Genetic and epigenetic cancer chemoprevention on molecular targets during multistage carcinogenesis

Kim, H. S.,Kacew, S.,Lee, B. M. Springer Science + Business Media 2016 Archives of toxicology Vol.90 No.10

<P>The main goal of cancer chemoprevention is to prevent or halt the progression of carcinogenesis with the administration of synthetic or natural compounds. Fundamental chemopreventive strategies include inhibition of genetic damage, anti-proliferation/cell cycle regulation, and induction of apoptosis and anti-inflammatory processes, which may be critical for carcinogenesis intervention. Recently, a new paradigm for identifying chemopreventive agents has been implemented. It focuses on defining new biomarkers that can be used to evaluate chemopreventive efficacy based on multistage carcinogenesis. The functional roles of chemopreventive agents are associated with the modulation of nuclear factor kappa B, nuclear factor erythroid 2-related factor, p53, AMPK/mTOR, phosphatidylinositol 3-kinase, epidermal growth factor receptor, cyclooxygenase-2, chemokine (C-X-C motif) receptor 2, and sphingosine-1-phosphate. This paper summarizes the genetic and epigenetic effects of chemopreventive agents on the expression of cancer-related target genes mediated by epigenetic alterations, such as DNA methylation and histone modifications. This review will provide unique and effective strategies for reducing cancer and aging-related diseases in humans.</P>

In vitro chemopreventive effects of plant polysaccharides(Aloe barbadensis Miller, Lentinus edodes, Ganoderma lucidum and Coriolus versicolor)

Kim, Hyung Sik,Kacew, Sam,Lee, Byung Mu 성균관대학교 약학연구소 1999 成均藥硏論文集 Vol.11 No.-

A plant polysaccharide, Aloe gel extract, was reported to have an inhibitory effect on benzo[α]pyrene (B[α]P)-DNA adduct formation in vitro and in vivo. Hence, chemopreventive effects of plant polysaccharides [Aloe barbadensis Miller(APS), Lentinus edodes (LPS), Ganoderma lucidum (GPS) and Coriolus versicolor (CPS)] were compared using in vitro short-term screening methods associated with both initiation and promotion processes in carcinogenesis. In B[α]P-DNA adduct formation, APS (180 ㎍/ml) was the most effective in inhibition of B[α]P binding to DNA in mouse liver cells. Oxidative DNA damage (by 8-hydroxydeoxy-guanosine) was significantly decreased by APS (180 ㎍/ml) and CPS (180 ㎍/ml). In induction of glutathione S-transferase activity, GPS was found to be the most effective among plant polysaccharides. In screening anti-tumor promoting effects, APS (180 ㎍/ml) significantly inhibited phorbol myristic acetate (PMA)-induced ornithine decarboxylase activity in Balb/3T3 cells. In addition, APS significantly inhibited PMA-induced tyrosine kinase activity in human leukemic cells. APS and CPS significantly inhibited superoxide anion formation. These results suggest that some plant polysaccharides produced both anti-geno-toxic and anti-tumor promoting activities in in vitro models and, therefore, might be considered as potential agents for cancer chemoprevention.

Determination of fragrance allergens and their dermal sensitization quantitative risk assessment (QRA) in 107 spray perfumes

Soo Lim, Duck,Min Choi, Seul,Kim, Kyu-Bong,Yoon, Kyungsil,Kacew, Sam,Sik Kim, Hyung,Lee, Byung-Mu Informa UK (TaylorFrancis) 2018 Journal of toxicology and environmental health. Pa Vol.81 No.22

Risk assessment of benzalkonium chloride in cosmetic products

Choi, Seul Min,Roh, Tae Hyun,Lim, Duck Soo,Kacew, Sam,Kim, Hyung Sik,Lee, Byung-Mu Informa UK (TaylorFrancis) 2018 Journal of toxicology and environmental health. Pa Vol.21 No.1

<P>A risk assessment of benzalkonium chloride (BAC) was conducted based upon its toxicological profile and exposure evaluation. Since 1935, BAC has been used in a wide variety of products such as disinfectants, preservatives, and sanitizers. It is well-established that BAC is not genotoxic nor does it display tumorigenic potential, but safety concerns have been raised in local usage such as for ocular and intranasal applications. The Foundation of Korea Cosmetic Industry Institute (KCII) reported that in a hair conditioner manufactured as a cosmetic or personal product in South Korea, BAC was present at concentrations of 0.5-2%. The systemic exposure dosage (SED) was determined using the above in-use concentrations and a risk assessment analysis was conducted. The Margin of Safety (MOS) values for hair conditioners were calculated to be between 621 and 2,483. The risk of certain personal and cosmetic products was also assessed based upon assumptions that BAC was present at the maximal level of regulation in South Korea and that the maximal amount was used. The MOS values for the body lotion were all above 100, regardless of the application site. Collectively, data indicate that there are no safety concerns regarding use of products that contain BAC under the current concentration restrictions, even when utilized at maximal permitted levels. However, a chronic dermal toxicity study on BAC and comprehensive dermal absorption evaluation needs to be conducted to provide a more accurate prediction of the potential health risks to humans.</P>

Discovery of urinary metabolomic biomarkers for early detection of acute kidney injury

Won, A Jin,Kim, Siwon,Kim, Yoon Gyoon,Kim, Kyu-Bong,Choi, Wahn Soo,Kacew, Sam,Kim, Kyeong Seok,Jung, Jee H.,Lee, Byung Mu,Kim, Suhkmann,Kim, Hyung Sik The Royal Society of Chemistry 2016 Molecular bioSystems Vol.12 No.1

<P>The discovery of new biomarkers for early detection of drug-induced acute kidney injury (AKI) is clinically important. In this study, sensitive metabolomic biomarkers identified in the urine of rats were used to detect cisplatin-induced AKI. Cisplatin (10 mg kg(-1), i.p.) was administered to Sprague-Dawley rats, which were subsequently euthanized after 1, 3 or 5 days. In cisplatin-treated rats, mild histopathological alterations were noted at day 1, and these changes were severe at days 3 and 5. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at days 3 and 5. The levels of new urinary protein-based biomarkers, including kidney injury molecule-1 (KIM-1), glutathione S-transferase-alpha (GST-alpha), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF), calbindin, clusterin, neutrophil, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin, were significantly elevated at days 3 and 5. Among urinary metabolites, trigonelline and 3-indoxylsulfate (3-IS) levels were significantly decreased in urine collected from cisplatin-treated rats prior to histological kidney damage. However, carbon tetrachloride (CCl4), a hepatotoxicant, did not affect these urinary biomarkers. Trigonelline is closely associated with GSH depletion and results in insufficient antioxidant capacity against cisplatin-induced AKI. The predominant cisplatin-induced AKI marker appeared to be reduced in urinary 3-IS levels. Because 3-IS is predominantly excreted via active secretion in proximal tubules, a decrease is indicative of tubular damage. Further, urinary excretion of 3-IS levels was markedly reduced in patients with AKI compared to normal subjects. The area under the curve receiver operating characteristics (AUC-ROC) for 3-IS was higher than for SCr, BUN, lactate dehydrogenase (LDH), total protein, and glucose. Therefore, low urinary or high serum 3-IS levels may be more useful for early detection of AKI than conventional biomarkers.</P>

Detoxifying effect of pyridoxine on acetaminophen-induced hepatotoxicity via suppressing oxidative stress injury

Roh, Taehyun,De, Umasankar,Lim, Seong Kwang,Kim, Min Kook,Choi, Seul Min,Lim, Duck Soo,Yoon, Sungpil,Kacew, Sam,Kim, Hyung Sik,Lee, Byung-Mu Elsevier 2018 Food and chemical toxicology Vol.114 No.-

<P><B>Abstract</B></P> <P>The detoxifying effect of pyridoxine against acetaminophen (APAP)-induced hepatotoxicity was investigated. HepG2 cells were co-treated with APAP and pyridoxine to compare with betaine or methionine for 24 h. LDH, ALT and AST activities were measured to determine direct cells damage <I>in vitro</I> and in vivo. Lipid peroxidation, antioxidant enzymes activity, and glutathione level were measured. Cytochrome c releaseand procaspase-3, cleaved caspase-3, Bcl-2, or Bax protein levels were measured to determine APAP-induced apoptotic cell death. Pyridoxine treatment significantly increased cell viability and decreased leakage of LDH activity against APAP-induced hepatotoxicity in HepG2 cells. ALT and AST activities were dose-dependently reduced by pyridoxine treatment compared to APAP-treated group. Significant increases in activities of GST and GPx were observed after co-treatment with APAP and pyridoxine. Although APAP-induced Nrf2 and HO-1 expression levels were gradually reduced in HepG2 cells by pyridoxine treatment, induction of antioxidant enzymes activities were dose-dependently increased. These protected effects of pyridoxine against APAP-induced hepatoxicity were closely associated with suppression of APAP-induced oxidative stress and apoptotic cell death in HepG2 cells. These data indicated that the protective action of pyridoxine against hepatic cell injuries was involved in the direct antioxidant activity which provides a pivotal mechanism for its potential hepatoprotective action.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Pyridoxine decreased LDH, ALT and AST activities against APAP-induced hepatotoxicity <I>in vitro</I> and in vivo. </LI> <LI> Increases in antioxidant enzymes (GST and GPx) and GSH levels were observed after co-treatment with APAP and pyridoxine. </LI> <LI> Cytochrome c and procaspase-3, Bcl-2, or Bax protein levels were measured to determine APAP-induced apoptotic cell death. </LI> <LI> The protective action of pyridoxine against hepatic cell injuries was involved in the direct antioxidant activity. </LI> <LI> Pyridoxine showed protective activity via HO-1 induction serving as a key player in APAP-induced cell survival pathway. </LI> </UL> </P>

Selenium-binding protein 1: a sensitive urinary biomarker to detect heavy metal-induced nephrotoxicity

Lee, E. K.,Shin, Y. J.,Park, E. Y.,Kim, N. D.,Moon, A.,Kwack, S. J.,Son, J. Y.,Kacew, S.,Lee, B. M.,Bae, O. N. Springer Science + Business Media 2017 Archives of toxicology Vol.91 No.4

<P>Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl2-treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and beta-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl2-exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl2, CdCl2, or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.</P>