PPARα/β agonist MHY2013 attenuates age-associated renal fibrosis

( Sugyeong Ha ),( Ki Wung Chung ),( Hee Jin Jung ),( Seong Min Kim ),( Hye Jin An ),( Hyung Ryoung Moon ),( Hae Young Chung ) 한국장기요양학회 2018 한국장기요양학회 추계학술대회자료집 Vol.2018 No.-

Recent studies have reported that maintaining adequate lipid metabolism is important in the prevention of renal fibrosis during aging. Although PPARα/β activation has been shown to give beneficial effects on age-associated renal changes, the effects of PPARα/β activation on age-associated renal fibrosis have not been investigated yet. Here, we show PPARα/β activator, MHY2013, can significantly alter lipid metabolism in NRK52E renal tubule epithelial cells and attenuate renal fibrosis in aged rat. We found that MHY2013 increased activity of PPARα/ β in NRK52E cells. The increased PPARα/β activity also exerted increase in FAO-associated PPARα/β target genes. In addition, TGF-β and oleic acid-induced lipid accumulation and fibrosis associated gene expression were decreased by MHY2013 in NRK52E cells. To evaluate the effects of MHY2013 on age-associated renal fibrosis, MHY2013 was per-orally administered in aged rat. MHY2013 increased PPARα/β activation and reduced renal lipid accumulation in aged kidney. Furthermore, renal fibrosis was significantly decreased by MHY2013 indicating importance of lipid metabolism on age-associated renal fibrosis. Decrease of fibrosis was followed by attenuation of inflammation in aged rat. Taken together, our results suggest that activation of PPARα/β signaling during aging alleviates abnormal lipid accumulation and reduces age-associated renal fibrosis.

Renal tubular PAR2 promotes interstitial fi brosis by increasing infl ammatory responses and EMT process

Sugyeong Ha,Ki Wung Chung,Jaewon Lee,Hae Young Chung,Hyung Ryong Moon 대한약학회 2022 Archives of Pharmacal Research Vol.45 No.3

Renal fi brosis is defi ned by excessive extracellularmatrix (ECM) accumulation and is associated witha decreased kidney function. Increased infl ammation andinfi ltration of infl ammatory cells are the key features ofrenal fi brosis development; however, the mechanism ofhow infl ammation starts is still un-known. Here, we showthat the activation of epithelial Protease-activating receptor2 (PAR2) signaling plays an important role in the initiationof infl ammation via increased chemokine expression andinfl ammatory cell induction. In the adenine diet-inducedrenal fi brosis mouse model, PAR2 expression was signifi -cantly increased in the renal tubule region. Kidneys fromPAR2-knockout mice were protected from adenine dietinducedrenal fi brosis, kidney dysfunction, and infl ammation. Using NRK52E kidney epithelial cells, we furtherelucidated the mechanisms underlying these processes. Activation of PAR2 signaling pathway by PAR2 agonistspecifi cally increased the levels of chemokines, includingMCP1 and MCP3, via the MAPK-NF-κB signaling pathway. Inhibition of the MAPK signaling pathway attenuated PAR2agonist-induced NF-κB activation, chemokine expression, and macrophage cell induction. Furthermore, PAR2 activationdirectly increased mesenchymal cell markers in epithelialcells. Taken together, we found that increased PAR2expression and the PAR2/MAPK signaling pathway promoterenal fi brosis by increasing the infl ammatory responses andpromoting EMT process.

Modulatory Effects of Calorie Restriction on Senoinflammation Underlying Aging Process

방은진,정희진,김대현,Sugyeong Ha,Byung Pal Yu,Hae Young Chung 대한약학회 2019 약학회지 Vol.63 No.5

Age-related chronic inflammation is characterized by dysregulated inflammation that is not resolved by themultivariate low, chronic, and systemic inflammatory reactions that aggravate aging progression. A novel concept ofsenoinflammation proposes an age-related senescent inflammation, which is an integrated systemic view of chronicinflammation and metabolism. It discusses multiphase inflammatory networks and pro-inflammatory pathways in aging,including hyperactivation of nuclear factor (NF)-κB signaling and persistent secretion of cytokines, chemokines andinduction of endoplasmic reticulum (ER) stress and lipids accumulation. Previously reporting evidence suggests that caloricrestriction (CR) lowers oxidative stress and mediates anti-inflammatory action in age-related diseases, including metabolicsyndrome and inflammatory diseases. This review focuses on senoinflammation and modulatory effects of CR, which is awell-known nutritional mediator of reduced energy intake. CR is known to increase maximum life expectancy and preventage-related illnesses. Therefore, CR is well-accepted standard for aging intervention studies to discover the basic molecularmechanism of the original aging process. The current focus of CR research is on beneficial effects on decline in agerelatedphysiological functions and preventing and delaying age-related diseases. The development of the non-human andhuman CR research studies provides assuring possibility for the beneficial effects of CR on healthy aging. Some majorissues in understanding the anti-aging mechanism in CR studies are the importance of modulating chronic inflammationat the molecular level and consequential gene expression regulation of chromatin and histone modification. Furthermore,beneficial effects of CR mimetics (CRM) are discussed in comparison with that of CR.

Synergistically enhanced photocatalytic activity of graphitic carbon nitride and WO₃ nanohybrids mediated by photo-Fenton reaction and H₂O₂

Yoon, Minji,Oh, Youngtak,Hong, Sugyeong,Lee, June Sang,Boppella, Ramireddy,Kim, Sun Hee,Marques Mota, Filipe,Kim, Sang Ouk,Kim, Dong Ha Elsevier 2017 Applied Catalysis B Vol.206 No.-

<P><B>Abstract</B></P> <P>The development of solar energy conversion in the production of fuels, water splitting and water purification systems, has become an important sidestep for traditional fossil energy. Herein we have investigated the coupling effect of a Photo-Fenton system on a conventional photocatalytic reaction with a novel Fe-doped C<SUB>3</SUB>N<SUB>4</SUB>/WO<SUB>3</SUB> hybrid structure. The decomposition of <I>p</I>-nitrophenol was selected as a model reaction in the context of the degradation of organic pollutants. Heterojunction nanocomposites consisting of g-C<SUB>3</SUB>N<SUB>4</SUB> nanosheets and WO<SUB>3</SUB> nanoparticles were shown to facilitate the separation of photo-induced electron and hole pairs. The photocatalytic activity was further maximized as a result of a synergism of the ‘Photo-Fenton cycle’ with Fe(II) or Fe(III)-doping in the presence of H<SUB>2</SUB>O<SUB>2</SUB> to generate additional hydroxyl radicals. As a result, after 4h under visible light the degradation of <I>p</I>-nitrophenol could be remarkably enhanced from 10 to 90% compared to the g-C<SUB>3</SUB>N<SUB>4</SUB> reference. To the best of our knowledge, this is the first time such a striking increase is reported with a Photo-Fenton system applied in the present photocatalytic system. The significance of the presence of hydroxyl radicals in the photo-Fenton performance of Fe-doped C<SUB>3</SUB>N<SUB>4</SUB>/WO<SUB>3</SUB> was assessed by scavenger and fluorescence tests. Additional light was shed into the reaction mechanism <I>via</I> spin trapping enabled by <I>in-situ</I> electron paramagnetic resonance.</P> <P><B>Highlights</B></P> <P> <UL> <LI> First report of Fe-coordinated C<SUB>3</SUB>N<SUB>4</SUB>/WO<SUB>3</SUB> hybrids as an effective photo-Fenton system. </LI> <LI> Degradation of PNP enhanced from 10 to 90% under visible light, compared to C<SUB>3</SUB>N<SUB>4</SUB>. </LI> <LI> C<SUB>3</SUB>N<SUB>4</SUB> and WO<SUB>3</SUB> facilitate the separation of photo-induced electron and hole pairs. </LI> <LI> Fe-species generate additional hydroxyl radicals in the presence of H<SUB>2</SUB>O<SUB>2</SUB>. </LI> <LI> Complementary analysis shed light on the mechanism and significance of OH radicals. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

항산화 및 암전이 관련 단백질의 발현에 미치는 콩잎낙엽 에탄올 추출물의 영향

송채은(Chaeeun Song),이수경(Su-Gyeong Lee),홍수경(Sugyeong Hong),류준하(Zoon Ha Ryu),김문무(Moon-Moo Kim),오영희(Yunghee Oh) 한국생명과학회 2016 생명과학회지 Vol.26 No.4

콩잎은 골다공증 및 유방암 발생을 예방한다고 널리 보고되고 있다. 이를 바탕으로 콩잎낙엽 에탄올 추출물(SBFL)을 제조하여 암 전이와 관련 있는 세포침윤에 대한 효과를 조사하기 위하여 섬유아육종세포(HT1080)에서 SBFL이 항산화와 matrix metalloproteinases (MMPs)에 미치는 영향을 분석하였다. 본 연구에서 활성산소의 소거효과에 대한 SBFL효과는 DPPH radical, 환원력 및 지질과산화실험으로 평가되었다, 본 연구에서 SBFL은 양성대조군으로 사용된 vitamin C 및 vitamin E와 비교 시 우수한 항산화 효과를 보여주었다. 다음으로 SBFL의 세포독성을 측정하기 위하여 MTT assay를 수행한 결과 16 μg/ml 이상의 농도에서 세포독성을 보여주었다. SBFL은 gelatin zymography 실험에서 phorbol 12-myristate 13-acetae (PMA) 혹은 phenazine methosulfate (PMS)로 자극된 암 전이에서 중요한 MMP-9의 활성을 감소시켰다. 특히 SBFL은 단백질 발현 실험에서 SOD-1, p-FoxO-1의 발현을 증가시켰다. 더욱이 vascular endothelial growth Factor (VEGF)로 자극된 세포 침윤이 SBFL처리에 의하여 억제되는 것으로 나타났다. 이러한 연구결과를 바탕으로 SBFL은 뛰어난 항산화 효과는 산화적 스트레스를 감소시키고 MMP-9의 활성과 세포침윤을 억제시켜 암 전이의 예방을 위한 유효성분으로 이용될 수 있다는 것을 암시하고 있다. Soybean leaves, a Korean edible plant material, have been reported to prevent the development of osteoporosis and breast cancer. Based on this rational, soybean fallen leaves ethanolic extract (SBFL) was used for the experiment of cell invasion related to metastasis and antioxidant activity. The effect of SBFL on matrix metalloproteinases (MMPs) in human fibrosarcoma cells, HT1080 as well as its antioxidant activity was investigated in this study. The effect of SBFL on scavenging activity of reactive oxygen species was evaluated in vitro using lipid peroxidation assay,DPPH radical and reducing power assay. SBFL showed the positive effects on antioxidant activity, compared with vitamin C and vitamin E used as positive controls. Furthermore, SBFL showed cytotoxicity above 16 μg/ml in MTT assay. In particular, it was found that SBFL decreased the activation of MMP-9 stimulated by phorbol 12-myristate 13-acetae (PMA) and phenazine methosulfate (PMS). SBFL treatment increased the expression levels of p-FoxO-1 and SOD-1. Moreover, SBFL inhibited cell invasion stimulated by vascular endothelial growth Factor (VEGF). These results indicate that SBFL could inhibit cell invasion related to the activation of MMP-9 and oxidative stress, suggesting that it could be available as a main ingredient for prevention of metastasis.

Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction

( Dae Hyun Kim ),( A Kyoung Lee ),( Min Kyung Hyun ),( Sugyeong Ha ),( Eun Jin Bang ),( Sang Gyun Noh ),( Byeong Moon Kim ),( Hee Jin Jung ),( Hae Young Chung ) 한국장기요양학회 2018 한국장기요양학회 추계학술대회자료집 Vol.2018 No.-

β-Hydroxybutyrate (HB) is a ketone body used as an energy source that has shown anti-inflammatory effects similar to calorie restriction (CR); however, its underlying mechanism remains unknown. Here, we examine the novel signaling mechanism of HB in aging-related inflammation. The FoxO has been proposed to promote resistance to oxidative stress and inhibits expression of pro-inflammatory genes through the PI3K/Akt pathway. Another pro-inflammatory transcription factor is NF-kB, which upregulates cytokine expressions. However, PGC-1α, an abundantly expressed co-factor in the kidney, was reported to interact with both FoxO1 and NF-kB although the definitive interactive mechanism has not yet been reported. In this study, we investigated whether renal aging-related inflammation is modulated by HB. We compared aged rats administered with HB to calorie restricted rats and examined the modulation of FoxO1 and the NF-kB pathway through interactions with PGC-1α. We found that in aged rats treated with HB, pro-inflammatory signaling changes were reversed and showed effects comparable to CR. As FoxO1 and its target genes catalase/MnSOD were upregulated by HB treatment and PGC-1α selectively interacted with FoxO1, not with NF-kB, and ameliorated the renal inflammatory response. These findings were further confirmed using FoxO1 overexpression and siRNA transfection in vitro. Our findings suggest that HB suppressed aging-related inflammation as a CR mimetic by enabling the co-activation and selective interaction between FoxO1 and PGC-1α. This study demonstrates the potential therapeutic role of HB as a CR mimetic, which ameliorates inflammation by a novel mechanism where FoxO1 outcompetes NF-kB by interacting with PGC-1α in aging kidneys.

A potent tyrosinase inhibitor, (E)-3-(2,4-dihydroxyphenyl)-1-(thiophen-2-yl)prop-2- en-1-one, with anti-melanogenesis properties in á-MSH and IBMX-induced B16F10 melanoma cells

( Hee Jin Jung ),( Sang Gyun Noh ),( Dae Hyun Kim ),( Eun Jin Bang ),( Sugyeong Ha ),( A Kyoung Lee ),( Min Kyung Hyun ),( Byeong Moo Kim ),( Chang Seok Kim ),( Hae Young Chung ) 한국장기요양학회 2018 한국장기요양학회 추계학술대회자료집 Vol.2018 No.-

In this study, we designed and synthesized eight heterocyclic chalcone derivatives (1a - 1h) as tyrosinase inhibitors and evaluated their mushroom tyrosinase inhibitory activities. Of these 8 compounds, (E)-3-(2,4-dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (1c) showed strong competitive inhibition activity against mushroom tyrosinase with IC50 values of 0.013 μM for tyrosine hydroxylase and 0.93 μM for dopa oxidase. As an underlying mechanism of 1c mediated anti-melanogenic effect, we investigated the inhibitory activity against melanin contents and cellular tyrosinase. In addition, we used a kinetics study and docking program to further evaluate the inhibitory mechanism of 1c toward tyrosinase. The enzyme kinetics and docking results supports that 1c highly interacts with tyrosinase residues in the tyrosinase active site and it can directly inhibit tyrosinase as competitive inhibitor. Moreover, we examined the inhibitory effect of 1c on tyrosinase expression through protein kinase A (PKA), cAMP response element-binding protein (CREB) and microphthalmia-associated transcription factor (MITF) signaling on á-melanocyte stimulating hormone (á-MSH) and IBMX-induced B16F10 melanoma cells. As the results, 1c decreased the expression levels of PKA, CREB, MITF, and tyrosinase pathways. Furthermore, 1c interfered with the phosphorylation of PKA and tyrosinase demonstrating potent anti-melanogenic effects on á-MSH and IBMX-induced B16F10 cells in cytosolic fractions. Overall, our results suggested that 1c might be considered potent candidates for use in the development of therapeutic agents for diseases associated with hyperpigment disorders.

Small RNAs induce the activation of the pro‐inflammatory TLR7 signaling pathway in aged rat kidney

Lee, Eun Kyeong,Chung, Ki Wung,Kim, Ye Ra,Ha, Sugyeong,Kim, Sung Dae,Kim, Dae Hyun,Jung, Kyung Jin,Lee, Bonggi,Im, Eunok,Yu, Byung Pal,Chung, Hae Young John Wiley and Sons Inc. 2017 Aging cell Vol.16 No.5

<P><B>Summary</B></P><P>We have recently reported that TLR‐related genes, including TLR7, are upregulated during aging. However, the role of TLR7 and its endogenous ligand in inflammation related to aging is not well defined. Here, we established that small RNAs trigger age‐related renal inflammation <I>via</I> TLR7 signaling pathway. We first investigated the expression changes of nine different TLRs in kidney of 6‐month‐old young rats and 20‐month‐old aged rats. The results revealed that the expression of TLR7 was the highest among nine TLRs in kidney of old rats compared to the young aged rats. Next, to assess the role of cellular RNA as a TLR7 ligand, we treated a renal tubular epithelial cell line with total RNA isolated from the kidney of young and old rats. The results showed that RNA isolated from old rats showed higher expression of TLR7, IL1β, and TNFα compared to that from young rats. Furthermore, RNA isolated from old rats induced IKKα/β/JNK/NF‐κB activation. To identify RNA that activates TLR7, we isolated small and large RNAs from old rat kidney and found that small RNAs increased TLR7 expression in cells. Finally, to investigate the local inflammatory response by small RNA, C57B/L6 mice were intraperitoneally injected with small RNAs isolated from young and old rats; thereby, RNA isolated from old rats induced higher inflammatory responses. Our study demonstrates that renal small RNAs from aged rats induce pro‐inflammatory processes <I>via</I> the activation of the TLR7/IKKα/β/JNK/NF‐κB signaling pathway, and highlights its causative role as a possible therapeutic target in age‐related chronic renal inflammation.</P>

(E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one 유도체들의 tyrosinase 활성억제 효과

이은경(Eun Kyeong Lee),김주현(Ju Hyun Kim),문경미(Kyoung Mi Moon),하수경(Sugyeong Ha),노상균(Sang-Gyun Noh),김대현(Dae Hyun Kim),이봉기(Bonggi Lee),김도현(Do Hyun Kim),김수정(Su Jeong Kim),울라술탄(Sultan Ullah),문형룡(Hyung Ryong Moo 한국생명과학회 2017 생명과학회지 Vol.27 No.2

본 연구에서는 (E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one 유도체들을 합성했으며, 합성된 유도체들이 멜라닌 생성과정의 주요 효소인 tyrosinase 활성을 저해할 수 있는지에 대하여 확인하였다. 19종류의 유도체들의 tyrosinase 저해활성을 측정해본 결과, MHY3655 (IC50 = 0.1456 μM)가 가장 큰 저해활성을 나타냈으며 이는 대조군인 코직산(IC50 = 17.2 μM) 보다 큰 효능을 보였다. 게다가, Lineweaver-Burk 분석법을 이용하여 MHY3655가 경쟁적 저해 기전으로 tyrosinase 활성을 저해하였고, docking simulation으로 MHY3655가 tyrosinase에 직접 결합함을 재확인하였다. 마지막으로, B16F10 melanoma 세포에서 MHY3655의 세포독성을 평가한 결과 1-20 μM 사이의 MHY3655는 세포독성을 나타내지 않았다. 이상의 결과에서, 신물질 MHY3655은 우수한 tyrosinase 저해활성을 나타내며, 이는 미백 화장품 소재로서 활용할 가치가 있으리라 사료된다. The inhibition of tyrosinase, a key enzyme in mammalian melanin synthesis, plays an important role in preventing skin pigmentation and melanoma. Therefore, tyrosinase inhibitors are very important in the fields of medicine and cosmetics. However, only a few tyrosinase inhibitors are currently available because of their toxic effects on skin or lack of selectivity and stability. Therefore, we synthesized a novel series of (E)-2-(substituted benzylidene)-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one derivatives and evaluated their inhibitory effects on mushroom tyrosinase, with the aim of discovering a novel tyrosinase inhibitor. Among 19 derivatives, MHY3655 (IC50 = 0.1456 μM) showed the strongest inhibitory effect on tyrosinase activity compared to kojic acid (IC50 = 17.2 μM), a well-known tyrosinase inhibitor. In addition, MHY3655 showed competitive inhibition on Lineweaver-Burk plots. We confirmed that MHY3655 strongly interacts with mushroom tyrosinase residues through the docking simulation. Substitutions with a hydroxy group at both R2 and R4 in the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase. Further, MHY3655 did not show cytotoxicity at the concentrations tested in B16F10 melanoma cells. In conclusion, the novel compound MHY3655 potentially shows tyrosinase inhibitory activity, and it could be used as an ingredient in whitening cosmetics.

Modulation of senoinflammation by calorie restriction based on biochemical and Omics big data analysis

( Eunjin Bang ),( Bonggi Lee ),( Sang-gyun Noh ),( Dae Hyun Kim ),( Hee Jin Jung ),( Sugyeong Ha ),( Byung Pal Yu ),( Hae Young Chung ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.1

Aging is a complex and progressive process characterized by physiological and functional decline with time that increases susceptibility to diseases. Aged-related functional change is accompanied by a low-grade, unresolved chronic inflammation as a major underlying mechanism. In order to explain aging in the context of chronic inflammation, a new integrative concept on age-related chronic inflammation is necessary that encompasses much broader and wider characteristics of cells, tissues, organs, systems, and interactions between immune and non-immune cells, metabolic and non-metabolic organs. We have previously proposed a novel concept of senescent (seno)-inflammation and provided its frameworks. This review summarizes senoinflammation concept and additionally elaborates modulation of senoinflammation by calorie restriction (CR). Based on aging and CR studies and systems-biological analysis of Omics big data, we observed that senescence associated secretory phenotype (SASP) primarily composed of cytokines and chemokines was notably upregulated during aging whereas CR suppressed them. This result further strengthens the novel concept of senoinflammation in aging process. Collectively, such evidence of senoinflammation and modulatory role of CR provide insights into aging mechanism and potential interventions, thereby promoting healthy longevity. [BMB Reports 2019; 52(1): 56-63]