• Journal of Korean Dental Science
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• v.14 no.2
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• pp.51-60
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• 2021

Purpose: Measuring viability of a three-dimensional in vitro organotypic human oral tissue model has been suggested as an alternative test method to the oral mucosa irritation test of oral care products. The aim of this study was to investigate the production of two different cytokines using organotypic human oral tissue model following exposure to chemicals that are commonly used in oral care products. Materials and Methods: The organotypic human oral tissues were exposed to ethanol, sodium lauryl sulphate or hydrogen peroxide for 90 minutes. Following exposure, interleukin (IL)-1α and IL-8 productions were assessed and correlated with cell viability testing as well as histology of the organotypic human oral tissues. Result: High levels of IL-8 were released from organotypic human oral tissues in all of the test and control groups without any significant differences between them. In contrast, differences were found in IL-1α release between the test and control groups. Additionally, the trend of IL-1α release corresponded to the phenotypes observed in histological analysis while different trend existed between IL-1α release and cell viability. Conclusion: The study concluded the non-specific release of IL-8 for the assessment of oral care product chemicals' toxicity, while potential of measuring IL-1α cytokine level as the possible alternative test method.

• Journal of Pharmaceutical Investigation
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• v.23 no.2
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• pp.111-118
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• 1993

The hemolytic characteristics of amphotericin B-containing liposomes have been investigated in vitro. From the hemolysis of human erythrocytes against free and liposomal amphotericin B, the marked reduction in the toxicity of amphotericin B was observed by incorporating the drug in egg PC liposomes. For 45 min, free amphotericin B at $9.6\;{\mu}g/ml$ could completely lyse 2 wt% human erythrocytes. However, liposomal amphotericin B had essentially no lytic effect even in the range over $9.6\;{\mu}g/ml$. In the 66 hr-hemolysis experiment, liposomal amphotericin B showed the slowly hemolysing chracteristics during the experimental period regardless of the concentration of amphotericin B but rapid hemolysis only for 12 hr was observed in the case of free amphotericin B and the degree of hemolysis for 12 hr was maintained after that time. Also the hemolysing ability of liposomal amphotericin B at $4\;{\mu}g/ml$ was lower than that of free amphotericin B at the same concentration for 66 hr. On the other hand, the dependence of hemolysis on amphotericin B contents in egg PC liposomes was significant between 1.64 mole% amphotericin B-containing liposomes and 15.79 or 27.27 mole% amphotericin B-containing liposomes. But no marked difference in hemolysis was observed between 15.79 and 27.27 mole% amphotericin B-containing liposomes. Especially, cholesterol as an excipient in amphotericin B-containing liposomes significantly reduced the hemolysis of human erythrocyte. The degree of hemolysis in 5 mole% amphotericin B-containing liposomes was reduced to approximately 50% of value in the cholesterol-free liposomes by adding 50% cholesterol.

• Proceedings of the Korea Society of Environmental Toocicology Conference
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• 2003.05a
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• pp.107-107
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• 2003

The heavy metal cadmium is a xenobiotic toxicant of environmental and occupational concern and it has been classified as a human carcinogen. Inhalation of cadmium has been implicated in the development of emphysema and pulmonary fibrosis, but, the detailed mechanism by which cadmium induces adverse biological effects is not yet known. Therefore, we undertook the investigation of genes that are induced after cadmium exposure to illustrate the mechanism of cadmium toxicity For this purpose, we employed the polymerase chain reaction-based suppression subtractive hybridization technique. We identified 29 different cadmium-inducible genes in human peripheral mononuclear cells, such as macrophage migration inhibitory factor, lysophosphatidic acid acyltransferase-${\alpha}$, enolase-1${\alpha}$, VEGF, Bax, neuron-derived orphan receptor-1, and Nur77, which are known to be associated with inflammation, cell survival, and apoptosis. Induction of these genes by cadmium treatment was further confirmed by semi-quantitative reverse-transcription polymerase chain reaction. Further, we found that these genes were also induced after cadmium exposure in normal human lung fibroblast cell line, WI-38, suggesting potential use of this induction profile to monitor cadmium toxicity in the lung. Next, Nur77, one of cadmium-inducible genes, was further studied since the products of Nur77 are known to be involved in the apoptotic process of lung cells. Following cadmium treatment, Nur77 gene expression was increased at protein-level in A549 cells. Consistently, the reporter containing Nur77 binding sequence was activated by 2.5-fold after exposure to cadmium in reporter gene analysis by transient transfection experiments. When the plasmid encoding dominant negative Nur77 that represses the transcriptional function of wild-type Nur77 was transfected into A549 cells, the expression of Bax was significantly reduced, suggesting that induction of Nur77 was an important process in cadmium-induced apoptosis in the cells. Cadmium induced the expression of Nur77 in vivo, confirming the relevance of the data obtained in viro. Together our results suggest that Nur77 gene expression in exposure to cadmium leads apoptosis of lung cells which may cause pathological changes in lung.

• Advances in Traditional Medicine
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• v.2 no.2
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• pp.119-124
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• 2002

Cigarette smoking contributes to lung cancer, cardiovascular diseases, oral diseases, etc. In desire to reduce their risk of disease, many cigarette smokers have tried to quit smoking. Sensory aspects of cigarette smoke are important for providing smoking satisfaction. Previously it was reported that citric acid aerosol significantly reduced craving for cigarettes and enhances smoking reduction and cessation. In this study, we tested whether a newly combined product Ciga-X, an aerosol for cessation aid, had toxicity in human embryonic lung fibroblast (MRC-9). The inhibitory effect of Ciga-X on cytotoxicity induced by cigarette smoke extract (CSE) or nicotine was examined in MRC-9, and craving for cigarettes and smorkers satisfaction after using Ciga-X was estimated. Ciga-X did not affect cell viability and had no toxicity in MRC-9. Ciga-X significantly inhibited not only CSE-induced cytotoxicity but also nicotine-induced cytotoxicity in MRC-9. One hundred and forty smokers rated the satisfaction for Ciga-X aerosol and craving reduction for cigarettes after using Ciga-X. The percentage of over 5 rating was 71.0% and 50.0% of subjects in satisfaction test for Ciga-X compared to their own brand and in craving reduction for cigarette, respectively. Besides, craving reduction for cigarette was highly correlated with the duration of smoking. Subjects have smoked under 10 years were more reduced in craving for cigarettes after using Ciga-X as compared to over 10 years (p=0.049). These results suggest that Ciga-X may be effective in promoting smoking abstinence with the reduction of CSE- or nicotine-induced human lung fibroblasts cytotoxicity.

• Toxicological Research
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• v.30 no.3
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• pp.149-157
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• 2014

Smoking is one of the most serious but preventable causes of cardiovascular disease (CVD). Key aspects of pathological process associated with smoking include endothelial dysfunction, a prothrombotic state, inflammation, altered lipid metabolism, and hypoxia. Multiple molecular events are involved in smoking-induced CVD. However, the dysregulations of reactive oxygen species (ROS) generation and metabolism mainly contribute to the development of diverse CVDs, and NADPH oxidase (NOX) has been established as a source of ROS responsible for the pathogenesis of CVD. NOX activation and resultant ROS production by cigarette smoke (CS) treatment have been widely observed in isolated blood vessels and cultured vascular cells, including endothelial and smooth muscle cells. NOX-mediated oxidative stress has also been demonstrated in animal studies. Of the various NOX isoforms, NOX2 has been reported to mediate ROS generation by CS, but other isoforms were not tested thoroughly. Of the many CS constituents, nicotine, methyl vinyl ketone, and ${\alpha}$,${\beta}$-unsaturated aldehydes, such as, acrolein and crotonaldehyde, appear to be primarily responsible for NOX-mediated cytotoxicity, but additional validation will be needed. Human epidemiological studies have reported relationships between polymorphisms in the CYBA gene encoding p22phox, a catalytic subunit of NOX and susceptibility to smoking-related CVDs. In particular, G allele carriers of A640G and $-930^{A/G}$ polymorphisms were found to be vulnerable to smoking-induced cardiovascular toxicity, but results for C242T studies are conflicting. On the whole, evidence implicates the etiological role of NOX in smoking-induced CVD, but the clinical relevance of NOX activation by smoking and its contribution to CVD require further validation in human studies. A detailed understanding of the role of NOX would be helpful to assess the risk of smoking to human health, to define high-risk subgroups, and to develop strategies to prevent or treat smoking-induced CVD.

• Korean Journal of Head & Neck Oncology
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• v.38 no.2
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• pp.7-13
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• 2022

Human papillomavirus (HPV) is a causative agent for a subset of oropharyngeal cancer (OPC). The current standard of care (SOC) for locally advanced OPC is 70 Gy definitive radiotherapy (RT) concurrent with cisplatin, which entails significant proportions of acute and late grade 3 or higher toxicities. Accordingly, discovery of favorable prognosis of HPV-related OPC has led to enthusiasm to attenuate subspecialties therapy in multidisciplinary treatment. Diverse deintensification strategies were investigated in multiple phase 2 trials with an assumption that attenuated treatments result in comparable oncologic outcome and less toxicities compared with SOC. Several trials on chemotherapy deintensification revealed that concomitant administration of cisplatin is not to be omitted or substituted for cetuximab without compromising progression-free survival or local control. A transoral robotic surgery (TORS) is investigated as alternative local treatment, but TORS plus SOC or mild deintensified adjuvant RT showed similar toxicities and inferior oncologic outcomes compared with SOC definitive RT or moderately deintensified RT. However, it has been reported that TORS plus deintensified 30-36 Gy adjuvant RT results in excellent outcome and less late toxicity compared with SOC adjuvant RT. Several phase 2 trials reported apparently equivalent progression-free survival and local control and similar adverse effects with moderately deintensified 60 Gy RT compared with SOC 70 Gy RT. Further dose reduction below 60 Gy has been investigated using biology-directed approaches, which use response to induction chemotherapy or metabolic images to triage HPV-positive OPC for deintensified RT. In summary, these trials provide valuable insights for future directions. Available evidence consistently showed that moderately deintensified RT is effective and safe for HPV-positive OPC in both definitive and adjuvant settings. Concurrent cisplatin remains an essential component without which progression-free survival is significantly compromised for advanced HPV-positive OPC. A simple incorporation of TORS to SOC may be detrimental for oncologic outcome without anticipated toxicity reduction. Given the lack of level 1 evidence, it is prudent to curb an unjustified deviation from the current SOC and limit any deintensified strategies to clinical trials and adhere to the current SOC.

• Molecular & Cellular Toxicology
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• v.3 no.4
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• pp.238-245
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• 2007

Chronic formaldehyde inhalation studies have suggested its relativity to teratogenicity, cancer incidence, neurodegenerative and vascular disorders. Many toxicological data on the formaldehyde toxicity are available, but proteomic results showing complete protein profiles are limited. Therefore, alterations of protein expression patterns upon formaldehyde treatment were investigated in the human lung epithelial cell line. Differentially expressed proteins following formaldehyde treatment were analyzed on 2-dimensional gels, and further analyzed by MALDI-TOF to identify the proteins. Among the identified proteins, 24 proteins were notably up-regulated and 6 proteins were down-regulated. In particular, cytoskeleton related protein named vinculin and Rho GDP dissociation inhibitor which plays a key role in apoptosis increased remarkably.

• Molecular & Cellular Toxicology
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• v.3 no.4
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• pp.222-230
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• 2007

Some drugs may be limited in their clinical application due to their propensity towards their adverse effects. Toxicogenomic technology represents a useful approach for evaluating the toxic properties of new drug candidates early in the drug discovery process. Nitrofurantoin (NF) is clinical chemotherapeutic agent and antimicrobial and used to treatment of urinary tract infections. However, NF has been shown to result in pulmonary toxic effects. In this research, we revealed the changing expression gene profiles in BEAS-2B, human bronchial epithelial cell line, exposed to NF by using human oligonucleotide chip. Through the clustering analysis of gene expression profiles, we identified 136 up-regulated genes and 379 down-regulated genes changed by more than 2-fold by NF. This study identifies several interesting targets and functions in relation to NF-induced toxicity through a gene ontology analysis method including biological process, cellular components, molecular function and KEGG pathway.

• Biomolecules & Therapeutics
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• v.3 no.1
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• pp.63-71
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• 1995

The local irritation studies of DA-3002, an authentic recombinant human growth hormone (rhGH), were carried out in rabbits after the following treatment ; application into the conjunctival sac of the eye (single), single subcutaneous and intramuscular injection, 7-day repeated subcutaneous and intramuscular injection. The results obtained were as follows. In the result of ocular irritation test, 0.16% solution of DA-3002 could be considered as a non-irritating material. In single subcutaneous and intramuscular irritation test, the irritancy of 0.16% DA-3002 solution was not so much different from that of saline. The local irritation of DA-3002 by 7-day repeated injection was negligible and similar to that of saline by both subcutaneous and intramuscular routes. These results suggest that DA-3002 has no irritating activity when injected through subcutaneous or intramuscular route for clinical practice as 0.16% solution.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.1
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• pp.1-9
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• 2012

Because the average human life span has recently increased, the number of patients who are diagnosed with neurodegenerative diseases has escalated. Recent advances in stem cell research have given us access to unlimited numbers of multi-potent or pluripotent cells for screening for new drugs for neurodegenerative diseases. Neural stem cells (NSCs) are a good model with which to screen effective drugs that increase neurogenesis. Recent technologies for human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) can provide human cells that harbour specific neurodegenerative disease. This article discusses the use of NSCs, ESCs and iPSCs for neurodegenerative drug screening and toxicity evaluation. In addition, we introduce drugs or natural products that are recently identified to affect the stem cell fate to generate neurons or glia.