• Experimental and Molecular Medicine
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• v.50 no.11
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• pp.8.1-8.14
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• 2018

We previously demonstrated that the direct transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the dentate gyrus ameliorated the neurological symptoms of Niemann-Pick type C1 (NPC1)-mutant mice. However, the clinical presentation of NPC1-mutant mice was not fully understood with a molecular mechanism. Here, we found 14,15-epoxyeicosatrienoic acid (14,15-EET), a cytochrome P450 (CYP) metabolite, from hUCB-MSCs and the cerebella of NPC1-mutant mice and investigated the functional consequence of this metabolite. Our screening of the CYP2J family indicated a dysregulation in the CYP system in a cerebellar-specific manner. Moreover, in Purkinje cells, CYP2J6 showed an elevated expression level compared to that of astrocytes, granule cells, and microglia. In this regard, we found that one CYP metabolite, 14,15-EET, acts as a key mediator in ameliorating cholesterol accumulation. In confirming this hypothesis, 14,15-EET treatment reduced the accumulation of cholesterol in human NPC1 patient-derived fibroblasts in vitro by suppressing cholesterol synthesis and ameliorating the impaired autophagic flux. We show that the reduced activity within the CYP system in the cerebellum could cause the neurological symptoms of NPC1 patients, as 14,15-EET treatment significantly rescued cholesterol accumulation and impaired autophagy. We also provide evidence that the intranasal administration of hUCB-MSCs is a highly promising alternative to traumatic surgical transplantation for NPC1 patients.

• The Korean Journal of Pharmacology
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• v.18 no.1
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• pp.55-63
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• 1982

Lipid peroxidation is the reaction of oxidative deterioration of polyunsaturated lipids and this peroxidation involves the direct reaction of oxygen and lipid to form free radical intermediates, which can lead to autocatalysis. As results of the extensive studies on the lipid peroxidation by many authors, the relationship between lipid peroxidation and the drug metabolizing system as well as the actions of free radicals on the peroxidation was reasonably well known. For a long time, the mechanism of hepatotoxicity of $CCl_4$ was not clearly understood. However, it is now quite well established that $CCl_4$ is activated in vivo to a free radical which is a highly reactive molecule. Therefore, lipid peroxidation which induces the reduction of cytochrome P-450 and aminopyrine demethylase activity is known as decisive event of $CCl_4$ hepatotoxicity. On the other hand, it was also reported that singlet molecular oxygen produces lipid peroxidation in liver microsomes. In this study the effects of benzoyl peroxide on the lipid peroxidation and drug-metabolizing enzyme were examined. Benzoyl peroxide mixed with starch and phosphates etc. is usually used as a food additive for flour bleaching and maturing purpose because of its oxidative property. Albino rats were used for the experimental animals. Benzoyl peroxide was suspended in soybean oil and sesame oil and administered intraperitoneally or orally. TBA value and aminopyrine demethylase activity were determined in liver microsomal fraction and serum. The results were summerized as following. 1) Body weights of animals administered benzoyl peroxide suspension were decreased while that of oil administered group were increased. 2) The activity of aminopyrine demethylase was generally decreased in animals administered oil suspension of benzoyl peroxide. Furthermore, the marked reduction of the enzyme activity was observed in animals administered benzoyl peroxide intraperitoneally. 3) Generally, microsomal TBA values as well as serum TBA were significantly elevated in benzoyl peroxide group in comparison with the control group. However, the more remarkable increase of serum TBA than microsomal TBA was observed in animals administered orally for 6 days. 4) Specifically, the changing pattern of TBA value was notable in serum rather than in liver microsome by intraperitoneal administration of benzoyl peroxide.

• Asian-Australasian Journal of Animal Sciences
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• v.31 no.1
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• pp.138-148
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• 2018

Objective: Fusarium mycotoxins deoxynivalenol (DON) and zearalenone (ZEN), common contaminants in the feed of farm animals, cause immune function impairment and organ inflammation. Consequently, the main objective of this study was to elucidate DON and ZEN effects on the mRNA expression of pro-inflammatory cytokines and other immune related genes in the kidneys of piglets. Methods: Fifteen 6-week-old piglets were randomly assigned to three dietary treatments for 4 weeks: control diet, and diets contaminated with either 8 mg DON/kg feed or 0.8 mg ZEN/kg feed. Kidney samples were collected after treatment, and RNA-seq was used to investigate the effects on immune-related genes and gene networks. Results: A total of 186 differentially expressed genes (DEGs) were screened (120 upregulated and 66 downregulated). Gene ontology analysis revealed that the immune response, and cellular and metabolic processes were significantly controlled by these DEGs. The inflammatory stimulation might be an effect of the following enriched Kyoto encyclopedia of genes and genomes pathway analysis found related to immune and disease responses: cytokine-cytokine receptor interaction, chemokine signaling pathway, toll-like receptor signaling pathway, systemic lupus erythematosus (SLE), tuberculosis, Epstein-Barr virus infection, and chemical carcinogenesis. The effects of DON and ZEN on genome-wide expression were assessed, and it was found that the DEGs associated with inflammatory cytokines (interleukin 10 receptor, beta, chemokine [C-X-C motif] ligand 9, CXCL10, chemokine [C-C motif] ligand 4), proliferation (insulin like growth factor binding protein 4, IgG heavy chain, receptor-type tyrosine-protein phosphatase C, cytochrome P450 1A1, ATP-binding cassette sub-family 8), and other immune response networks (lysozyme, complement component 4 binding protein alpha, oligoadenylate synthetase 2, signaling lymphocytic activation molecule-9, ${\alpha}$-aminoadipic semialdehyde dehydrogenase, Ig lambda chain c region, pyruvate dehydrogenase kinase, isozyme 4, carboxylesterase 1), were suppressed by DON and ZEN. Conclusion: In summary, our results indicate that high concentrations of DON and ZEN suppress the inflammatory response in kidneys, leading to potential effects on immune homeostasis.

• Journal of Haehwa Medicine
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• v.8 no.1
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• pp.593-623
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• 1999

This experimental study was designed to verify the anti-aging efficacy of Eukmigihwangtang (EMGHT) and Rehmannia Radix, and determine the specific role and actions of Rehmannia Radix. Normal rat (2 months old), aging rat (8 months old), and pathologically induced rat (2 months old, injected 30mg/kg of streptozotocin) are observed to study the aging eliciting factors such as peroxide contents and enzyme activities. The following results were obtained in this study: 1. For the body weight changes, normal group given Rehmannia Radix showed decrease in the body weight compared to the control group, aging group given EMGHT and Rehmannia Radix showed significant decrease in the body weight, and STZ injected group showed suppression to the body weight loss when given EMGHT and Rehmannia Radix. 2. For the content changes in serum lipid peroxide, normal group showed increasing level as the rat gets older. Aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the lipid peroxide level compared to the control group. Decrease was more prominant in the group given EMGHT. 3. For the changes in serum hydroxyl radical, normal group did not show significant changes, but aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the hydroxyl radical level compared to the control group. Decrease was more prominant in the group given EMGHT. 4. For the changes in serum superoxide dismutase (SOD) activity, normal group did not show significant changes, but aging group given EMGHT and Rehmannia Radix showed significant increase in the SOD activity compared to the control group. STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the SOD activity compared to the control group. 5. For the content changes in hepatic lipid peroxide, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the lipid peroxide level compared to the control group. 6. For the changes in hepatic cytochrome P-450 activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease compared to the control group. Cytochrome b5 activity was significantly decreased only in the STZ injected group given EMGHT and Rehmannia Radix. 7. For the changes in hepatic aminopyrine demethylase and aniline hydroxylase activity, aging group given EMGHT and Rehmannia Radix showed significant decrease compared to the control group. STZ injected group given EMGHT and Rehmannia Radix showed significant increase in the aminopyrine demethylase activity, and showed significant decrease in the aniline hydroxylase activity compared to the control group. 8. For the content changes in hepatic protein bound-SH and nonprotein bound-SH, againg group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase compared to the control group. 9. For the content changes in hepatic glutathione level, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase compared to the control group. 10. For the changes in hepatic glutathione S-transferase activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase and decrease, respectively, compared to the control group. 11. For the changes in hepatic glutathione reductase activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase compared to the control group, while $\gamma$-Glutamylcystein synthetase activity did not show significant changes. 12. For the changes in hepatic superoxide dismutase activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease compared to the control group. From the above results, the antioxidant effects of EMGHT and Rehmannia Radix were proved, as well as the role of Rehmannia Radix, a chief of EMGHT, was examined. In addition, since no change was reconized as the quantity of Rehmannia Radix and the order herbs increased, the reasonableness on EMGHT was proven with respect to its composition and quantity. Thus, the significance of EMGHT could be objectively exmined in terms of its composition and quantity. Considering animals used in the experiment, there were obvious changes in aging rats and pathologically induced rats than in normal rats. Consequently, it was noticeable that EMGHT and Rehmannia Radix were working selectively on the subjects.

• Journal of Life Science
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• v.20 no.1
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• pp.133-141
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• 2010

The protective effect of a mixed powder from solid-cultured and liquid-cultured Lentinus edodes mycelia (2:1, w/w) (designate LED) on the carbon tetrachloride ($CCl_4$)- and ethanol-induced hepatotoxicity of male Sprague-Dawley (SD) rat was investigated. In the $CCl_4$-induced rat hepatotoxicity experiment, rats of 4 groups (6 rats/group) were administere with Normal (0.2 ml distilled water), Control (0.2 ml distilled water), LED (LED 200 mg/kg BW + 0.2 ml distilled water), and Silymarin (200 mg/kg BW + 0.2 ml distilled water), p.o., daily for 2 weeks. Afterwards, all groups except for the Normal group were subjected to abdominal injection with $CCl_4$ ($CCl_4$ : corn oil, 1:1 v/v; 0.5 ml/kg BW). For the ethanol- induced rat hepatotoxicity experiment, rats were divided into 5 groups (5 rats/group): Normal; Pair-fed control (PFC); Control (ethanol); LED (ethanol + LED 200 mg/kg BW); and Silymarin (ethanol + silymarin 200 mg/kg BW). Rats of the Normal and PFC groups were fed a basal liquid diet, and rats of the Control, LED, and Silymarin groups were fed a liquid ethanol diet containing LED or Silymarin. Eight weeks later, blood and liver samples were collected to analyze biomarkers. In $CCl_4$-induced SD rats, LED elevated hepatic superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH peroxidase) activities and thiobarbituric reactive substances (TBARS) were reduced, resulting in the reduction of glutamate-oxalate transaminase (GOT), glutamate-pyruvate transaminase (GPT) and lactic dehydrogenase (LDH) activities in plasma. Similar results of these enzymes and biochemical markers in both liver tissues and plasma were seen in ethanol-induced hepatotoxicity of SD rats. In addition, elevated alcohol dehydrogenase (ADH) activity and reduced expression of cytochrome p450 mixed monooxygenase enzyme (CYP2E1) were seen in liver tissues from ethanol-treated rats by LED treatment. These effects of LED were similar to those of Silymarin. In in vitro experiments, LED showed antioxidant activity in a 2,2-diphenyl-1-picrylhydrazyl (DPPH) system and mouse liver mitochondria system induced by NADPH/$Fe^{2+}$ and cumine hydroperoxide (CuOOH). These results indicate that LED protected SD rat hepatotoxicity, induced by $CCl_4$ and ethanol, through its antioxidative activity and might be useful as a material for protection from hepatoxicity in humans.