Genistein from Vigna angularis Extends Lifespan in Caenorhabditis elegans

( Eun Byeol Lee ),( Dalrae Ahn ),( Ban Ji Kim ),( So Yeon Lee ),( Hyun Won Seo ),( Youn Soo Cha ),( Hoon Jeon ),( Jae Soon Eun ),( Dong Seok Cha ),( Dae Keun Kim ) 한국응용약물학회 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.1

The seed of Vigna angularis has long been cultivated as a food or a folk medicine in East Asia. Genistein (4′,5,7-trihydroxyisoflavone), a dietary phytoestrogen present in this plant, has been known to possess various biological properties. In this study, we investigated the possible lifespan-extending effects of genistein using Caenorhabditis elegans model system. We found that the lifespan of nematode was significantly prolonged in the presence of genistein under normal culture condition. In addition, genistein elevated the survival rate of nematode against stressful environment including heat and oxidative conditions. Further studies demonstrated that genistein-mediated increased stress tolerance of nematode could be attributed to enhanced expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). Moreover, we failed to find genistein-induced significant change in aging-related factors including reproduction, food intake, and growth, indicating genistein exerts longevity activity independent of affecting these factors. Genistein treatment also led to an up-regulation of locomotory ability of aged nematode, suggesting genistein affects healthspan as well as lifespan of nematode. Our results represent that genistein has beneficial effects on the lifespan of C. elegans under both of normal and stress condition via elevating expressions of stress resistance proteins.

Transcriptomic analysis of neutrophil apoptosis induced by diffuse large B-cell lymphoma unveils a potential role in neutropenia

Jeon Byeol-Eun,Lee Ji-Eun,Park Jungwook,Jung Hyejung,Park Eun Gyung,Lee Du Hyeong,Seo Young-Su,Kim Heui-Soo,Shin Ho-Jin,Kim Sang-Woo 한국유전학회 2023 Genes & Genomics Vol.45 No.8

Background Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that arises from malignant transformation of B lymphocytes. Outcome of patients with DLBCL has been significantly improved by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, which is regarded “gold standard” of DLBCL therapy. It is unfortunate that febrile neutropenia, a decrease of the neutrophil count in the blood accompanying fever, is one of the most common complications that DLBCL patients receiving R-CHOP regimen experience. Given the critical role of neutrophils against bacterial and fungal infections, neutropenia could be deadly. While the association between R-CHOP therapy and neutropenia has been well-established, the negative effect of DLBCL cells on the survival of neutrophils has not been clearly understood. Our previous study have shown that conditioned medium (CM) derived from Ly1 DLBCL cells induces apoptosis in murine neutrophils ex vivo. Additionally, Ly1 CM and doxorubicin synergize to further enhance apoptotic rate in neutrophils, possibly contributing to neutropenia in DLBCL patients. Objective We investigated the mechanism and genes that regulate neutrophil apoptosis induced by secretome of DLBCL cells, which would give insight into the potential role of DLBCL in neutropenia. Method Murine neutrophils were isolated from bone marrow in C57BL6/J mice using flow cytometry. QuantSeq 3' mRNA-sequencing was conducted on neutrophils following exposure to CM derived from Ly1 DLBCL cells or murine bone marrow cells (control). Quantseq 3′mRNA sequencing data were aligned to identify differentially expressed mRNAs. Next, the expression of genes related to neutrophil apoptosis and proliferation were analyzed and Gene classification and ontology were analyzed. Result We identified 1196 (198 upregulated and 998 downregulated) differentially expressed genes (DEGs) in Ly1 DLBCL co-culture group compared to the control group. The functional enrichment analyses of DEGs in co-culture group revealed significant enriched in apoptosis process, and immune system process in gene ontology and the highly enriched pathway of various bacterial infection, leukocyte transendothelial migration, apoptosis, and cell cycle in KEGG pathway. Importantly, Bcl7b, Bnip3, Bmx, Mcl1, and Pim1 were identified as critical regulators of neutrophil apoptosis, which may be potential drug targets for the treatment of neutropenia. We are currently testing the efficacy of the activators/inhibitors of the proteins encoded by these genes to investigate whether they would block DLBCL-induced neutrophil apoptosis. Conclusion In the present study, bioinformatic analyses of gene expression profiling data revealed the crucial genes involved in neutrophil apoptosis and gave insight into the underlying mechanism. Given our data, it may be likely that novel opportunities for the treatment of neutropenia, and eventually improvement of prognosis of DLBCL patients, might emerge.

Lifespan Extending and Stress Resistant Properties of Vitexin from Vigna angularis in Caenorhabditis elegans

( Eun Byeol Lee ),( Jun Hyeong Kim ),( Youn-soo Cha ),( Mina Kim ),( Seuk Bo Song ),( Dong Seok Cha ),( Hoon Jeon ),( Jae Soon Eun ),( Sooncheon Han ),( Dae Keun Kim ) 한국응용약물학회 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.6

Several theories emphasize that aging is closely related to oxidative stress and disease. The formation of excess ROS can lead to DNA damage and the acceleration of aging. Vigna angularis is one of the important medicinal plants in Korea. We isolated vitexin from V. angularis and elucidated the lifespan-extending effect of vitexin using the Caenorhabditis elegans model system. Vitexin showed potent lifespan extensive activity and it elevated the survival rates of nematodes against the stressful environments including heat and oxidative conditions. In addition, our results showed that vitexin was able to elevate antioxidant enzyme activities of worms and reduce intracellular ROS accumulation in a dose-dependent manner. These studies demonstrated that the increased stress tolerance of vitexin-mediated nematode could be attributed to increased expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). In this work, we also studied whether vitexin-mediated longevity activity was associated with aging-related factors such as progeny, food intake, growth and movement. The data revealed that these factors were not affected by vitexin treatment except movement. Vitexin treatment improved the body movement of aged nematode, suggesting vitexin affects healthspan as well as lifespan of nematode. These results suggest that vitexin might be a probable candidate which could extend the human lifespan.

NF-κB 신호경로에서 CLK3의 새로운 음성 조절자로서의 기능

전별은(Byeol-Eun Jeon),권찬성(Chan-Seong Kwon),이지은(Ji-Eun Lee),우예린(Ye-Lin Woo),김상우(Sang-Woo Kim) 한국생명과학회 2022 생명과학회지 Vol.32 No.11

만성 염증은 종양의 발생 및 진행과 밀접하게 연관되어 있다. 핵인자 kappa B (NF-κB)는 5개의 전사인자로 구성되며 염증 반응에 필수적인 역할을 한다. 다양한 암에서 NF-κB의 조절장애가 보고되고 있으며 NF-κB 조절이 암 치료에 있어 핵심 표적이 된다. 본 연구에서는 CDC Like Kinase 3 (CLK3)를 NF-κB 신호전달 경로를 조절하는 새로운 키네이스임을 확인하였다. 우리는 CLK3가 정규 및 비정규 NF-κB 신호전달경로를 억제하는 것을 밝혔다. CLK3 과발현 또는 knock-down 세포주를 이용한 루시퍼레이즈 분석 결과, 이 키네이스는 TNFα와 PMA가 유도하는 정규 NF-κB 신호전달경로 활성을 억제하였다. 또한 CLK3 과발현은 잘 알려진 비정규 NF-κB 신호경로 유도제인 NF-κB-inducing kinase (NIK) 또는 CD40에 의한 NF-κB 활성을 저해하였다. 추가적으로 CLK3의 NF-κB 신호전달 저해기전을 설명하고자 TNFα 처리 후 웨스턴 블롯 분석으로 이 키네이스 영향권 내에 있는 NF-κB 신호경로 분자들을 식별하였다. 그 결과 CLK3가 TAK1, IKKα/β, p65, IκBα 및 ERK1/2-MAPK의 인산화/활성화를 저해하여 TNFα 처리로 유도된 NF-κB 및 MAPK 신호경로를 모두 억제함을 밝혔다. 앞으로의 연구는 CLK3가 정규 및 비정규 NF-κB 경로를 억제하는 기작을 밝히는데 초점을 맞출 것이다. 위 연구 결과들을 토대로 CLK3가 NF-κB 신호전달경로의 새로운 음성 조절자로써 기능함을 제시하였다. Chronic inflammation has been shown to be closely associated with tumor development and progression. Nuclear factor kappa B (NF-κB) is composed of a family of five transcription factors. NF-κB signaling plays a crucial role in the inflammatory response and is often found to be dysregulated in various types of cancer, making it an attractive target in cancer therapeutics. In this study, CDC-like kinase 3 (CLK3) was identified as a novel kinase that regulates the NF-κB signaling pathway. Our data demonstrate that CLK3 inhibits the canonical and non-canonical NF-κB pathways. Luciferase assays following the transient or stable expression of CLK3 indicated that this kinase inhibited NF-κB activation mediated by Tumor necrosis factor-alpha (TNFα) and Phorbol 12-myristate 13-acetate (PMA), which are known to activate NF-κB signaling via the canonical pathway. Consistent with data on the ectopic expression of CLK3, CLK3 knockdown using shRNA constructs increased NF-κB activity 1.5-fold upon stimulation with TNFα in HEK293 cells compared with the control cells. Additionally, overexpression of CLK3 suppressed the activation of this signaling pathway induced by NF-κB-inducing kinase (NIK) or CD40, which are well-established activators of the non-canonical pathway. To further examine the negative impact of CLK3 on NF-κB signaling, we performed Western blotting following the TNFα treatment to directly identify the molecular components of the NF-κB pathway that are affected by this kinase. Our results revealed that CLK3 mitigated the phosphorylation/activation of transforming growth factor-β-activated kinase 1 (TAK1), inhibitor of NF-κB kinase alpha/beta (IKKα/β), NF-κB p65 (RelA), NF-κB inhibitor alpha (IκBα), and Extracellular signal-regulated kinase 1/2-Mitogen-activated protein kinase (ERK1/2-MAPK), suggesting that CLK3 inhibits both the NF-κB and MAPK signaling activated by TNFα exposure. Further studies are required to elucidate the mechanism by which CLK3 inhibits the canonical and non-canonical NF-κB pathways. Collectively, these findings reveal CLK3 as a novel negative regulator of NF-κB signaling.

Lifespan Extending and Stress Resistant Properties of Vitexin from Vigna angularis in Caenorhabditis elegans

Lee, Eun Byeol,Kim, Jun Hyeong,Cha, Youn-Soo,Kim, Mina,Song, Seuk Bo,Cha, Dong Seok,Jeon, Hoon,Eun, Jae Soon,Han, Sooncheon,Kim, Dae Keun The Korean Society of Applied Pharmacology 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.6

Several theories emphasize that aging is closely related to oxidative stress and disease. The formation of excess ROS can lead to DNA damage and the acceleration of aging. Vigna angularis is one of the important medicinal plants in Korea. We isolated vitexin from V. angularis and elucidated the lifespan-extending effect of vitexin using the Caenorhabditis elegans model system. Vitexin showed potent lifespan extensive activity and it elevated the survival rates of nematodes against the stressful environments including heat and oxidative conditions. In addition, our results showed that vitexin was able to elevate antioxidant enzyme activities of worms and reduce intracellular ROS accumulation in a dose-dependent manner. These studies demonstrated that the increased stress tolerance of vitexin-mediated nematode could be attributed to increased expressions of stress resistance proteins such as superoxide dismutase (SOD-3) and heat shock protein (HSP-16.2). In this work, we also studied whether vitexin-mediated longevity activity was associated with aging-related factors such as progeny, food intake, growth and movement. The data revealed that these factors were not affected by vitexin treatment except movement. Vitexin treatment improved the body movement of aged nematode, suggesting vitexin affects healthspan as well as lifespan of nematode. These results suggest that vitexin might be a probable candidate which could extend the human lifespan.

Medicinal Chemistry : Article ; A Series of Novel Terpyridine-Skeleton Molecule Derivants Inhibit Tumor Growth and Metastasis by Targeting Topoisomerases

( Han Byeol Kwon ),( Chan Mi Park ),( Kyung Hwa Jeon ),( Eun Young Lee ),( Song Eun Park ),( Kyu Yeon Jun ),( Tara Man Kadayat ),( Pritam Thapa ),( Radha Karki ),( Young Hwa Na ),( Mi Sun Park ),( Seu 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo[4,5]-furo[3,2,-ь]pyridine core and 15 comprising chromeno[4,3-ь]pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-phenylbenzo[4,5]furo[3,2-ь]pyridin-2-yl)phenol (8) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno[4,3-ь]pyridine-2yl)phenol (22) was determined to be a non-intercalative tope IIa specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds 8 and 22 significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds 8 and 22 with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenly)-4-4phenylbenzofuro[ 3,2,] pyridine (8-M) and 3-(4-phenylchromeno-[4,3-ь]pyridine-2-yl)methoxybenzene (22-M), respectively).

Supplement of Zinc in Porcine in vitro Maturation Medium Improves the Porcine Embryonic Development Competence

Yu byeol Jeon,Seung A Jeong,Jun chul Yoon,Lian Cai,Seon Ung Hwang,Eun hye Kim,Sang Hwan Hyun 대한수의학회 2013 대한수의학회 학술대회발표집 Vol.2013 No.-

A Series of Novel Terpyridine-Skeleton Molecule Derivants Inhibit Tumor Growth and Metastasis by Targeting Topoisomerases

Kwon, Han-Byeol,Park, Chanmi,Jeon, Kyung-Hwa,Lee, Eunyoung,Park, So-Eun,Jun, Kyu-Yeon,Kadayat, Tara Man,Thapa, Pritam,Karki, Radha,Na, Younghwa,Park, Mi Sun,Rho, Seung Bae,Lee, Eung-Seok,Kwon, Youngjo American Chemical Society 2015 Journal of medicinal chemistry Vol.58 No.3

<P>A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo[4,5]furo[3,2-<I>b</I>]pyridine core and 15 comprising chromeno[4,3-<I>b</I>]pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-Phenylbenzo[4,5]furo[3,2-<I>b</I>]pyridin-2-yl)phenol (<B>8</B>) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno[4,3-<I>b</I>]pyridine-2-yl)phenol (<B>22</B>) was determined to be a nonintercalative topo IIα specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds <B>8</B> and <B>22</B> significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds <B>8</B> and <B>22</B> with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenyl)-4-phenylbenzofuro[3,2-<I>b</I>]pyridine (<B>8-M</B>) and 3-(4-phenylchromeno[4,3-<I>b</I>]pyridine-2-yl)methoxybenzene (<B>22-M</B>), respectively).</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2015/jmcmar.2015.58.issue-3/jm501023q/production/images/medium/jm-2014-01023q_0017.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm501023q'>ACS Electronic Supporting Info</A></P>

Reproductive Efficiency and Characteristics of Cloned Miniature Piglets Produced from Domestic Commercial Gilts

You, Jin-Young,Jeon, Yu-Byeol,Hyun, Sang-Hwan,Park, Soo-Bong,Lee, Eun-Song 韓國受精卵移植學會 2010 한국동물생명공학회지 Vol.25 No.4

The objective of this study was to examine the reproductive characteristics of cloned miniature piglets produced from surrogate domestic pigs. Somatic cell nuclear transfer (SCNT) miniature pig embryos were transferred into domestic pigs. As controls, domestic pigs of the same breed with surrogates for SCNT embryos and miniature pigs of the same breed with the somatic cell donor were bred by artificial insemination and natural mating, respectively. Surrogate domestic pigs that farrowed cloned miniature piglets had a significantly longer gestation length (118.1 days) than conventionally bred domestic (115.4 days) and miniature (115.5 days) pigs. Furthermore, the birth weight of cloned miniature piglets produced from domestic pigs (743 g) was significantly greater than that of miniature piglets produced by natural breeding (623 g). Also, cloned miniature piglets had a significantly lower weaning rate (49.7%) than conventionally produced domestic (91.5%) and miniature (100%) piglets. No differences were observed between female and male cloned piglets in gestation length, litter size, birth weight, or weaning rate. Our results demonstrate that gestation length is extended in domestic pigs that are transferred with SCNT miniature pig embryos and that cloned miniature piglets have increased birth weight and high pre-weaning mortality.

Antioxidant and Lifespan Extending Property of Quercetin-3-O-dirhamnoside from Curcuma longa L. in Caenorhabditis elegans

Ahn, Dalrae,Lee, Eun Byeol,Kim, Ban Ji,Lee, So Yeon,Lee, Tae Gwan,Ahn, Min-Sil,Lim, Hye Won,Cha, Dong Seok,Jeon, Hoon,Kim, Dae Keun The Korean Society for Applied Biological Chemistr 2014 Applied Biological Chemistry (Appl Biol Chem) Vol.57 No.6

Quercetin-3-O-${\alpha}$-$\small{L}$-rhamnopyranosyl($1{\rightarrow}2$)-O-${\alpha}$-$\small{L}$-rhamnopyranoside (QDR) was isolated from the remaining underground parts of Curcuma longa after harvesting the medicinal parts, and the antioxidant activities in vitro and lifespan-extending effect of QDR were elucidated using the Caenorhabditis elegans model system. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect of QDR showed similar potent activities in comparison with vitamin C. QDR also showed strong superoxide quenching activities as measured by the riboflavin- and xanthine-originated superoxide quenching activities. QDR demonstrated potent lifespan extension of worms under normal culture condition. Subsequently, the protective effect of QDR on the stress conditions such as thermal and oxidative stresses was determined. In the case of heat stress, QDR-treated worms exhibited enhanced survival rate, as compared to control worms. In addition, QDR-fed worms lived longer than control worms under oxidative stress induced by paraquat. To verify the possible mechanism of QDR-mediated increased lifespan and stress resistance of worms, we investigated whether QDR might alter superoxide dismutase (SOD) activity and intracellular reactive oxygen species (ROS) levels. Our results showed that QDR was able to elevate SOD activity of worms and reduce intracellular ROS accumulation in a dose-dependent manner.