• Toxicological Research
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• 제32권1호
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• pp.73-80
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• 2016

Chronic exposure to cadmium (Cd) is known to adversely affect renal function. Our previous studies indicated that Cd induces p53-dependent apoptosis by inhibiting gene expression of the ubiquitin-conjugating enzyme (Ube) 2d family in both human and rat proximal tubular cells. In this study, the effects of Cd on protein expression of p53 and apoptotic signals in the kidney and liver of mice exposed to Cd for 12 months were examined, as well as the effects of Cd on p53 protein levels and gene expression of the Ube2d family in various cell lines. Results showed that in the kidney of mice exposed to 300 ppm Cd for 12 months, there was overaccumulation of p53 proteins in addition to the induction of apoptosis, which was triggered specifically in the proximal tubules. Interestingly, the site of apoptosis was the same as that of p53 accumulation in the proximal tubules. In the liver of mice chronically exposed to Cd, gene expression of the Ube2d family tended to be slightly decreased, together with slight apoptosis without the accumulation of p53 protein. In rat small intestine epithelial (IEC-6) cells, Cd decreased not only the p53 protein level but also gene expression of Ube2d1, Ube2d2 and Ube2d4. In human brain microvascular endothelial cells (HBMECs), Cd did not suppress gene expression of the Ube2d family, but increased the p53 protein level. In human brain astrocytes (HBASTs), Cd only increased gene expression of UBE2D3. These results suggest that Cd-induced apoptosis through p53 protein is associated with renal toxicity but not hepatic toxicity, and the modification of p53 protein by Cd may vary depending on cell type.

• Toxicological Research
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• 제32권1호
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• pp.57-64
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• 2016

Recently several studies reported that the renal toxicity of lead (Pb) and cadmium (Cd) may exist in even a low level exposure. In terms of the deterioration of tubular function, it affects the loss of divalent metals and leads to other complications, so renal tubular effect of heavy metals should be well managed. Considering the exposure to heavy metals in reality, it is hard to find the case that human is exposed to only one heavy metal. We designed a cross-sectional study using Korean Research Project on the Integrated Exposure Assessment (KRIEFS) data to investigate the renal effects of multiple metal exposure in general population. We used blood Pb and urinary Cd as exposure measures, and urinary N-acetyl-${\beta}$-D-glucosaminidase (NAG) and ${\beta}_2$-microglobulin (${\beta}_2$-MG) as renal tubular impairment outcome. We conducted linear regression to identify the association between each heavy metal and urinary NAG and ${\beta}_2$-MG. And then, we conducted linear regression including the interaction term. Of 1953 adults in KRIEFS (2010~2011), the geometric mean of blood Pb and urinary Cd concentration was $2.21{\mu}g/dL$ (geometric $SD=1.49{\mu}g/dL$) and $1.08{\mu}g/g\;cr$ (geometric $SD=1.98{\mu}g/g\;cr$), respectively. In urinary Cd, the strength of the association was also high after adjusting (urinary NAG: ${\beta}=0.44$, p < 0.001; urinary ${\beta}_2$-MG: ${\beta}=0.13$, p = 0.002). Finally, we identified the positive interactions for the two renal biomarkers. The interaction effect of the two heavy metals of ${\beta}_2$-MG was greater than that of NAG. It is very important in public health perspective if the low level exposure to multiple heavy metals has an interaction effect on kidney. More epidemiological studies for the interaction and toxicological studies on the mechanism are needed.

• Toxicological Research
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• 제30권1호
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• pp.7-11
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• 2014

Malondialdehyde (MDA), used as an oxidative stress marker, is commonly assayed by measuring the thiobarbituric acid reactive substances (TBARS) using HPLC, as an indicator of the MDA concentration. Since the HPLC method, though highly specific, is time-consuming and expensive, usually it is not suitable for the rapid test in large-scale environmental epidemiologic surveys. The purpose of this study is to develop a simple and rapid method for estimating TBARS levels by using a multiple regression equation that includes TBARS levels measured with a microplate reader as an independent variable. Twelve hour urine samples were obtained from 715 subjects. The concentration of TBARS was measured at three different wavelengths (fluorescence: ${\lambda}-_{ex}$ 530 nm and ${\lambda}-_{em}$ 550 nm; ${\lambda}-_{ex}$ 515 nm and ${\lambda}-_{em}$ 553 nm; and absorbance: 532 nm) using microplate reader as well as HPLC. 500 samples were used to develop a regression equation, and the remaining 215 samples were used to evaluate the validity of the regression analysis. The induced multiple regression equation is as follows: TBARS level (${\mu}M$) = -0.282 + 1.830 ${\times}$ (TBARS level measured with a microplate reader at the fluorescence wavelengths ${\lambda}-_{ex}$ 530 nm and ${\lambda}-_{em}$ 550 nm, ${\mu}M$) -0.685 ${\times}$ (TBARS level measured with a microplate reader at the fluorescence wavelengths ${\lambda}-_{ex}$ 515 nm and ${\lambda}-_{em}$ 553 nm, ${\mu}M$) + 0.035 ${\times}$ (TBARS level measured with a microplate reader at the absorbance wavelength 532 nm, ${\mu}M$). The estimated TBARS levels showed a better correlation with, and are closer to, the corresponding TBARS levels measured by HPLC compared to the values obtained by the microplate method. The TBARS estimation method reported here is simple and rapid, and that is generally in concordance with HPLC measurements. This method might be a useful tool for monitoring of urinary TBARS level in environmental epidemiologic surveys with large sample sizes.

• Toxicological Research
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• 제29권1호
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• pp.53-60
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• 2013

Studies on milk transfer of drugs in non-human primates (NHPs) are among the crucial components in the assessment of peri- and postnatal toxicity because of the similarity between NHPs and humans. To evaluate the milk transfer of valproic acid (VPA) in NHPs, the toxicokinetics of VPA, an antiepileptic drug, were studied in pregnant cynomolgus monkeys. VPA was administered once daily to pregnant cynomolgus monkeys at doses of 0, 30, 90, and 270 mg/kg by oral gavage from Day 100 of gestation (GD 100) to Day 31 of lactation (LD 31). Concentrations of VPA and its metabolite, 4-ene-VPA, in the maternal plasma on GD 100, GD 140, and LD 30, and concentrations of VPA and 4-ene-VPA in the offspring plasma and milk on LDs 30 and 31, respectively, were quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS). After administration of a single oral dose of VPA to pregnant monkeys on GD 100, the concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma of all treatment groups up to 24 hr after administration, which showed that VPA was absorbed and that the monkeys were systemically exposed to VPA and 4-ene-VPA. After administration of multiple doses of VPA to the monkeys, VPA was detected in the pup's plasma and in milk taken on LD 30 and LD 31, respectively, which showed that VPA was transferred via milk, and the pup was exposed to VPA. Further, the concentration of VPA in the milk increased with an increase in the dose. Extremely low concentrations of 4-ene VPA were detected in the milk and in the pup plasma. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at doses of 30, 90, and 270 mg/kg/day from GD 100 to LD 31. VPA was transferred via milk, and the VPA exposure to the pup increased with an increase in the dose of VPA. The metabolite, 4-ene VPA, was present in extremely low concentrations (< 0.5 ${\mu}g/ml$) in the milk and in the pup plasma. In this study, we established methods to confirm milk transfer in NHPs, such as mating and diagnosis of pregnancy by examining gestational sac with ultrasonography, collection of milk and pup plasma and determination of toxicokinetics, using cynomolgus monkeys.

• Toxicological Research
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• 제29권1호
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• pp.43-52
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• 2013

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium that are found in cereals and agricultural products. ZEN has been implicated in mycotoxicosis in farm animals and in humans. The toxic effects of ZEN are well known, but the ability of an alkaline Comet assay to assess ZEN-induced oxidative DNA damage in Chang liver cells has not been established. The first aim of this study was to evaluate the Comet assay for the determination of cytotoxicity and extent of DNA damage induced by ZEN toxin, and the second aim was to investigate the ability of N-acetylcysteine amide (NACA) to protect cells from ZEN-induced toxicity. In the Comet assay, DNA damage was assessed by quantifying the tail extent moment (TEM; arbitrary unit) and tail length (TL; arbitrary unit), which are used as indicators of DNA strand breaks in SCGE. The cytotoxic effects of ZEN in Chang liver cells were mediated by inhibition of cell proliferation and induction of oxidative DNA damage. Increasing the concentration of ZEN increased the extent of DNA damage. The extent of DNA migration, and percentage of cells with tails were significantly increased in a concentration-dependent manner following treatment with ZEN toxin (p < 0.05). Treatment with a low concentration of ZEN toxin (25 ${\mu}M$) induced a relatively low level of DNA damage, compared to treatment of cells with a high concentration of ZEN toxin (250 ${\mu}M$). Oxidative DNA damage appeared to be a key determinant of ZEN-induced toxicity in Chang liver cells. Significant reductions in cytolethality and oxidative DNA damage were observed when cells were pretreated with NACA prior to exposure to any concentration of ZEN. Our data suggest that ZEN induces DNA damage in Chang liver cells, and that the antioxidant activity of NACA may contribute to the reduction of ZEN-induced DNA damage and cytotoxicity via elimination of oxidative stress.

• Toxicological Research
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• 제29권1호
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• pp.21-25
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• 2013

The selective targeting of an integrin ${\alpha}_v{\beta}_3$ receptor using radioligands may enable the assessment of angiogenesis and integrin ${\alpha}_v{\beta}_3$ receptor status in tumors. The aim of this research was to label a peptidomimetic integrin ${\alpha}_v{\beta}_3$ antagonist (PIA) with $^{99m}Tc(CO)_3$ and to test its receptor targeting properties in nude mice bearing receptor-positive tumors. PIA was reacted with tris-succinimidyl aminotriacetate (TSAT) (20 mM) as a PIA per TSAT. The product, PIA-aminodiacetic acid (ADA), was radiolabeled with $[^{99m}Tc(CO)_3(H_2O)_3]^{+1}$, and purified sequentially on a Sep-Pak C-18 cartridge followed by a Sep-Pak QMA anion exchange cartridge. Using gradient C-18 reverse-phase HPLC, the radiochemical purity of $^{99m}Tc(CO)_3$-ADA-PIA (retention time, 10.5 min) was confirmed to be > 95%. Biodistribution analysis was performed in nude mice (n = 5 per time point) bearing receptor-positive M21 human melanoma xenografts. The mice were administered $^{99m}Tc(CO)_3$-ADA-PIA intravenously. The animals were euthanized at 0.33, 1, and 2 hr after injection for the biodistribution study. A separate group of mice were also co-injected with 200 ${\mu}g$ of PIA and euthanized at 1 hr to quantify tumor uptake. $^{99m}Tc(CO)_3$-ADA-PIA was stable in phosphate buffer for 21 hr, but at 3 and 6 hr, 7.9 and 11.5% of the radioactivity was lost as histidine, respectively. In tumor bearing mice, $^{99m}Tc(CO)_3$-ADA-PIA accumulated rapidly in a receptor-positive tumor with a peak uptake at 20 min, and rapid clearance from blood occurring primarily through the hepatobiliary system. At 20 min, the tumor-to-blood ratio was 1.8. At 1 hr, the tumor uptake was 0.47% injected dose (ID)/g, but decreased to 0.12% ID/g when co-injected with an excess amount of PIA, indicating that accumulation was receptor mediated. These results demonstrate successful $^{99m}TC$ labeling of a peptidomimetic integrin antagonist that accumulated in a tumor via receptor-specific binding. However, tumor uptake was very low because of low blood concentrations that likely resulted from rapid uptake of the agent into the hepatobiliary system. This study suggests that for $^{99m}Tc(CO)_3$-ADA-PIA to be useful as a tumor detection agent, it will be necessary to improve receptor binding affinity and increase the hydrophilicity of the product to minimize rapid hepatobiliary uptake.

• 대한통합의학회지
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• 제8권3호
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• pp.181-188
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• 2020

Purpose : The purpose of this study is to compare the effects on abdominal muscle thickness and breathing by applying trunk strength exercise and deep stabilization exercise along with breathing exercise, which is the main respiratory muscle during breathing, to present an efficient exercise method with diaphragm breathing. Methods : This study was performed on normal 6 females and 14 males subjects. They were divided into 2 groups which trunk strength exercise and deep stabilization exercise group. The trunk strength exercise group (TSE) attended prone press-up, crunch and pelvic tiling. The deep stabilization exercise group (DSE) attended abdominal drawing, horizontal side-support and bridging exercise. Breathing exercise was performed for each set break time for 1 minute. Results : First, in the comparison of the change in the thickness of the abdominal muscle between the trunk strength training group and the deep stabilization group before and after exercise, there was a statistically significant difference in the comparison of transverse abdominis (TrA), rectus femoris (RF), external oblique (EO), internal oblique (IO) (p<.05). However, there was no significant difference in any comparison between groups (p>.05). Second, in the comparison of changes in respiratory function between the trunk strength exercise group and the deep stabilization exercise group before and after exercise, there were statistically significant differences in the exerted forced vital capacity (FVC), forced expiratory volume at one second (FEV₁), peak expiratory flow (PEF) in the comparison before and after the experiment (p<.05). However, there was no significant difference in any comparison between groups (p>.05). Conclusion : As a result of this study, it can be said that both trunk strength exercises and deep stabilization exercises along with diaphragm breathing are exercises that strengthen deep and superficial muscles, and have a positive effect on breathing function as well as muscle strength. However, it is not known which exercise was more effective, and because it was combined with breathing exercise, the interference effect appeared.

• 생명과학회지
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• 제21권3호
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• pp.400-405
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• 2011

Autophagy는 항상성 유지와 스트레스반응을 효율적으로 조정하기 위해 필수적인 세포 내 질적 조절작용이다. 노화가 진행되는 동안 autopahgy에 의한 degradation 효율성 저하와 그로 인한 세포 내 부산물의 축적이 증가하여 결국, 근육의 약화를 초래한다. 그러므로 본 연구의 목적은 골격근에서 운동에 의한 autopahgy 관련 단백질의 변화를 규명하는데 있다. 이를 위해 24마리의 Young 그룹과 Old 그룹을 나누어 각각 대조군(n=6)과 운동군(n=6)으로 배정하였다. 운동은 8주간 주 5회 실시하였고, 트레드밀 속도 16.4 m/min와 경사도 4%로 설정하여 40분간 지속적인 운동을 실시하였다. autopahgy 관련 단백질에 대한 검증 결과 Young 그룹과 비교하여 Old 그룹에서 LC3-1, Beclin-1, Atg7은 모두 유의하게 감소하였다. 그러나 8주간의 규칙적인 운동에 의하여 autophagy 관련 단백질은 증가하는 것으로 나타났다. 따라서 노화에 의해 약화된 autopahgy 기능은 규칙적인 운동에 의해 개선될 수 있을 것으로 사료된다.

• 한국의학물리학회지:의학물리
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• 제13권4호
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• pp.224-228
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• 2002

MR영상에 Spatial Modulation of Magnetization (SPAMM)과 같은 lagging 기법을 이용하여 심근의 움직임을 분석하여 임상에 적용하려는 많은 노력들이 이루어지고 있다. Tagging 대조도는 자동 tagline 검출 알고리즘을 사용하는 경우, 그 정확도에 영향을 미칠 수 있으며, 이는 tagline들 간의 간격에 의해 영향을 받을 수 있다. 본 연구의 목적은 SPAMM 영상에서 tagline 간격과 tagging 대조도와의 관계를 생체내 연구를 통해 알아보고자 하였다. 두 명의 건강한 지원자를 대상으로 1.5T MR 시스템에서 SPAMM 기반의 ECG triggered MR 영상을 획득하였다. 영상을 획득할 때, 먼저 3.6 mm에서 9.6 mm 사이의 간격을 가지는 수평 tagging stripe pattern의 tagline을 가하였다. 심실의 영상은 심장주기가 진행되는 동안 field echo EPI (FE-EPI) 기법을 이용하여 심실 중간 부분에서 얻었다 각 영상에 대한 tagging contrast-to-noise ratio (CNR)는 IDL을 이용한 프로그램을 사용하여 측정하였다. 분석 결과는, 심근의 수축이 진행되는 동안, tagline 간격이 좁은 경우 CNR은 급격한 감소를 나타내었으나, 간격이 넓은 경우에서는 CNR 감소 현상이 보이지 않았다. 같은 심장 위상에서, CNR은 tagline 간격이 넓어짐에 따라 증가하는 경향을 보였다. 특히, 완전히 수축한 심장 위상에서는, CNR의 변화가 다른 위상일 때와 비교해서 그 증가율이 높음을 알 수 있었다. 이러한 양상은 움직임이 없는 다른 주변 조직에서는 관찰되지 않았다. 결론적으로, 본 연구에서는 lagging 대조도가 tagline 간격 및 심근의 수축에 영향을 받을 수 있음을 알 수 있었으며, 앞으로 정확한 심근 움직임 연구를 위한 기초 자료로 쓰여질 수 있을 것이라 생각된다.

• 한국임상수의학회지
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• 제29권5호
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• pp.416-421
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• 2012

10살령의 4 kg 암컷 치와와가 심한 울혈성심부전의 수술적 치료를 위해서 내원하였다. 여러 가지 진단을 통해 이 환자는 심한 이첨판 폐쇄부전과 중등도의 삼천판 폐쇄부전이 확인되었다. 약물에 대한 치료적인 반응이 여의치 않아, 수술적으로 이첨판을 교정하는 치료방법으로 지시되었다. 체외순환을 이용한 심폐순환기하에서 이첨판교정술이 실시되었다. 하지만 이 환자는 교정 후에 마취에서 회복되지 못하고 사망하였다. 심장수술에 있어 실패를 유발하는 여러 가지 원인들에는 심폐순환기 운용, 저체온증, 장기부전, 출혈, 저혈압, 전해질과 산-염기 불균형, 그리고 감염 등이 있다. 비록 이 환자는 사망하였지만, 그 원인을 밝혀 내는 일은 수의학 분야에서 중요한 일이다. 이 증례의 사망원인을 고찰해 본 결과, 심한 저체온증에 의한 가스환기와 산소공급의 이상 그리고 심장수술과 관련한 저심박출량 증후군으로 인한 낮은 심박동수를 동반한 저혈압으로 사망한 것으로 생각되었다. 이 증례의 원인 규명을 위한 고찰은 이첨판성형술의 성공을 위해서는 좀더 세심한 주의가 요구됨을 알 수 있게 해주었고, 나아가 앞으로의 수술에서 성공률을 높일 수 있는 중요한 계기가 될 것이다.