• Journal of Life Science
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• v.27 no.2
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• pp.233-240
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• 2017

Previously, we have shown that Schisandra chinensis (Turcz.) Baill. (S. chinensis) has a protective effect against endoplasmic reticulum (ER) stress-induced hepatic steatosis. Gomisin A is a bioactive phytoestrogen derived from S. chinensis. In the present study, the in vitro and in vivo effects of gomisin A on ER stress and hepatic steatosis were investigated. We quantified the expression of markers of ER stress, including glucose regulated protein 78 (GRP78), C/EBP homolog protein (CHOP), and X-box-binding protein-1 (XBP-1), in HepG2 cells treated with tunicamycin or palmitate. Tunicamycin treatment in HepG2 cells induced the expression of markers of ER stress, including GRP78, CHOP, and XBP-1c. However, treatment with gomisin A reduced the expression of markers of ER stress. These inhibitory effects were also observed in palmitate-incubated HepG2 cells. The in vivo inhibitory effects of gomisin A were assessed in mice injected with tunicamycin or fed with a high fat diet (HFD). Gomisin A reduced the expression of markers of ER stress and decreased triglyceride levels in the livers of mice after tunicamycin injection or HFD feeding. Furthermore, gomisin A decreased the expression of inflammatory genes in palmitate-incubated HepG2 cells and the liver of HFD-fed obese mice. These results suggest that gomisin A inhibits ER stress and ameliorates hepatic steatosis induced by ER stress.

• Journal of Ginseng Research
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• v.44 no.4
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• pp.664-671
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• 2020

Background: Ginsenoside compound-Mc1 (Mc1) is a member of the deglycosylated ginsenosides obtained from ginseng extract. Although several ginsenosides have a cardioprotective effect, this has not been demonstrated in ginsenoside Mc1. Methods: We treated H9c2 cells with hydrogen peroxide (H₂O₂) and ginsenoside Mc1 to evaluate the antioxidant effects of Mc1. The levels of antioxidant molecules, catalase, and superoxide dismutase 2 (SOD2) were measured, and cell viability was determined using the Bcl2-associated X protein (Bax):B-cell lymphoma-extra large ratio, a cytotoxicity assay, and flow cytometry. We generated mice with high-fat diet (HFD)-induced obesity using ginsenoside Mc1 and assessed their heart tissues to evaluate the antioxidant effect and the fibrosis-reducing capability of ginsenoside Mc1. Results: Ginsenoside Mc1 significantly increased the level of phosphorylated AMP-activated protein kinase (AMPK) in the H9c2 cells. The expression levels of catalase and SOD2 increased significantly after treatment with ginsenoside Mc1, resulting in a decrease in the production of H₂O₂-mediated reactive oxygen species. Treatment with ginsenoside Mc1 also significantly reduced the H₂O₂-mediated elevation of the Bax:Bcl2 ratio and the number of DNA-damaged cells, which was significantly attenuated by treatment with an AMPK inhibitor. Consistent with the in vitro data, ginsenoside Mc1 upregulated the levels of catalase and SOD2 and decreased the Bax:B-cell lymphoma-extra large ratio and caspase-3 activity in the heart tissues of HFD-induced obese mice, resulting in reduced collagen deposition. Conclusion: Ginsenoside Mc1 decreases oxidative stress and increases cell viability in H9c2 cells and the heart tissue isolated from HFD-fed mice via an AMPK-dependent mechanism, suggesting its potential as a novel therapeutic agent for oxidative stress-related cardiac diseases.

• Journal of Yeungnam Medical Science
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• v.36 no.1
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• pp.26-35
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• 2019

Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner

• Korean Journal of Medicinal Crop Science
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• v.28 no.6
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• pp.395-411
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• 2020

Background: This study investigated the anti-obesity effect of the flavonoid rich fraction (FRF) and its constituent, rutin obtained from the leaf of Morus alba L., on the lipid accumulation mechanism in 3T3-L1 adipocyte and C57BL/6 mouse models. Methods and Results: In Oil Red O staining, FRF (1,000 ㎍/㎖) treatments showed inhibition rate of 35.39% in lipid accumulation compared to that in the control. AdipoRedTM assay indicated that the triglyceride content in 3T3-L1 adipocytes treated with FRF (1,000 ㎍/㎖) was reduced to 23.22%, and free glycerol content was increased to 106.04% that of the control. FRF and its major constituent, rutin affected mRNA gene expression. Rutin contributed to the inhibition of Sterol regulatory element binding protein-1c (SREBP-1c) gene expression, and inhibited the transcription factors SREBP-1c, peroxisome proliferator-activated receptor gamma (PPAR-γ), CCAAT/enhancer binding protein α (C/EBPα), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). In addition, the effect of FRF administration on obesity development in C57BL/6 mice fed high-fat diet (HFD) was investigated. FRF suppressed weight gain, and reduced liver triglyceride and leptin secretion. FRF exerted potential anti-inflammatory effects by improving insulin resistance and adiponectin levels, and could thus be used to help counteract obesity. The mRNA expressions of PPAR-γ, FAS, ACC, and CPT-1 were determined in liver tissue. Quantitative real-time PCR analysis was also performed to evaluate the expression of IL-1β, IL-6, and TNF-α in epididymal adipose tissue. Compared to the control group, mice fed the HFD showed the up-regulation in PPAR-γ, FAS, IL-6, and TNF-α genes, and down-regulation in CPT1 gene expression. FRF treatement markedly reduced the expression of PPAR-γ, FAS, IL-6, and TNF-α compared to those in HFD control, whereas increased the expression level of CPT1. Conclusions: These results suggest that the FRF and its major active constituent, rutin, can be used as effective anti-obesity agents.

• Journal of the Korean Society of Food Science and Nutrition
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• v.41 no.4
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• pp.501-509
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• 2012

The dietary intake of whole grains is known to reduce the incidence of chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer. In our previous study, hog millet (HM, $Panicum$ $miliaceum$ L.) water extract showed the highest anti-lipogenic activity among nine cereal types in 3T3-L1 cells. In this study, the effect of hog millet water extract on hepatic steatosis and lipid metabolism in mice fed a high fat diet was investigated. Mice were fed a normal-fat diet (ND), high-fat diet (HFD) or HFD containing 1% or 2% (w/w) HM for 7 weeks. Body weight and food intake were monitored during the study period. Insulin resistance by homeostasis model assessment (HOMA-IR), fasting lipid profile, hepatic fatty acid metabolism-related gene expression determined, and intraperitoneal glucose tolerance test (IGTT) were performed at the study's end. The results indicated that 1% and 2% HM diets effectively decreased liver weights, blood TG and T-cholesterol levels (p<0.05), while the HDL-cholesterol level was increased (p<0.05) compared to HFD-induced steatotsis mice. Hepatic lipogenic-related gene ($PPAR{\alpha}$, L-FABP, and SCD1) expressions decreased, whereas lipolysis- related gene (CPT1) expression increased in animals fed the 2% PME diet (p<0.05). In addition, mice fed 1% or 2% HM diet had markedly decreased IGTT and HOMA-IR, compared to the those of the HFD-induced hepatic steatosis control group (p<0.05). These results indicated that HM inhibited hepatic lipid accumulation by regulating fatty acid metabolism, and suggested that HM is useful in the chemoprevention or treatment of high fat-induced hepatic steatosis and hepatic steatosis-related disorders including hyperlipidemia, glucose sensitivity, and insulin resistance.

• Archives of Pharmacal Research
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• v.29 no.3
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• pp.256-264
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• 2006

Salicornia herbacea L. (Chenopodiaceae) has been used as a seasoned vegetable by living in coastal areas. S. herbacea (SH) has been demonstrated to stimulate cytokine production, nitric oxide release, and to show anti-oxidative effect. In a series of investigations to develop potential anti-diabetic and/or anti-hyperlipidemic agents from Korean indigenous plants, 50% ethanol extract of Salicornia herbacea was found to prevent the onset of the hyperglycemia and hyperlipidemia induced by high fat diet in ICR mice. At 6 week old, the ICR mice were randomly divided into five groups; two control and three treatment groups. The control mice were to receive either a regular diet (RD) or high-fat diet (HFD), and the treatment groups were fed a high fat diet with either 350 mg/kg, 700 mg/kg of SH (SH350 and SH700) or 250 mg/kg of met-formin (MT250) for a 10-week period. SH not only reduced body weight but also corrected associated hyperglycemia and hyperlipidemia in a dose dependent manner. SH exerted beneficial effects on the plasma glucose and lipid homeostasis possibly ascribed to its specific effects on lipogenesis related genes (SREBP1a, FAS, GAPT), and PEPCK, glucose 6-phosphatase gene expressions in liver. Ethanol extract of S. herbacea has potential as a preventive agent for type 2 diabetes (and possibly hyperlipidemia) and deserves future clinical trial.

• Biomedical Science Letters
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• v.18 no.1
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• pp.56-62
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• 2012

This study was to investigate the effects of high-fat diet feeding for a very long period of time on gene expression of inflammatory cytokines in mouse adipose tissue and to determine whether caloric restriction (CR) or insulin sensitizer treatment changes the cytokine gene expressions even in obese mice fed a high-fat diet for a very long term-period. Gene expression levels of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were examined by real-time PCR in subcutaneous abdominal adipose tissue (SubQ) from obese and non-obese male C57BL/6 mice at 16, 26, 36, 47, and 77 weeks of age on either normal diet (ND) or high-fat diet (HFD) after starting at 6 weeks of age. In addition, gene expression levels of TNF-${\alpha}$, IL-6 and MCP-1 were determined in SubQ before and after rosiglitazone treatment or CR on 47-week-old obese mice. The results demonstrated that gene expression levels of TNF-${\alpha}$, IL-6 and MCP-1 were significantly increased with aging in SubQ of mice in both groups of diet. MCP-1 gene expression of SubQ in all ages tested was significantly or marginally increased in mice on HFD compared with ND. While TNF-${\alpha}$ expression was significantly reduced by rosiglitazone, IL-6 and MCP-1 were significantly decreased by CR. The basic data in this study will be useful for characterizing the C57BL/6 mouse as an animal model of obesity induced by high-fat diet feeding for a very long period of time, and a better understanding of inflammatory cytokine regulation in diet induced obesity which may facilitate the development of new therapeutic strategies to prevent the complications of obesity.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.4
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• pp.638-645
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• 2010

The aim of this study was to investigate the effect of Taeeumjowuitanggagam-bang (TJV) on the mRNA expression of Sterol regulatory element binding proteins (SREBPs), Tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and Interlukin-6 (IL-6) that are considered to play an important role in lipid and glucose metabolism. For diet-induced obese studies, we split mice into 2 groups. The low fat diet group (LFD, n=8) were supplied with general diet for 10 weeks and the high fat diet group (HFD, n=18) were supplied with 60 kcal% fat diet for 10 weeks. And then The HFD group, the diet-induced obese group, were divided into 3 groups ; a group supplied with normal saline, a group treated with TJV 200 mg/kg and a group treated with TJV 500 mg/kg. They were treated orally with TJV and measured their body weight every day during 10 weeks. After that, we measured mRNA expressions of TNF-$\alpha$, IL-6 and SREBP-1c in liver, and blood concentrations of glucose, total cholesterol and triglyceride too. The results are as follows. The TJV reduced glucose and total cholesterol of blood concentration. The TJV reduced the mRNA expressions of TNF-$\alpha$ and SREBPs in liver. However, We couldn't find the TJV effects on the mRNA expression of IL-6, triglyceride blood concentration, and body weight among groups. The TJV stained liver tissue less red than control group. These results suggest that TJV may be effective for regulation of lipid and glucose metabolism in liver.

• YAKHAK HOEJI
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• v.51 no.5
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• pp.307-312
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• 2007

Thiazolidinediones (TZDs) induce insulin sensitization through the activation of PPAR${\gamma}$. However, the undesirable effect such as weight gain was observed. The purpose of this study was to find out an herbal drug that could reduce the side effects of pioglitazone. Among herbal formula that we have searched, oryung-san (OR) inhibited the differentiation of preadipocytes and did not affect on glucose uptake in 3T3-L1 adipocytes. In vitro, glucose uptake assay and Oil Red-O staining in 3T3-L1 adipocytes were conducted. In vivo, pioglitazone (PIO, 30 mg/kg), oryung-san (OR, 300 mg/kg), or pioglitazone co-administered with oryung-san (PIO+OR) were administered orally for 7 weeks in high fat diet (HFD) fed ICR mice and measured the body weight and blood glucose level every week. PIO+OR group significantly reduced body weight gain, triglyceride, and total cholesterol compared to PIO group. In addition, PIO+OR group showed a significant reduction of plasma glucose level (72%) compared to HFD control group. Insulin levels in PIO+OR group was also markedly decreased by 85% and 41% compared to HFD control and PIO group, respectively. Diameter of white adipocytes was decreased in the PIO+OR group compared to that in PIO group. Moreover, PIO+OR group reduced expression of PPAR${\gamma}$ and SREBP1a compared to PIO group. Taken together, oryung-san can improve side effects of pioglitazone, such as weight gain and edema, and shows a synergistic effect in plasma insulin levels.

• Toxicological Research
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• v.30 no.1
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• pp.49-54
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• 2014

In this study, we investigated the hepatoprotective effects of aged black garlic (ABG) in rodent models of liver injury. ABG inhibited carbon tetrachloride-induced elevation of aspartate transaminase (AST) and alanine transaminase (ALT), which are markers of hepatocellular damage, in SD rats. D-galactosamine-induced hepatocellular damage was also suppressed by ABG treatment. However, ABG does not affect the elevation of alkaline phosphatase (ALP), a marker of hepatobilliary damage, in rats treated with carbon tetrachloride or D-galactosamine. We also examined the effect of ABG on high-fat diet (HFD)-induced fatty liver and subsequent liver damage. ABG had no significant effect on body weight increase and plasma lipid profile in HFD-fed mice. However, HFD-induced increase in AST and ALT, but not ALP, was significantly suppressed by ABG treatment. These results demonstrate that ABG has hepatoprotective effects and suggest that ABG supplementation might be a good adjuvant therapy for the management of liver injury.