• Biomolecules & Therapeutics
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• v.27 no.2
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• pp.178-184
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• 2019

Parkinson's disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether ${\beta}-Lapachone$ (${\beta}-LAP$), a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia avellanedae), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. ${\beta}-LAP$ reduced the tyrosine hydroxylase (TH)-immunoreactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test. In addition, ${\beta}-LAP$ protected against MPTP-induced loss of TH positive neurons, and upregulated B-cell lymphoma 2 protein (Bcl-2) expression in the substantia nigra. Based on previous reports on the neuroprotective role of nuclear factor-E2-related factor-2 (Nrf2) in neurodegenerative diseases, we investigated whether ${\beta}-LAP$ induces upregulation of the Nrf2-hemeoxygenae-1 (HO-1) signaling pathway molecules in MPTP-injected mouse brains. Western blot and immunohistochemical analyses indicated that ${\beta}-LAP$ increased HO-1 expression in glial fibrillary acidic protein-positive astrocytes. Moreover, ${\beta}-LAP$ increased the nuclear translocation and DNA binding activity of Nrf2, and the phosphorylation of upstream adenosine monophosphate-activated protein kinase (AMPK). ${\beta}-LAP$ also increased the localization of p-AMPK and Nrf2 in astrocytes. Collectively, our data suggest that ${\beta}-LAP$ exerts neuroprotective effect in MPTP-injected mice by upregulating the p-AMPK/Nrf2/HO-1 signaling pathways in astrocytes.

• Korean Journal of Food Science and Technology
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• v.52 no.2
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• pp.138-143
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• 2020

Black chokeberry (Aronia melanocarpa) has been suggested to exert antioxidant and anti-inflammatory effects due to its high polyphenol content. However, the mechanisms underlying the effects of black chokeberry on the alterations of nuclear factor E2-related factor 2 (NRF2) and nuclear factor κB (NF-κB) in macrophages have not been thoroughly studied. In this study, we investigated the protective effects of polyphenol-rich black chokeberry extract (CBE) against lipopolysaccharide (LPS)-induced oxidative stress and inflammation in RAW 264.7 macrophages. CBE significantly attenuated the increase of cellular reactive oxygen species (ROS) levels and the nuclear translocation of NRF-2 in LPS-stimulated macrophages. The mRNA abundances of Nrf2 and its downstream antioxidant genes were significantly decreased in LPS-stimulated macrophages. The LPS-induced mRNA expression of proinflammatory cytokines was significantly inhibited by reducing the nuclear translocation of NF-κB by CBE. These data suggest that black chokeberry may be used for the prevention of oxidative stress and inflammation-associated disease.

• Korean Journal of Pharmacognosy
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• v.46 no.2
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• pp.116-122
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• 2015

Keratinocytes are first barrier against outer challenges on skin. However, it is still largely unknown about effective protectors against ultraviolet B (UVB), and oxidative stress in human keratinocyte, HaCaT cells. Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a role in the pathogenesis of skin disorders. Therefore, the purpose of this study was to evaluate the effect of Portulaca oleracea 70% EtOH extracts against hydrogen peroxide (H₂O₂)-induced oxidative stress in human keratinocytes, HaCaT cells. P. oleracea 70% EtOH extracts showed the potent protective effects on H₂O₂-induced toxicity by induced the expression of HO-1 in human keratinocyte, HaCaT cells. Furthermore, P. oleracea 70 % EtOH extracts caused the nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2) in human keratinocytes, HaCaT cells. In addition, we found that treatment with c-Jun N-terminal kinase (JNK) inhibitor (SP600125) reduced P. oleracea 70% EtOH extracts-induced HO-1 expression, and JNK inhibitor (SP600125) also inhibited protective effects by P. oleracea 70% EtOH extracts. Therefore, these results suggest that P. oleracea 70 % EtOH extracts increases cellular resistance to H₂O₂-induced oxidative injury in human keratinocyte, HaCaT cells, presumably through JNK pathway-Nrf2-dependent HO-1 expression.

• BMB Reports
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• v.48 no.11
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• pp.636-641
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• 2015

There are controversial findings regarding the roles of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway on bone metabolism under oxidative stress. We investigated how Nrf2/HO-1 pathway affects osteoblast differentiation of MC3T3-E1 cells in response to hydrogen peroxide (H₂O₂), N-acetyl cysteine (NAC), or both. Exposing the cells to H₂O₂ decreased the alkaline phosphatase activity, calcium accumulation, and expression of osteoblast markers, such as osteocalcin and runt-related transcription factor-2. In contrast, H₂O₂ treatment increased the expression of Nrf2 and HO-1 in the cells. Treatment with hemin, a chemical HO-1 inducer, mimicked the inhibitory effect of H₂O₂ on osteoblast differentiation by increasing the HO-1 expression and decreasing the osteogenic marker genes. Pretreatment with NAC restored all changes induced by H₂O₂ to near normal levels in the cells. Collectively, our findings suggest that H₂O₂-mediated activation of Nrf2/HO-1 pathway negatively regulates the osteoblast differentiation, which is inhibited by NAC.

• Nutrition Research and Practice
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• v.16 no.5
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• pp.577-588
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• 2022

BACKGROUND/OBJECTIVES: Poorly regulated inflammation is believed to be the most predominant factor that can result in a wide scope of diseases including atopic dermatitis (AD). Despite many studies on the effect of pear pomace in obesity-related disorders including dysregulated gut microbiota, the protective effect of pear pomace in AD is still unknown. This study aimed to evaluate the effect of pear pomace ethanol extract (PPE) on AD by inhibiting inflammation. MATERIALS/METHODS: In the in vivo experiment, 2, 4-dinitrochlorobenzene (DNCB) was applied to NC/Nga mice to induce AD-like skin lesions. After the induction, PPE was administered daily by oral gavage for 4 weeks. The clinical severity score, serum IgE levels, spleen weight, histological changes in dorsal skin, and inflammation-related proteins were measured. In the cell study, RAW 264.7 cells were pretreated with PPE before stimulation with lipopolysaccharide (LPS). Nitrite oxide (NO) production and nuclear factor kappa B (NF-𝛋B) protein expression were detected. RESULTS: Compared to the AD control (AD-C) group, IgE levels were dramatically decreased via PPE treatment. PPE significantly reduced scratching behavior, improved skin symptoms, and decreased ear thickness compared to the AD-C group. In addition, PPE inhibited the DNCB-induced expression of inducible nitrite oxide synthase (iNOS), the receptor for advanced glycation end products, extracellular signal-regulated kinase (ERK) 1/2, and NF-𝛋B. PPE inhibited the LPS-induced overproduction of NO and the enhanced expression of iNOS and cyclooxygenase-2. Moreover, the phosphorylation of ERK1/2 and NF-𝛋B in RAW 264.7 cells was suppressed by PPE. CONCLUSIONS: These results suggest that PPE could be explored as a therapeutic agent to prevent AD.

• YAKHAK HOEJI
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• v.56 no.4
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• pp.240-247
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• 2012

Sabaek-san has been used for the treatment of inflammatory diseases derived from the cold with high fever, cough, and lung dysfunction in Korea and China. There is no study for the comparison between different solvent extracts of Sabaek-san. We made two samples, one is Sabaek-san water extract (SBSW) and the other is Sabaek-san 30% EtOH extract (SBSE). Both extracts inhibited inducible nitric oxide synthase(iNOS) protein, reduced iNOS-derived nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Also, they reduced tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and interleukin-$1{\beta}$ (IL-$1{\beta}$) production. These anti-inflammatory effects caused by induction of heme oxygenase (HO)-1. HO-1 enzyme plays an important role of cellular anti-oxidant and anti-inflammatory systems. The induction of HO-1 is primarily regulated at the transcriptional level, and its induction by various inducers is related to the nuclear transcription factor-E2-related factor 2 (Nrf2). However, it is worth taking note that SBSE has more powerful anti-inflammatory effects than SBSW. In this study we suggest that different solvent extraction makes different therapeutic actions.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.46 no.3
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• pp.253-263
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• 2020

Reactive oxygen species (ROS) plays an important role in maintaining homeostasis. However, excessive ROS production damages cellular components such as proteins, lipids, and nucleic acids and promotes skin aging. In this study, we confirmed the antioxidant effect of CSYJE to prevent excessive oxidative stress. First, DPPH and ABTS assays were performed to confirm the antioxidant effect of CSYJE and the radical scavenging activity was confirmed depending on the concentration. As a result of performing the MTT assay to confirm the cell viability, it was confirmed that there was no cytotoxicity at a concentration of 1,000 ㎍/mL. As a result of western blotting to confirm the expression levels of the antioxidant-related proteins nuclear-E2-related factor 2 (Nrf2) and Heme oxygenase-1 (HO-1), it was confirmed that the expression was increased in a concentration-dependent manner. After inducing ROS with lipopolysaccharide (LPS), an intracellular ROS-causing substance, DCF-DA was performed to confirm the inhibitory effect of ROS production, and the inhibition of ROS production was confirmed to concentration-dependent. Real-time RT-PCR was performed to confirm the mRNA expression level of inflammatory cytokines and inflammatory mediator caused by ROS generation, mRNA expression was reduced in a dose dependent manner. Therefore, this study confirmed the antioxidant effect of CSYJE through the Nrf2/HO-1 signaling pathway, which suggests that CSYJE can be used as an antioxidant cosmetic material by inhibiting free radicals.

• Journal of Gastric Cancer
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• v.18 no.3
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• pp.218-229
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• 2018

Purpose: This study investigated whether the metabolic avidity of primary tumors and/or metastatic lymph nodes (LNs) measured by $^{18}F$-fluorodeoxyglucose ($^{18}F-FDG$) positron emission tomography/computed tomography (PET/CT) was related to survival after surgery in patients with advanced gastric cancer (AGC). Materials and Methods: One hundred sixty-eight patients with AGC who underwent preoperative $^{18}F-FDG$ PET/CT and curative resection were included. The $^{18}F-FDG$ avidity of the primary gastric tumor and LNs was determined quantitatively and qualitatively. The diagnostic performance of $^{18}F-FDG$ PET/CT was calculated, and the prognostic significance of $^{18}F-FDG$ avidity for recurrence-free survival (RFS) and overall survival (OS) was assessed. Results: In all, 51 (30.4%) patients experienced recurrence, and 32 (19.0%) died during follow-up (median follow-up duration, 35 months; range, 3-81 months); 119 (70.8%) and 33 (19.6%) patients showed $^{18}F-FDG$-avid primary tumors and LNs, respectively. $^{18}F-FDG$ PET/CT showed high sensitivity (73.8%) for the detection of advanced pathologic T ($pT{\geq}3$) stage and high specificity (92.2%) for the detection of advanced pN (${\geq}2$) stage. $^{18}F-FDG$ avidity of LNs was significantly associated with RFS (P=0.012), whereas that of primary tumors did not show significance (P=0.532). Univariate and multivariate analyses revealed that $^{18}F-FDG$ avidity of LNs was an independent prognostic factor for RFS (hazard ratio=2.068; P=0.029). Conclusions: $^{18}F-FDG$ avidity of LNs is an independent prognostic factor for predicting RFS. Preoperative $^{18}F-FDG$ PET/CT can be used to determine the risk and prognosis of patients with AGC after curative resection.

• Molecules and Cells
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• v.27 no.3
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• pp.279-282
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• 2009

"Two-cysteine" peroxiredoxins are antioxidant enzymes that exert a cytoprotective effect in many models of oxidative stress. However, under highly oxidizing conditions they can be inactivated through hyperoxidation of their peroxidatic active site cysteine residue. Sulfiredoxin can reverse this hyperoxidation, thus reactivating peroxiredoxins. Here we review recent investigations that have shed further light on sulfiredoxin's role and regulation. Studies have revealed sulfiredoxin to be a dynamically regulated gene whose transcription is induced by a variety of signals and stimuli. Sulfiredoxin expression is regulated by the transcription factor AP-1, which mediates its up-regulation by synaptic activity in neurons, resulting in protection against oxidative stress. Furthermore, sulfiredoxin has been identified as a new member of the family of genes regulated by Nuclear factor erythroid 2-related factor (Nrf2) via a conserved cis-acting antioxidant response element (ARE). As such, sulfiredoxin is likely to contribute to the net antioxidative effect of small molecule activators of Nrf2. As discussed here, the proximal AP-1 site of the sulfiredoxin promoter is embedded within the ARE, as is common with Nrf2 target genes. Other recent studies have shown that sulfiredoxin induction via Nrf2 may form an important part of the protective response to oxidative stress in the lung, preventing peroxiredoxin hyperoxidation and, in certain cases, subsequent degradation. We illustrate here that sulfiredoxin can be rapidly induced in vivo by administration of CDDO-TFEA, a synthetic triterpenoid inducer of endogenous Nrf2, which may offer a way of reversing peroxiredoxin hyperoxidation in vivo following chronic or acute oxidative stress.

• Journal of Society of Preventive Korean Medicine
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• v.17 no.2
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• pp.169-178
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• 2013

Objectives : Many cancers acquired resistance to chemotherapy, thus limiting its anticancer efficacy. It is known that Glutathione (GSH) is related to the development of drug resistance. The expression of GSH synthesizing glutamylcysteine ligase (GCL) was controlled by nuclear factor-E2-related factor(Nrf2). Previous studies showed that pharmacological depletion of GSH results in ROS increase, apoptotic response, and sensitization to oxidizing stimuli. In the current study, we examined Saussurea Lappa (SL) have the inhibitory effect on Nrf2 activity using human lung cancer A549 cells overexpressing Nrf2. Methods : Cell viability of A549 cells on SL treatment was determined by MTT assay. To detect the apeptosis in SL-treated A549 cells, sub-G1 population was measured by flow cytometry analysis (FACS). The level ROS was determined by FACS and fluorescence microscopy. To investigate whether SL have effect the suppression on Nrf2, we performed western blotting analysis. The GSH content was measured since GSH plays an important role in response to oxidative stress and was regulated by Nrf2. Results : A549 cells treated with an SL extract showed a substantial decrease in cell viability, along with a concomitant increase in apoptosis compared to untreated cells. Treatment of the SL extract led to increased Reactive oxygen species (ROS) production and a suppression of Nrf2. In addition, the antioxidant NAC attenuated SL-induced ROS generation, Nrf2 inhibition, and apoptosis. Taken together, these data show that the SL extract induced the production of ROS, and the inhibition of Nrf2, consequently resulting in A549 cell death. Conclusions : These results suggest that SL might be an effective agent to enhance anticancer drug sensitivity via Nrf2 inhibition.