• Proceedings of the Korean Biophysical Society Conference
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• 2003.06a
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• pp.61-61
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• 2003

We have cloned the CGR1 gene encoding glutathione reductase (GR) which catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) from Candida albicans. The cgr1/cgr1 mutants were not viable when CaMAL2 promoter repressed the CGR1 expression. The growth of the mutants could be partially overcome by thiol compounds such as GSH, dithiothreitol, cysteine, N-acetylcysteine and GSSG. Interestingly, C. albicans with CGR1 overexpressed showed defective hyphal growth on solid medium and attenuated virulence. We have also cloned the GCS1 gene encoding ${\gamma}$-glutamylcysteine synthetase which catalyzes the first step of glutathione biosynthesis. The gcs1/gcs1 mutants were nonviable in minimal defined medium. The growth of the mutants could be resumed by supplementing with GSH, GSSG and ${\gamma}$-glutamylcysteine in the medium. The mutants had increased intracellular D-erythroascorbic acid level up to 2.25-fold when transferred to GSH-free medium. When the mutants were depleted of GSH, they showed typical markers of apoptosis. In conclusion, these results suggest that glutathione is an essential metabolite, and involved in hyphal growth, virulence and apoptosis in C. albicans.

• Journal of Acupuncture Research
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• v.30 no.1
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• pp.43-55
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• 2013

I investigated whether snake venom toxin(SVT) from Vipera lebetina turanica enhances the apoptosis ability of tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL) in cancer cells. TRAIL inhibited HCT116 cell growth in a dose-dependent manner. Consistent with cell growth inhibition, the expression of TRAIL receptors; DR4 and DR5 was significantly increased as well as apoptosis related proteins such as cleaved caspase-3, 8, 9 and Bax. However, the expression of survival proteins(eg, cFLIP, survivin, XIAP and Bcl2) was suppressed by the combination treatment of SVT and TRAIL. Pretreatment with the reactive oxygen species(ROS) scavenger N-acetylcysteine reduced the SVT and TRAIL-induced upregulation of DR4 and DR5 expression and expression of the apoptosis related protein such as caspase-3 and-9 as well as cell growth inhibitory effects. The collective results suggest that SVT facilitates TRAIL-induced apoptosis in human colorectal cancer HCT116 cells through up-regulation of the TRAIL receptors; DR4 and DR5 via ROS pathway signals.

• Childhood Kidney Diseases
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• v.23 no.2
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• pp.77-85
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• 2019

Contrast-associated acute kidney injury (CA-AKI) is a major concern when iodinated contrast material is administered, especially in patients at risk. Efforts have been undertaken to understand the detrimental effects of contrast media (CM). With the use of low-osmolar or iso-osmolar CM the incidence of CA-AKI has steadily decreased within the past decade; however, especially in the pediatric population information is scarce. Incidence rates have been reported to range between 0% to 18.75%, particularly depending on indication, selection of population (i.e. preexisting co-morbidities), and definition of AKI. Different biomarkers have been proposed, but confirmatory studies are either lacking or have contributed to their lack of diagnostic power. Proteomic approaches have been employed and may pave the way to such discovery. Prevention strategies have been tested and proposed, but the recently published AMACING and PRESERVE trials have shown that commonly used strategies (such as systematic hydration or administration of N-acetylcysteine) have no role in the prevention of CA-AKI. We propose that thoughtful assessment of one's fluid state is the most appropriate approach and depending on the hydration status diuretics or fluid administration should be provided to achieve an euvolemic state ahead of contrast exposure.

• Journal of Marine Bioscience and Biotechnology
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• v.12 no.2
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• pp.91-98
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• 2020

Stichopus japonicas (red sea cucumbers) inhabit the coastal sea surrounding Jeju Island, South Korea, and are thought to have various medicinal properties. In this study, we investigated the anticancer activity of a red sea cucumber (S. japonicus) collected from Jeju Island. We obtained the red sea cucumber extract (RSCE), and observed that it inhibited the tumor cell growth and increased reactive oxygen species (ROS) production associated with the induction of apoptosis through the mitogen-activated protein kinase (MAPK) pathway in murine colon carcinoma cells (CT-26). Treatment with RSCE and N-acetylcysteine, which is a ROS scavenger, increased ROS production and apoptosis via the regulation by the MAPK pathway on the ERK and JNK compared with the nontreated group. Therefore, RSCE promotes ROS-mediated suppression of the ERK and JNK activation, and subsequently inhibits cancer progression, suggesting that RSCE may be beneficial in treating colon carcinoma.

• Journal of Applied Biological Chemistry
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• v.63 no.4
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• pp.457-462
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• 2020

Pancreatic cancer is among the most difficult-to-treat tumors. More than half of patients with this cancer have very few symptoms at the early stages, allowing the development of distant metastases and resistance to cancer treatment. In this study, we found that Juniperus chinensis extract (JCX) decreased the cell viability and migration activity of PANC-1 and SNU-213 pancreatic cancer cells in a dose-dependent manner. JCX increased caspase-3 activation and generation of reactive oxygen species (ROS). N-acetylcysteine treatment blocked JCX-induced ROS generation and the negative effects on pancreatic cancer cell viability. In addition, JCX down-regulated the levels of phospho-focal adhesion kinase (p-FAK) and phospho-extracellular signal-regulated kinase (p-ERK). Together, these results indicate that JCX induces apoptosis in human pancreatic cancer cell lines through ROS production, downregulating FAK/ERK signaling and activating caspase-3. We propose that JCX-derived compounds represent candidates for the development of alternative medicines for the treatment of pancreatic cancer.

• BMB Reports
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• v.54 no.2
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• pp.130-135
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• 2021

Voltage-gated potassium (Kv) channels are involved in many important cellular functions and play pivotal roles in cancer progression. The expression level of Kv2.1 was observed to be higher in the highly metastatic prostate cancer cells (PC-3), specifically in their membrane, than in immortalized prostate cells (WPMY-1 cells) and comparatively less metastatic prostate cancer cells (LNCaP and DU145 cells). However, Kv2.1 expression was significantly decreased when the cells were treated with antioxidants, such as N-acetylcysteine or ascorbic acid, implying that the highly expressed Kv2.1 could detect reactive oxygen species (ROS) in malignant prostate cancer cells. In addition, the blockade of Kv2.1 with stromatoxin-1 or siRNA targeting Kv2.1 significantly inhibited the migration of malignant prostate cancer cells. Our results suggested that Kv2.1 plays an important role as a ROS sensor and that it is a promising therapeutic molecular target in metastasis of prostate cancer.

• Nutrition Research and Practice
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• v.15 no.1
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• pp.12-25
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• 2021

BACKGROUND/OBJECTIVES: The study was conducted to investigate the efficacy of the combination treatment of phytochemical resveratrol and the anticancer drug docetaxel (DTX) on prostate carcinoma LNCaP cells, including factors related to detailed cell death mechanisms. MATERIALS/METHODS: Using 2-dimensional monolayer and 3-dimensional spheroid culture systems, we examined the effects of resveratrol and DTX on cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential, apoptosis, and necroptosis by MTT, flow cytometry, and Western blotting. RESULTS: At concentrations not toxic to normal human prostate epithelial cells, resveratrol effectively decreased the viability of LNCaP cells depending on concentration and time. The combination treatment of resveratrol and DTX exhibited synergistic inhibitory effects on cell growth, demonstrated by an increase in the sub-G0/G1 peak, Annexin V-phycoerythrin positive cell fraction, ROS, mitochondrial dysfunction, and DNA damage response as well as concurrent activation of apoptosis and necroptosis. Apoptosis and necroptosis were rescued by pretreatment with ROS scavenger N-acetylcysteine. CONCLUSIONS: We report resveratrol as an adjuvant drug candidate for improving the outcome of treatment in DTX therapy. Although the underlying mechanisms of necroptosis should be investigated comprehensively, targeting apoptosis and necroptosis simultaneously in the treatment of cancer can be a useful strategy for the development of promising drug candidates.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.89-96
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• 2023

Uric acid produced by guanine deaminase (GDA) is involved in photoaging and hyperpigmentation. Reactive oxygen species (ROS) generated by uric acid plays a role in photoaging. However, the mechanism by which uric acid stimulates melanogenesis in GDA-overexpressing keratinocytes is unclear. Keratinocyte-derived paracrine factors have been identified as important mechanisms of ultraviolet-induced melanogenesis. Therefore, the role of paracrine melanogenic growth factors in GDA-induced hypermelanosis mediated by uric acid was examined. The relationships between ROS and these growth factors were examined. Primary cultured normal keratinocytes overexpressed with wild type or mutant GDA and those treated with xanthine or uric acid in the presence or absence of allopurinol, H₂O₂, or N-acetylcysteine (NAC) were used in this study. Intracellular and extracellular bFGF and SCF levels were increased in keratinocytes by wild type, but not by loss-of-function mutants of GDA overexpression. Culture supernatants from GDA-overexpressing keratinocytes stimulated melanogenesis, which was restored by anti-bFGF and anti-SCF antibodies. Allopurinol treatment reduced the expression levels of bFGF and SCF in both GDA-overexpressing and normal keratinocytes exposed to exogenous xanthine; the exogenous uric acid increased their expression levels. H₂O₂-stimulated tyrosinase expression and melanogenesis were restored by NAC pretreatment. However, H₂O₂ or NAC did not upregulate or downregulate bFGF or SCF, respectively. Overall, uric acid could be involved in melanogenesis induced by GDA overexpression in keratinocytes via bFGF and SCF upregulation not via ROS generation.

• Biomolecules & Therapeutics
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• v.18 no.2
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• pp.145-151
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• 2010

Oxygen supply into inside solid tumor is often diminished, which is called hypoxia. Many gene transcriptions were activated by hypoxia-inducible factor (HIF)-$1{\alpha}$. Here, we investigated the effect of hypoxia on paclitaxel-resistance induction in HeLa cervical tumor cells. When HeLa cells were incubated under hypoxia condition, HIF-$1{\alpha}$ level was increased. In contrast, paclitaxel-mediated tumor cell death was reduced by the incubation under hypoxia condition. Paclitaxel-mediated tumor cell death was also inhibited by treatment with DMOG, chemical HIF-$1{\alpha}$ stabilizer, in a dose-dependent manner. A significant increase in intracellular ROS level was detected by the incubation under hypoxia condition. A basal level of cell density was increased in response to 10 nM $H_2O_2$. HIF-$1{\alpha}$ level was increased by treatment with various concentration of $H_2O_2$. The increased level of HIF-$1{\alpha}$ by hypoxia was reduced by the treatment with N-acetylcysteine (NAC), a well-known ROS scavenger. Paclitaxel-mediated tumor cell death was increased by treatment with NAC. Taken together, these findings demonstrate that hypoxia could play a role in paclitaxel-resistance induction through ROS-mediated HIF-$1{\alpha}$ stabilization. These results suggest that hypoxia-induced ROS could, in part, control tumor cell death through an increase in HIF-$1{\alpha}$ level.

• Toxicological Research
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• v.32 no.2
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• pp.133-140
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• 2016

Sulfasalzine is a widely administered drug against inflammatory-based disorders in human. However several cases of liver injury are associated with its administration. There is no stabilized safe protective agent against sulfasalazine-induced liver injury. Current investigation was designed to evaluate if N-acetylcysteine (NAC) and dithioteritol (DTT) as thiol reducing agents and/or vitamins C and E as antioxidants have any protective effects against sulfasalazine-induced hepatic injury in an ex vivo model of isolated rat liver. Rat liver was canulated and perfused via portal vein in a closed recirculating system. Different concentrations of sulfasalazine and/or thiol reductants and antioxidants were administered and markers of organ injury were monitored at different time intervals. It was found that 5 mM of sulfasalazine caused marked liver injury as judged by rise in liver perfusate level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) (p < 0.05). A significant amount of lipid peroxidation and hepatic glutathione depletion were detected in drug-treated livers, accompanied with significant histopathological changes of the organ. Administration of NAC ($500{\mu}M$), DTT (${400\mu}M$), Vitamin C ($200{\mu}M$), or vitamin E ($200{\mu}M$) significantly alleviated sulfasalazine-induced hepatic injury in isolated perfused rat liver. The data obtained from current investigation indicate potential therapeutic properties of thiol reductants and antioxidants against sulfasalazine-induced liver injury.