Role of CYP2E1 in Hepatocarcinogenesis and Hepatotoxicity

Jin Seok Kang(강진석) 한국실험동물학회 2008 한국실험동물학회 학술발표대회 논문집 Vol.2008 No.-

CYP2E1 metabolize many low-molecular-weight toxins and carcinogens, such as N-nitrosamines, benzene, acetaminophen and carbon tetrachloride. Roles of CYP2E1 in diethylnitrosoamine (DEN)-mediated carcinogenesis and in thioacetamide (TAA)-induced hepatotoxicity are not fully understood in vivo. To clarify this, we carried out DEN-induced hepatocarcinogenesis and TAA-induced hepatotoxicity test using CYP2E1-null mice. For liver carcinogenesis, male wild-type and CYP2E1-null mice were treated with DEN at 14-day of age, and were sacrificed at weeks 24 and 36 for investigation of tumors and at 6 h, days 1 and 2 for examination of apoptosis and its relating genes after DEN treatment. Liver weight of wild-type mice significantly different compared to that of CYP2E1-null mice at weeks 24 and 36 (p<0.01). Liver tumor incidence of CYP2E1-null mice significantly decreased compared to that of wild-type mice (p<0.01), and tumor multiplicities were also significantly decreased compared to wild mice at weeks 24 and 36 (p<0.05, p<0.01, respectively). In short-term study, apoptotic index, caspase-3 mRNA and Bax mRNA of CYP2E1-null mice were significantly different compared to those of wild-type mice (p<0.05). For liver toxicity, male wild-type and CYP2E1-null mice were treated with TAA (200 mg/kg of body weight, single, i.p.) at 6 weeks of age, and toxicity examined 24 and 48 h after TAA treatment. Relative liver weights of CYP2E1-null mice were significantly different at 24 h compared to wild-type mice (p<0.01). Serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase in CYP2E1-null mice were significantly different at both time points compared to wild-type mice (p<0.01). Histopathological examination showed CYP2E1-null mice represented no hepatototoxic lesions, in clear contrast to severe centriobular necrosis, inflammation and hemorrhage at both time points in wild-type mice. Marked lipid peroxidation was only limited to wild-type mice (p<0.01). Similarly, TNF-α, IL-6 and glutathione peroxidase mRNA expression in CYP2E1-null mice did not significantly differ from the control levels, contrasting with the marked alteration in wild-type mice (p<0.01). Western blot analysis further revealed no increase in iNOS expression in CYP2E1-null mice. Taken together, we conclude CYP2E1-null mice show lower tumor incidence and multiplicity in DEN-induced hepatocarcinogenesis and no acute damage in TAA-induced hepatotoxicity compared to wild-type mice. And it suggests high frequency of tumors in wild-type mice could be associated with the increase of apoptosis in early time, and severe hepatic damage could be associated with increased oxidative stress.

MICE 참가자 여객운송 담당 항공사 직원의 직무스트레스와 역할갈등에 관한 연구

정유림 ( Yu Rim Jeong ),홍성화 ( Sung Hwa Hong ) (사)한국마이스관광학회(구 한국컨벤션학회) 2012 MICE관광연구 Vol.12 No.2

This research is intended to show that what is needed to strengthen the competitiveness by researching of work stress and work conflict occurred when airline staff members servers MICE participants. This study assume that airline staffs will feel differently when the staffs transport MICE participants and when they transport normal passengers. The result shows that airline CORP needs to make a place for a rest especially for women and more time for a refresh, compensation for employees who has long years of services, and specific segmentation of roles of their work. Another point in this study suggests that developing formal manual which helps airline staff MICE participants who visit JEJU island. Study also shows that perception of individual`s understanding of MICE industry generates work stress and when there is no exact work guideline for airline staff, this also makes work conflict. For this reason, airline staff needs to be trained by education program which is intended to staff to full understand of MICE industry, and airline CORP needs to allocate proper amount of works and to classify works for airline staff. In the transporting of MICE participants, airline staff shows different work stress and work conflict so the airline CORP should consider how to reduce this damages occurred to airline staff so they can minimize employment separation rate, and through this way, they can also expect that regain of their productivity and satisfaction of work environment.

Effect of cold stress on infanticide by female Swiss albino mice Mus musculus: a pilot study

( Tabassum Zafar ),( Ab Qayoom Naik ),( Vinoy K. Shrivastava ) 한국축산학회 2018 한국축산학회지 Vol.60 No.4

Background: Mice are widely accepted research models of great clinical significance. Maintenance of laboratory mice breed is an essential aspect for performing research activities in various fields of science. Infanticide is one of the prominent causes of litter loss during maintenance of laboratory mice stock. The present study is an effort to monitor the effect of change in ambient temperature of female mice below the normal range on cannibalism and infanticide during early postparturition phase. Adult female Swiss albino mice have been divided into two groups of control and treatment. On the day of litter group one was maintained under controlled temperature conditions (minimum 20 °C to maximum 23 °C) throughout, while female mice belong to group two have been exposed to variation of room temperature (maximum 15 °C to minimum 10 °C for two nights and one day) until 36 h postparturition. Results: The effects of temperature changes were observed on the infanticide behaviour of dams along with the survival of pups in early postparturition phase till 36 h after delivery. The significant statistical difference (P < 0.05) was reported in infanticide behaviour of dams when control and treatment group was compared. It is observed that decrement in surrounding temperature promotes decrement in the ambient body temperature of dams during early postparturition. It is proposed that alteration of hypothalamic homeostasis due to temperature change induces cannibalism and infanticide behaviour. Lack of thermoregulation during early postparturition creates the sense of insecurity, in-satiety, anxiety and stress. Conclusions: Authors strongly recommend the maintenance of body and surrounding temperature to prevent infanticidal behaviour and cannibalism within Swiss albino mice population. Further investigations are advisable to authenticate the active behavioural and biochemical pathway behind the phenomena.

Effects of Gamisoyosan on In Vitro Fertilization and Ovulation of Stressed Mice by Electric Shock

김지연,Dong Hoon Kwak,Eun Jin Ju,Sung Min Kim,Dae Hoon Lee,Kyung Su Keum,Seo Ul Lee,Kyu Yong Jung,Byoung Bu Seo,Young Kug Choo 대한약학회 2004 Archives of Pharmacal Research Vol.27 No.11

Exposure to stress is known to precipitate or exacerbate many reproductive dysfunctions such as dysmenorrhea and infertility. Abnormalities of the reproductive system, as shown by reduced ovulation, fertilization and early embryonic development, are frequently seen in dysmenorrhea and infertility. It has been generally accepted that Gamisoyosan (GSS) is a useful prescription for treating insomnia, dysmenorrhea and infertility induced by a stress. Also GSS has been used traditionally to improve systemic circulation and biological energy production. Based on these, this study investigates whether GSS improved ovarian dysfunction caused by stress in mice. Mice were subjected to stress by electric shock on the foot for 30 min daily for a week and treated with GSS at 500 / body weight per day for one week. Thereafter, changes body weight, adrenal weight, ovulation rate, in vitro and in vivo fertilization, embryonic development and estradiol concentrations were measured. GSS markedly increased the body weight of mice with stress, but not normal mice. The administration of GSS caused a reduction in adrenal weight in stressed mice. GSS also had significant positive effects on ovulation rate, estradiol production, in vivo and in vitro fertilization rates and embryonic development. These results indicate that GSS can improve the reproductive dysfunctions caused by stress, and these may production biological energy.

Comparative analysis of restraint stress-induced depressive-like phenotypes in C57BL/6N mice derived from three different sources

황동주,권기천,황대연,서민수,김길수,정영석,조준용 한국실험동물학회 2020 Laboratory Animal Research Vol.36 No.3

C57BL/6NKorl mice are a novel mouse stock recently developed by the National Institute of Food and Drug Safety Evaluation in Korea. Extensive research into the nature of C57BL/6NKorl mice is being conducted. However, there is no scientific evidence for the phenotypic response to restraint stress (RST), a stress paradigm for modeling depressive disorders, in rodents. In this study, we investigated the repeated RST-induced depressive-like phenotypes in C57BL/6 N mouse substrains (viz., C57BL/6NKorl mice from Korea, C57BL/6NA mice from the United States, and C57BL/6NB mice from Japan) obtained from different sources. The results showed that C57BL/6 N mice derived from various sources exposed to repeated RST resulted in depressive-like phenotypes reflected by a similar degree of behavioral modification and susceptibility to oxidative stress in a duration-dependent manner, except for the distinctive features (increased body weight (BW) and tolerance to the suppression of BW gain by exposure to repeated RST) in C57BL/6NKorl mice. Taken together, the duration-dependent alteration in depressive-like phenotypes by repeated exposure to RST observed in this study may provide valuable insights into the nature of C57BL/6NKorl mice as an alternative animal resource for better understanding of the etiology of depressive disorders and the mechanisms of antidepressant actions.

Effects of Gamisoyosan on In Vitro Fertilization and Ovulation of Stressed Mice by Electric Shock

Kim, Ji-Yeun,Kwak, Dong-Hoon,Ju, Eun-Jin,Kim, Sung-Min,Lee, Dae-Hoon,Keum, Kyung-Su,Lee, Seo-Ul,Jung, Kyu-Yong,Seo, Byoung-Bu,Choo, Young-Kug The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.11

Exposure to stress is known to precipitate or exacerbate many reproductive dysfunctions such as dysmenorrhea and infertility. Abnormalities of the reproductive system, as shown by reduced ovulation, fertilization and early embryonic development, are frequently seen in dysmenorrhea and infertility. It has been generally accepted that Gamisoyosan (GSS) is a useful prescription for treating insomnia, dysmenorrhea and infertility induced by a stress. Also GSS has been used traditionally to improve systemic circulation and biological energy production. Based on these, this study investigates whether GSS improved ovarian dysfunction caused by stress in mice. Mice were subjected to stress by electric shock on the foot for 30 min daily for a week and treated with GSS at 500 / body weight per day for one week. Thereafter, changes body weight, adrenal weight, ovulation rate, in vitro and in vivo fertilization, embryonic development and estradiol concentrations were measured. GSS markedly increased the body weight of mice with stress, but not normal mice. The administration of GSS caused a reduction in adrenal weight in stressed mice. GSS also had significant positive effects on ovulation rate, estradiol production, in vivo and in vitro fertilization rates and embryonic development. These results indicate that GSS can improve the reproductive dysfunctions caused by stress, and these may production biological energy.

Strain Differences in the Chronic Mild Stress Animal Model of Depression and Anxiety in Mice

( Yang Hee Jung ),( Sa Ik Hong ),( Shi Xun Ma ),( Ji Young Hwang ),( Jun Sup Kim ),( Ju Hyun Lee ),( Jee Yeon Seo ),( Seok Yong Lee ),( Choon Gon Jang ) 한국응용약물학회 2014 Biomolecules & Therapeutics(구 응용약물학회지) Vol.22 No.5

Chronic mild stress (CMS) has been reported to induce an anhedonic-like state in mice that resembles some of the symptoms of human depression. In the present study, we used a chronic mild stress animal model of depression and anxiety to examine the responses of two strains of mice that have different behavioral responsiveness. An outbred ICR and an inbred C57BL/6 strain of mice were selected because they are widely used strains in behavioral tests. The results showed that the inbred C57BL/6 and outbred ICR mice were similarly responsive to CMS treatment in sucrose intake test (SIT) and open field test (OFT). However, the two strains showed quite different responses in forced swimming test (FST) and novelty-suppressed feeding (NSF) test after 3 weeks of CMS treatment. Only C57BL/6 mice displayed the depression- and anxiety-like behavioral effects in response to CMS treatment in FST and NSF test. Our results suggest that there are differences in responsiveness to CMS according to the different types of strain of mice and behavioral tests. Therefore, these results provide useful information for the selection of appropriate behavioral methods to test depression- and anxiety-like behaviors using CMS in ICR and C57BL/6 mice.

Betaine Alleviates Hypertriglycemia and Tau Hyperphosphorylation in db/db Mice

Ga-young Jung,Sae-Bom Won,Juhae Kim,Sookyoung Jeon,Anna Han,Young Hye Kwon 한국독성학회 2013 Toxicological Research Vol.29 No.1

Betaine supplementation has been shown to alleviate altered glucose and lipid metabolism in mice fed a high-fat diet or a high-sucrose diet. We investigated the beneficial effects of betaine in diabetic db/db mice. Alleviation of endoplasmic reticulum (ER) and oxidative stress was also examined in the livers and brains of db/db mice fed a betaine-supplemented diet. Male C57BL/KsJ-db/db mice were fed with or without 1% betaine for 5 wk (referred to as the db/db-betaine group and the db/db group, respectively). Lean non-diabetic db/+ mice were used as the control group. Betaine supplementation significantly alleviated hyperinsulinemia in db/db mice. Betaine reduced hepatic expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a major transcription factor involved in gluconeogenesis. Lower serum triglyceride concentrations were also observed in the db/db-betaine group compared to the db/db group. Betaine supplementation induced hepatic peroxisome proliferator-activated receptor alpha and carnitine palmitoyltransferase 1a mRNA levels, and reduced acetyl-CoA carboxylase activity. Mice fed a betaine-supplemented diet had increased total glutathione concentrations and catalase activity, and reduced lipid peroxidation levels in the liver. Furthermore, betaine also reduced ER stress in liver and brain. c-Jun N-terminal kinase activity and tau hyperphosphorylation levels were lower in db/db mice fed a betaine-supplemented diet, compared to db/db mice. Our findings suggest that betaine improves hyperlipidemia and tau hyperphosphorylation in db/db mice with insulin resistance by alleviating ER and oxidative stress.

Betaine Alleviates Hypertriglycemia and Tau Hyperphosphorylation in db/db Mice

Jung, Ga-Young,Won, Sae-Bom,Kim, Juhae,Jeon, Sookyoung,Han, Anna,Kwon, Young Hye Korean Society of ToxicologyKorea Environmental Mu 2013 Toxicological Research Vol.29 No.1

Betaine supplementation has been shown to alleviate altered glucose and lipid metabolism in mice fed a high-fat diet or a high-sucrose diet. We investigated the beneficial effects of betaine in diabetic db/db mice. Alleviation of endoplasmic reticulum (ER) and oxidative stress was also examined in the livers and brains of db/db mice fed a betaine-supplemented diet. Male C57BL/KsJ-db/db mice were fed with or without 1% betaine for 5 wk (referred to as the db/db-betaine group and the db/db group, respectively). Lean non-diabetic db/+ mice were used as the control group. Betaine supplementation significantly alleviated hyperinsulinemia in db/db mice. Betaine reduced hepatic expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a major transcription factor involved in gluconeogenesis. Lower serum triglyceride concentrations were also observed in the db/db-betaine group compared to the db/db group. Betaine supplementation induced hepatic peroxisome proliferator-activated receptor alpha and carnitine palmitoyltransferase 1a mRNA levels, and reduced acetyl-CoA carboxylase activity. Mice fed a betaine-supplemented diet had increased total glutathione concentrations and catalase activity, and reduced lipid peroxidation levels in the liver. Furthermore, betaine also reduced ER stress in liver and brain. c-Jun N-terminal kinase activity and tau hyperphosphorylation levels were lower in db/db mice fed a betaine-supplemented diet, compared to db/db mice. Our findings suggest that betaine improves hyperlipidemia and tau hyperphosphorylation in db/db mice with insulin resistance by alleviating ER and oxidative stress.

Amelioration of UVB-induced oxidative stress and inflammation in <i>fat-1</i> transgenic mouse skin

Yum, Hye-Won,Kim, Seong Hoon,Kang, Jing X.,Surh, Young-Joon Elsevier 2018 Biochemical and biophysical research communication Vol.502 No.1

<P><B>Abstract</B></P> <P>ω-3 polyunsaturated fatty acids (PUFAs), which are abundant in fish oils, are known to scavenge lipid peroxyl radicals and potentiate host immune defence. As UVB-induced oxidative stress and inflammation have been implicated in apoptotic cell death, this study was aimed to investigate the anti-inflammatory, anti-oxidative, and anti-apoptotic capacity of <I>fat-1</I> transgenic mice capable of converting ω-6 to ω-3 PUFAs. Wild-type (WT) C57BL/6 mice and <I>fat-1</I> mice were maintained on the AIN-93 diet supplemented with 10% safflower oil rich in ω-6 PUFAs for 5 weeks. The ω-3/ω-6 PUFA ratio was significantly higher in the dorsal skin of <I>fat-1</I> mice than that in the WT mice. Upon single exposure to UVB (5.0 kJ/m<SUP>2</SUP>) radiation, <I>fat-1</I> mice showed inflammatory as well as oxidative tissue damage and the expression of pro-inflammatory enzymes, cyclooxygenases-2 and inducible nitric oxide synthase in the skin to a much lesser extent than the WT mice. The protection of <I>fat-1</I> mice from UVB-induced skin inflammation was associated with decreased phosphorylation of STAT3. Moreover, UVB-induced apoptosis was attenuated in <I>fat-1</I> mouse skin. In comparison to WT animals, higher levels of Nrf2 and its target proteins, such as heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1 and thioredoxin-1, were found in the skin of <I>fat-1</I> mice.</P>