Design of PPAR-γ agonist based on algal metabolites and the endogenous ligand 15-deoxy-Δ^{12, 14}-prostaglandin J₂

Ju, Zhiran,Su, Mingzhi,Hong, Jongki,Ullah, Sultan,La Kim, Eun,Zhao, Chang-Hao,Moon, Hyung Ryong,Kim, Suhkmann,Jung, Jee H. Elsevier 2018 European journal of medicinal chemistry Vol.157 No.-

<P><B>Abstract</B></P> <P>In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ<SUP>12, 14</SUP>-prostaglandin J<SUB>2</SUB> (15 d-PGJ<SUB>2</SUB>). The exocyclic enone moiety of 15 d-PGJ<SUB>2</SUB> is essential for covalent bonding with the Cys<SUP>285</SUP> residue in the PPAR-γ ligand-binding domain (LBD). <I>In silico</I> analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ<SUB>2</SUB>. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(<I>R,E</I>)-<B>6a1</B> was suggested as a potential PPAR-γ ligand.</P> <P><B>Highlights</B></P> <P> <UL> <LI> New PPAR-γ ligands were designed based on algal metabolites and endogenous ligand. </LI> <LI> Synthetic analogs were evaluated for PPAR-γ activation by luciferase reporter assay. </LI> <LI> The stereoisomers of the selected analog were compared for PPAR-γ activation. </LI> <LI> (+)-(<I>R</I>,<I>E</I>)-<B>6a1</B> was proposed as a potential PPAR-γ agonist. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Peroxisome Proliferator-Activated Receptor (PPAR) α/γ 작용제

이지현 ( Ji Hyun Lee ) 대한내과학회 2014 대한내과학회지 Vol.87 No.1

PPAR을 활성화시키는 약제는 혈당을 낮추고 인슐린저항성을 감소시키며 동맥경화증 발생에 관여하는 지질대사를 개선하고 염증 반응을 줄여주는 효과가 있어 중요한 당뇨병 치료약제로 생각된다. 하지만 기존의 약제들은 체중증가, 심부전 발생, 심혈관 질환 발생과 골절 등이 증가하여 임상에 서의 사용에 제약이 많다. 새로운 PPAR α/γ 이중 작용제는 당뇨병성 이상지질혈증, 인슐린저항성, 고혈당, 염증반응 등과 같은 심혈관 질환 발생 위험인자를 주 치료 타겟으로 하는 약제이므로 이들 약제의 복합적인 효과는 혈당 조절과 더불어 심혈관 질환 발생을 줄여줄 수 있는 새로운 흥미로운 치료 약제로 기대해 볼 수있다. 현재 임상연구가 진행되고 있는 약제인 aleglitazar의 최근 연구 결과는 적절한 용량에서 충분한 혈당 조절과 지질대사의 효과가 있으며 상대적으로 부작용의 발생을 최소화하는 결과를 보여주고 있다. 최근에는 급성 관상동맥 질환이 발생한 고위험군의 당뇨병 환자를 대상으로 aleglitazar 약제가 심혈관 질환 발생에 미치는 영향에 대한 연구가 진행되고 있으며 연구 결과에 따라 새로운 약제에 대한 임상 적용이 가능해질 것으로 기대된다. Peroxisome proliferator-activated receptor (PPAR) agonists improve glucose control and insulin sensitivity, reduce concentrations of atherogenic lipoproteins, and decrease circulating levels of inflammatory mediators. PPAR activation is considered an important pharmacologic target for patients with type 2 diabetes. However, the PPAR agonists in clinical use have undesirable side effects, including weight gain, heart failure, and bone fractures. PPAR α/γ dual agonists each target one or more of the key cardiometabolicrisk factors of diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation; thus, combining their benefits to provide glucose control and ameliorate cardiovascular risks has emerged as an attractive treatment option. Aleglitazar, which was designed to balance the activation of PPAR α/γ, proved efficacious in improving glycemic control and lipid homeostasis and is anticipated to minimize PPAR-related side effects. Whether the effects of aleglitazar on cardiometabolic risk factors translate into improved cardiovascular outcomes, particularly in high-risk patients, is currently being evaluated by AleCardio, a large, long-term, time-, and event-driven outcome study of type 2 diabetics with recent acute coronary syndrome. (Korean J Med 2014;87:19-25)

Cyclooxygenase-2 Inhibitor Parecoxib Was Disclosed as a PPAR-γ Agonist by In Silico and In Vitro Assay

( Bin Xiao ),( Dan-dan Li ),( Ying Wang ),( Eun La Kim ),( Na Zhao ),( Shang-wu Jin ),( Dong-hao Bai ),( Li-dong Sun ),( Jee H. Jung ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.5

In a search for effective PPAR-γ agonists, 110 clinical drugs were screened via molecular docking, and 9 drugs, including parecoxib, were selected for subsequent biological evaluation. Molecular docking of parecoxib to the ligand-binding domain of PPAR-γ showed high binding affinity and relevant binding conformation compared with the PPAR-γ ligand/antidiabetic drug rosiglitazone. Per the docking result, parecoxib showed the best PPAR-γ transactivation in Ac2F rat liver cells. Further docking simulation and a luciferase assay suggested parecoxib would be a selective (and partial) PPAR-γ agonist. PPAR-γ activation by parecoxib induced adipocyte differentiation in 3T3-L1 murine preadipocytes. Parecoxib promoted adipogenesis in a dose-dependent manner and enhanced the expression of adipogenesis transcription factors PPAR-γ, C/EBPα, and C/EBPβ. These data indicated that parecoxib might be utilized as a partial PPAR-γ agonist for drug repositioning study.

A Novel Partial PPARα/γ Dual Agonist SN159 Improves Insulin Sensitivity

정유정,Yongkai Cao,Suresh Paudel,김기현,윤구,천승훈,Jee-Young Lee,김수남,김용기 대한화학회 2016 Bulletin of the Korean Chemical Society Vol.37 No.2

We here demonstrate that (E)-1-(3-aminophenyl)-3-(5-bromo-4-hydroxy-2-methoxyphenyl)prop-2-en-1-one (SN159) is a novel peroxisome proliferator-activated receptor (PPAR) partial agonist that improves insulin sensitivity. SN159 interacted directly with PPARα and PPARγ, which were confirmed by LanthaScreen ligand binding assay and molecular docking study. SN159 treatment leads to a significant improvement of insulin sensitivity, resulting in enhancing glucose uptake in muscle cells. SN159 stimulated adipogenic differentiation of 3T3-L1 preadipocytes, however, the effects were much weaker than those of PPARγ agonist troglitazone. In parallel, SN159 increased weakly the transcriptional activities of PPARα/γ, compared to the positive control. Furthermore, PPARγ activation and adipogenic differentiation by troglitazone were significantly reduced by treatment with SN159, indicating that SN159 is a partial agonist of PPARs. SN159 was able to enhance fatty acid oxidation and glucose utilization through the dual activation of PPARα/γ. Taken together, these results suggest that SN159 is a novel PPAR partial agonist, which can be used as potential therapeutic agents against type 2 diabetes and related metabolic disorders by enhancing glucose and lipid metabolism.

Anti-adipogenic Effect of Undaria pinnatifida Extracts by Ethanol in 3T3-L1 Adipocytes

HyeJin Kim(김혜진),Chang-Han Kang(강창한),Sung-Koo Kim(김성구) 한국생명과학회 2012 생명과학회지 Vol.22 No.8

미역(Undaria pinnatifada)은 낮은 칼로리 및 요오드의 원료로써 천연체중조절식품으로 알려져 있다. 미역이 체중조절식품으로 알려져 있음에도 불구하고, 지방세포 분화 및 지방축적에 관한 저해 기작은 연구가 미비하다. 본 연구에서는 3T3-L1에서 지방세포로 분화가 일어나는 단계에서 미역에탄올추출물의 효과 및 기작을 확인하였다. 미역에탄올추출물의 독성과 지방축적저해효과는 MTT assay, Oil red O staining, RT-PCR과 western blot으로 분석하였다. 미역에탄올추출물은 50 μg/ml의 농도에서 독성을 띄지 않았다. 3T3-L1의 분화 및 지방세포에서 triglyceride축적과정동안 50 μg/ml의 미역에탄올추출물을 처리하였으며, 미역에탄올추출물은 지방세포에서triglyceride의 축적을 40% 감소시켰다. 지방세포 특이적 단백질인 Peroxisome proliferator activated receptor γ (PPARγ), leptin과 Hormone sensitive lipase (HSL)의 발현은 RT-PCR과 western blot으로 확인하였다. PPARγ의 과발현은 지방세포의 분화를 촉진시킨다. 또한 지방세포 크기의 증가와 세포 내 triglyceride의 함량에 따라 leptin은 세포 외로 분비된다. 그러므로 PPAR γ와 leptin은 비만의 지표로 사용된다. 첨가한 미역에탄올추출물의 농도가 높아질수록 PPARγ와 leptin의 발현이 억제되었다. 이상의 결과를 통하여, 미역의 에탄올 추출물은 지방전구세포의 분화를 억제시키며, 지방세포 내 triglyceride의 축적을 저해하는 것으로 판단된다. Undaria pinnatifada has been used as a natural diet food with few calories and as a source of iodine. Even though U. pinnatifida has been regarded as a diet food, the mechanisms of its inhibitory effects on adipocyte differentiation and the accumulation of fat in adipocytes are poorly understood. In this study, the effect and mechanism of U. pinnatifida ethanol extract on 3T3-L1 differentiation into adipocytes were investigated. The effects of U. pinnatifida ethanol extract on cell viability and the anti-adipogenic effect were investigated via MTT assay, Oil red O staining, RT-PCR, and western blot. The U. pinnatifida ethanol extract did not show toxicity up to a concentration of 50 μg/ml. The addition of U. pinnatifida ethanol extract decreased triglyceride contents by 40% when 50 μg/ml of U. pinnatifida ethanol extract was added during 3T3-L1 differentiation and adipocyte triglyceride formation. The transcription and expression of peroxisome proliferator-activated receptor γ (PPARγ), leptin, and hormone-sensitive lipase (HSL) as adipocyte-specific proteins were determined by RT-PCR and western blot. The overexpression of PPARγ could accelerate adipocyte differentiation. Also, leptin was secreted for triglyceride accumulation in the adipocytes and the increase of adipocyte cell size. Thus, PPARγ and leptin were used as indicators of obesity. PPARγ and leptin were repressed by the increased addition of U. pinnatifida ethanol extract. This indicates that U. pinnatifida was effective as an anti-obesity agent by repressing the differentiation of 3T3-L1 into adipocytes and inhibiting triglyceride formation in adipocytes.

ACT001 alleviates inflammation and pyroptosis through the PPAR-γ/NF-κB signaling pathway in LPS-induced alveolar macrophages

Fu Qiang,Shen Na,Fang Tao,Zhang Hewei,Di Yanbo,Liu Xuan,Du Chao,Guo Jianshuang 한국유전학회 2024 Genes & Genomics Vol.46 No.3

Background ACT001 is an anti-inflammatory agent that has been widely investigated for its role in tumors, intracranial diseases, and fibrotic diseases, but its effect on acute lung injury is less known. Objective The purpose of this study was to investigate the effect and mechanism of ACT001 on regulating inflammation and pyroptosis in lipopolysaccharide (LPS)-induced alveolar macrophages. Methods NR8383 alveolar macrophages treated with LPS were used to replicate the proinflammatory macrophage phenotype observed during acute lung injury. After ACT001 treatment, we measured the secretion and expression levels of critical inflammatory cytokines, the rate of pyroptosis, and the expression of NLRP3 inflammasome-associated proteins and pyroptosis-associated proteins. In addition, we assessed the role of the PPAR-γ/NF-κB signaling pathways and further validated the results with a PPAR-γ inhibitor. Results Our findings confirmed that ACT001 reduced the expression and release of inflammatory factors, attenuated cell pyroptosis, and downregulated the expression of NLRP3, ASC, caspase-1 p20, and GSDMD-N. These effects may be achieved by activating PPAR-γ expression and then inhibiting the NF-κB signaling pathway. When macrophages were treated with the PPAR-γ inhibitor, the protective effects of ACT001 were reversed. Conclusion ACT001 significantly ameliorated inflammation and pyroptosis via the PPAR-γ/NF-κB signaling pathways in LPS-induced NR8383 alveolar macrophages. Background ACT001 is an anti-inflammatory agent that has been widely investigated for its role in tumors, intracranial diseases, and fibrotic diseases, but its effect on acute lung injury is less known. Objective The purpose of this study was to investigate the effect and mechanism of ACT001 on regulating inflammation and pyroptosis in lipopolysaccharide (LPS)-induced alveolar macrophages. Methods NR8383 alveolar macrophages treated with LPS were used to replicate the proinflammatory macrophage phenotype observed during acute lung injury. After ACT001 treatment, we measured the secretion and expression levels of critical inflammatory cytokines, the rate of pyroptosis, and the expression of NLRP3 inflammasome-associated proteins and pyroptosis-associated proteins. In addition, we assessed the role of the PPAR-γ/NF-κB signaling pathways and further validated the results with a PPAR-γ inhibitor. Results Our findings confirmed that ACT001 reduced the expression and release of inflammatory factors, attenuated cell pyroptosis, and downregulated the expression of NLRP3, ASC, caspase-1 p20, and GSDMD-N. These effects may be achieved by activating PPAR-γ expression and then inhibiting the NF-κB signaling pathway. When macrophages were treated with the PPAR-γ inhibitor, the protective effects of ACT001 were reversed. Conclusion ACT001 significantly ameliorated inflammation and pyroptosis via the PPAR-γ/NF-κB signaling pathways in LPS-induced NR8383 alveolar macrophages.

Opuntia humifusa Supplementation Reduces Fat Weight by Increasing PPAR-γ and PGC-1α Protein Expression in the Skeletal Muscle of Rats

Daekeun Kwon(권대근),Junyong Kang(강준용),Jaeseung Kim(김재승),Youngju Song(송영주) 한국생명과학회 2014 생명과학회지 Vol.24 No.1

본 연구는 안정 시 고지방식이 흰쥐의 골격근에서 PPAR-δ, PPAR-γ 그리고 PGC-1α 단백질 발현에 손바닥선인장 보충이 미치는 효과에 대하여 연구하였다. SD계 수컷 흰쥐 16마리를 무작위로 대조군(CG, n=8)과 실험군(EG, n=8)으로 분류하였다. 8주 동안 대조군은 고지방식이를 부하하였으며, 실험군은 5% 손바닥선인장을 보충식이하였다. 본 실험결과, 복부지방과 고환부 지방 중량은 EG군이 CG군에 비해 유의하게 낮게 나타났다(p<0.01). 또한 혈당, 중성지방, 총콜레스테롤의 농도도 EG군이 CG군에 비해 유의하게 낮게 나타났다(p<0.01). 한편, 골격근에서 PPAR-γ와 PGC-1α 단백질 발현은 EG군이 CG군에 비해 유의하게 높게 나타났다(p<0.05). 이상의 결과로부터 손바닥선인장 보충이 고지방식이 흰쥐의 혈당과 중성지방 농도의 감소와 골격근에서 PPAR-γ와 PGC-1α 단백질 발현을 증가시킴으로서 체지방을 감소시켜 체중증가 억제에 긍정적인 영향을 미치는 것으로 나타났다. This study was conducted to investigate the effects of supplementation with Opuntia humifusa on the expression of peroxisome proliferator-activated receptor-delta (PPAR-δ), peroxisome proliferator-activated receptor-gamma (PPAR-γ) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) in the skeletal muscle of rats fed a high-fat diet. Sixteen Sprague-Dawley male rats at 6 weeks of age were randomly divided into 2 groups: a control diet group (CG, n=8) and an experimental diet group (EG, n=8). The rats were fed a high-fat diet (CG) or a high-fat diet supplemented with 5% O. humifusa (EG) for 8 weeks. The results showed that the abdominal fat pad and epididymal fat pad weights were significantly lower in the EG than in the CG (p<0.01). In the blood, serum glucose, triglycerides, and total cholesterol in the EG group were lower than in the CG (p<0.01). The expression of PPAR-γ and PGC-1α protein in the skeletal muscle of the EG was increased compared with that of the CG (p<0.05). These results indicate that 8 weeks of O. humifusa supplementation lowers serum glucose and triglyceride levels and suppresses weight gain by reducing fat weight through an increase in the expression of PPAR-γ and PGC-1α in the muscle tissue of rats.

OxLDL에 의한 신호전달 체계 연구

한창엽,박수영,김영미 국립보건연구원 2000 국립보건원보 Vol.37 No.-

임신 중 저강도 운동량이 태어난 새끼 쥐의 근육에서 PPARs 및 Adiponectin 발현에 미치는 영향

김동현(Kim, Dong-Hyun),김재호(Kim, Jea-Ho),김승석(Km, Seung-Suk) 한국체육과학회 2012 한국체육과학회지 Vol.21 No.2

The purpose of this study, is to learn about the continuous low intensity exercise for pregnant women between the muscles and the effects of obesity-related gene expression. The ICR strain mouse studied low intensity exercise groups for periods of 20 minutes, 30 minutes, and 40 minutes and divided them into groups while comparisons were carried out. The exercise groups were held 4 times a week for three weeks after conducting low intensity exercise and muscle PPARs in the liver of obesity-related genes. Through this Adiponectin gene expression differences were identified. The data collected using ANOVA with intergroup differences were validated. Continuous low intensity exercise in pregnant women with obesity-related gene affects were confirmed and the following conclusions were drawn. 1. PPARa protein expression of PPARs in the group and the non exercise group showed no significant difference from 40 minutes (p<.05), to the non exercise group and the 20 minute group , 30 minute group. Although there was no statistically significant level (p>.05). There was no significant difference in the PPARγ expression of the protein group and the non exercise group the 30 minute groupds and the, 40 minute groups,(p<.05). Also the 20 and 40 minute buneseodo exercise group showed significant differences (p<.05). In the non expression of groups, exercise groups, 20 mins of roasting the exercise group and the 20 minute group the difference was higher, but there were no statistically significant levels (p>.05). 2. Adiponectin expression in the non exercise group and the 20 minute, 30 minute, and 40 minute groups had more expression which was progressively reduced as a result of the differences in the level of statistical significance. (p>.05). Taken together, these results PPARs gene in the non exercise group rather than the control group showed more expression levels, especially in the PPARa exercise group which had no statistically significant results during five to 40 minutes. Therefore it is considered that exercise during pregnancy, will cause the fetus to be affected too much. In addition, the exercise group PPARγ 40 minutes to 30 minutes showed a statistically significant result, this result showed that movement during pregnancy may affect fetal salryodoemyeo a lot. The Adiponectin biundong group the expression levels were higher than in the exercise group, suggesting the effects of the exercise group. However you can see that there is no significant difference. Therefore, the movement of PPARs during pregnancy is a more effective expression of genetic information which appears to be the difference between the amount of feed, and exercise affects that the unborn baby can be effected by. These data suggest that mothers will be able to measure the momentum, maternal fetal and movement which can affect for the better.

Peroxisome Proliferator-Activated Receptor Gamma의 골 작용

박경록,안도환 고신대학교의과대학 2008 고신대학교 의과대학 학술지 Vol.23 No.4

Peroxisome proliferator-activated receptor (PPAR) is a class of the nuclear transcription factors that regulates lipid metabolism and cell differentiation. Among three different PPAR isotypes, PPARγis known to be a critical regulator of adipogenesis. Because osteoblasts and adipocytes are originated from common marrow mesenchymal progenitors, PPARγ can also impact on osteogenesis. Recent evidences have shown that PPARγ plays a certain role in bone metabolism and bone turnover. In this review, we summarize its general bone actions of PPARγ including bone cell growth and differentiation, bone formation and loss.