Design, Synthesis, and Biological Evaluation of Resveratrol Derivatives as $PPAR{\alpha}$ Agonists

Kim, Mi Kyoung,Chong, Youhoon 한국응용생명화학회 2013 Applied Biological Chemistry (Appl Biol Chem) Vol.56 No.3

The peroxisome proliferator-activated receptor subtype ${\alpha}$ ($PPAR{\alpha}$) was established as a molecular target in drug discovery research for new lipid-lowering drugs. Pterostilbene is a naturally occurring $PPAR{\alpha}$ agonist that has been shown to lower plasma lipid concentrations via the activation of $PPAR{\alpha}$. In this study, various pterostilbene conjugates with methyl, amino acid, and pivaloxymethyl (POM) groups at the 4-OH position were synthesized, and the activating effect on $PPAR{\alpha}$ were investigated. Of the conjugates investigated, 4-OMe-pterostilbene had lower activating effect than pterostilbene, but the pterostilbenes with either amino acid (4a and 4b) or POM moiety (5) showed a small but significant increase in $PPAR{\alpha}$ activation of $PPAR{\alpha}$ activity compared to pterostilbene. Therefore, the structure-activity relationship of the pterostilbene conjugates studied indicates that substitution of the free 4-OH moiety of pterostilbene with a nonmethyl group can increase $PPAR{\alpha}$ agonistic activity. This finding warrants further investigation of the structure-activity relationship of the pterostilbene conjugates as potent $PPAR{\alpha}$ agonists.

The SMILE transcriptional corepressor inhibits cAMP response element–binding protein (CREB)–mediated transactivation of gluconeogenic genes

Lee, Ji-Min,Han, Hye-Sook,Jung, Yoon Seok,Harris, Robert A.,Koo, Seung-Hoi,Choi, Hueng-Sik American Society for Biochemistry and Molecular Bi 2018 The Journal of biological chemistry Vol.293 No.34

<P>Under fasting conditions, activation of several hepatic genes sets the stage for gluconeogenesis in the liver. cAMP response element-binding protein (CREB), CREB-regulated transcription coactivator 2 (CRTC2), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) are essential for this transcriptional induction of gluconeogenic genes. PGC-1insight that may help inform potential therapeutic approaches targeting PGC-l alpha-mediated regulation of hepatic glucose metabolism. induction is mediated by activation of a CREB/CRTC2 signaling complex, and recent findings have revealed that small heterodimer partner-interacting leucine zipper protein (SMILE), a member of the CREB/ATF family of basic region-leucine zipper (bZIP) transcription factors, is an insulin-inducible corepressor that decreases PGC-1 alpha expression and abrogates its stimulatory effect on hepatic gluconeogenesis. However, the molecular mechanism whereby SMILE suppresses PGC-1a expression is unknown. Here, we investigated SMII.E's effects on the CREB/CRTC2 signaling pathway and glucose metabolism. We found that SMILE significantly inhibits CREB/ CRTC2-induced PGC-1 alpha expression by interacting with and disrupting the CREB/CRTC2 complex. Consequently, SMILE decreased PGC-1 alpha-induced hepatic gluconeogenic gene expression. Furthermore, SMILE inhibited CREB/CRTC2-induced phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene expression by directly repressing the expression of these genes and by indirectly inhibiting the expression of PGC-1 alpha via CREB/CRTC2 repression. Indeed, enhanced gluconeogenesis and circulating blood glucose levels in mice injected with an adenovirus construct containing a constitutively active CRTC2 variant (CRTC2-S171A) were significantly reduced by WT SMILE, but not by leucine zipper-mutated SMILE. These results reveal that SMILE represses CREB/CRTC2-induced PGC-1 alpha expression, an insight that may help inform potential therapeutic approaches targeting PGC-1 alpha-mediated regulation of hepatic glucose metabolism.</P>

Expression of peroxisome proliferator-activated receptor (PPAR)-${\alpha}$ and PPAR-${\gamma}$ in the lung tissue of obese mice and the effect of rosiglitazone on proinflammatory cytokine expressions in the lung tissue

Ryu, Seung Lok,Shim, Jae Won,Kim, Duk Soo,Jung, Hye Lim,Park, Moon Soo,Park, Soo-Hee,Lee, Jinmi,Lee, Won-Young,Shim, Jung Yeon The Korean Pediatric Society 2013 Clinical and Experimental Pediatrics (CEP) Vol.56 No.4

Purpose: We investigated the mRNA levels of peroxisome proliferator-activated receptor (PPAR)-${\alpha}$, PPAR-${\gamma}$, adipokines, and cytokines in the lung tissue of lean and obese mice with and without ovalbumin (OVA) challenge, and the effect of rosiglitazone, a PPAR-${\gamma}$ agonist. Methods: We developed 6 mice models: OVA-challenged lean mice with and without rosiglitazone; obese mice with and without rosiglitazone; and OVA-challenged obese mice with and without rosiglitazone. We performed real-time polymerase chain reaction for leptin, leptin receptor, adiponectin, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-${\alpha}$, transforming growth factor (TGF)-${\beta}$, PPAR-${\alpha}$ and PPAR-${\gamma}$ from the lung tissue and determined the cell counts and cytokine levels in the bronchoalveolar lavage fluid. Results: Mice with OVA challenge showed airway hyperresponsiveness. The lung mRNA levels of PPAR${\alpha}$ and PPAR-${\gamma}$ increased significantly in obese mice with OVA challenge compared to that in other types of mice and decreased after rosiglitazone administeration. Leptin and leptin receptor expression increased in obese mice with and without OVA challenge and decreased following rosiglitazone treatment. Adiponectin mRNA level increased in lean mice with OVA challenge. Lung VEGF, TNF-${\alpha}$, and TGF-${\beta}$ mRNA levels increased in obese mice with and without OVA challenge compared to that in the control mice. However, rosiglitazone reduced only TGF-${\beta}$ expression in obese mice, and even augmented VEGF expression in all types of mice. Rosiglitazone treatment did not reduce airway responsiveness, but increased neutrophils and macrophages in the bronchoalveolar lavage fluid. Conclusion: PPAR-${\alpha}$ and PPAR-${\gamma}$ expressions were upregulated in the lung tissue of OVA-challenged obese mice however, rosiglitazone treatment did not downregulate airway inflammation in these mice.

Fenofibrate decreases radiation sensitivity via peroxisome proliferator-activated receptor ${\alpha}$-mediated superoxide dismutase induction in HeLa cells

Liu, Xianguang,Jang, Seong-Soon,An, Zhengzhe,Song, Hye-Jin,Kim, Won-Dong,Yu, Jae-Ran,Park, Woo-Yoon The Korean Society for Radiation Oncology 2012 Radiation Oncology Journal Vol.30 No.2

Purpose: The fibrates are ligands for peroxisome proliferator-activated receptor (PPAR) ${\alpha}$ and used clinically as hypolipidemic drugs. The fibrates are known to cause peroxisome proliferation, enhance superoxide dismutase (SOD) expression and catalase activity. The antioxidant actions of the fibrates may modify radiation sensitivity. Here, we investigated the change of the radiation sensitivity in two cervix cancer cell lines in combination with fenofibrate (FF). Materials and Methods: Activity and protein expression of SOD were measured according to the concentration of FF. The mRNA expressions were measured by using real time reverse-transcription polymerase chain reaction. Combined cytotoxic effect of FF and radiation was measured by using clonogenic assay. Results: In HeLa cells total SOD activity was increased with increasing FF doses up to 30 ${\mu}M$. In the other hand, the catalase activity was increased a little. As with activity the protein expression of SOD1 and SOD2 was increased with increasing doses of FF. The mRNAs of SOD1, SOD2, $PPAR{\alpha}$ and $PPAR{\gamma}$ were increased with increasing doses of FF. The reactive oxygen species (ROS) produced by radiation was decreased by preincubation with FF. The surviving fractions (SF) by combining FF and radiation was higher than those of radiation alone. In Me180 cells SOD and catalase activity were not increased with FF. Also, the mRNAs of SOD1, SOD2, and $PPAR{\alpha}$ were not increased with FF. However, the mRNA of $PPAR{\gamma}$ was increased with FF. Conclusion: FF can reduce radiation sensitivity by ROS scavenging via SOD induction in HeLa. SOD induction by FF is related with $PPAR{\alpha}$.

Pioneering PGC-1αα–boosted secretome: a novel approach to combating liver fibrosis

Chang Ho Seo,Gun Hyung Na,Dosang Lee,Jung Hyun Park,Tae Ho Hong,Ok-Hee Kim,Sang Chul Lee,Kee-Hwan Kim,Ho Joong Choi,Say-June Kim 대한외과학회 2024 Annals of Surgical Treatment and Research(ASRT) Vol.106 No.3

Purpose: Liver fibrosis is a critical health issue with limited treatment options. This study investigates the potential of PGC-Sec, a secretome derived from peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)- overexpressing adipose-derived stem cells (ASCs), as a novel therapeutic strategy for liver fibrosis. Methods: Upon achieving a cellular confluence of 70%–80%, ASCs were transfected with pcDNA-PGC-1α. PGC-Sec, obtained through concentration of conditioned media using ultrafiltration units with a 3-kDa cutoff, was assessed through in vitro assays and in vitro mouse models. Results: In vitro , PGC-Sec significantly reduced LX2 human hepatic stellate cell proliferation and mitigated mitochondrial oxidative stress compared to the control-secretome. In an in vivo mouse model, PGC-Sec treatment led to notable reductions in hepatic enzyme activity, serum proinflammatory cytokine concentrations, and fibrosis-related marker expression. Histological analysis demonstrated improved liver histology and reduced fibrosis severity in PGC-Sec–treated mice. Immunohistochemical staining confirmed enhanced expression of PGC-1α, optic atrophy 1 (a mitochondrial function marker), and peroxisome proliferator-activated receptor alpha (an antifibrogenic marker) in the PGC-Sec–treated group, along with reduced collagen type 1A expression (a profibrogenic marker). Conclusion: These findings highlight the therapeutic potential of PGC-Sec in combating liver fibrosis by enhancing mitochondrial biogenesis and function, and promoting antifibrotic processes. PGC-Sec holds promise as a novel treatment strategy for liver fibrosis.

Expression of the genes for peroxisome proliferator-activated receptor-γ, cyclooxygenase-2, and proinflammatory cytokines in granulosa cells from women with polycystic ovary syndrome

Lee, Joong Yeup,Tae, Jin Cheol,Kim, Chung Hyon,Hwang, Doyeong,Kim, Ki Chul,Suh, Chang Suk,Kim, Seok Hyun The Korean Society for Reproductive Medicine 2017 Clinical and Experimental Reproductive Medicine Vol.44 No.3

Objective: To identify differences in the expression of the genes for peroxisome proliferator-activated receptor $(PPAR)-{\gamma}$, cyclooxygenase (COX)-2, and the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor $(TNF)-{\alpha}$ in granulosa cells (GCs) from polycystic ovary syndrome (PCOS) patients and controls undergoing controlled ovarian stimulation. Methods: Nine patients with PCOS and six controls were enrolled in this study. On the day of oocyte retrieval, GCs were collected from pooled follicular fluid. Total mRNA was extracted from GCs. Reverse transcription was performed and gene expression levels were quantified by realtime quantitative polymerase chain reaction. Results: There were no significant differences in age, body mass index, and total gonadotropin dose, except for the ratio of luteinizing hormone to follicle-stimulating hormone between the PCOS and control groups. $PPAR-{\gamma}$ and COX-2 mRNA was significantly downregulated in the GCs of PCOS women compared with controls (p= 0.034 and p= 0.018, respectively), but the expression of IL-6 and $TNF-{\alpha}$ mRNA did not show significant differences. No significant correlation was detected between the expression of these mRNA sequences and clinical characteristics, including the number of retrieved oocytes, oocyte maturity, cleavage, or the good embryo rate. Positive correlations were found among the $PPAR-{\gamma}$, COX-2, IL-6, and $TNF-{\alpha}$ mRNA levels. Conclusion: Our data may provide novel clues regarding ovarian GC dysfunction in PCOS, and indirectly provide evidence that the effect of $PPAR-{\gamma}$ agonists in PCOS might result from alterations in the ovarian follicular environment. Further studies with a larger sample size are required to confirm these proposals.

Expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ in the lung tissue of obese mice and the effect of rosiglitazone on proinflammatory cytokine expressions in the lung tissue

류성록,심재원,김덕수,정혜림,박문수,박수희,이진미,이원영,심정연 대한소아청소년과학회 2013 Clinical and Experimental Pediatrics (CEP) Vol.56 No.4

Purpose: We investigated the mRNA levels of peroxisome proliferator-activated receptor (PPAR)-α,PPAR-γ, adipokines, and cytokines in the lung tissue of lean and obese mice with and without ovalbumin (OVA) challenge, and the effect of rosiglitazone, a PPAR-γ agonist. Methods: We developed 6 mice models: OVA-challenged lean mice with and without rosiglitazone;obese mice with and without rosiglitazone; and OVA-challenged obese mice with and without rosiglitazone. We performed real-time polymerase chain reaction for leptin, leptin receptor, adiponectin,vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, PPAR-α and PPAR-γ from the lung tissue and determined the cell counts and cytokine levels in the bronchoalveolar lavage fluid. Results: Mice with OVA challenge showed airway hyperresponsiveness. The lung mRNA levels of PPARα and PPAR-γ increased significantly in obese mice with OVA challenge compared to that in other types of mice and decreased after rosiglitazone administeration. Leptin and leptin receptor expression increased in obese mice with and without OVA challenge and decreased following rosiglitazone treatment. Adiponectin mRNA level increased in lean mice with OVA challenge. Lung VEGF, TNF-α, and TGF-β mRNA levels increased in obese mice with and without OVA challenge compared to that in the control mice. However, rosiglitazone reduced only TGF-β expression in obese mice, and even augmented VEGF expression in all types of mice. Rosiglitazone treatment did not reduce airway responsiveness,but increased neutrophils and macrophages in the bronchoalveolar lavage fluid. Conclusion: PPAR-α and PPAR-γ expressions were upregulated in the lung tissue of OVA-challenged obese mice however, rosiglitazone treatment did not downregulate airway inflammation in these mice.

Peroxisome Proliferator-Activated Receptor-Gamma Expression in the Lung Tissue of Obese Rats

Su Jin Hwang,Jung Yeon Shim,김정호,심재원,김덕수,정혜림,박문수,이원영,김세연 연세대학교의과대학 2011 Yonsei medical journal Vol.52 No.3

Purpose: Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator-activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats. Materials and Methods: Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1,AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR. Results: PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats. Conclusion: PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.

Design, Synthesis, and Biological Evaluation of Resveratrol Derivatives as PPARα Agonists

김미경,정유훈 한국응용생명화학회 2013 Applied Biological Chemistry (Appl Biol Chem) Vol.56 No.3

The peroxisome proliferator-activated receptor subtype α (PPARα) was established as a molecular target in drug discovery research for new lipid-lowering drugs. Pterostilbene is a naturally occurring PPARα agonist that has been shown to lower plasma lipid concentrations via the activation of PPARα. In this study,various pterostilbene conjugates with methyl, amino acid, and pivaloxymethyl (POM) groups at the 4-OH position were synthesized, and the activating effect on PPARα were investigated. Of the conjugates investigated, 4-OMe-pterostilbene had lower activating effect than pterostilbene, but the pterostilbenes with either amino acid (4a and 4b) or POM moiety (5) showed a small but significant increase in PPARα activation of PPARα activity compared to pterostilbene. Therefore, the structure-activity relationship of the pterostilbene conjugates studied indicates that substitution of the free 4-OH moiety of pterostilbene with a nonmethyl group can increase PPARα agonistic activity. This finding warrants further investigation of the structure-activity relationship of the pterostilbene conjugates as potent PPARαagonists.

Fibrates Revisited: Potential Role in Cardiovascular Risk Reduction

김남훈,김신곤 대한당뇨병학회 2020 Diabetes and Metabolism Journal Vol.44 No.2

Fibrates, peroxisome proliferator-activated receptor-α agonists, are potent lipid-modifying drugs. Their main effects are reduction of triglycerides and increase in high-density lipoprotein levels. Several randomized controlled trials have not demonstrated their benefits on cardiovascular risk reduction, especially as an “add on” to statin therapy. However, subsequent analyses by major clinical trials, meta-analyses, and real-world evidence have proposed their potential in specific patient populations with atherogenic dyslipidemia and metabolic syndrome. Here, we have reviewed and discussed the accumulated data on fibrates to understand their current status in cardiovascular risk management.