• Toxicological Research
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• v.30 no.3
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• pp.193-198
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• 2014

Degradation of glucose is aberrantly increased in hyperglycemia, which causes various harmful effects on the liver. Methylglyoxal is produced during glucose degradation and the levels of methylglyoxal are increased in diabetes patients. In this study we investigated whether methylglyoxal induces mitochondrial impairment and apoptosis in HepG2 cells and induces liver toxicity in vivo. Methylglyoxal caused apoptotic cell death in HepG2 cells. Moreover, methylglyoxal significantly promoted the production of reactive oxygen species (ROS) and depleted glutathione (GSH) content. Pretreatment with antioxidants caused a marked decrease in methylglyoxal-induced apoptosis, indicating that oxidant species are involved in the apoptotic process. Methylglyoxal treatment induced mitochondrial permeability transition, which represents mitochondrial impairment. However, pretreatment with cyclosporin A, an inhibitor of the formation of the permeability transition pore, partially inhibited methylglyoxal-induced cell death. Furthermore, acute treatment of mice with methylglyoxal increased the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating liver toxicity. Collectively, our results showed that methylglyoxal increases cell death and induces liver toxicity, which results from ROS-mediated mitochondrial dysfunction and oxidative stress.

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.2
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• pp.121-130
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• 2019

Glutamate toxicity-mediated mitochondrial dysfunction and neuronal cell death are involved in the pathogenesis of several neurodegenerative diseases as well as acute brain ischemia/stroke. In this study, we investigated the neuroprotective mechanism of dieckol (DEK), one of the phlorotannins isolated from the marine brown alga Ecklonia cava, against glutamate toxicity. Primary cortical neurons ($100{\mu}M$, 24 h) and HT22 neurons (5 mM, 12 h) were stimulated with glutamate to induce glutamate toxic condition. The results demonstrated that DEK treatment significantly increased cell viability in a dose-dependent manner ($1-50{\mu}M$) and recovered morphological deterioration in glutamate-stimulated neurons. In addition, DEK strongly attenuated intracellular reactive oxygen species (ROS) levels, mitochondrial overload of $Ca^{2+}$ and ROS, mitochondrial membrane potential (${\Delta}{\Psi}_m$) disruption, adenine triphosphate depletion. DEK showed free radical scavenging activity in the cell-free system. Furthermore, DEK enhanced protein expression of heme oxygenase-1 (HO-1), an important anti-oxidant enzyme, via the nuclear translocation of nuclear factor-like 2 (Nrf2). Taken together, we conclude that DEK exerts neuroprotective activities against glutamate toxicity through its direct free radical scavenging property and the Nrf-2/HO-1 pathway activation.

• Journal of the Korean Applied Science and Technology
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• v.36 no.1
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• pp.258-268
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• 2019

The extracts of AS contain in alloxanthin, halocynthiaxanthin, astaxanthin and 13 kinds of carotenoids. The aim of the study was to assess the anti-oxidant activity and cell viability of AS. The anti-oxidant activity was determined by using DPPH radical inhibition activity and superoxide dismutase (SOD)-like activity. The results of cell viability assay showed that the extracts from AS were cytotoxic at concentrations above $5.0mg/m{\ell}$. This study was designed to examine inflammation induced by LPS, protection effect by UVB and the toxicity of Ascidian shell extract(ASE) as a functional cosmetic ingredient. Evaluation of embryo toxicity resulted in embryo coagulation and mortality when treated at 5.0, 10.0, $20.0mg/m{\ell}$. At the lowest concentration of $1.0mg/m{\ell}$, hatchability resulted in 100.0 % rate. The results of arrhythmia measurement in larvae showed similarity to the evaluation of embryo toxicity. This result demonstrated that toxicity is present at concentrations greater than $5.0mg/m{\ell}$. The protective effect of ASE on LPS and UVB-induced in the zebrafish was investigated. Intracellular reactive oxygen species(ROS) generated by the exposure of zebrafish to LPS, UVB-radiation were significantly decreased after treatment with ASE at $0.1mg/m{\ell}$. As a result, ASE similarly reduced UVB-induced ROS generation and cell death in live zebrafsih. Therefore, it is suggested that ASE has anti-Inflammatory effects and can possibly be used as a functional substance for skin protection in the future.

• Molecules and Cells
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• v.46 no.8
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• pp.496-512
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• 2023

A fructose-enriched diet is thought to contribute to hepatic injury in developing non-alcoholic steatohepatitis (NASH). However, the cellular mechanism of fructose-induced hepatic damage remains poorly understood. This study aimed to determine whether fructose induces cell death in primary hepatocytes, and if so, to establish the underlying cellular mechanisms. Our results revealed that treatment with high fructose concentrations for 48 h induced mitochondria-mediated apoptotic death in mouse primary hepatocytes (MPHs). Endoplasmic reticulum stress responses were involved in fructose-induced death as the levels of phosho-eIF2α, phospho-C-Jun-N-terminal kinase (JNK), and C/EBP homologous protein (CHOP) increased, and a chemical chaperone tauroursodeoxycholic acid (TUDCA) prevented cell death. The impaired oxidation metabolism of fatty acids was also possibly involved in the fructose-induced toxicity as treatment with an AMP-activated kinase (AMPK) activator and a PPAR-α agonist significantly protected against fructose-induced death, while carnitine palmitoyl transferase I inhibitor exacerbated the toxicity. However, uric acid-mediated toxicity was not involved in fructose-induced death as uric acid was not toxic to MPHs, and the inhibition of xanthine oxidase (a key enzyme in uric acid synthesis) did not affect cell death. On the other hand, treatment with inhibitors of the nicotinamide adenine dinucleotide (NAD)⁺-consuming enzyme CD38 or CD38 gene knockdown significantly protected against fructose-induced toxicity in MPHs, and fructose treatment increased CD38 levels. These data suggest that CD38 upregulation plays a role in hepatic injury in the fructose-enriched diet-mediated NASH. Thus, CD38 inhibition may be a promising therapeutic strategy to prevent fructose-enriched diet-mediated NASH.

• Toxicological Research
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• v.28 no.1
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• pp.57-65
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• 2012

In this study, the 4-week oral toxicity and anti-cancer activity of the hexane layer of Melia azedarach L. var. japonica Makino's bark extract were investigated. We carried out a hollow fiber (HF) assay and 28-day repeated toxicity study to confirm the anti-cancer effect and safety of the hexane layer. The HF assay was carried out using an A549 human adenocarcinoma cell via intraperitoneal (IP) site with or without cisplatin. In the result, the 200 mg/kg b.w of hexane layer with 4 mg/kg b.w of cisplatin treated group, showed the highest cytotoxicity aginst A549 carcinoma cells. For the 28-day repeated toxicity study, 6 groups of 10 male and female mice were given by gavage 200, 100, or 50 mg/kg b.w hexane layer with or without 4 mg/kg b.w of cisplatin against body weight, and were then sacrificed for blood and tissue sampling. The subacute oral toxicity study in mice with doses of 200, 100, and 50 mg/kg b.w hexane layer showed no significant changes in body weight gain and general behavior. The cisplatin-treated group significantly decreased in body weight compared to the control group but regained weight with 100 and 200 mg/kg b.w of hexane layer. The biochemical analysis showed significant increase in several parameters (ALT, total billirubin, AST, creatinine, and BUN) in cisplatin-treated groups. However, in the group given a co-treatment of hexane layer (200 mg/kg b.w), levels of these parameters decreased. In hematological analysis, cisplatin induced the reduction of WBCs and neutrophils but co-treatment with hexane layer (100 and 200 mg/kg b.w) improved these toxicities caused by cisplatin. The histological profile of the livers showed eosinophilic cell foci in central vein and portal triad in cisplatin treated mice. These results show that hexane layer might have an anti-cancer activity and could improve the toxicity of cisplatin.

• Journal of Korean Society of Occupational and Environmental Hygiene
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• v.26 no.2
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• pp.119-138
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• 2016

Objectives: The purpose of this study is to review size, shape, and crystal structure-dependent toxicity of major metal oxide particles such as silicon dioxide, tungsten trioxide, aluminum oxide, and titanium dioxide as byproducts generated in semiconductor fabrication facility. Methods: To review the toxicity of major metal oxide particles, we used various reported research and review papers. The papers were searched by using websites such as Google Scholar and PubMed. Keyword search terms included '$SiO_2$(or $WO_3$ or $Al_2O_3$ or $TiO_2$) toxicity', 'health effects $SiO_2$(or $WO_3$ or $Al_2O_3$ or $TiO_2$). Additional papers were identified in references cited in the searched papers. Results: In various cell lines and organs of human and animals, cytotoxicity, genotoxicity, hepatoxicity, fetotoxicity, neurotoxicity, and histopathological changes were induced by silicon dioxide, tungsten trioxide, aluminium oxide, and titanium dioxide particles. Differences in toxicity were dependent on the cell lines, organs, doses, as well as the chemical composition, size, surface area, shape, and crystal structure of the particles. However, the doses used in the reported papers were higher than the possible exposure level in general work environment. Oxidative stress induced by the metal oxide particles plays a significant role in the expression of toxicity. Conclusions: The results cannot guarantee human toxicity of the metal oxide particles, because there is still a lack of available information about health effects on humans. In addition, toxicological studies under the exposure conditions in the actual work environment are needed.

• KSBB Journal
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• v.9 no.3
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• pp.266-271
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• 1994

Lipsome system composed of egg phosphatidylcholine was employed to reduce the membrane toxicity of Amphotericin B(Amp. B). Liposomal Amp. B, which showed a free drug equivalent antibiotic effect on fungi, displayed a remarkable reduction of toxicity of the drug against the membrane of red blood cell than that of fungizone which has been used in clinical treatment, and it shows conspicuously lowered toxicity on red blood cells. However liposomal Amp. B which contains cholesterol as a component of liposome lowered the antibiotic effect and toxicity than that phosphatidylcholine liposome. This due to the affinity between Amp. B and cholesterol. In addition to this, ${\beta}$-glucuronidase from snail juice crude enzyme reveals synergistic effect on liposomal Amp. B and free Amp. B. We also obtained positively raised antibiotic effect, when enzyme which is coupled with palmitic acid using NHSP inserted into liposome bilayer From these results, we suppose that the use of liposomal system in the case of Amp. B shows increasing antibiotic effect and dramatically lowered toxicity, thus, we think that we can solve the problem of Amp. B toxicity, which cause hesitate of clinical use.

• Journal of Life Science
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• v.7 no.4
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• pp.377-383
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• 1997

The acute toxicity effect of triorganotin of trioganotin on the growth of microalgae and shellfish was investigated through flask culture. The value of 120 hr-LC$_{50}$ that is the median lethal concentration of TBTO on the shellfish (R. philipinarum) was found to be 6 $\mu$g/L. The acute toxicity effect of TBTO on T. suecica was obviously shown even at the concentration of 0.5 $\mu$g/L, and the effect diminished as the initial cell density increased. The effect also diminished less in the experiment done under aeration than in that done under non-aeration. To design a chemostat system for the test of chronic toxicity, the culture of T. suecica was executed in photobioreactor. In batch culture, the profiles of chlorophyII a and D.C.W. showed the growth of T. suecica very well, and the maximum specific growth rate was estimated to be 0.54 d$^{-1}$. with this value, as a dilution rate in contimuous culture, pH was nicely maintained between 7 and 9 when air was supplied with 3% CO$_{2}$. From all results and the natural environment of clam, a novel chemostat system was invented. Through this system, we can observe each independent toxicity effect of TBTO and plankton and combined toxicity effect as well.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6267-6271
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• 2013

Objective: To determine clinical efficacy, safety and prognostic factors of pemetrexed plus platinum as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). Materials and Methods: Clinical characteristics, short-term efficacy, survival and adverse reactions of 47 advanced non-squamous NSCLC patients who had received pemetrexed plus platinum as first-line treatment in Shanghai Pulmonary Hospital from January 2009 to June 2011 were retrospectively analyzed. The Chi-squared test was applied to statistically analyze the overall response rate (ORR), disease control rate (DCR) and toxicity reactions in both groups, while survival data wereanalyzed by Kaplan-Meier and logrank methods, and the COX proportional hazards model was adopted for a series of multi-factor analyses. Results: Only two patients were lost to follow-up. The ORR, DCR, medium progression-free survival time (PFS) and medium overall survival (OS) were 31.9%, 74.5%, 5 months and 15.2 months, while 1- and 2-year survival rates were 63.8% (30/47) and 19.2% (9/47), respectively. Single-factor analysis showed that tumor pathological patterns and efficacy were in association with medium PFS (P<0.05), whereas tumor pathological patterns, smoking history and efficacy were closely connected with medium OS (P<0.05). Multi-factor analyses demonstrated that pathological patterns and efficacy were independent factors influencing OS (P<0.05). The rate of toxicity reactions in degree III/IV was low, including hematologic toxicity marked by decline in white blood cell count and decrease in the platelet count (PLT), and non-hematologic toxicity manifested by gastrointestinal reactions, such as nausea and vomiting. Conclusions: Pemetrexed plus platinum as first-line treatment has excellent efficacy and slight adverse reactions with favorable drug-tolerance in patients with advanced non-squamous NSCLC.

• Journal of Radiation Industry
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• v.6 no.3
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• pp.217-221
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• 2012

The purpose of this study is to reduce the immune toxicity of lipopolysaccharide (LPS) by gamma irradiation. LPS was gamma-irradiated at the various doses of 20, 100 and 200 kGy and then evaluated on the immune toxicity through the cell proliferation, nitricoxide production and cytokine release. Cell proliferation significantly decreased in the intact LPS treated groups, whereas gamma-irradiated LPS treated group were not reduced the cell proliferation. Similarly, the production of nitric oxide and cytokine showed the high levels in the intact LPS treated group. However, gamma-irradiated LPS treated group remarkably decreased the production of nitric oxide and cytokine in dose-dependent manner. Therefore, gamma irradiation may effective method to reduce the immune toxicity of LPS.