC and GSS expression. In accordance with the effects on GCLC and GSS expression, fucoxanthin induced the level of GSH. In addition, fucoxanthin treatment recovered the level of GSH reduced by ultraviolet B irradiation. Taken together, these findings suggest that fucoxanthin treatment augments cellular antioxidant defense by inducing Nrf2-driven expression of enzymes involved in GSH synthesis via PI3K/Akt signaling.

Glutathione S-transferase π-1 (GSTP-1) is a member of the glutathione S-transferase enzyme superfamily, which catalyzes the conjugation of electrophiles to glutathione during the process of detoxification. In this study, the epigenetic alterations of GSTP-1 expression in human colorectal cancers and the underlying mechanisms were investigated. In 10 colon cancer patients, proteomic analysis revealed that expression of GSTP-1 protein was higher in tumor tissues than in paired adjacent normal tissues. Likewise, in 7 of 10 colon cancer patients, GSTP-1 protein expression was more than 1.5-fold higher in tumor tissues than in adjacent normal tissues, as determined by western blotting. Immunohistochemical data confirmed that GSTP-1 protein was expressed at higher levels in colon cancer tissues compared to normal mucosa. GSTP-1 enzyme activity was closely correlated with GSTP-1 protein expression in colon cancer patients. Consistent with this, GSTP-1 mRNA, protein and activity levels were higher in the colorectal cancer cell lines Caco-2, HCT-116, HT-29, SNU-407 and SNU-1033 compared to the normal colon cell line FHC. Methylation-specific PCR results indicated that the high levels of GSTP-1 in human colorectal cancer cell lines were likely due to the lower degree of promoter methylation in colon cancer cell lines compared to the normal colon cell line, consistent with findings in colon cancer patients. Moreover, the levels of specific activator-protein complexes and histone marks were higher in human colorectal cancer cells compared to the normal human colon cell line, whereas the repressor protein complexes exhibited the opposite pattern. Furthermore, chromatin immunoprecipitation assays demonstrated that expression levels of the transcription factors AP-1 and SP-1 were correlated with the upregulation of GSTP-1 expression in colorectal cancer cells. Finally, knockdown of GSTP-1 promoted the sensitivity of SNU-407 cells to the anticancer agent 5-fluorouracil. These data indicate that GSTP-1 may serve as a clinically useful biomarker of colon cancer and a target for anti-colon cancer drugs.

Our previous work demonstrated that an ethyl acetate extract derived from Sargassum muticum (Yendo) Fenshol (SME) protected human HaCaT keratinocytes against ultraviolet B (UVB)-induced oxidative stress by increasing antioxidant activity in the cells, thereby inhibiting apoptosis.The aim of the current study was to further elucidate the anti-apoptotic mechanism of SME against UVB-induced cell damage.The expression levels of several apoptotic-associated and mitogen-activated kinase (MAPK) signaling proteins were determined by western blot analysis of UVB-irradiated HaCaT cells with or without prior SME treatment. In addition, the loss of mitochondrial membrane potential (Δψm) was detected using flow cytometry or confocal microscopy and the mitochondria membrane-permeate dye, JC-1. Apoptosis was assessed by quantifying DNA fragmentation and apoptotic body formation. Furthermore, cell viability was evaluated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.SME absorbed electromagnetic radiation in the UVB range (280-320 nm) of the UV/visible light spectrum. SME also increased Bcl-2 and Mcl-1 expression in UVB-irradiated cells and decreased the Bax expression. Moreover, SME inhibited the UVB-induced disruption of mitochondrial membrane potential and prevented UVB-mediated increases in activated caspase-9 and caspase-3 (an apoptotic initiator and executor, respectively) levels. Notably, treatment with a pan-caspase inhibitor enhanced the anti-apoptotic effects of SME in UVB-irradiated cells. Finally, SME reduced the UVB-mediated phosphorylation of p38 MAPK and JNK, and prevented the UVB-mediated dephosphorylation of Erk1/2 and Akt.The present results indicate that SME safeguards HaCaT keratinocytes from UVB-mediated apoptosis by inhibiting a caspase-dependent signaling pathway.

We investigated the protective effects of chlorogenic acid (CGA), a polyphenol compound, on oxidative damage induced by UVB exposure on human HaCaT cells. In a cell-free system, CGA scavenged 1,1-diphenyl-2-picrylhydrazyl radicals, superoxide anions, hydroxyl radicals, and intracellular reactive oxygen species (ROS) generated by hydrogen peroxide and ultraviolet B (UVB). Furthermore, CGA absorbed electromagnetic radiation in the UVB range (280-320 nm). UVB exposure resulted in damage to cellular DNA, as demonstrated in a comet assay; pre-treatment of cells with CGA prior to UVB irradiation prevented DNA damage and increased cell viability. Furthermore, CGA pre-treatment prevented or ameliorated apoptosis-related changes in UVB-exposed cells, including the formation of apoptotic bodies, disruption of mitochondrial membrane potential, and alterations in the levels of the apoptosis-related proteins Bcl-2, Bax, and caspase-3. Our findings suggest that CGA protects cells from oxidative stress induced by UVB radiation.

Fucodiphlorethol G (6'-[2,4-dihydroxy-6-(2,4,6-trihydroxyphenoxy)phenoxy]biphenyl-2,2',4,4',6-pentol) is a compound purified from Ecklonia cava, a brown alga that is widely distributed offshore of Jeju Island. This study investigated the protective effects of fucodiphlorethol G against oxidative damage-mediated apoptosis induced by ultraviolet B (UVB) irradiation. Fucodiphlorethol G attenuated the generation of 2, 2-diphenyl-1-picrylhydrazyl radicals and intracellular reactive oxygen species in response to UVB irradiation. Fucodiphlorethol G suppressed the inhibition of human keratinocyte growth by UVB irradiation. Additionally, the wavelength of light absorbed by fucodiphlorethol G was close to the UVB spectrum. Fucodiphlorethol G reduced UVB radiation-induced 8-isoprostane generation and DNA fragmentation in human keratinocytes. Moreover, fucodiphlorethol G reduced UVB radiation-induced loss of mitochondrial membrane potential, generation of apoptotic cells, and active caspase-9 expression. Taken together, fucodiphlorethol G protected human keratinocytes against UVB radiation-induced cell damage and apoptosis by absorbing UVB radiation and scavenging reactive oxygen species.

In this study, we investigated the molecular mechanisms underlying the anti-proliferative effects of Compound K, with specific reference to histone modification. Exposure of HT-29 human colon cancer cells to Compound K resulted in time-dependent inhibition of histone deacetylase (HDAC) activity, mRNA and protein expression. Compound K treatment induced unmethylation of the RUNX3 promoter region such as TSA treatment and an accumulation of acetylated histones H3 and H4 within the total cellular chromatin, resulting in an enhanced ability of these histones to bind to the promoter sequences of the tumor suppressor gene Runt-related transcription factor 3 (RUNX3). Treatment of cells with Compound K increased the mRNA and protein expression of RUNX3, as well as p21, a downstream target of RUNX3. These alterations were consistent with cell cycle arrest at the G0/G1 phases and induction of apoptosis. Our results provide new insights into the mechanisms of Compound K action in human colorectal cancer cells and suggest that HDAC inhibition presents a novel approach to prevent or treat colorectal cancer.

6'-O-galloylpaeoniflorin (GPF) is a galloylated derivate of paeoniflorin and a key chemical constituent of the peony root, a perennial flowering plant that is widely used as an herbal medicine in East Asia. This study is the first investigation of the cytoprotective effects of GPF against hydrogen peroxide (H2O2)-induced cell injury and death in human HaCaT keratinocytes. GPF demonstrated a significant scavenging capacity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical, H2O2-generated intracellular reactive oxygen species (ROS), the superoxide anion radical (O2 (-)), and the hydroxyl radical (•OH). GPF also safeguarded HaCaT keratinocytes against H2O2-provoked apoptotic cell death and attenuated oxidative macromolecular damage to DNA, lipids, and proteins. The compound exerted its cytoprotective actions in keratinocytes at least in part by decreasing the number of DNA strand breaks, the levels of 8-isoprostane (a stable end-product of lipid peroxidation), and the formation of carbonylated protein species. Taken together, these results indicate that GPF may be developed as a cytoprotector against ROS-mediated oxidative stress.

We investigated the role of autophagy in SNUC5/5-FUR, 5-fluorouracil (5-FU) resistant SNUC5 colon cancer cells. SNUC5/5- FUR cells exhibited low level of autophagy, as determined by light microscopy, confocal microscopy, and flow cytometry following acridine orange staining, and the decreased level of GFP-LC3 puncta. In addition, expression of critical autophagic proteins such as Atg5, Beclin-1 and LC3-II and autophagic flux was diminished in SNUC5/5-FUR cells. Whereas production of reactive oxygen species (ROS) was significantly elevated in SNUC5/5-FUR cells, treatment with the ROS inhibitor N-acetyl cysteine further reduced the level of autophagy. Taken together, these results indicate that decreased autophagy is linked to 5-FU resistance in SNUC5 colon cancer cells.

In recent years, applications like multimedia, video and audio stream communications, 3D movies, to name a few, have spurred the proliferation of multiprocessor systems, particularly for real-time embedded systems. However, the complex architecture and heavy computing demands of such systems increase power consumption. Therefore, energy conservation has become a critical issue. In this paper, we propose a novel tasks scheduling algorithm for real-time multiprocessor systems. The algorithm works by reducing the workload in high speed processors with the aid of task migration so that the entire system can switch to low speed/low voltage as soon as it can reduce power consumption. The overhead of transitioning to low voltage is also analyzed and used as a criterion to determine whether the transition is beneficial. The effect of important parameters such as task granularity on the performance is also investigated, and simulation results based on realistic processor power consumption models are shown to be promising.

The cytoprotective mechanism of 7, 8-dihydroxyflavone (DHF) against oxidative stress-induced cell damage with respect to its stimulatory effect on the expression of heme oxygenase-1 (HO-1), a potent antioxidant enzyme, was investigated in the present study. Up-regulation of HO-1 expression by DHF was both dose and time dependent in lung fibroblast V79-4 cells. DHF also increased the protein expression level of the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), and induced the translocation of Nrf2 from the cytosol into the nucleus, leading to elevated HO-1 expression. The siNrf2 RNA-transfection attenuated HO-1 expression induced by DHF treatment. In addition, DHF induced the activation of extracellular signal-regulated kinase (ERK), while U0126 (a specific pharmacological inhibitor of ERK kinase) abrogated DHF-activated Nrf2 and HO-1 expression. This suggests that DHF increased the levels of Nrf2 and HO-1 via ERK-dependent pathways. Furthermore, DHF significantly prevented the reduction of cell viability in response to oxidative stress; however, U0126 attenuated the protective effect of DHF. Taken together, these results demonstrate that DHF protected cells from oxidative stress via the activation of an ERK/Nrf2/HO-1 signaling pathway.

This study investigated the effect of 7,8-dihydroxyflavone (DHF) on the expression and activity of heme oxygenase-1 (HO-1), an enzyme with potent antioxidant properties, as well as the molecular mechanisms involved. DHF markedly upregulated HO-1 mRNA and protein expression in human keratinocytes (HaCaT cells), resulting in increased HO-1 activity. DHF also increased the protein level of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates HO-1 expression by binding to the antioxidant response element (ARE) within the HO-1 gene promoter, in a time-dependent manner. Moreover, DHF decreased the expression of Kelch-like ECH-associated protein 1, a repressor of Nrf2 activity, and induced the translocation of Nrf2 from the cytosol into the nucleus, thereby allowing its association with the ARE site. DHF activated extracellular-regulated kinase (ERK) and protein kinase B (PKB, Akt) in keratinocytes, while the ERK and Akt inhibitors attenuated DHF-enhanced Nrf2 and HO-1 expression. DHF also protected the keratinocytes against hydrogen peroxide- and ultraviolet B-induced oxidative damage, while HO-1, ERK and Akt inhibitors markedly suppressed DHF-mediated cytoprotection. Taken together, the results suggested that DHF activates ERK- and Akt-Nrf2 signaling cascades in HaCaT cells, leading to the upregulation of HO-1 and cytoprotection against oxidative stress.

Hydrogen peroxide (H2O2) can induce cell damage by generating reactive oxygen species (ROS), resulting in DNA damage and cell death. The aim of this study is to elucidate the protective effects of fisetin (3,7,3′,4′,-tetrahydroxy flavone) against H2O2-induced cell damage. Fisetin reduced the level of superoxide anion, hydroxyl radical in cell free system, and intracellular ROS generated by H2O2. Moreover, fisetin protected against H2O2-induced membrane lipid peroxidation, cellular DNA damage, and protein carbonylation, which are the primary cellular outcomes of H2O2 treatment. Furthermore, fisetin increased the level of reduced glutathione (GSH) and expression of glutamate-cysteine ligase catalytic subunit, which is decreased by H2O2. Conversely, a GSH inhibitor abolished the cytoprotective effect of fisetin against H2O2-induced cells damage. Taken together, our results suggest that fisetin protects against H2O2-induced cell damage by inhibiting ROS generation, thereby maintaining the protective role of the cellular GSH system.

In this paper, we introduce a factor 'internet shopping anxiety' that influences the behaviours of online consumers while engaging in e-tailing services. In previous studies which deal with anxiety, consumer anxiety and its associated coping behaviours were of particular concern. Here, we explore and empirically validate the relationships between internet shopping anxiety and coping behaviour of online consumer, and use e-tailing service quality and trust in website (system) as moderating factors. All of the survey participants were screened with the shopping experience on retailers' websites and 221 questionnaires were returned. Internet shopping anxiety is found to have a negative relationship with active coping and expressive support-seeking, whereas it is positively associated with avoidance. The results also support our speculation of e-tailing service quality in interacting with internet shopping anxiety on online consumer coping.