• Nutrition Research and Practice
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• v.12 no.6
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• pp.486-493
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• 2018

BACKGROUND/OBJECTIVE: The honeysuckle berry (HB) contains ascorbic acid and phenolic components, especially anthocyanins, flavonoids, and low-molecular-weight phenolic acids. In order to examine the potential of HB as a hepatoprotective medicinal food, we evaluated the in vitro anti-oxidant and anti-inflammatory activities of Korean HB (HBK) and Chinese HB (HBC). MATERIALS/METHODS: Antioxidant and anti-inflammatory effects of the extracts were examined in HepG2 and RAW 264.7 cells, respectively. The anti-oxidant capacity was determined by DPPH, SOD, CAT, and ARE luciferase activities. The production of nitric oxide (NO) as an inflammatory marker was also evaluated. The Nrf2-mediated mRNA levels of heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase [quinone] 1 (Nqo1), and glutamate-cysteine ligase catalytic subunit (Gclc) were measured. The concentrations of HB extracts used were 3, 10, 30, 100, and $300{\mu}g/mL$. RESULTS: The radical scavenging activity of all HB extracts increased in a concentration-dependent manner (P < 0.01 or P < 0.05). SOD (P < 0.05) and CAT (P < 0.01) activities were increased by treatment with $300{\mu}g/mL$ of each HB extract, when compared to those in the control. NO production was observed in cells pretreated with 100 or $300{\mu}g/mL$ of HBC and HBK (P < 0.01). Treatment with $300{\mu}g/mL$ of HBC significantly increased Nqo1 (P < 0.01) and Gclc (P < 0.05) mRNA levels compared to those in the control. Treatment with $300{\mu}g/mL$ of HBK (P < 0.05) and HBC (P < 0.01) also significantly increased the HO-1 mRNA level compared to that in the control. CONCLUSIONS: Thus, the Korean and Chinese HBs were found to possess favorable in vitro anti-oxidant and anti-inflammatory activities. Nrf2 and its related anti-oxidant genes were associated with both anti-oxidant and anti-inflammatory activities in HB-treated cells. Further studies are needed to confirm these in vivo effects.

• Korean Journal of Food Science and Technology
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• v.50 no.6
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• pp.688-696
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• 2018

This study aimed to investigate the effects of red ginseng-derived saponin fraction (SF) on lipid accumulation, reactive oxygen species (ROS) production, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling during adipocyte differentiation. SF effectively inhibited lipid accumulation, with the downregulation of adipogenic factors such as peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) and CCAAT/enhancer-binding protein alpha ($C/EBP{\alpha}$). A high dose of SF decreased the protein levels of $PPAR{\gamma}$ and $C/EBP{\alpha}$ by over 90% compared to the control. SF-mediated downregulation of adipogenic factors was due to the regulation of early adipogenic factors including $C/EBP{\beta}$ and $Kr{\ddot{u}}ppel$-like Factor 2 (KLF2). In addition, SF ($200{\mu}g/mg$) decreased intracellular ROS generation by 40% during adipocyte differentiation. However, the SF significantly upregulated Nrf2 and its target proteins, hemoxygenase-1 (HO-1) and NADPH dehydrogenase quinone 1 (NQO1). Furthermore, SF ($200{\mu}g/mg$) promoted the nuclear translocation of Nrf2. The SF-mediated reduction of lipid accumulation was associated with the regulation of the Nrf2/Keap1 pathway.

• Animal Bioscience
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• v.34 no.8
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• pp.1403-1414
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• 2021

Objective: This study explored the mechanism of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway under conditions of zearalenone (ZEA)-induced oxidative stress in the duodenum of post-weaning gilts. Methods: Forty post-weaning gilts were randomly allocated to four groups and fed diets supplemented with 0, 0.5, 1.0, or 1.5 mg/kg ZEA. Results: The results showed significant reductions in the activity of the antioxidant enzymes total superoxide dismutase and glutathione peroxidase and increases the malondialdehyde content with increasing concentrations of dietary ZEA. Immunohistochemical analysis supported these findings by showing a significantly increased expression of Nrf2 and glutathione peroxidase 1 (GPX1) with increasing concentrations of ZEA. The relative mRNA and protein expression of Nrf2, GPX1 increased linearly (p<0.05) and quadratically (p<0.05), which was consistent with the immunohistochemical results. The relative mRNA expression of Keap1 decreased linearly (p<0.05) and quadratically (p<0.05) in the duodenum as the ZEA concentration increased in the diet. The relative mRNA expression of modifier subunit of glutamate-cysteine ligase (GCLM) increased quadratically (p<0.05) in all ZEA treatment groups and the relative mRNA expression of quinone oxidoreductase 1 (NQO1) catalytic subunit of glutamate-cysteine ligase decreased linearly (p<0.05) and quadratically (p<0.05) in the ZEA1.0 group and ZEA1.5 group. The relative protein expression of Keap1 and GCLM decreased quadratically (p<0.05) in the duodenum as the ZEA concentration increased in the diet, respectively. The relative protein expression of NQO1 increased linearly (p<0.05) and quadratically (p<0.05) in all ZEA treatment groups in the duodenum. Conclusion: These findings suggest that ZEA regulates the expression of key factors of the Keap1-Nrf2 signaling pathway in the duodenum, which enables resistance to ZEA-induced oxidative stress. Further studies are needed to examine the effects of ZEA induced oxidative stress on other tissues and organs in post-weaning gilts.

• Archives of Pharmacal Research
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• v.23 no.6
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• pp.554-558
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• 2000

Synthesized 5-arylamino-2-methyl-4,7-dioxobenzothiazoles 3a-3o were evaluated for modulation of NAD(P)H: quinone oxidoreductase (NQOl) activity with the cytosolic fractions derived from cultured human lung cancer cells and their cytotoxicity in cultured several human solid cancer cell lines. The 4,7-dioxobenzothiazoles affected the reduction potential by NQOl activity and showed a potent cytotoxic activity against human cancer cell lines. The tested compounds 3a, 3b, 3g, 3h, 3n and 3o were considered as more potent cytotoxic agents, and comparable modulators of NQOl activity.

• Molecular & Cellular Toxicology
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• v.3 no.4
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• pp.231-237
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• 2007

Exposure to DNA-damaging agents can elicit a variety of stress-related responses that may alter the expression of genes associated with numerous biological pathways. We used 19 k whole human genome chip to detect gene expression profiles and potential signature genes in human normal hepatocytes (THLE-3) by treatment of five direct acting mutagens, furylfuramide (AF-2), N-nitroso-N-methylurea (MNU), methylmethanesulfonate (MMS), 4-nitroquinoline-N-oxide (4-NQO) and 2-nitrofluorene (2NF) of the $IC_{20}$ concentration for 3 h. Fifty one up-regulated common genes and 45 down-regulated common genes above 1.5-fold by five direct-acting mutagens were identified by clustering analysis. Many of these changed genes have some association with apoptosis, control of cell cycle, regulation of transcription and signal transduction. Genes related to these functions, as TP73L, E2F5, MST016, SOX5, MAFB, LIF, SII3, TFIIS, EMR1, CYTL1, CX3CR1 and RHOH are up-regulated. Down-regulated genes are ALOX15B, xs155, IFITM1, BATF, VAV2, CD79A, DCDC2, TNFSF8 and KOX8. We suggest that gene expression profiling on mutagens by toxicogenomic analysis affords promising opportunities to reveal potential new mechanistic markers of genotoxicity.

• Journal of the Korean Society of Food Science and Nutrition
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• v.27 no.6
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• pp.1177-1182
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• 1998

The antimutagenic and cancer cell growth inhibitory effects of woorimil contained herb and seaweed powders were examined. While woorimil itself showed only 40% antimutagenic effect on S. typhymurium TA98 against 4NQO(0.15 g/plate), water extracts of mountain herbs and seweeds including Comfrey, wormwood, Kale, Angelica utilis and pine leaves showed 80~90% antimutagenicity. On the other hand, these extracts along with woorimil showed 68 to 80% antimutagenic activities. Low antimutagenic activities of less than 50% were shown when these extracts were tested on TA98 against Trp P 1(0.5 g/plate), but high antimutagenic activities of 80~93.3% were shown on TA100. Water extracts of Capsella bursa pastoris and Allium grayi exhibited 60~80% of the activites in cytotoxicity tests of woorimil water extracts(0.5mg/ml) on human lung carcinoma cell. A549 showed 10% cell growth inhibitory effect. When mixed with Comfrey and Angelica utilis extracts, it showed 23~25% inhibition and other extracts showed only 12~23% inhibition. Cytotoxicity test of woorimil extracts on human liver cancer cell Hep3B revealed 20% inhibition. The additions of pine needle extracts, Angelica utilis and Comfrey showed 33%, 29% and 25% inhibition, respectively. But other extracts showed only 20% inhibition.

• Microbiology and Biotechnology Letters
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• v.27 no.1
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• pp.15-22
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• 1999

Various lactic acid bacteria were isolated from Korean Kimchi in order to study their antimutagenic substances. Ames test using Salmonella typhimurium TA98 and TA100 showed the strain KLAB21 to have the highest antimutagenic activity among the 230 isolated strains against MNNG (N-methyl-N'-nitro-N-nitrosoguanidine), NPD (4-nitro-O-phenylenediamine), NQO (4-nitrosoquinoline-1-oxide) and AFB1 (aflatoxin B1). The strain was identified as Lactobacillus plantarum based on its morphological, cultural and physiological characteristics. Antimutagenic activity of L. plantarum KLAB21 was found in culture supernatant suggesting the bacterium secrete antimutagenic substance in the media. No mutagenic activity was found in the culture supernatant. The isolated strain L. plantarum KLAB21 showed much higher antimutagenic activity than L. plantarum IAM1261 which is being used industrially for fermented milk production. The antimutagenic activity of L.plantarum KLAB21 was reconfirmed by the spore-rec assay using spores of Bacillus subtilis H17($Rec^+$) and M45($Rec^-$).

• Korean Journal of Pharmacognosy
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• v.32 no.4 s.127
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• pp.338-343
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• 2001

The extract and fractions of Rumex acetosa (Polygonaceae), a Korean medicinal plant, were examined for their cytotoxicities against five cultured human tumor cell lines, i.e. A549 (non-small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nerve system) and HCY15 (colon), using the SRB (sulforhodamine-B) method in vitro and antimutagenic activities by Ames test with Salmonella typhimurium TA98 and TA100 and SOS chromotest with E. coli PQ37. Among the tested samples, the methylene chloride fraction strongly inhibited the proliferation of each examined tumor cell line with $IC_{50}$ values ranged from 13.2 to $18.7\;{\mu}g/ml$ and showed potent antimutagenic activities with 96.1% and 96.7% at the concentration of 1 mg/plate against the mutagens, NPD and sodium azide, respectively. Its antigenotoxic activity was also very effective at the final concentration of $10\;{\mu}g/reaction$ tube against the mutagens, MNNG and NQO by SOS chromotest.

• Journal of Food Hygiene and Safety
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• v.10 no.3
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• pp.133-138
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• 1995

In vitro antimutagenic activity of methanol extract from brrwn rice and its physico-chemical characteristics were investigated using Salmonella typhimurium reversion assay and SOS chromotest. Methanol extracts of brown rice were not mutagenic compared with direct and indirect, mutagenicities of 4NQO (4-nitroquinoline oxide), 2NF(2-nitrofluorene), Trp-p-1(3-Amino-1,4-dimethyl-5H-pyrido-[4,3-b]indole), and Trp-p-2(3-Amino-1-methy-5H-pyrido-[4,3-b]indole). Antimutagenic activity against the indirect mutagenicties induced by Trp-p-1, Trp-p-2 and AFB1 (aflatoxin B1) was found in methanol extract. Even though antimutagenic activity showed dose-dependent, it remained constant at inhibition rate ranging 60~90% when the concentration was abov 3mg/plate in the S. typhimurium reversion assay and 0.2~0.6 mg/assay in the SOS chromotest. The antimutagenic activity of the methanol extracts was stable at various pH (2, 7 and 10), temperatures (60, 80 and 10$0^{\circ}C$)and heation times (2, 4, 6, 8, 10 min at 10$0^{\circ}C$).

• YAKHAK HOEJI
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• v.52 no.1
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• pp.67-72
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• 2008

The use of doxorubicin, which is one of the most effective anticancer agents, is often limited by occurrence of acquired resistance in tumor cells. GSH has been shown to be involved in the development of this drug resistance. Transcription factor Nrf2 governs the expression of GSH synthesizing glutamylcysteine ligase (GCL), as well as multiple phase 2 detoxifying enzymes. Here we show that Nrf2 is one of factors determining doxorubicin sensitivity. Nrf2-deficient fibroblasts (murine embryonic fibroblasts, MEF) were more susceptible to doxorubicin mediated cell death than wild-type cells. Doxorubicin treatment elevated levels of Nrf2-regulated genes including NAD(P)H: quinone oxidoreductase (Nqo1) and GCL in wild-type fibroblasts, while no induction was observed in Nrf2-deficient cells. Doxorubicin resistance in human ovarian SK-OV cells was reversed by treatment with L-buthionine-sulfoxamine (BSO), which is depleting intracellular GSH. Finally, transfection of SK-OV cells with Nrf2 siRNA resulted in exacerbated cytotoxicity following doxorubicin treatment compared to scrambled RNA control. These results indicate that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to anticancer agents.