• Molecules and Cells
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• v.38 no.4
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• pp.327-335
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• 2015

Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic ${\alpha},{\beta}$-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine.

• The Korea Journal of Herbology
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• v.35 no.1
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• pp.57-68
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• 2020

Objective : The aim of present study was to clarify the effect of Areca Semen and Toosendan Fructus Mixture (AT-mix) on chronic reflux esophagitis (CRE) in rats. Methods : The antioxidant activity of AT-mix was measured through DPPH and ABTS radical scavenging activities in vitro. CRE was induced in SD rats (5 weeks, male) by ligating the border forestomach and granular portion with 2-0 silk and the duodenum near the pyloric portion was covered with 2-mm wide piece of 18-Fr Nélaton catheter. And then rats were treated AT-mix 200 mg/kg one daily for 14 days. The anti-oxidant and inflammatory protein levels were evaluated using western blotting. Results : Gross lesion of esophageal mucosa after AT-mix treatment showed a superior enhancement compared with that of CRE control rats. AT-mix treatment strongly reduced both DPPH and ABTS radical scavenging activities (DPPH, IC₅₀ 8.15±0.14 ㎍/mL; ABTS, IC₅₀ 24.69±0.03 ㎍/mL, repspectively). Levels of the NADPH oxidase subunit including NOX4 and p22^phox increased in CRE control rats. Otherwise, AT-mix treatment significantly reduced. The activation of Nuclear factor-erythroid 2-related factor 2 (Nrf2) led to significantly the up-regulation of HO-1. The inhibition of IκBα phosphorylation led to NF-κB inactivation. Subsequently, NF-κB inactivation significantly induced the decrease of COX-2, iNOS, TNF-α, and IL-6 protein expressions. Conclusion : Taken together, these results suggest that AT-mix treatment can attenuate the esophageal mucosal ulcer though inhibiting NF-κB pathway and enhancing Nrf2/HO-1 pathway. Thus, the additional mechanism study about AT-mix would need for the development as a safe herbal therapy for CRE.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.368-378
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• 2024

Cordycepin, a valuable bioactive component isolated from Cordyceps militaris, has been reported to possess anti-cancer potential and the property to enhance the effects of chemotherapeutic agents in various types of cancers. However, the ability of cordycepin to chemosensitize cholangiocarcinoma (CCA) cells to gemcitabine has not yet been evaluated. The current study was performed to evaluate the above, and the mechanisms associated with it. The study analyzed the effects of cordycepin in combination with gemcitabine on the cancer stem-like properties of the CCA SNU478 cell line, including its anti-apoptotic, migratory, and antioxidant effects. In addition, the combination of cordycepin and gemcitabine was evaluated in the CCA xenograft model. The cordycepin treatment significantly decreased SNU478 cell viability and, in combination with gemcitabine, additively reduced cell viability. The cordycepin and gemcitabine co-treatment significantly increased the Annexin V+ population and downregulated B-cell lymphoma 2 (Bcl-2) expression, suggesting that the decreased cell viability in the cordycepin+gemcitabine group may result from an increase in apoptotic death. In addition, the cordycepin and gemcitabine co-treatment significantly reduced the migratory ability of SNU478 cells in the wound healing and trans-well migration assays. It was observed that the cordycepin and gemcitabine cotreatment reduced the CD44^highCD133^high population in SNU478 cells and the expression level of sex determining region Y-box 2 (Sox-2), indicating the downregulation of the cancer stem-like population. Cordycepin also enhanced oxidative damage mediated by gemcitabine in MitoSOX staining associated with the upregulated Kelch like ECH Associated Protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) expression ratio. In the SNU478 xenograft model, co-administration of cordycepin and gemcitabine additively delayed tumor growth. These results indicate that cordycepin potentiates the chemotherapeutic property of gemcitabine against CCA, which results from the downregulation of its cancer-stem-like properties. Hence, the combination therapy of cordycepin and gemcitabine may be a promising therapeutic strategy in the treatment of CCA.

• Journal of Ginseng Research
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• v.47 no.1
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• pp.106-116
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• 2023

Background: Pirarubicin (THP) is an anthracycline antibiotic used to treat various malignancies in humans. The clinical usefulness of THP is unfortunately limited by its dose-related cardiotoxicity. Ginsenoside F1 (GF1) is a metabolite formed when the ginsenosides Re and Rg1 are hydrolyzed. However, the protective effects and underlying mechanisms of GF1 on THP-induced cardiotoxicity remain unclear. Methods: We investigated the anti-apoptotic and anti-oxidative stress effects of GF1 on an in vitro model, using H9c2 cells stimulated by THP, plus trigonelline or AKT inhibitor imidazoquinoxaline (IMQ), as well as an in vivo model using THP-induced cardiotoxicity in rats. Using an enzyme-linked immunosorbent test, the levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (c-TnT), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione (GSH) were determined. Nuclear factor (erythroid-derived2)-like 2 (Nrf2) and the expression of Nrf2 target genes, including heme oxygenase-1 (HO-1), glutathione-S-transferase (Gst), glutamate-cysteine ligase modifier subunit (GCLM), and expression levels of AKT/Bcl-2 signaling pathway proteins were detected using Western blot analysis. Results: THP-induced myocardial histopathological damage, electrocardiogram (ECG) abnormalities, and cardiac dysfunction were reduced in vivo by GF1. GF1 also decreased MDA, BNP, CK-MB, c-TnT, and LDH levels in the serum, while raising SOD and GSH levels. GF1 boosted Nrf2 nuclear translocation and Nrf2 target gene expression, including HO-1, Gst, and GCLM. Furthermore, GF1 regulated apoptosis by activating AKT/Bcl-2 signaling pathways. Employing Nrf2 inhibitor trigonelline and AKT inhibitor IMQ revealed that GF1 lacked antioxidant and anti-apoptotic effects. Conclusion: In conclusion, GF1 was found to alleviate THP-induced cardiotoxicity via modulating Nrf2 and AKT/Bcl-2 signaling pathways, ultimately alleviating myocardial oxidative stress and apoptosis.

• Journal of Nutrition and Health
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• v.50 no.3
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• pp.236-245
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• 2017

Purpose: The aim of this study was to assess the effects of guava leaf extract (GLE) supplementation on antioxidant enzyme activity and expression of endothelial nitric oxide synthase (eNOS) mRNA in ovariectomized rats. Methods: All animals were randomly assigned to four groups (n = 7 for each group): non-ovariectomized control (Sham), the ovariectomized control (OVX), ovariectomy + 150 mg/kg b.w. of GLE ($OVX{\cdot}GL$), and ovariectomy + 300 mg/kg b.w. of GLE ($OVX{\cdot}GH$). Treatment groups were administered GLE for 8 weeks every day. Results: Body weight gain was significantly reduced in the $OVX{\cdot}GL$ group compared with the OVX group (p < 0.05). The level of serum $17{\beta}$-estradiol (E2) was significantly lower in the OVX groups than the Sham group (p < 0.05). Serum triglyceride (TG) and HDL-cholesterol levels were not significantly different between all groups. However, serum total cholesterol (TC) level was significantly reduced in the $OVX{\cdot}GH$ group compared with the OVX group (p < 0.05). Serum free fatty acid (FFA) level and liver TG level were significantly reduced in both $OVX{\cdot}GL$ and $OVX{\cdot}GH$ groups compared with the OVX group (p < 0.05). Furthermore, serum glutathione peroxidase (GPx) activity was significantly elevated in the GLE groups (p < 0.05). The mRNA expression level of GPx was not affected by ovariectomy. However, administration of GLE resulted in significantly increased nuclear factor erythroid 2-related factor (Nrf2) and catalase (CAT) mRNA expression levels in the liver (p < 0.05). In addition, liver nitric oxide (NO) level was significantly reduced in the $OVX{\cdot}GH$ group compared with the OVX group (p < 0.05). Expression level of endothelial nitric oxide synthase (eNOS) was significantly elevated in the $OVX{\cdot}GH$ group compared with the OVX group (p < 0.05). Conclusion: These results suggest that GLE could have protective effects in OVX rats by stimulating eNOS expression and improving the antioxidant defense system.

• Journal of Ginseng Research
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• v.45 no.6
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• pp.617-630
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• 2021

Chemotherapy-induced side effects affect the quality of life and efficacy of treatment of cancer patients. Current approaches for treating the side effects of chemotherapy are poorly effective and may cause numerous harmful side effects. Therefore, developing new and effective drugs derived from natural nontoxic compounds for the treatment of chemotherapy-induced side effects is necessary. Experiments in vivo and in vitro indicate that Panax ginseng (PG) and its ginsenosides are undoubtedly non-toxic and effective options for the treatment of chemotherapy-induced side effects, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, immunotoxicity, and hematopoietic inhibition. The mechanism focus on anti-oxidation, anti-inflammation, and anti-apoptosis, as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), P62/keap1/Nrf2, c-jun Nterminal kinase (JNK)/P53/caspase 3, mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERK), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase 4 (MKK4)/JNK, and phosphatidylinositol 3-kinase (PI3K)/AKT. Since a systemic review of the effect and mechanism of PG and its ginsenosides on chemotherapy-induced side effects has not yet been published, we provide a comprehensive summarization with this aim and shed light on the future research of PG.

• Animal Bioscience
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• v.35 no.12
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• pp.1892-1903
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• 2022

Objective: A series of experiment were conducted to evaluate the effects of replacing a part of soybean meal (SBM) at 6% of broiler diets with fermented soybean meal (FSBM) obtained by single or two-stage fermentation by measuring growth performance, antioxidant activity in the jejunum and distal intestinal microflora. Methods: Soybean meal samples were prepared by single-stage fermentation using Bacillus velezensis (Bv) (FSBM_B), or Lactobacillus spp. (as commercial control) (FSBM_L). Additional SBM sample was prepared by two-stage fermentation using Bv and subsequently using Lactobacillus brevis ATCC 367 (Lb) (FSBM_B+L). Enzyme activity, chemical composition, trichloroethanoic acid-nitrogen solubility index (TCA-NSI) and antioxidant activity were measured. Then, in an in vivo study, 320 Ross308 broilers were divided into four groups with ad libitum supply of feed and water. Four groups were fed either a corn-soybean meal diet (SBM), or one of fermented SBM diets (FSBM_B+L, FSBM_B, and FSBM_L). Growth, serum characteristics, microflora, and the mRNA expression of selected genes were measured. Results: Compared to SBM, FSBM_B+L contained lower galacto-oligosaccharide, allergic protein, and trypsin inhibitor, and higher TCA-NSI by about three times (p<0.05). Reducing power and 1,1-diphenyl-2-picrylhydrazyl free radical scavenging ability correlated positively with the TCA-NSI content in FSBM. Growth performances were not significantly different among four groups. In jejunum of 35-day-old broilers, partial replacement of SBM by FSBM_B+L increased the activity of superoxide dismutase and catalase (CAT), and the FSBM_B group had the highest catalase activity (p<0.05). Partial replacement of SBM by FSBM increased relative mRNA expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and peptide transporter 1 (PepT1) (p<0.05); however, FSBM_B+L increased CAT mRNA level to 5 times of the control (p<0.05). Conclusion: Using Bv- and Lb-processed SBM through two-stage fermentation to partially replace 6% of diets will improve the gut's antioxidant activity under commercial breeding in broilers.

• Animal Bioscience
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• v.35 no.9
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• pp.1434-1443
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• 2022

Objective: This study was designed to investigate the hypothesis that dietary quercetin (QUE) and coated sodium butyrate (SB) supplementation alleviate oxidative stress in the small intestine of diquat (DIQ)-challenged pullets. Methods: A total of 200 13-week-old pullets were divided into four groups: the control group (CON), the DIQ group, the QUE group, and the coated SB group, and injected intraperitoneally with either saline (CON) or diquat (DIQ, QUE, and SB) to induce oxidative stress on day 0. Results: On the first day, the malondialdehyde and superoxide dismutase (SOD) concentrations in the SB group were significantly different from those in the DIQ and QUE groups (p<0.05), and dietary supplementation with SB increased serum glutathione peroxidase (GSH-PX) levels compared with the DIQ group (p<0.05). Quercetin and SB increased the levels of CLAUDIN-1 and zonula occludens-1 (ZO-1) in the jejunum. On the tenth day of treatment, QUE attenuated the decrease in GSH-PX levels compared to those of the CON group (p<0.05), while SB increased SOD, GSH-PX, and total antioxidant capacity levels compared to those of the DIQ group. Nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) mRNA levels in the QUE and SB groups increased (p<0.05) and CLAUDIN-1 mRNA levels in the QUE and SB groups were upregulated compared to those in the DIQ group ileum tissue. Conclusion: Supplementation of QUE and SB demonstrated the ability to relieve oxidative stress in pullets post DIQ-injection with a time-dependent manner and QUE and SB may be potential antioxidant additives for relieving oxidative stress and protecting the intestinal barrier of pullets.

• Journal of Life Science
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• v.28 no.2
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• pp.207-215
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• 2018

Inflammatory response and oxidative stress play critical roles in the development and progression of many human diseases. Therefore, a great deal of attention has been focused on finding functional materials that can control inflammation and oxidative stress simultaneously. The purpose of this study was to investigate the effects of Socheongja and Socheong 2, Korean black seed coat soybean varieties, on the inflammatory and oxidative stress induced by lipopolysaccharide (LPS) in RAW 264.7 macrophages. Our data indicated that the extracts of Socheongja (SCJ) and Socheong 2 (SC2) significantly suppressed LPS-induced production of nitrite oxide (NO) and prostaglandin $E_2$, key pro-inflammatory mediators, by suppressing the expression of inducible NO synthase and cyclooxygenase-2. It was also found that SCJ and SC2 reduced the LPS-induced secretion of pro-inflammatory cytokines, such as tumor necrosis $factor-{\alpha}$ and $interleukin-1{\beta}$, which was concomitant with a decrease in the protein levels. In addition, SCJ and SC2 markedly diminished LPS-stimulated intracellular reactive oxygen species accumulation, and effectively enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1 expression. Furthermore, LPS-induced activation of mitogen-activated protein kinases (MAPKs) was abrogated by SCJ and SC2. Taken together, these data suggest that SCJ and SC2 may offer protective roles against LPS-induced inflammatory and oxidative responses in RAW 264.7 macrophages through attenuating MAPKs pathway, and these effects are mediated, at least in part, through activating Nrf2/HO-1 pathway. Given these results, we propose that SCJ and SC2 have therapeutic potential in the treatment of inflammatory and oxidative disorders caused by over-activation of macrophages.

• Journal of Life Science
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• v.28 no.4
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• pp.454-464
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• 2018

Black soybeans are used as food sources as well as for traditional medicines because they contain an abundance of natural phenolic compounds. In this study, total phenolic contents (TPCs) of Korean black seed coat soybean varieties Socheongja (SCJ), Socheong 2 (SC2) and Cheongja 2 (CJ2) as well as their antioxidant capacities were investigated. Among them, TPCs were abundantly present in the order of CJ2$H_2O_2$-stimulated HaCaT human keratinocytes. Our results revealed that treatment with SCJ and SC2 prior to $H_2O_2$ exposure significantly increases the viability of HaCaT cells, indicating that the exposure of HaCaT cells to SCJ and SC2 conferred a protective effect against oxidative stress. SCJ and SC2 also effectively inhibited $H_2O_2$-induced apoptotic cell death through the blocking of mitochondrial dysfunction. SCJ and SC2 also attenuated the phosphorylation of Histone H2AX. Furthermore, they effectively induced the levels of thioredoxin reductase (TrxR) 1, a potent antioxidant enzyme, which is associated with the induction of nuclear transcription factor erythroid-2-like factor 2 (Nrf2); however, the protective effects of SCJ and SC2 were significantly reversed by Auranofin, a TrxR inhibitor. These results indicate that they have protective activity through the blocking of cellular damage related to oxidative stress via the Nrf2 signaling pathway. In conclusion, our study indicated that SCJ and SC2 might potentially serve as novel agents for the treatment and prevention of skin disorders caused by oxidative stress.