• 생명과학회지
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• 제34권4호
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• pp.227-235
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• 2024

약물이나 허브 제품으로 인한 간세포 손상은 이러한 화합물을 만성적으로 투여할 때 일어날 수 있는 중요한 문제 중 하나이다. 따라서 여러 가지의 치료 과정 중 간세포 생존율을 향상시키는 것은, 약물 적용에 있어 광범위한 기회를 제공할 수 있다. Valproic acid (VPA)는 자연적으로 발생하는 발레르산에서 파생된 분지형 단사슬 지방산으로 뇌전증과 발작을 치료하는 데 일반적으로 사용된다. 뿐만 아니라 VPA는 암, HIV 치료, 신경 퇴행성 질환에 수많은 효과를 발휘하지만, 간에 대한 VPA의 잠재적인 영향과 그 작용 메커니즘은 완전히 설명되지 않았다. 여기서, 우리는 VPA의 처리가 쥐 간세포(Hepa1c1c7)에서 PPAR 알파(PPAR-α)와 섬유아세포 성장 인자 21(FGF21)의 전사 수준을 증가시킨다는 것을 입증했다. VPA에 의해 유도된 FGF21 발현은 PPAR-α 결손 조건에서 상당히 억제되었다. 후속 실험에서 FGF21 신호 경로가 FGF 수용체 억제제에 의해 차단되었을 때, 간세포 생존력이 크게 억제되었음을 보여주었다. 마지막으로, 우리는 AMPK 인산화가 VPA에 의해 유도된 PPAR-α 증가에 작용하지 않는다는 것을 추가로 확인했다. 이러한 결과는 FGF21 발현의 증가가 VPA에 의해 유도된 간 독성을 완화시킬 수 있다는 것을 제시하며, 이와 같은 결과는 FGF21의 증감 여부가 VPA 치료 중 나타날 수 있는 간 손상을 예측하는 잠재적인 바이오마커로 사용될 수 있음을 제시한다.

• Biomolecules & Therapeutics
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• 제25권5호
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• pp.504-510
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• 2017

Inhibitor of nuclear factor kappa-B kinase beta ($IKK{\beta}$) plays a critical role in cell proliferation and inflammation in various cells by activating $NF-{\kappa}B$ signaling. However, the interrelationship between peroxisome proliferator-activated receptor ${\alpha}$ ($PPAR{\alpha}$) and $IKK{\beta}$ in cell proliferation is not clear. In this study, we investigated the possible role of $PPAR{\alpha}$ in the hepatic cell death in the absence of $IKK{\beta}$ gene using liver-specific Ikkb-null ($Ikkb^{F/F-AlbCre}$) mice. To examine the function of $PPAR{\alpha}$ activation in hepatic cell death, wild-type ($Ikkb^{F/F}$) and $Ikkb^{F/F-AlbCre}$ mice were treated with $PPAR{\alpha}$ agonist Wy-14,643 (0.1% w/w chow diet) for two weeks. As a result of Wy-14,643 treatment, apoptotic markers including caspase-3 cleavage, poly (ADP-ribose) polymerase (PARP) cleavage and TUNEL-positive staining were significantly decreased in the $Ikkb^{F/F-AlbCre}$ mice. Surprisingly, Wy-14,643 increased the phosphorylation of p65 and STAT3 in both Ikkb and $Ikkb^{F/F-AlbCre}$ mice. Furthermore, BrdU-positive cells were significantly increased in both groups after treatment with Wy-14,643. Our results suggested that $IKK{\beta}-derived$ hepatic apoptosis could be altered by $PPAR{\alpha}$ activation in conjunction with activation of $NF-{\kappa}B$ and STAT3 signaling.

• 약학회지
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• 제54권2호
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• pp.91-96
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• 2010

Berberine, an isoquinoline alkaloid, has a wide range of pharmacological effects, including anti-inflammation. It has been reported that berberine inhibits experimental colitis through inhibition of IL-8, and that inhibitory effect of berberine on inflammatory cytokine expression is mediated through peroxisome proliferator activated receptor (PPAR)-$\gamma$. In this study, we examined the effects and action mechanism of berberine on the tumor necrosis factor (TNF)-$\alpha$-induced monocyte adhesion to HT29 human colonic epithelial cells, which is commonly used as an in vitro model of inflammatory bowel disease (IBD). Berberine significantly inhibited the TNF-$\alpha$-induced monocyte adhesion to HT29, which is similar to the effect of PDTC, a nuclear factor (NF)-$\kappa$B inhibitor. However, ciglitazone and GW, the ligands of PPAR-$\gamma$, did not suppress the TNF-$\alpha$-induced monocyte adhesion to HT29 cells. In addition, TNF-$\alpha$-induced chemokine expression and NF-$\kappa$B transcriptional activity were significantly inhibited by berberine in a concentration-dependent manner. The results suggest that inhibitory effect of berberine on colitis is mediated through suppression of NF-$\kappa$B and NF-$\kappa$B-dependent chemokine expression.

• Food Science and Biotechnology
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• 제17권2호
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• pp.267-273
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• 2008

Water-soluble fraction (WSF) from edible mushroom hinmogi (Tremella fuciformis) were obtained by water extraction, and polysaccharides in the WSF were separated by ethanol precipitation. The inhibitory effects of the polysaccharides on 3T3-L1 adipocyte differentiation were evaluated by the reduction of peroxisome proliferators-activated receptor ${\gamma}$ ($PPAR{\gamma}$) translation, triglyceride accumulation, Oil Red-O staining, and expression levels of $PPAR{\gamma}$, CCAAT/enhancer binding protein a (C/$EBP{\alpha}$), and leptin. The $PPAR{\gamma}$ translation in 3T3-L1 cells was inhibited by the treatment with polysaccharide precipitated by 80% ethanol (P80) which showed highest inhibitory activity among polysaccharides tested. In addition, treatment of P80 to 3T3-L1 cells significantly inhibited the triglyceride accumulation, Oil Red-O staining, and mRNA expression of $PPAR{\gamma}$, C/$EBP{\alpha}$, and leptin in a dose-dependent manner. Based upon these results, P80 from edible mushroom hinmogi shows the inhibitory activity on the differentiation of 3T3-L1 adipocytes. Therefore, it might be employed as a potential anti-obesity material.

• Journal of Nutrition and Health
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• 제40권3호
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• pp.221-228
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• 2007

We determined the effects of dietary manipulations on messenger RNA of peroxisome proliferators activated receptor isoforms (i.e., PPAR ${\alpha},\;{\beta}/{\delta},\;{\gamma}$) in red vastus lateralis muscle of rats. Total 16 male Sprague-Dawley rats were used, and animals were divided into one of two dietary conditions: either chow diet group (CHOW; n=8) in which animals were 134 with standard rodent chow (61.8% carbohydrate, 15.7% fat, 22.5% protein) or high fat diet group (FAT n=8) in which animals were fed 24.3% carbohydrate, 52.8% fat, 22.9% protein. At the end of the 8 weeks of experimental period, red vastus lateralis muscle was dissected out from all animals, and PPAR ${\alpha},\;{\beta}/{\delta},\;{\gamma}$ mRNA expression was determined. There was no significant difference in body mass (BM) between CHOW and FAT. As expected, blood glucose and free fatty acid (FFA) concentration was higher in FAT than CHOW (p<0.05), and lactate concentration was significantly lower in FAT compared to CHOW (p<0.05). Insulin concentration tended to higher in FAT than CHOW ($67.2{\pm}21.9\;vs.\;27.0{\pm}5.2$ pmol/L), but it did not reach to the statistical significance. Gene expression of PPAR ${\alpha}$ was not significantly different between CHOW and FAT. It was not also significantly different in PPAR ${\beta}/{\delta}$. Interestingly, expression of mRNA in PPAR ${\gamma}$ however, was markedly depressed in FAT compared to CHOW (approximately 3 fold higher in CHOW; p<0.05). Results obtained from present study implies that PPAR ${\gamma}$ (as compensatory function of PPAR ${\alpha}$ is expressed) possibly exerts another major tuning roles in fatty acid transport, utilization, as well as biosynthesis in skeletal muscle cells. The situations and conditions that can be postulated for this implication need to be further examined.

• 대한한방내과학회지
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• 제30권2호
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• pp.257-269
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• 2009

Objective : Obesity is an important cause of diabetes, and lipotoxicity causes insulin resistance. Recently a lot of research is being done on PPAR-${\alpha}$. TNF-${\alpha}$. adiponectin, and leptin, which are important obesity related factors. In this study, we investigated the effects of Supungsunki-hwan on high fat. high carbohydrate diet-induced obese type 2 diabetic mouse models. Methods: Diabetes was induced in ICR male mouse (30${\pm}$5g) with Surwit's high fat, high sucrose diet. Mice were divided into 4 groups(n=10) of Normal. Control. Supungsunkj-hwan group. and acarbose group. The Supungsunki-hwsn group was given 10% Supungsunkj-hwan in their diet. and the acarbose group was given 0.5% acarbose in their diet. After 6 weeks. body weight. food intake, FBS and OGTT. lipid profile and liver enzymes, epididymal fat weight, and gene expression of leptin, adiponectin, TNF-${\alpha}$ and PPAR-${\alpha}$ were measured. Leptin. adiponectin. tumor necrosis factor(TNF)-${\alpha}$ and peroxisome proliferator-activated receptor (PPAR)-${\alpha}$ were evaluated by reverse transcription-polymerase chain reaction. Results : Supungsunkj-hwan increased the gene expression of PPAR-${\alpha}$, which reduces lipotoxicity and insulin resistance. Supungsunkj-hwan also significantly reduced triglyceride. AST. ALT serum levels. and 1 hour oral glucose tolerance levels. Conclusion : These results show that Supungsunkj-hwan improves insulin resistance in the liver and muscles, by reducing triglyceride levels and lipotoxicity through increased PPAR-${\alpha}$ gene expression. This is supported by the fact that Supungsunkj-hwan significantly reduces 1 hour oral glucose tolerance levels. Therefore we suggest that Supungsunkj-hwan would be an effective treatment for obese type 2 diabetic patients.

• 한국응용과학기술학회지
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• 제31권1호
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• pp.101-112
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• 2014

본 연구는 고콜레스테롤 식이를 섭취한 랫드에서 파리유충 에탄올추출물(Ethanolic extract of fly maggot, EM)의 경구투여가 혈액 지질감소에 미치는 영향을 조사하였다. Sprague-Dawley 수컷 랫드를 이용하여 4 처리구(EM 투여량; 대조군=0, 5.0, 7.0, 9.0 mg/100 g 체중)로 구분해서 6주 동안 진행하였다. EM 투여군은 대조군과 비교할 때 혈청 중성지방, 총콜레스테롤, LDL-C가 유의하게 낮았다(p<0.05). HMG-CoA reductase activity는 대조군과 비교할 때 EM 투여군에서 낮았으나 총스테롤, 중성스테롤 및 담즙산 배설량은 EM 투여군에서 유의하게 높았다(p<0.05). EM의 혈액 콜레스테롤 감소와 관련한 생물학적 작용기작을 규명하기 위해서 고콜레스테롤 식이를 섭취한 랫드에서 유도된 생체유전자 sterol response element binding proteins (SREBPs) 및 the peroxisome proliferator-activated receptors ($PPAR{\alpha}$) 발현을 측정하였다. EM은 고콜레스테롤 식이를 공급받은 랫드의 간에서 SREBP-$1{\alpha}$, SREBP-2 mRNA 발현을 억압함과 동시에 $PPAR{\alpha}$ mRNA 발현을 촉진시키는 것으로 나타났다(p<0.05). 본 연구의 결과는 파리유충 에탄올추출물이 고콜레스테롤 식이를 섭취한 랫드에서 지질대사와 관련한 생화학적 매개변수 및 유전자발현 조절을 통하여 혈액 콜레스테롤을 낮춘다는 새로운 사실을 발견하였다.

• 한국축산식품학회지
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• 제30권5호
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• pp.787-794
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• 2010

Calcium plays a role as a signaling molecule in various cellular events. It has been reported that calcium suppresses adipocyte differentiation only in the early phase of adipogenesis. Herein, we demonstrate that treatment of A23187, a mobilizer of intracellular calcium, on day 4 post adipocyte differentiation could still reduce lipid accumulation in differentiating 3T3-L1 cells for 48 h. In addition, luciferase reporter gene and RT-Q-PCR assays demonstrate that A23187 can selectively inhibit transcriptional activities and expression of PPAR$\gamma$ and LXR$\alpha$, suggesting that A23187 may reduce lipid accumulation in the late phase of adipogenesis via downregulation of PPAR$\gamma$ and LXR$\alpha$ expression and transactivation. Moreover, inhibition of HDAC activity by trichostatin A (TSA) partially blocked A23187-mediated downregulation of transcriptional activities of PPAR$\gamma$ and LXR$\alpha$. Together, our data demonstrate that calcium mobilization inhibits expression and transcriptional activities of PPAR$\gamma$ and LXR$\alpha$, resulting in reduced lipid accumulation in differentiating adipocytes, and thus, mobilization of intracellular calcium in adipocytes may serve as a new preventive and therapeutic approach for obesity.

• 생명과학회지
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• 제20권11호
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• pp.1617-1624
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• 2010

$\alpha$-MSH는 세포내 cAMP를 증폭시켜 멜라닌세포의 증식과 색소 증가에 관여한다. 본 연구에서는 $\alpha$-MSH로 자극한 B16F10 세포에서 세신추출물의 hypopigmenting 효과를 조사하고 그 억제기전에 대하여 조사하였다. 세신추출물은 $\alpha$-MSH에 의해 유도된 tyrosinase 활성과 멜라닌생성을 효과적으로 억제시켰으며, 이는 tyrosinase 발현을 조절하는 전사인자인 MITF의 발현억제와 연관성이 있었다. 즉 세신추출물은 MEK/ERK와 PI3K/Akt의 활성화를 통하여 MITF를 조절함으로서 $\alpha$-MSH에 의해 유도되는 tyrosinase, TRP-1, Dct 등 멜라닌생성관련 단백질을 억제함으로서 멜라닌생성을 저해하는 것으로 사료된다.

• 동의생리병리학회지
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• 제20권1호
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• pp.93-97
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• 2006

To investigate whether GyeongshinhaeGihwan 1(GGT1), an anti-obesity herbal medicine widely used in oriental medicine, regulates the expression of obesity-related genes, we measured the changes in mRNA levels of these genes by GGT1 in human growth hormone transgenic (hGHTg) obese male rats, and these effects by GGT1 were compared with those of reductil (RD), an anti-obesity drug approved by FDA. Rats received once daily oral administrations of autoclaved water, RD, or GGT1 for 8 weeks. At the end of study, rats were sacrificed and tissues were harvested. Total RNA from adipose tissue, liver and kidney was prepared and the mRNA levels for LPL (lipoprotein lipase), PPAR $\gamma$ (peroxisome proliferator activated receptor-gamma), PPAR$\delta$ (peroxisome proliferator activated receptor-delta), leptin, TNF$\alpha$ (tumor necrosis factor-alpha), and internal standard G3PDH (glyceraldehyde-3- phosphate dehydrogenase) were analyzed by RT-PCR. PPAR$\gamma$ mRNA levels of liver and kidney were decreased in drug-treated groups compared with control group and the decrease of PPAR$\gamma$ expression was more prominent in GGT1 group than in RD group, suggesting that GGT1 is effective in the inhibition of adipogenesis and lipid storage by decreasing the PPAR$\gamma$ expression. In contrast, PPAR$\delta$ mRNA levels of adipose tissue and kidney were increased by RD and GGT1 , and the magnitudes of increase were higher in GGT1 group than in RD group, indicating that GGT1 stimulates fatty acid oxidation and energy metabolism by activating PPAR$\delta$ expression, Compared with control and RD groups, GGT1 group had higher concentrations of serum leptin, a well-known inhibitor of appetite. However, The mRNA levels of leptin, LPL, and TNF$\alpha$ were not changed by GGT1 and RD, compared with DW. These results demonstrate that GGT1 not only decreases PPAR$\gamma$ expression of liver and kidney, but also increases PPAR$\delta$ expression of adipose tissue and kidney, leading to the regulation of obesity and that these effects were more pronounced in GGT1 group compared with RD group. In addition, GGT1 seems to prevent obesity by increasing the serum leptin levels.