Comparative study of active and inactive hepatocarcinogens using a QSAR-based prediction model

Kang, Jin Seok,Kang, Sukmo,Ryu, Doug-Young,Lee, Yun-Seok,Lee, Jong Kwon,Kang, Tae Seok,Park, Han-Jin,Yoon, Seokjoo 대한독성유전단백체학회 2012 Molecular & cellular toxicology Vol.8 No.4

In this study, we investigated global gene expression in primary rat hepatocytes treated with three active hepatocarcinogens (prednisolone, dehydroepiandrosterone and monocrotaline), three inactive hepatocarcinogens (hydrocortisone, glycyrrhetinic acid and lithocholic acid) and two unclassified chemicals (griseofulvin (possibly active) and prednisone (possibly inactive)). At 48 h after treatment with these eight chemicals, cells were harvested for RNA extraction. Global gene expression analyses were conducted using oligonucleotide microarrays to detect genes whose expression was altered. Differentially expressed genes (DEG) analysis, principal component analysis (PCA), gene set enrichment analysis (GSEA) and KEGG pathway analysis were also conducted. Seven-hundred and sixty genes whose expression was altered >1.2-fold (P<0.05; unpaired Welch's t-test) were identified as DEGs for the active and inactive carcinogens. In PCA, prednisolone and dehydroepiandrosterone were located away from the inactive carcinogens. In contrast, monocrotaline was close to the inactive carcinogens. Hydrocortisone, glycyrrhetinic acid and lithocholic acid were separate from the active carcinogens. PCA identified griseofulvin as an active carcinogen and prednisone as an inactive carcinogen. GSEA detected several genes associated with hepatocarcinogenesis, such as glutathione S-transferase A2 and NADPH oxidase. KEGG pathway analysis showed that several pathways might be associated with hepatocarcinogenesis. Our results suggest that it may be feasible to differentiate active and inactive hepatocarcinogens by PCA, GSEA and KEGG pathway analysis.

Trace element analysis of three tissues from Eurasian otters (Lutra lutra) in South Korea.

Kang, Sukmo,Kang, Jung-Hoon,Kim, Soohee,Lee, Seung Heon,Lee, Seungwoo,Yu, Hee Jeong,Oh, Su-Jun,Park, Jung-Duck,Nam, Ki-Hoan,Han, Sung Yong,Lim, Jong-Deock,Ryu, Doug-Young Chapman Hall ; Kluwer Academic Publishers 2015 Ecotoxicology Vol.24 No.5

<P>Eurasian otters (Lutra lutra) are endangered worldwide, but the specific cause of their decline has not been determined. This study analyzed the concentrations of potentially toxic trace elements, including As, Cd, Pb, Hg, Se, Cu, Mn, and Zn, in the liver, kidney, and lung tissues of Eurasian otters in South Korea. There were high individual variations in the tissue concentrations of all the elements analyzed. The kidneys had the highest concentrations of Cd and Se among the three tissue groups, and the livers had the highest concentrations of Cu, Mn, Zn, and Hg. The Pb and As concentrations in the livers were not significantly different from those in the kidneys, and the lungs had the lowest concentrations of all the elements analyzed. The age-related bioaccumulation of Cd and Hg was evident in the three tissue groups, and of Se in the kidneys. The Pb concentration was higher in the livers of juveniles compared with those of adults and the Zn concentration was higher in the lungs of juveniles. There were no apparent gender differences in the concentrations of the elements analyzed among the tissue groups. The Se concentration correlated with the Hg concentration in the livers and kidneys, and with the Cd concentration in the kidneys. The Hg and Cd levels correlated in the three tissue groups. The Cu and Zn levels also correlated in the livers and kidneys. In general, the element concentrations were within the ranges reported by previous studies of this species from European countries, except for Cd and Hg, the levels of which were mostly lower than those reported previously. These findings may provide baseline information to facilitate the conservation of the Eurasian otter. To the best of our knowledge, this is the first available study of trace element concentrations in the tissues of Eurasian otters from South Korea or Asian countries.</P>

Self-assembled nanoparticles comprising aptide–SN38 conjugates for use in targeted cancer therapy

Kim, Hyungjun,Lee, Yonghyun,Kang, Sukmo,Choi, Minsuk,Lee, Soyoung,Kim, Sunghyun,Gujrati, Vipul,Kim, Jinjoo,Jon, Sangyong IOP 2016 Nanotechnology Vol.27 No.48

<P>Self-assembled nanoparticles (NPs) have been intensively utilized as cancer drug delivery carriers because hydrophobic anticancer drugs may be efficiently loaded into the particle cores. In this study, we synthesized and evaluated the therapeutic index of self-assembled NPs chemically conjugated to a fibronectin extra domain B-specific peptide (APT<SUB>EDB</SUB>) and an anticancer agent SN38. The APT<SUB>EDB</SUB>–SN38 formed self-assembled structures with a diameter of 58?±?3 nm in an aqueous solution and displayed excellent drug loading, solubility, and stability properties. A pharmacokinetic study revealed that the blood circulation half-life of SN38 following injection of the APT<SUB>EDB</SUB>–SN38 NPs was markedly higher than that of the small molecule CPT-11. The APT<SUB>EDB</SUB>–SN38 NPs delivered SN38 to tumor sites by both passive and active targeting. Finally, the APT<SUB>EDB</SUB>–SN38 NPs exhibited potent antitumor activities and low toxicities against EDB-expressing tumors (LLC, U87MG) in mice. This system merits further preclinical and clinical investigations for SN38 delivery.</P>

Targeted Cancer Therapy Using Fusion Protein of TNFα and Tumor-Associated Fibronectin-Specific Aptide

Jeon, Hyungsu,Kim, Daejin,Choi, Minsuk,Kang, Sukmo,Kim, Jin Yong,Kim, Sunghyun,Jon, Sangyong American Chemical Society 2017 Molecular Pharmaceutics Vol.14 No.11

<P>Tumor necrosis factor-alpha has shown potent antitumor effects in preclinical and clinical studies. However, severe side effects at less than therapeutic doses have limited its systemic delivery, prompting the need for a new strategy for targeted delivery of the protein to tumors. Here, we report a fusion protein of mouse tumor necrosis factor (TNF)-alpha (mTNF alpha) and a cancer-targeting, high-affinity aptide and investigate its therapeutic efficacy in tumor-bearing mice. A fusion protein consisting of mTNF alpha, a linker, and an aptide specific to extra domain B (EDB) of fibronectin (APT(EDB)), designated mTNF alpha-APT(EDB), was successfully produced by expression in Escherichia coli. mTNF alpha-APTEDB retained specificity and affinity for its target, EDB. In mice bearing EDB-overexpressing fibrosarcomas, mTNF alpha-APT(EDB) showed greater efficacy in inhibiting tumor growth than mTNF alpha alone or mTNF alpha linked to a nonrelevant aptide, without causing an appreciable loss in body weight. Moreover, in vivo antitumor efficacy was further significantly increased by combination treatment with the chemotherapeutic drug, melphalan, suggesting a synergistic effect attributable to enhanced drug uptake into the tumor as a result of TNF alpha-mediated enhanced vascular permeability. These results suggest that a fusion protein of mTNF alpha with a cancer-targeting peptide could be a new anticancer therapeutic option for ensuring potent antitumor efficacy after systemic delivery.</P>

Bilirubin Nanoparticle Preconditioning Protects against Hepatic Ischemia-Reperfusion Injury

( Jin Yong Kim ),( Dong Yun Lee ),( Sukmo Kang ),( Yonghyun Lee ),( Sangyong Jon ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatic ischemia-reperfusion injury (IRI) represents a serious clinical problem after liver transplantation and resection. The main pathogenesis of IRI is inflammatory cascade caused by excessive generation of reactive oxygen species (ROS). Accumulating evidence suggests that bilirubin possess potent antioxidant and anti-inflammatory properties. However, despite obvious potential health benefits of bilirubin, its clinical applications are limited by its poor solubility. So, we recently developed bilirubin-based nanoparticles consisting of polyethylene glycol (PEG)-conjugated bilirubin. The aim of this study was to investigate the protective effect of bilirubin nanoparticles (BRNPs) on hepatic IRI and explore its potential mechanisms. Methods: The effect of BRNPs was studied in a mouse model of hepatic IRI with 90 minutes of partial ischemia and, followed by 6 hours of reperfusion. Liver and serum samples were collected and analyzed in order to evaluate the severity of IRI. We assessed oxidative stress, inflammatory cytokine response, and immune cell profiles using molecular analyses and flow cytometry. The biodistribution of BRNPs were examined by real-time fluorescence imaging in live mice. Results: BRNPs preconditioning significantly attenuated the severity of IRI, as indicated by lower ALT and reduced IRI-associated histopathologic changes, compared with equivalent dose of free bilirubin and vehicle. BRNPs reduced oxidative stress, early pro-inflammatory cytokines, cell adhesion molecules, and recruitment of inflammatory cells, especially CD11b+Gr1+ cells, to the ischemic lobe. Also, IRI-induced mice showed a higher fluorescence intensity compared to sham-operated mice and it allowed to find the prolonged retention of BRNPs in inflammatory lesion. Conclusions: These findings indicate that BRNPs may be the first nanomedicine to show potent therapeutic effects in hepatic IRI. BRNPs not only retains unique biological roles of bilirubin but also are able to preferentially accumulate in the IRI-induced inflammatory lesion. Further, we anticipate that BRNPs may have therapeutic potential for other organ IRI, including heart and brain.

Involvement of c-Met- and Phosphatidylinositol 3-Kinase Dependent Pathways in Arsenite-Induced Downregulation of Catalase in Hepatoma Cells

Kim, Soohee,Lee, Seung Heon,Kang, Sukmo,Lee, Lyon,Park, Jung-Duck,Ryu, Doug-Young Pharmaceutical Society of Japan 2011 BIOLOGICAL & PHARMACEUTICAL BULLETIN Vol.34 No.11

<P>Catalase protects cells from reactive oxygen species-induced damage by catalyzing the breakdown of hydrogen peroxide to oxygen and water. Arsenite decreases catalase activity; it activates phosphatidylinositol 3-kinase (PI3K) and its key downstream effector Akt in a variety of cells. The PI3K pathway is known to inhibit catalase expression. c-Met, an upstream regulator of PI3K and Akt, is also involved in the regulation of catalase expression. To examine the involvement of c-Met and PI3K pathways in the arsenite-induced downregulation of catalase, catalase mRNA and protein expression were analyzed in the human hepatoma cell line HepG2 treated with arsenite and either an inhibitor of c-Met (PHA665752 (PHA)) or of PI3K (LY294002 (LY)). Arsenite treatment markedly activated Akt and decreased the levels of both catalase mRNA and protein. Both PHA and LY attenuated arsenite-induced activation of Akt. PHA and LY treatment also prevented the inhibitory effect of arsenite on catalase protein expression but did not affect the level of catalase mRNA. These findings suggest that arsenite-induced inhibition of catalase expression is regulated at the mRNA and post-transcriptional levels in HepG2 cells, and that the post-transcriptional regulation is mediated <I>via</I> c-Met- and PI3K-dependent mechanisms.</P>

Bilirubin nanoparticle preconditioning protects against hepatic ischemia-reperfusion injury

Kim, Jin Yong,Lee, Dong Yun,Kang, Sukmo,Miao, Wenjun,Kim, Hyungjun,Lee, Yonghyun,Jon, Sangyong Elsevier 2017 Biomaterials Vol.133 No.-

<P><B>Abstract</B></P> <P>Hepatic ischemia-reperfusion injury (IRI) remains a major concern in liver transplantation and resection, despite continuing efforts to prevent it. Accumulating evidence suggests that bilirubin possesses antioxidant, anti-inflammatory and anti-apoptotic properties. However, despite obvious potential health benefits of bilirubin, its clinical applications are limited by its poor solubility. We recently developed bilirubin nanoparticles (BRNPs) consisting of polyethylene glycol (PEG)-conjugated bilirubin. Here, we sought to investigate whether BRNPs protect against IRI in the liver by preventing oxidative stress. BRNPs exerted potent antioxidant and anti-apoptotic activity in primary hepatocytes exposed to hydrogen peroxide, a precursor of reactive oxygen species (ROS). In a model of hepatic IRI in mice, BRNP preconditioning exerted profound protective effects against hepatocellular injury by reducing oxidative stress, pro-inflammatory cytokine production, and recruitment of neutrophils. They also preferentially accumulated in IRI-induced inflammatory lesions. Collectively, our findings indicate that BRNP preconditioning provides a simple and safe approach that can be easily monitored in the blood like endogenous bilirubin, and could be a promising strategy to protect against IRI in a clinical setting.</P>

Magnetic Resonance Imaging-Guided Drug Delivery to Breast Cancer Stem-Like Cells

Sun, Yujin,Kim, Hoe Suk,Kang, Sukmo,Piao, Yin Ji,Jon, Sangyong,Moon, Woo Kyung Wiley (John WileySons) 2018 Advanced Healthcare Materials Vol.7 No.21

Selective electric and magnetic sensitivity of aperture probes.

Singh, Dilip K,Ahn, Jae Sung,Koo, Sukmo,Kang, Taehee,Kim, Joonyeon,Lee, Sukho,Park, Namkyoo,Kim, Dai-Sik Optical Society of America 2015 Optics express Vol.23 No.16

<P>We report the effect of geometrical factors governing the polarization profiles of near-field scanning optical microscope (NSOM) probes. The most important physical parameter controlling the selective electric or magnetic field sensitivity is found to be the width of the metal rim surrounding aperture. Probes with metal rim width w < 관/2 selectively senses the optical electric field, while those with w > 관/2 selectively senses the optical magnetic field. Intensity variation of optical Hertz standing wave formed upon reflection at oblique incidence shows a phase difference of ??/2 between electric and magnetic probes: an analogue of the classical Wiener's experiment. Our work paves way towards electromagnetic engineering of nanostructures.</P>

Antibody-Assisted Delivery of a Peptide-Drug Conjugate for Targeted Cancer Therapy

Kim, Hyungjun,Hwang, Dobeen,Choi, Minsuk,Lee, Soyoung,Kang, Sukmo,Lee, Yonghyun,Kim, Sunghyun,Chung, Junho,Jon, Sangyong American Chemical Society 2019 MOLECULAR PHARMACEUTICS Vol.16 No.1