• Biomolecules & Therapeutics
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• 제29권1호
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• pp.22-30
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• 2021

Till the 21st century, fatty acids were considered as merely building blocks for triglycerides, phospholipids, or cholesteryl esters. However, the discovery of G protein-coupled receptors (GPCRs) for free fatty acids at the beginning of the 21st century challenged that idea and paved way for a new field of research, merged into the field of receptor pharmacology for intercellular lipid mediators. Among the GPCRs for free fatty acids, free fatty acid receptor 4 (FFA4, also known as GPR120) recognizes long-chain polyunsaturated fatty acids such as DHA and EPA. It is significant in drug discovery because it regulates obesity-induced metaflammation and GLP-1 secretion. Our study reviews information on newly developed FFA4 agonists and their application in pathophysiologic studies and drug discovery. It also offers a potency comparison of the FFA4 agonists in an AP-TGF-α shedding assay.

• Biomolecules & Therapeutics
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• 제28권3호
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• pp.267-271
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• 2020

Gut microbiota produce dietary metabolites such as short-chain fatty acids, which exhibit anti-inflammatory effects. Free fatty acid receptor 2 (FFA2, formerly known as GPR43) is a specific receptor for short-chain fatty acids, such as acetate that regulates inflammatory responses. However, the therapeutic potential of FFA2 agonists for treatment of atopic dermatitis has not been investigated. We investigated the efficacy of the FFA2 agonist, 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide (4-CMTB), for treatment of atopic dermatitis induced by 2,4-dinitrochlorobenzene (DNCB). Long-term application of DNCB to the ears of mice resulted in significantly increased IgE in the serum, and induced atopic dermatitis-like skin lesions, characterized by mast cell accumulation and skin tissue hypertrophy. Treatment with 4-CMTB (10 mg/kg, i.p.) significantly suppressed DNCB-induced changes in IgE levels, ear skin hypertrophy, and mast cell accumulation. Treatment with 4-CMTB reduced DNCB-induced increases in Th2 cytokine (IL-4 and IL-13) levels in the ears, but did not alter Th1 or Th17 cytokine (IFN-γ and IL-17) levels. Furthermore, 4-CMTB blocked DNCB-induced lymph node enlargement. In conclusion, activation of FFA2 ameliorated DNCB-induced atopic dermatitis, which suggested that FFA2 is a therapeutic target for atopic dermatitis.

• Biomolecules & Therapeutics
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• 제29권4호
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• pp.427-433
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• 2021

Free fatty acid receptor 2 (FFA2, also known as GPR43), a G-protein-coupled receptor, has been known to recognize short-chain fatty acids and regulate inflammatory responses. FFA2 gene deficiency exacerbated disease states in several models of inflammatory conditions including asthma. However, in vivo efficacy of FFA2 agonists has not been tested in allergic asthma. Thus, we investigated effect of 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide (4-CMTB), a FFA2 agonist, on antigen-induced degranulation in RBL-2H3 cells and ovalbumin-induced allergic asthma in BALB/c mice. Treatment of 4-CMTB inhibited the antigen-induced degranulation concentration-dependently. Administration of 4-CMTB decreased the immune cell numbers in the bronchoalveolar lavage fluid and suppressed the expression of inflammatory Th2 cytokines (IL-4, IL-5, and IL-13) in the lung tissues. Histological studies revealed that 4-CMTB suppressed mucin production and inflammation in the lungs. Thus, results proved that FFA2 functions to suppress allergic asthma, suggesting 4-CMTB activation of FFA2 as a therapeutic tool for allergic asthma.

• Natural Product Sciences
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• 제25권2호
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• pp.165-171
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• 2019

Although the functions of a standardized extract of Gingko biloba leaves (EGb $761^{(R)}$) has been reported with regard to neurobiological properties, no attention has been paid to the impact of EGb $761^{(R)}$ on the neuronal regulation of energy homeostasis. To evaluate the hypothesis that EGb $761^{(R)}$ affect the secretion of peptide tyrosine tyrosine (PYY) and the activation of free fatty acid receptor 4 (FFA4), which are involved in the neuronal circuitries that control energy homeostasis by inducing the transfer of information about the influx of energy to the brain, we examined whether EGb $761^{(R)}$ can stimulate PYY secretion in the enteroendocrine NCI-H716 cells and if EGb $761^{(R)}$ can activate FFA4 in FFA4-expressing cells. In NCI-H716 cells, EGb $761^{(R)}$ stimulated PYY secretion and the EGb $761^{(R)}$-induced PYY secretion was involved in the increase in intracellular $Ca^{2+}$ concentration and the activation of FFA4. Furthermore, in FFA4-expressing cells, EGb $761^{(R)}$ activated FFA4. These results suggest that EGb $761^{(R)}$ may affect the control of energy homeostasis via the regulation of PYY secretion and FFA4 activation.

• Preventive Nutrition and Food Science
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• 제4권3호
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• pp.203-208
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• 1999

The effect of the polyunsaterated fatty acids, linoleic acid(LA), arachidonic acid(AA) and conjugated dienoic linoleic acid(CLA) on IEC-6 cells (rat intestinal cell)proliferation and cell transduction have been determined in vitro. IEC-6 cells proliferation was assessed by cell growth and [3H]-thymidine incroporation analysis. At 10 μM concentration , the proliferationof cells supplemented with AA or LA was significantly higher than that of CLA. [3H]-thymidine uptake showed the same results. LA and AA increased [3H]-thymidine uptake more than CLA. The stimulatory effect of LA or AA was even more pronounced in the presence of IGF. Both cell number analysis and [3H]-thymidine incorporation revealed that IEC-6 cell proliferation was influenced differently by exogenous free fatty acids, in which AA or LA stimulated IEC-6 cell proliferation and CLA inhibited it. Tyorosine phosphorylation provides a key switch to regulate celluar acitivity in response to extracellular stimuli. At 20 μM and 10μM, AA with IGF-1 stimulated protein tyrosine phophorylation in IEC-6 cells, but LA's impact was less than that of AA. CLA and CLA with IGF-1 inhibited protein tyrosine phosphorylation in IEC-6 cells. These results suggest there is a possible correlation between cell proliferation and IGF receptor tyrosine knase activity driven by AA.

• 한국식품영양과학회지
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• 제23권3호
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• pp.402-408
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• 1994

인체의 혈장 저밀도 지단백(LDL)은 관상동맥경화 발병의 주 요인이다. 그러나 최근의 연구들은, 정상적인 LDL은 산소 자류라디칼에 의해 쉽게 산화되며, 결과 LDL 수용채와 결합하지 못한다고 밝히고 있다. 따라서 이 변형된 형태의 산화된 LDL은 macrophage scavernger receptor에 의해 인식되어 foam cell을 형성하여, 동맥혈관이 좁아지는 역할을 수행한다고 알려지고 있다. 지리과 산화에는 지방산이 중요한 작용을 하므로, 한국인의 LDL의 지방산 조성을 분석하여 서양인과 비교하였다. 결과, 한국인의 불포화 지방산의 비율이 총 지방산 함량의 약 30%인 반면 서양인은 약 70%의 분포를 갖고 있는 것으로 발표되었다. 따라서 한국인이 서양인에 비해 LDL의 산화에 대한 영향을 적게 받을 수 있으며, 따라서 동맥경화나 심장병의 발생률이 훨씬 적을 것으로 결론을 내릴 있다. 정상적인 LDL을 황산구리와 함께 배양하여, 지방의 산화를 유도하였으며 이의 정도를 지방산 산화의 생성물인 TBARS를 측정하여, LDL이 산화될 때 생성되는 자유라디칼의 양을 측정하므로서 비교하였다. 이 때, 항상화제인 비타민 C; 비타민 E와 히알우로닉산을 첨가하면 LDL의 산화가 억제되는 효과를 확인하였다. 자유 라디탈이 증가함에 따라 산화의 정도도 증가하였으며, 자유라디칼 형성의 경시적 변화는 TBARS와 유사하였다. 따라서 luminometer에 의한 자유라디칼의 정량은 TBARS에 의한 것보다 훨씬 간편한 것으로 나타났다.

• Journal of Ginseng Research
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• 제47권4호
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• pp.572-582
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• 2023

Background: Free fatty acid-induced lipotoxicity is considered to play an important role in pancreatic β-cell dysfunction. The effect of ginsenosides on palmitic acid-induced pancreatic beta-cells cell death and failure of glucose-stimulated secretion of insulin (GSIS) was evaluated in this study. Methods: Enzyme-linked immunosorbent assay kit for a rat insulin was used to quantify glucose-stimulated insulin secretion. Protein expression was examined by western blotting analysis. Nuclear condensation was measured by staining with Hoechst 33342 stain. Apoptotic cell death was assessed by staining with Annexin V. Oil Red O staining was used to measure lipid accumulation. Results: We screened ginsenosides to prevent palmitic acid-induced cell death and impairment of GSIS in INS-1 pancreatic β-cells and identified protopanaxadiol (PPD) as a potential therapeutic agent. The protection effect of PPD was likely due to a reduction in apoptosis and lipid accumulation. PPD attenuated the palmitic acid-induced increase in the levels of B-cell lymphoma-2-associated X/B-cell lymphoma 2, poly (ADP-ribose) polymerase and cleaved caspase-3. Moreover, PPD prevented palmitic acid-induced impairment of insulin secretion, which was accompanied by an increase in the activation of phosphatidylinositol 3-kinase, peroxisome proliferator-activated receptor γ, insulin receptor substrate-2, serine-threonine kinase, and pancreatic and duodenal homeobox-1. Conclusion: Our results suggest that the protective effect of PPD on lipotoxicity and lipid accumulation induced by palmitic acid in pancreatic β-cells.

• 대한한방부인과학회지
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• 제34권1호
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• pp.48-65
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• 2021

Objectives: This study was designed to evaluate the efficacy of Changbudodam-tang on obesity by using high-fat diet rats. Methods: Rats were divided into five groups. Normal group: Normal diet, Control group: High-fat diet, Positive control group: High-fat diet+Dietamin 4 mg/kg/day, Changbudodam-tang-Low group: High-fat diet+Changbudodam-tang 250 mg/kg/day, Changbudodam-tang-High group: High-fat diet+Changbudodam-tang 500 mg/kg/day. Weight, food intake were measured every week. After 7 weeks, total cholesterol, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol, Triglyceride, free fatty acid, aspartate aminotransferase, alanine aminotransferase, complete blood count were measured and messenger ribonucleic acid expression of adiponectin, peroxisome proliferator-activated receptor-γ, leptin were observed using Reverse transcription polymerase chain reaction of liver cells. Results: There was no difference in food intake between groups. Body weight tended to decrease compared with the Control group, but it wasn't statistically meaningfull. The total cholesterol, low density lipoprotein-cholesterol, Triglyceride, free fatty acid tended to decrease compared with the Control group. High density lipoprotein-cholesterol tended to decrease compared with the Control group, but it wasn't statistically meaningfull. White blood cell, red blood cell, hemoglobin, platelet, aspartate aminotransferase, alanine aminotransferase were not affected by Changbudodam-tang. The messenger ribonucleic acid expression of Adiponectin, peroxisome proliferator-activated receptor-γ, leptin, which are involved in the differentiation of adipocytes, was decreased compared with the Control group. Conclusions: Based on the results above, it is suggested that Changbudodam-tang can be applied to improving serum lipid levels in obese patients caused by high fat diets.

• 생명과학회지
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• 제21권7호
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• pp.932-938
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• 2011

Ginsenoside Rg1은 인삼에서 분리한 약물학적인 활성을 가지는 물질이다. 본 연구는 Rg1이 제2형 당뇨병 모델 동물에서 혈당과 지질대사에 유익한 효과를 가지는지를 확인하기 위한 목적으로 수행되었다. 10주령의 db/db 마우스에 Rg1을 10 mg/kg 농도로 15일간 경구투여한 결과 공복혈당이 감소하였고, 포도당 내성이 개선되었다. 특히 혈중 중성지방과 유리지방산이 유의적으로 감소하였고 혈중 HDL-콜레스테롤이 증가되었다. 또한 chimeric GAL4-PPAR${\alpha}$ receptor 활성 프로모터를 활성화시켰고 PPAR${\alpha}$ gene인 CPT-1 (carnitine palmitoyltransferase-1)과 ACO (acyl-CoA oxidase)의 발현을 증가시켰는데 이것으로 Rg1의 지질대사 개선이 PPAR${\alpha}$ 활성에 의한 지방산 산화에 의한 것임을 확인할 수 있었다. 모든 결과를 종합해 볼 때, Rg1은 제2형 당뇨병과 관련된 고혈당증과 고지혈증에 유용한 효과를 가짐을 확인하였다.

• Asian-Australasian Journal of Animal Sciences
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• 제22권4호
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• pp.576-583
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• 2009

G protein-coupled receptor 43 (GPR43) is a newly-discovered short-chain free fatty acid receptor and its functions remain to be defined. The objective of this study was to investigate the function of GPR43 on lipolysis. We successfully cloned the GPR43 gene from the pig (EU122439), and measured the level of GPR43 mRNA in different tissues and primary pig adipocytes. The expression level of GPR43 mRNA was higher in adipose tissue and increased gradually with adipocyte differentiation. Then we examined GPR43 mRNA level in different types, growth-stages and various regions of adipose tissue of pigs. The results showed that the expression level of GPR43 mRNA was significantly higher in adipose tissue of obese pigs than in lean pigs, and the expression level also gradually increased as age increased. We further found that the abundance of GPR43 mRNA level increased more in subcutaneous fat than visceral fat. Thereafter, we studied the correlation between GPR43 and lipid metabolism-related genes in adipose tissue and primary pig adipocytes. GPR43 gene had significant negative correlation with hormone-sensitive lipase gene (HSL, r = -0.881, p<0.01) and triacylglycerol hydrolase gene (TGH, r = -0.848, p<0.01) in adipose tissue, and had positive correlation with peroxisome proliferator-activated receptor $\gamma$ gene ($PPAR_{\gamma}$, r = 0.809, p<0.01) and lipoprotein lipase gene (LPL, r = 0.847, p<0.01) in adipocytes. In addition, we fed different concentrations of docosahexaenoic acid (DHA) to mice, and analyzed expression level changes of GPR43, HSL and TGH in adipose. The results showed that DHA down-regulated GPR43 and up-regulated HSL and TGH mRNA levels; GPR43 also had significant negative correlation with HSL (low: r = -0.762, p<0.01; high: r = -0.838, p<0.01) and TGH (low: r = -0.736, p<0.01; high: r = -0.586, p<0.01). Our results suggested that GPR43 is a potential factor which regulates lipolysis in adipose tissue, and DHA as a receptor of GPR43 might promote lipolysis through down-regulating the expression of GPR43 mRNA.