Dequalinium-based functional nanosomes show increased mitochondria targeting and anticancer effect

Bae, Yoonhee,Jung, Min Kyo,Lee, Seulgi,Song, Su Jeong,Mun, Ji Young,Green, Eric S.,Han, Jin,Ko, Kyung Soo,Choi, Joon Sig WISSENSCHAFTLISCHE VERLAGSGESELLSCHAFT MBH 2018 EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEU Vol.124 No.-

<P><B>Abstract</B></P> <P>Mitochondria are targets with great potential for therapeutics for many human disorders. However, drug delivery systems for such therapeutics remain in need of more efficient mitochondrial-targeting carriers. In this study, we report that nanosomes composed of Dequalinium/DOTAP (1,2-dioleoyl-3-trimethylammonium-propane)/DOPE (1,2-dioleoyl-<I>sn</I>-glycero-3-phosphoethanolamine), called DQA80s, can act in the dual role of mitochondrial-targeting carrier and anticancer agent for therapeutic interventions against mitochondrial diseases. In cytotoxicity assays, DQA80s were shown to be more toxic than DQAsomes. The DQA80s showed significantly increased cellular uptake as compared to that of DQAsomes, and DQA80s also showed more efficient escape from the endolysosome to the cytosol. We observed the efficient targeting of DQA80s to mitochondria in living cells using flow cytometry, confocal microscopy, and TEM imaging. We also found evidence of anticancer potential that mitochondrial-targeted DQA80s induced apoptosis by production of reactive oxygen species (ROS) via MAPK signaling pathways, loss of mitochondrial membrane potential, and the caspase-3 activation. The present study demonstrates that DQA80s have excellent dual potential both as a carrier and as an anticancer therapeutic for mitochondria-related disease therapy <I>in vivo</I>.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Functional nanosome for enhanced mitochondria-targeted gene delivery and expression

Bae, Yoonhee,Jung, Min Kyo,Song, Su Jeong,Green, Eric S.,Lee, Seulgi,Park, Hyun-Sook,Jeong, Seung Hun,Han, Jin,Mun, Ji Young,Ko, Kyung Soo,Choi, Joon Sig Elsevier 2017 Mitochondrion Vol.37 No.-

<P><B>Abstract</B></P> <P>Mitochondria dysfunction plays a role in many human diseases. Therapeutic techniques for these disorders require novel delivery systems that can specifically target and penetrate mitochondria. In this study, we report a novel nanosome composed of dequalinium-DOTAP-DOPE (1,2 dioleoyl-3-trimethylammonium-propane-1,2-dioleoyl-<I>sn</I>-glycero-3-phosphoethanolamine) (DQA80s) as a potential mitochondria-targeting delivery vector. The functional DQAsome, DQA80s, showed enhanced transfection efficiency compared to a vector DQAsomes in HeLa cells and dermal fibroblasts. In addition, DQA80s/pDNA complexes exhibited rapid escape from the endosome into the cytosol. We observed the delivery of pDNA to mitochondria in living cells using flow cytometry, confocal microscopy, and TME imaging. More specifically, we confirmed our results by co-localization of hmtZsGreen constructs to mitochondria when delivered via DQAsomes and DQA80s in living cells. The mitochondria-targeting DQAsomes and DQA80s induced mitochondrial dysfunction through depolarization of mitochondrial membrane potential. Our data demonstrate that DQA80s show promise for use as a mitochondria-targeted carrier system for treatment of mitochondria diseases in vivo.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Formulation and characterization of novel nanosome as a potential mitochondria-targeting delivery vector </LI> <LI> DQA80s/pDNA complexes exhibited a rapid endolysosomal escape and enhanced mitochondrial targeting in living cells. </LI> <LI> DQA80s/hmtGFP construct complexes showed expression at mitochondrial region in living cells. </LI> <LI> DQA80s induced mitochondria dysfunction via depolarization of mitochondrial membrane potential in cancer cells. </LI> </UL> </P>

Gallic acid-mitochondria targeting sequence-H3R9 induces mitochondria-targeted cytoprotection

Yoonhee Bae,Goo-Young Kim,Flores Jessa,Kyung Soo Ko,Jin Han 대한생리학회-대한약리학회 2022 The Korean Journal of Physiology & Pharmacology Vol.26 No.1

The development of selective targeting of drug molecules towards the mitochondria is an important issue related to therapy efficacy. In this study, we report that gallic acid (GA)-mitochondria targeting sequence (MTS)-H3R9 exhibits a dual role as a mitochondria-targeting vehicle with antioxidant activity for disease therapy. In viability assays, GA-MTS-H3R9 showed a better rescue action compared to that of MTS-H3R9. GA-MTS-H3R9 dramatically exhibited cell penetration and intercellular uptake compared to MTS and fit escape from lysosome release to the cytosol. We demonstrated the useful targeting of GA-MTS-H3R9 towards mitochondria in AC16 cells. Also, we observed that the antioxidant properties of mitochondrial-accrued GA-MTSH3R9 alleviated cell damage by reactive oxygen species production and disrupted mitochondrial membrane potential. GA-MTS-H3R9 showed a very increased cytoprotective effect against anticancer activity compared to that of MTS-H3R9. We showed that GA-MTS-H3R9 can act as a vehicle for mitochondria-targeting and as a reagent for therapeutic applications intended for cardiovascular disease treatment.

Apoptin gene delivery by a PAMAM dendrimer modified with a nuclear localization signal peptide as a gene carrier for brain cancer therapy

Yoonhee Bae,Jell Lee,Changwon Kho,Joon Sig Choi,Jin Han 대한생리학회-대한약리학회 2021 The Korean Journal of Physiology & Pharmacology Vol.25 No.5

In this study, we aimed to synthesize PAMAMG3 derivatives (PAMAMG3- KRRR and PAMAMG3-HKRRR), using KRRR peptides as a nuclear localization signal and introduced histidine residues into the KRRR-grafted PAMAMG3 for delivering a therapeutic, carcinoma cell-selective apoptosis gene, apoptin into human primary glioma (GBL-14) cells and human dermal fibroblasts. We examined their cytotoxicity and gene expression using luciferase activity and enhanced green fluorescent protein PAMAMG3 derivatives in both cell lines. We treated cells with PAMAMG3 derivative/ apoptin complexes and investigated their intracellular distribution using confocal microscopy. The PAMAMG3-KRRR and PAMAMG3-HKRRR dendrimers were found to escape from endolysosomes into the cytosol. The JC-1 assay, glutathione levels, and Annexin V staining results showed that apoptin triggered cell death in GBL-14 cells. Overall, these findings indicated that the PAMAMG3-HKRRR/apoptin complex is a potential candidate for an effective nonviral gene delivery system for brain tumor therapy in vitro.

Apoptin Gene Delivery by the Functionalized Polyamidoamine Dendrimer Derivatives Induces Cell Death of U87-MG Glioblastoma Cells

Bae, Yoonhee,Rhim, Hyang-Shuk,Lee, Seulgi,Ko, Kyung Soo,Han, Jin,Choi, Joon Sig John Wiley & Sons 2017 Journal of Pharmaceutical Sciences Vol.106 No.6

<P>Malignant glioma is the most common and aggressive form of primary brain tumor in adults. In this study, we describe the efficacy of nonviral gene delivery carriers, histidine-and arginine-or histidine- and lysine-grafted polyamidoamine (PAMAM) dendrimers (PAMAM-H-R and PAMAM-H-K), in delivering a therapeutic and a tumor-selective killer gene, apoptin, using human glioma cells (U87-MG) and newborn human dermal fibroblast cells. We analyzed transfection efficiency using luciferase and a plasmid DNA encoding for enhanced green fluorescent protein and assessed cell viability in both cells. The results show that transfection efficiency of PAMAM-H-R and PAMAM-H-K was greatly increased compared with that of native PAMAM. Moreover, among PAMAM derivatives, cytotoxicity of PAMAM-H-K was very low. We treated both cells with complexes of PAMAM-H-R or PAMAM-H-K and apoptin and analyzed their cellular uptake by flow cytometry and localization by confocal microscopy. Furthermore, cell cycle distribution, caspase 3 activity assay, and JC-1 analysis showed cell death induced by apoptin in U87-MG cells. The present study demonstrates that a PAMAM-H-R/apoptin complex is an effective gene carrier system in glioma cell culture. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.</P>

Dipeptide-functionalized polyamidoamine dendrimer-mediated apoptin gene delivery facilitates apoptosis of human primary glioma cells

Bae, Yoonhee,Green, Eric S.,Kim, Goo-Young,Song, Su Jeong,Mun, Ji Young,Lee, Sunray,Park, Jong-Il,Park, Jong-sang,Ko, Kyung Soo,Han, Jin,Choi, Joon Sig Elsevier 2016 International journal of pharmaceutics Vol.515 No.1

<P><B>Abstract</B></P> <P>Glioblastoma multiform (GBM) is the most frequent and aggressive form of brain tumors in adults. However, the development of more efficient and safe nonviral vector gene therapy represents a promising therapeutic approach, using a tumor-specific killer gene, named apoptin. In this study, we describe the efficacy of non-viral gene delivery vectors, the amino acid-conjugated PAMAM derivatives (PAMAM-H-R and PAMAM-H-K) in delivering a therapeutic gene, displaying affinity toward human primary glioma cells (GBL-14 cells) and dermal fibroblasts. We analyzed transfection efficiency, using luciferase (Luci) and a pDNA encoding for enhanced fluorescent protein (EGFP), and cytotoxicity in both cells. The results show that transfection efficiency of PAMAM-H-R improved compared to native PAMAM dendrimer, but cytotoxicity of PAMAM-H-R and PAMAM-H-K were very low. We treated both cells with a polyplex formation of PAMAM-H-R or PAMAM-H-K/apoptin, and analyzed their cellular uptake and localization by flow cytometry and confocal microscopy. Furthermore, we analyzed the endosomal escape effect using TEM images, and found that PAMAM-H-R showed very fast escape from endosome to the cytosol. Caspase 3 activity assay, cell cycle distribution, and JC-1 analysis showed apoptosis induced by apoptin in GBL-14 cells. This indicates that PAMAM-H-R can be a potential nonviral vector gene delivery carrier for brain tumor therapy. The present study demonstrates that PAMAM-H-R/apoptin gene polyplex can be used as an effective therapeutic candidate for GBM due to its selective induction of apoptosis in primary glioma cells as a potential nonviral gene delivery carrier for brain tumor therapy.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

A Study on the Collagen Extraction from Eggshell Membrane Proteins

Yoonhee Lee,Ja-Kyung Koo,Namjun Cho,Dongjun Bae,Byung Jhip Ha 한국생물공학회 2007 한국생물공학회 학술대회 Vol.2007 No.10

Preliminary evaluation of the dosimetric accuracy of cone-beam computed tomography for cases with respiratory motion

Kim, Dong Wook,Bae, Sunhyun,Chung, Weon Kuu,Lee, Yoonhee 한국물리학회 2014 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol. No.

학생선수들의 스포츠인성 모형 검증: 구조발달론적 관점

장창용 ( Chang-yong Jang ),배준수 ( Junsu Bae ),이유나 ( Yoona Lee ),김윤희 ( Yoonhee Kim ) 한국스포츠심리학회 2021 한국스포츠심리학회지 Vol.32 No.1

목적: 이 연구는 중고등학교 학생선수들을 대상으로 (a) 스포츠인성 모형을 검증하고 (b) 스포츠인성에 영향을 미치는 요인들과의 구조적 관계를 규명했다. 방법: 연구 참여자는 12개 종목에 참여하고 있는 학생선수 350명(남자=295명, 여자=55명)이었고, 측정도구는 스포츠인성 질문지, 동기분위기 질문지, 케어링 분위기 질문지, 그리고 목표성향 질문지를 사용하였다. 각 측정도구에 대한 신뢰도를 분석하였고, 기술통계와 상관관계 그리고 구조방정식 모형을 분석하였다. 결과: 첫째, 스포츠인성의 네 단계 기본모형은 통계적으로 유의한 것으로 나타났다. 특히, 공정성 요인은 반사회적 태도에 부적인 영향을 주었고 스포츠퍼슨십에는 정적인 영향을 주었다. 한편, 반사회적 태도는 일치성에 통계적으로 유의한 영향을 미치지 못했다. 기본모형에 대한 모델 적합도 지수들은 적합한 것으로 나타났다(CFI=.916, TLI=.881, RMSEA=.087, SRMR=.056). 둘째, 스포츠인성 모델과 각 과정에 영향을 주는 요인들 즉, 사회심리적 분위기와 목표성향을 추가하여 조건 모델을 검증하였다. 조건 모델에서 숙달 분위기는 스포츠퍼슨십에, 수행 분위기는 반사회적 태도에 정적인 영향을 주었다. 케어링 분위기는 반사회적 태도에 정적인 영향을 미쳤지만, 스포츠퍼슨십에는 유의한 영향을 주지 못했다. 한편, 목표성향의 두 가지 요인(과제성향과 자기성향) 모두 스포츠인성 요소에 유의한 효과가 없었다. 조건 모델은 좋은 적합도 지수를 보였다(CFI=.918, TLI=.898, RMSEA=.072, SRMR=.053) 결론: 이 연구는 학생선수들의 스포츠인성 발달 단계와 이 과정에 영향을 미치는 상황적·개인적 요인에 대한 이론적 모델을 통계적으로 검증하였다. 이는 국내 학생선수들의 스포츠인성 발달에 대한 유용한 정보와 스포츠인성 연구의 확장에 기여할 것이다. Purpose: This study (a) examined the model of sport character and (b) identified effects of influences on sport character model reflecting cognitive processes in student-athletes. Methods: Participants were 350 student-athletes (male = 295, female=55) in 12 sports and this study used four measures such as Sport Character Scale, the Caring Climate Scale, the Perceived motivational Climate in Sport Questionnaire, and Task and Ego Orientation in Sport Questionnaire. Data were analysed by using descriptive analysis, reliability, correlation and structural equation modeling. Results: First, the basic path model of sport character indicated significant causal effects. Model fit indices were acceptable (CFI=.916, TLI=.881, RMSEA=.087, SRMR=.056). Second, the conditional model with influences factors including motivational climate, caring climate, and achievement goal orientation was examined. Mastery climate showed positive relationship with sportspersonship and performance climate was positively related to antisocial attitude. Caring climate positively influenced on antisocial attitude while it revealed non-significant relationship with sportspersonship. Goal orientations with task and ego orientation indicated non-significant effects with sport character. Model fit indices with the conditional model were good (CFI=.918, TLI=.898, RMSEA=.072, SRMR=.053). Conclusion: This study not only verified structural developmental processes of the sport character model, but also extended the basic structural path model into the conditional model with situational and personal influences in student-athletes of middle and high school. This would contribute to giving useful information and extending the research regarding sport character.

ZnO nanoparticles induce TNF-α expression via ROS-ERK-Egr-1 pathway in human keratinocytes

( Sang Hoon Jeong ),( Hwa Jeong Ryu ),( Hee Joo Kim ),( Woo In Ryu ),( Yoonhee Park ),( Hyuncheol Bae ),( Yeon Sue Jang ),( Sang Wook Son ) 대한피부과학회 2012 대한피부과학회 학술발표대회집 Vol.64 No.3