• The Korean Journal of Physiology and Pharmacology
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• v.22 no.6
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• pp.607-616
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• 2018

The effect of melatonin on juveniles with cardio fibrosis is poorly understood. We investigated whether HDACs participate in the anti-fibrotic processes regulated by melatonin during hypertrophic remodeling. Abdominal aortic constriction (AAC) was employed in juvenile rats resulting in pressure overload-induced ventricular hypertrophy and melatonin was subsequently decreased via continuous light exposure for 5 weeks after surgery. AAC rats displayed an increased cross-sectional area of myocardial fibers and significantly elevated collagen deposition compared to sham-operated rats, as measured by HE and Masson Trichrome staining. Continuous light exposure following surgery exacerbated the increase in the cross-sectional area of myocardial fibers. The expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 genes were all significantly enhanced in AAC rats with light exposure relative to the other rats. Moreover, the protein level of $TNF-{\alpha}$ was also upregulated in the AAC light exposure groups when compared with the sham. However, Smad4 protein expression was unchanged in the juveniles' hearts. In contrast, beginning 5 weeks after the operation, the AAC rats were treated with melatonin (10 mg/kg, intraperitoneal injection every evening) or vehicle 4 weeks, and sham rats were given vehicle. The changes in the histological measures of cardio fibrosis and the gene expressions of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 were attenuated by melatonin administration. The results reveal that melatonin plays a role in the development of cardio fibrosis and the expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 in cardiomyocytes.

• IMMUNE NETWORK
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• v.3 no.3
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• pp.211-218
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• 2003

Background: Vitamin C is an essential nutrient, taken as a daily supplement by many people. Recently, high-dose vitamin C is considered as a therapeutic regimen in some clinical situations. Until now, few studies have been done with the effects of high-dose vitamin C on the immune response. Methods: In this experiment, the effects of high-dose vitamin C on cell-mediated immune response in immunologically competent mice were evaluated. After intraperitoneal injection of 2.5, 5, or 10 mg/day of vitamin C for 10 days, delayed type hypersensitivity (DTH) was provoked against DNFB in the pinnae as a model for cell-mediated immune response. Severity of DTH reaction was evaluated as the thickness of pinnae, and the vitamin C levels were measured in the serum, liver, kidney, lung, pinnae, and splenocytes. Results: After challenge, the thickness increased at its peak on the $2^{nd}$ day in all groups. On the first day, the pinnae were thicker in the injected groups than in the control. On the contrary, the increment of the pinnae thickness was attenuated and the number of cells infiltrated in the site of DTH decreased proportionately to the amount of vitamin C administered from the second day on. With vitamin C exogenously given, the serum level peaked at 30 min after injection, and returned abruptly to its basal level without accumulation. However, it accumulated in the liver, kidney, and especially in the pinnae inflamed and splenopcytes, proportionately to the amount administered. Conclusion: Based on these results, it is suggested that, in one hand, exogenously administered high-dose vitamin C accumulated in the splenocytes and presumably changed the function of them resulting in the augmented cell-mediated immune response, as was revealed in the first day of DTH reaction. On the other hand, it seems likely that the vitamin C also showed anti-inflammatory effects.

• YAKHAK HOEJI
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• v.35 no.2
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• pp.99-110
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• 1991

This study was initiated to investigate the effects of organic germanium on cadmium and mercury intoxication. The effect was determined by the metallothionein induction in liver and kidney. Male rats (Sprague-Dawley) were treated with CdCI$_{2}$ (2mg/kg), HgCI$_{2}$ (1 mg/kg) and organic germanium (GE-132) (100 mg/kg) in single and in combination via intraperitoneal injection or intragastric administration every other days for 17 days. Experimental animals were sacrificed after 7, 12 and 17 days treatment. The serum transaminase activities (SGOT, SGPT), concentration of metal and metallothionein, metal-binding capacity of metallothionein in liver and kidney were determined and pathomorphological observations were undertaken. The combined treatment of GE-132 and CdCI$_{2}$ significantly decreased the increment of serum transaminase activities in rats treated with CdCI$_{2}$ only, but the combined treatment of GE-132 and HgCI$_{2}$ did not affect to activities of transaminases induced by mercury only. The concentration of metals (Cd and Hg) except Ge in the liver and kidney of rats increased with the time of treatment. Mercury concentration in kidney of rat treated with HgCI$_{2}$ only was significantly higher than the combined treatment of GE-132 and HgCI$_{2}$. The combined treatment of GE-132 and CdCI$_{2}$ significantly increased the concentration of metallothionein in liver compared to the CdCI$_{2}$ only, although the concentration of cadmium in liver were not significantly different between two groups. This indicates that GE-132 decreased toxicity of cadmium in liver by promoting metallothionein induction. There were no significant differences in metallothionein concentration in liver and kidney of rats between the combined treatment of GE-132 and HgCI$_{2}$ and HgCI$_{2}$ only. Metal-binding capacity of metallothionein varied with each time intervals in liver and kidney of metals treated rats except the liver of the combined treatment of GE-132 and CdCI$_{2}$. This finding explains the concentration of metallothionein in liver keeps abreast with the concention of metal. Furthermore, the combined treatment of GE-132and CdCl$_{2}$ revealed pathologically less changes in liver tissue than CdCl$_{2}$ only; the damages of liver cell, such as lobular necrosis and portal inflammation, were relieved and appeared more later. From the above results, organic germanium is considered to have some beneficial effect on the protection of liver from the cadmium intoxication.

• Journal of the Korean Society of Food Science and Nutrition
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• v.33 no.1
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• pp.218-221
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• 2004

This study was performed to investigate the effect of rosiglitazone, a new antidiabetic agent, on in vivo synthesis of bone collagen. The mice were divided into low-fat diet group (LF), high-fat diet group (HF), and high-fat diet with rosiglitazone (6.3 $\mu\textrm{g}$/kcal diet) group (HF-Rosi), The synthesis of bone collagen was measured by stable isotope-mass spectrometric technique using $^2$$H_2O$ as a tracer. The $^2$$H_2O$ labeling protocol consisted of an initial intraperitoneal injection of 99.9% $^2$$H_2O$, to achieve approximately 2.5% body water enrichment followed by administration of 4％ $^2$$H_2O$ in drinking water for 3 weeks. Although body weight gain and daily diet intake were not significantly different between groups, HF-Rosi had slightly higher body weight gain and daily diet intake than LF and HF. In addition, HF-Rosi showed significantly higher body fat content than LF and HF. Bone collagen synthesis was reduced in HF than LF and further decreased by the treatment of rosiglitazone. These results suggest rosiglitazone affect body fat content and bone turnover in mice.

• Journal of Korean Biological Nursing Science
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• v.4 no.2
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• pp.19-40
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• 2002

The purpose of this study was to determine the effect of DHEA on Type I(soleus) and II muscles(plantaris, gastrocnemius) in a focal brain ischemia model rat. Thirty-seven male Sprague-Dawley rats with $200{\sim}250g$ body weights were randomly divided into four groups : CINS(cerebral ischemia + normal saline), CIDH(cerebral ischemia + DHEA), SHNS(sham + normal saline), SHDH (sham + DHEA). Both the CINS and CIDH groups were undergone a transient right middle cerebral artery occlusion operation. In the SHNS and SHDH groups, a sham operation was done. DHEA was administered daily at a dose of 0.34mmol/kg, and normal saline was administered daily at the same dose by intraperitoneal injection for 7days after operation. Cerebral infarction in the CINS and CIDH groups was identified by staining with 2% triphenyltetrazolium chloride solution for 60 minutes. The data were analyzed by Kruskal-Wallis test and Mann-Whitney U test using the SPSSWIN 9.0 program. The results were summarized as follows: 1) The muscle weights of soleus(Type I), plantaris and gastrocnemius(Type II) in CINS group were significantly less than those of the SHNS group(p<.01). The muscle fiber cross-sectional area of the CINS group was significantly less than that of the SHNS group in Type I muscle fiber of the soleus and Type II muscle fiber of the plantaris and gastrocnemius(p<.05). The myofibrillar protein content of the CINS group was significantly less than that of the SHNS group in the left gastrocnemius and right soleus(p<.05). 2) The muscle weights of the soleus, plantaris and gastrocnemius except the unaffected side of the plantaris in the CIDH significantly increased compared to those of the CINS group(p<.05). The muscle fiber cross-sectional area of the CIDH group significantly increased compared to that of the CINS group in Type II muscle fiber of the plantaris and gastrocnemius(p<.05). The myofibrillar protein content of the CIDH group significantly increased compared to that of the CINS group in the left soleus(p<.05). 3) On the post-op 8 day, the body weight of the CINS group was significantly less than that of the CIDH, SHNS and SHDH groups(p<.01). Total diet intake of the CINS and CIDH groups was significantly less than that of the SHNS and SHDH groups(p<.01). Based on these results, it was identified that muscle atrophy could be induced during the 7 days after cerebral infarction, and DHEA administration during the early stage of cerebral infarction might attenuate muscle atrophy.

• Clinical and Experimental Pediatrics
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• v.52 no.1
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• pp.105-110
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• 2009

Purpose : Perinatal asphyxia is an important cause of neonatal mortality and subsequent lifelong neurodevelopmental handicaps. Although many treatment strategies have been tested, there is currently no clinically effective treatment to prevent or reduce the harmful effects of hypoxia and ischemia in humans. Erythropoietin (Epo) has been shown to exert neuroprotective effects in various brain injury models although the exact mechanisms through which Epo functions are not completely understood. This study investigates the effect of Epo on hypoxic-ischemic (HI) brain injury and the possibility that its neuroprotective actions may be associated with iron-mediated metabolism. Methods : HI brain injury was produced in 7-day-old rats by unilateral carotid artery ligation followed by hypoxia with 8% oxygen for 2 h. At the end of HI brain injury, the rats received an intraperitoneal injection of 5,000 units/kg erythropoietin. Random premedication with iron, deferoxamine, iron-deferoxamine, or saline were performed 23 d before HI brain injury. The severity of the brain injury was assessed at 7 d after HI. Results : Single Epo treatment post-HI brain injury reduced the gross and histopathological findings of brain injury. Iron premedication did not increase the incidence or severity of the injury as measured by the damage score. Deferoxamine administration before HI brain injury improved the brain injury as compared to no treatment or Epo treatment. Conclusion : These findings indicate that Epo provides neuroprotective benefits after HI in the developing brain. These findings suggest that Epos neuroprotective actions may involve reducing iron in tissues that mediate the formation of free radicals.

• Asian-Australasian Journal of Animal Sciences
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• v.28 no.12
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• pp.1784-1793
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• 2015

This study was carried out to investigate the effects of tributyrin (TB) on the growth performance, pro-inflammatory cytokines, intestinal morphology, energy status, disaccharidase activity, and antioxidative capacity of broilers challenged with lipopolysaccharide (LPS). A total of 160 one-day-old Cobb broilers were allocated to 1 of 4 treatments, with 4 replicated pens per treatment and 10 birds per pen. The experiment consisted of a $2{\times}2$ factorial arrangements of treatments with TB supplementation (0 or 500 mg/kg) and LPS challenge (0 or $500{\mu}g/kg$ body weight [BW]). On days 22, 24, and 26 of the trial, broilers received an intraperitoneal administration of $500{\mu}g/kg$ BW LPS or saline. Dietary TB showed no effect on growth performance. However, LPS challenge decreased the average daily gain of broilers from day 22 to day 26 of the trial. Dietary TB supplementation inhibited the increase of interleukin-$1{\beta}$ (in the jejunum and ileum), interleukin-6 (in the duodenum and jejunum), and prostaglandin $E_2$ (in the duodenum) of LPS-challenged broilers. Similar inhibitory effects of TB in the activities of total nitric oxide synthase (in the ileum) and inducible nitric oxide synthase (in the jejunum) were also observed in birds challenged with LPS. Additionally, TB supplementation mitigated the decrease of ileal adenosine triphosphate, adenosine diphosphate and total adenine nucleotide and the reduction of jejunal catalase activity induced by LPS. Taken together, these results suggest that the TB supplementation was able to reduce the release of pro-inflammatory cytokines and improve the energy status and anti-oxidative capacity in the small intestine of LPS-challenged broilers.

• Toxicological Research
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• v.24 no.4
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• pp.263-271
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• 2008

Recently we reported that 2-bromopropane (2-BP) has maternal toxicity, embryotoxicity, and teratogenicity in Sprague-Dawley rats. The aims of this study are to examine the potential effects of 2-BP administration on pregnant dams and embryo-fetal development, and to investigate the effects of metabolic activation induced by phenobarbital (PB) on developmental toxicities of 2-BP. Pregnant rats received 1000 mg/kg/day subcutaneous 2-BP injections on gestational days (GD) 6 through 10 (Group II and Group IIII) or 11 through 15 (Group IV). Pregnant rats in Group III received an intraperitoneal PB injection once daily at 80 mg/kg/day on GD 3 through 5 for induction of the liver metabolic enzyme system. Control rats received vehicle injections only on GD 6 through 15. All dams underwent caesarean sections on GD 20 and their fetuses were examined for external, visceral, and skeletal abnormalities. Significant adverse effects on pregnant dams and embryo-fetal development were observed in all the treatment groups, and the maternal and embryo-fetal effects of 2-BP observed in Group II were higher than those seen in Group IV. Conversely, maternal and embryo-fetal developmental toxicities observed in Group III were comparable to those seen in Group II. These results suggest that the potential effects of 2-BP on pregnant dams and embryo-fetal development are more likely in the first half of organogenesis (days $6{\sim}10$ of pregnancy) than in the second half and that the metabolic activation induced by PB pre-treatment did not modify the developmental toxic effects of 2-BP in rats.

• Radiation Oncology Journal
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• v.34 no.3
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• pp.223-229
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• 2016

Purpose: This study is to investigate the effect of captopril when combined with irradiation. Materials and Methods: 4T1 (mouse mammary carcinoma) cells were injected in the right hind leg of Balb/c mice. Mice were randomized to four groups; control (group 1), captopril-treated (group 2), irradiated (group 3), irradiated and captopril-treated concurrently (group 4). Captopril was administered by intraperitoneal injection (10 mg/kg) daily and irradiation was delivered on the tumor-bearing leg for 15 Gy in 3 fractions. Surface markers of splenic neutrophils (G-MDSCs) and intratumoral neutrophils (tumor-associated neutrophils [TANs]) were assessed using flow cytometry and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 alpha ($HIF-1{\alpha}$) of tumor was evaluated by immunohistochemical (IHC) staining. Results: The mean tumor volumes (${\pm}$standard error) at the 15th day after randomization were $1,382.0({\pm}201.2)mm^3$ (group 1), $559.9({\pm}67.8)mm^3$ (group 3), and $370.5({\pm}48.1)mm^3$ (group 4), respectively. For G-MDSCs, irradiation reversed decreased expression of CD101 from tumor-bearing mice, and additional increase of CD101 expression was induced by captopril administration. Similar tendency was observed in TANs. The expression of tumor-necrosis factor-associated molecules, CD120 and CD137, are increased by irradiation in both G-MDSCs and TANs. Further increment was observed by captopril except CD120 in TANs. For IHC staining, VEGF and $HIF-1{\alpha}$ positivity in tumor cells were decreased when treated with captopril. Conclusion: Captopril is suggested to have additional effect when combined to irradiation in a murine tumor model by modulation of MDSCs and angiogenesis.

• The Korean Journal of Pharmacology
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• v.21 no.2
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• pp.99-110
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• 1985

Majarine that was isolated from Berberis Koreasra Palibin (Berberidaceae) is the isoquinoline alkaloid. The effects of dopaminergic and serotonergic antagonists on majarine induced changes in body temperature were studied in the mouse. Intraperitoneal administration of majarine produced dose-dependent hypothermia. At a dose of 0.1 mg/kg, majarine caused a slight increase in body temperature. Majarine-induced hyperthermia was attenuated by the 5-HT antagonist, cyproheptadine However, it caused hyothermia in mice pretreated with the DA antagonist, haloperidol, and hyperthermia in mice pretreated with haloperidol and cyproheptadine in comparision with haloperidol pretreatment. At a dose of 2.0 mg/kg, majarine-induced hypothermia was attenuated by haloperidol and cyproheptadine, respectively. In reserpine pretreated mice, majarine produced dose-dependent hypothermia. At a dose of 0.1 mg/kg, majarine pretreated with haloperidol caused no significant effect in body temperature. At a dose of 2.0 mg/kg, majarine-induced hypothermia was attenuated by haloperidol pretreatment in mice treated with reserpine and ${\alpha}$-methyl-p-tyrosine. These data suppose that both dopaminergic and serotonergic mechanisms in the brain mediate the effects of majarine on body temperature. We propose that majarine directly stimulate DA receptor, which secondarilly activate 5-HT neurons to cause changes in body temperature.