• Proceedings of the Korean Society of Life Science Conference
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• 2008.10a
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• pp.87.2-87.2
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• 2008

• Journal of Ginseng Research
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• v.44 no.2
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• pp.247-257
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• 2020

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.

• Biomolecules & Therapeutics
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• v.31 no.6
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• pp.599-610
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• 2023

According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis. Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

• Journal of Life Science
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• v.29 no.4
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• pp.402-409
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• 2019

Korean red ginseng made from steaming and drying fresh ginseng has long been used as a traditional herbal medicine due to its effects on the immune, endocrine, and central nerve systems and its anti-inflammatory activity. In this study, we investigated the molecular mechanism responsible for the anti-inflammatory effects of a formulated Korean red ginseng extract (RGE) in response to lipoteichoic acid (LTA), a cell wall component of gram-positive bacteria. RGE inhibited LTA-induced nitric oxide (NO) secretion and inducible nitric oxide synthase (iNOS) expression in BV-2 microglial cells, without affecting cell viability. RGE also inhibited nuclear translocation of nuclear factor kappa B ($NF-{\kappa}B$) p65 and degradation of $I{\kappa}B-{\alpha}$. In addition, RGE increased the expression of heme oxygenase-1 (HO-1) in a dose-dependent manner, and the inhibitory effect of RGE on iNOS expression was abrogated by small interfering RNA-mediated knockdown of HO-1. Moreover, RGE induced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates HO-1 expression. Furthermore, the phosphoinositide-3-kinase (PI-3K) inhibitor and mitogen-activated protein kinase (MAPK) inhibitors suppressed RGE-mediated expression of HO-1, and RGE enhanced the phosphorylation of Akt, extracellular signal-regulated kinases (ERKs), p38, and c-JUN N-terminal kinases (JNKs). These results suggested that RGE suppressed the production of NO, a proinflammatory mediator, by inducing HO-1 expression via PI-3K/Akt- and MAPK-dependent signaling in LTA-stimulated microglia. The findings indicate that RGE could be used for the treatment of neuroinflammation induced by grampositive bacteria and that it may have therapeutic potential for various neuroinflammation-associated disorders.

• Journal of Life Science
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• v.27 no.12
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• pp.1437-1444
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• 2017

Sargassum macrocarpum is a widely distributed marine brown algae found in the North Pacific. The objective of this study was to evaluate the anti-inflammatory activity of an ethanol extract of S. macrocarpum (EESM). First, we investigated the anti-inflammatory activities of EESM in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. EESM treatment suppressed nitric oxide (NO) and prostaglandin $E_2$ ($PGE_2$) production and inhibited the expressions of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels. In addition, the expression of pro-inflammatory cytokines, such as tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$) and interleukin-1 beta ($IL-1{\beta}$), was decreased in a dose dependent manner. Investigation of the signaling pathways of nuclear factor kappa B ($NF-{\kappa}B$), phosphoinositide-3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) revealed suppression of $NF-{\kappa}B$ translocation from the cytosol to nucleus by EESM treatment. The phosphorylation of the Akt and ERK proteins was also inhibited by EESM treatment. EESM treatment also stimulated the expression of the heme oxygenase-1 (HO-1) enzyme and its upstream transcription factor, nuclear factor-E2-related factor 2 (Nrf2). These results suggest that EESM has anti-inflammatory activity and could have potential uses in the field of nutraceuticals.

• Journal of Microbiology and Biotechnology
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• v.32 no.9
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• pp.1168-1177
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• 2022

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79^T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3β signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.

• Journal of Ginseng Research
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• v.44 no.3
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• pp.435-441
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• 2020

Background: As a process of aging, skeletal muscle mass and function gradually decrease. It is reported that ginsenoside Rb1 and Rb2 play a role as AMP-activated protein kinase activator, resulting in regulating glucose homeostasis, and Rb1 reduces oxidative stress in aged skeletal muscles through activating the phosphatidylinositol 3-kinase/Akt/Nrf2 pathway. We examined the effects of Rb1 and Rb2 on differentiation of the muscle stem cells and myotube formation. Methods: C2C12 myoblasts treated with Rb1 and/or Rb2 were differentiated and induced to myotube formation, followed by immunoblotting for myogenic marker proteins, such as myosin heavy chain, MyoD, and myogenin, or immunostaining for myosin heavy chain or immunoprecipitation analysis for heterodimerization of MyoD/E-proteins. Results: Rb1 and Rb2 enhanced myoblast differentiation through accelerating MyoD/E-protein heterodimerization and increased myotube hypertrophy, accompanied by activation of Akt/mammalian target of rapamycin signaling. In addition, Rb1 and Rb2 induced the MyoD-mediated transdifferentiation of the rhabdomyosarcoma cells into myoblasts. Furthermore, co-treatment with Rb1 and Rb2 had synergistically enhanced myoblast differentiation through Akt activation. Conclusion: Rb1 and Rb2 upregulate myotube growth and myogenic differentiation through activating Akt/mammalian target of rapamycin signaling and inducing myogenic conversion of fibroblasts. Thus, our first finding indicates that Rb1 and Rb2 have strong potential as a helpful remedy to prevent and treat muscle atrophy, such as age-related muscular dystrophy.

• Journal of The Korean Society of Integrative Medicine
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• v.12 no.1
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• pp.1-10
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• 2024

Purpose: Lycopene is abundantly contained in Tomatoes and is known for diverse biological activities such as antioxidant, anti-inflammatory, and anticancer effects. In this study, the antioxidative potential of lycopene was investigated through the induction of hemeoxygenase (HO)-1 by nuclear factor-erythroid 2 p45-related factor2 (Nrf2) and upstream signaling molecules, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Aktin RAW 264.7 cells. Methods: The antioxidative potential of lycopene against oxidative stress and its molecular mechanisms were determined by the cell viability assay, intracellular reactive oxygen species (ROS) formation assay, and Western blot analysis in RAW 264.7 cells. Results: Lycopene treatment significantly attenuated tert-butyl hydroperoxide (t-BHP) induced intracellular ROS formation in a dose-dependent manner without any cytotoxicity. In addition, 50 µM of lycopene for 6 h treatment induced potent HO-1 expression and its transcription factor, Nrf2. MAPK and PI3K/Aktwere also analyzed due to their critical roles in the regulation of cellular redox homeostasis against oxidative damage. As a result, phosphorylation of extracellular regulated kinase (ERK) was significantly induced by lycopene treatment while the activated status of c-Jun NH2-terminal kinase (JNK), p38, and Akt, were not given any effect. To confirm the antioxidative mechanism of HO-1 mediated by ERK activation, each selective inhibitor was employed in a protection assay, in which oxidative damage occurred by t-BHP. Lycopene, SnPP, and CoPP treatments reflected accelerated HO-1 expression could be a protective role against oxidative damage-initiated cell death. A selective inhibitor for ERK significantly inhibited the lycopene-induced cytoprotective effect but selective inhibitors for other signaling molecules did not attenuate the rate of t-BHP-induced cell death. Conclusion: In conclusion, lycopene potently scavenged intracellular ROS formation and enhanced the HO-1 mediated antioxidative potential through the modulation of Nrf2, MAPK signaling pathway in RAW 264.7 cells.

• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.134-134
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• 2003

Oxidative stress induced by reactive oxygen intermediates (ROIs) has been implicated in a variety of human diseases including cancer, diabetes, rheumatoid arthritis and neurodegenerative disorders. Hydrogen peroxide (H2O2), a representative ROI which is produced during the cellular redox process, can cause cell death via apoptosis and/or necrosis depending on its concentrations.(omitted)

• Journal of Life Science
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• v.27 no.1
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• pp.8-14
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• 2017

Died Gardenia jasminoides fruit is used as a dye in the food and clothes industries in Asia. The present study investigated the anti-inflammatory effects of aqueous extract of G. jasminoides fruits (GJ) in BV-2 microglial cells. GJ inhibited lipopolysaccharide-induced nitric oxide (NO) secretion, inducible nitric oxide synthase (iNOS) expression, and reactive oxygen species production, without affecting cell viability. Furthermore, GJ increased the expression of heme oxygenase-1 (HO-1) in a dose-dependent manner. Moreover, the inhibitory effect of GJ on iNOS expression was abrogated by small interfering RNA-mediated knock-down of HO-1. In addition, GJ induced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates HO-1 expression. GJ-mediated expression of HO-1 was suppressed by LY294002, a phosphoinositide 3-kinase (PI-3K) inhibitor, and SB203580, a p38 kinase inhibitor, but not by the extracellular signal-regulated kinase (ERK) inhibitor PD98059 or c-Jun N-terminal kinase (JNK) inhibitor SP600125. GJ also enhanced the phosphorylation of Akt and p38. These results suggest that GJ suppresses the production of NO, a pro-inflammatory mediator, by inducing HO-1 expression via PI-3K/Akt/p38 signaling. These findings illustrate a novel molecular mechanism by which extract from G. jasminoides fruits inhibits neuroinflammation.