Publications by authors named "Chung-Hyun Cho"

91 Publications

Correction to: Potential causes and consequences of rapid mitochondrial genome evolution in thermoacidophilic Galdieria (Rhodophyta).

BMC Evol Biol 2020 Oct 7;20(1):132. Epub 2020 Oct 7.

Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, South Korea.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12862-020-01686-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542961PMC
October 2020

Potential causes and consequences of rapid mitochondrial genome evolution in thermoacidophilic Galdieria (Rhodophyta).

BMC Evol Biol 2020 09 7;20(1):112. Epub 2020 Sep 7.

Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, South Korea.

Background: The Cyanidiophyceae is an early-diverged red algal class that thrives in extreme conditions around acidic hot springs. Although this lineage has been highlighted as a model for understanding the biology of extremophilic eukaryotes, little is known about the molecular evolution of their mitochondrial genomes (mitogenomes).

Results: To fill this knowledge gap, we sequenced five mitogenomes from representative clades of Cyanidiophyceae and identified two major groups, here referred to as Galdieria-type (G-type) and Cyanidium-type (C-type). G-type mitogenomes exhibit the following three features: (i) reduction in genome size and gene inventory, (ii) evolution of unique protein properties including charge, hydropathy, stability, amino acid composition, and protein size, and (iii) distinctive GC-content and skewness of nucleotides. Based on GC-skew-associated characteristics, we postulate that unidirectional DNA replication may have resulted in the rapid evolution of G-type mitogenomes.

Conclusions: The high divergence of G-type mitogenomes was likely driven by natural selection in the multiple extreme environments that Galdieria species inhabit combined with their highly flexible heterotrophic metabolism. We speculate that the interplay between mitogenome divergence and adaptation may help explain the dominance of Galdieria species in diverse extreme habitats.
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http://dx.doi.org/10.1186/s12862-020-01677-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487498PMC
September 2020

Amoeba Genome Reveals Dominant Host Contribution to Plastid Endosymbiosis.

Mol Biol Evol 2021 01;38(2):344-357

Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.

Eukaryotic photosynthetic organelles, plastids, are the powerhouses of many aquatic and terrestrial ecosystems. The canonical plastid in algae and plants originated >1 Ga and therefore offers limited insights into the initial stages of organelle evolution. To address this issue, we focus here on the photosynthetic amoeba Paulinella micropora strain KR01 (hereafter, KR01) that underwent a more recent (∼124 Ma) primary endosymbiosis, resulting in a photosynthetic organelle termed the chromatophore. Analysis of genomic and transcriptomic data resulted in a high-quality draft assembly of size 707 Mb and 32,361 predicted gene models. A total of 291 chromatophore-targeted proteins were predicted in silico, 208 of which comprise the ancestral organelle proteome in photosynthetic Paulinella species with functions, among others, in nucleotide metabolism and oxidative stress response. Gene coexpression analysis identified networks containing known high light stress response genes as well as a variety of genes of unknown function ("dark" genes). We characterized diurnally rhythmic genes in this species and found that over 49% are dark. It was recently hypothesized that large double-stranded DNA viruses may have driven gene transfer to the nucleus in Paulinella and facilitated endosymbiosis. Our analyses do not support this idea, but rather suggest that these viruses in the KR01 and closely related P. micropora MYN1 genomes resulted from a more recent invasion.
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http://dx.doi.org/10.1093/molbev/msaa206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826189PMC
January 2021

The genome of Ectocarpus subulatus - A highly stress-tolerant brown alga.

Mar Genomics 2020 Aug 11;52:100740. Epub 2020 Jan 11.

Sorbonne Université, CNRS, Integrative Biology of Marine Models (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France; Centre for Novel Agricultural Products, Department of Biology, University of York, York YO10 5DD, United Kingdom.

Brown algae are multicellular photosynthetic stramenopiles that colonize marine rocky shores worldwide. Ectocarpus sp. Ec32 has been established as a genomic model for brown algae. Here we present the genome and metabolic network of the closely related species, Ectocarpus subulatus Kützing, which is characterized by high abiotic stress tolerance. Since their separation, both strains show new traces of viral sequences and the activity of large retrotransposons, which may also be related to the expansion of a family of chlorophyll-binding proteins. Further features suspected to contribute to stress tolerance include an expanded family of heat shock proteins, the reduction of genes involved in the production of halogenated defence compounds, and the presence of fewer cell wall polysaccharide-modifying enzymes. Overall, E. subulatus has mainly lost members of gene families down-regulated in low salinities, and conserved those that were up-regulated in the same condition. However, 96% of genes that differed between the two examined Ectocarpus species, as well as all genes under positive selection, were found to encode proteins of unknown function. This underlines the uniqueness of brown algal stress tolerance mechanisms as well as the significance of establishing E. subulatus as a comparative model for future functional studies.
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http://dx.doi.org/10.1016/j.margen.2020.100740DOI Listing
August 2020

Role of Inflammation in Classification of Diabetic Macular Edema by Optical Coherence Tomography.

J Diabetes Res 2019 20;2019:8164250. Epub 2019 Dec 20.

Department of Ophthalmology, Ajou University School of Medicine, Suwon, Republic of Korea.

Diabetic macular edema (DME) is the abnormal accumulation of fluid in the subretinal or intraretinal spaces in the macula in patients with diabetic retinopathy and leads to severely impaired central vision. Technical developments in retinal imaging systems have led to many advances in the study of DME. In particular, optical coherence tomography (OCT) can provide longitudinal and microstructural analysis of the macula. A comprehensive review was provided regarding the role of inflammation using OCT-based classification of DME and current and ongoing therapeutic approaches. In this review, we first describe the pathogenesis of DME, then discuss the classification of DME based on OCT findings and the association of different types of DME with inflammation, and finally describe current and ongoing therapeutic approaches using OCT-based classification of DME. Inflammation has an important role in the pathogenesis of DME, but its role appears to differ among the DME phenotypes, as determined by OCT. It is important to determine how the different DME subtypes respond to intravitreal injections of steroids, antivascular endothelial growth factor agents, and other drugs to improve prognosis and responsiveness to treatment.
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http://dx.doi.org/10.1155/2019/8164250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939426PMC
June 2020

A muscular hypotonia-associated STIM1 mutant at R429 induces abnormalities in intracellular Ca movement and extracellular Ca entry in skeletal muscle.

Sci Rep 2019 12 16;9(1):19140. Epub 2019 Dec 16.

Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.

Stromal interaction molecule 1 (STIM1) mediates extracellular Ca entry into the cytosol through a store-operated Ca entry (SOCE) mechanism, which is involved in the physiological functions of various tissues, including skeletal muscle. STIM1 is also associated with skeletal muscle diseases, but its pathological mechanisms have not been well addressed. The present study focused on examining the pathological mechanism(s) of a mutant STIM1 (R429C) that causes human muscular hypotonia. R429C was expressed in mouse primary skeletal myotubes, and the properties of the skeletal myotubes were examined using single-cell Ca imaging of myotubes and transmission electron microscopy (TEM) along with biochemical approaches. R429C did not interfere with the terminal differentiation of myoblasts to myotubes. Unlike wild-type STIM1, there was no further increase of SOCE by R429C. R429C bound to endogenous STIM1 and slowed down the initial rate of SOCE that were mediated by endogenous STIM1. Moreover, R429C increased intracellular Ca movement in response to membrane depolarization by eliminating the attenuation on dihydropyridine receptor-ryanodine receptor (DHPR-RyR1) coupling by endogenous STIM1. The cytosolic Ca level was also increased due to the reduction in SR Ca level. In addition, R429C-expressing myotubes showed abnormalities in mitochondrial shape, a significant decrease in ATP levels, and the higher expression levels of mitochondrial fission-mediating proteins. Therefore, serial defects in SOCE, intracellular Ca movement, and cytosolic Ca level along with mitochondrial abnormalities in shape and ATP level could be a pathological mechanism of R429C for human skeletal muscular hypotonia. This study also suggests a novel clue that STIM1 in skeletal muscle could be related to mitochondria via regulating intra and extracellular Ca movements.
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http://dx.doi.org/10.1038/s41598-019-55745-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915709PMC
December 2019

Phylogenetic analysis of ABCG subfamily proteins in plants: functional clustering and coevolution with ABCGs of pathogens.

Physiol Plant 2019 Dec 11. Epub 2019 Dec 11.

Department of Life Science, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Korea.

ABCG subfamily proteins are highly enriched in terrestrial plants. Many of these proteins secrete secondary metabolites that repel or inhibit pathogens. To establish why the ABCG subfamily proteins proliferated extensively during evolution, we constructed phylogenetic trees from a broad range of eukaryotic organisms. ABCG proteins were massively duplicated in land plants and in oomycetes, a group of agronomically important plant pathogens, which prompted us to hypothesize that plant and pathogen ABCGs coevolved. Supporting this hypothesis, full-size ABCGs in host plants (Arabidopsis thaliana and Glycine max) and their pathogens (Hyaloperonospora arabidopsidis and Phytophthora sojae, respectively) had similar divergence times and patterns. Furthermore, generalist pathogens with broad ranges of host plants have diversified more ABCGs than their specialist counterparts. The hypothesis was further tested using an example pair of ABCGs that first diverged during multiplication in a host plant and its pathogen: AtABCG31 of A. thaliana and HpaP802307 of H. arabidopsidis. AtABCG31 expression was activated following infection with H. arabidopsidis, and disrupting AtABCG31 led to increased susceptibility to H. arabidopsidis. Together, our results suggest that ABCG genes in plants and their oomycete pathogens coevolved in an arms race, to extrude secondary metabolites involved in the plant's defense response against pathogens.
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http://dx.doi.org/10.1111/ppl.13052DOI Listing
December 2019

Angiopoietin 1 attenuates interleukin-6-induced endothelial cell permeability through SHP-1.

Biochem Biophys Res Commun 2019 10 16;518(2):286-293. Epub 2019 Aug 16.

Vascular Microenvironment Laboratory, Department of Biomedical Sciences and Pharmacology, College of Medicine, Seoul National University, Seoul, Republic of Korea; Ischemic/Hypoxic Disease Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea. Electronic address:

The regulation of endothelial cell (EC) permeability is critical for the physiological homeostasis of blood vessels and tissues. The elevation of pro-inflammatory cytokines is highly associated with lesions, such as the increased vascular permeability of diabetic retinas. We have previously reported that interleukin-6 (IL-6) increases EC permeability through the downregulation of tight junction protein expression. Angiopoietin 1 (Ang1) has an anti-permeability function, but the effect of Ang1 on vascular permeability induced by inflammatory cytokines is unclear. In the present study, we investigated the effect of Ang1 on IL-6-induced EC permeability and its underlying molecular mechanisms. We demonstrated that Ang1 inhibited the IL-6-induced increase in EC permeability by inhibiting the reductions in the levels of tight junction protein ZO-1 and occludin, which was related to the decrease in vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 activation by Ang1. Mechanistically, Ang1 induced the dissociation of the tyrosine phosphatase SHP-1 from the Tie2 receptor and increased the binding of SHP-1 to JAK1, JAK2, and STAT3, which are IL-6 downstream signaling proteins. We conclude that SHP-1 plays an important role in the Ang1-induced inhibition of JAK/STAT3 signaling. These results provide evidence for a potential beneficial role of Ang1 in suppressing the vascular permeability induced by the pro-inflammatory cytokine IL-6 in diabetic retinopathy.
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http://dx.doi.org/10.1016/j.bbrc.2019.08.048DOI Listing
October 2019

Optimization and validation of a method to identify skin sensitization hazards using IL-1 α and IL-6 secretion from HaCaT.

Toxicol In Vitro 2019 Dec 2;61:104589. Epub 2019 Jul 2.

Institute of Human Environment Interface Biology, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Although many methods to assess sensitization have been investigated to replace animal testing, it is still imperative to develop an in vitro method to minimize the use of animals and to classify sensitizers. Recently, an assay using the human keratinocyte cell line (HaCaT) was developed as an alternative method. Our aim was to optimize this method and validate its ability to assess sensitization. The highest dose that resulted in 75% cell viability was determined for each test substance. Then, serial dilutions of the dose were applied to measure the levels of secreted proinflammatory cytokines. To optimize the assay, statistical analyses were performed to determine whether all of the doses tested were necessary to maintain the predictive values. Exclusion of the 0.5× dose did not change the predictive values drastically. To validate the optimized method, 22 substances were evaluated without the 0.5× dose, resulting in overall predictive values of 83.3% for sensitivity, 80.0% for specificity, and 81.8% for accuracy, which are comparable to results from other validated assays. These results suggest that statistical analysis can assist in development of alternative in vitro methods and that the optimized HaCaT cell assay is reproducible.
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http://dx.doi.org/10.1016/j.tiv.2019.104589DOI Listing
December 2019

Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood-retinal barrier in diabetic retinopathy.

Glia 2019 02 16;67(2):321-331. Epub 2018 Nov 16.

Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Inner and outer blood-retinal barriers (BRBs), mainly composed of retinal endothelial cells and retinal pigment epithelial (RPE) cells, respectively, maintain the integrity of the retinal tissues. In this study, we aimed to investigate the mechanisms of the outer BRB disruption regarding the interaction between RPE and microglia. In mice with high-fat diet-induced obesity and streptozotocin-induced hyperglycemia, microglia accumulated on the RPE layer, as in those after intravitreal injection of interleukin (IL)-6, which is elevated in ocular fluids of patients with diabetic retinopathy. Although IL-6 did not directly affect the levels of zonula occludens (ZO)-1 and occludin in RPE cells, IL-6 increased VEGFA mRNA in RPE cells to recruit microglial cells. In microglial cells, IL-6 upregulated the mRNA levels of MCP1, MIP1A, and MIP1B, to amplify the recruitment of microglial cells. In this manner, IL-6 modulated RPE and microglial cells to attract microglial cells on RPE cells. Furthermore, IL-6-treated microglial cells produced and secreted tumor necrosis factor (TNF)-α, which activated NF-κB and decreased the levels of ZO-1 in RPE cells. As STAT3 inhibition reversed the effects of IL-6-treated microglial cells on the RPE monolayer in vitro, it reduced the recruitment of microglial cells and the production of TNF-α in RPE tissues in streptozotocin-treated mice. Taken together, IL-6-treated RPE and microglial cells amplified the recruitment of microglial cells and IL-6-treated microglial cells produced TNF-α to disrupt the outer BRB in diabetic retinopathy.
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http://dx.doi.org/10.1002/glia.23542DOI Listing
February 2019

Microgravity induces autophagy via mitochondrial dysfunction in human Hodgkin's lymphoma cells.

Sci Rep 2018 10 2;8(1):14646. Epub 2018 Oct 2.

Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.

Gravitational forces can impose physical stresses on the human body as it functions to maintain homeostasis. It has been reported that astronauts exposed to microgravity experience altered biological functions and many subsequent studies on the effects of microgravity have therefore been conducted. However, the anticancer mechanisms of simulated microgravity remain unclear. We previously showed that the proliferation of human Hodgkin's lymphoma (HL) cells was inhibited when these cells were cultured in time-averaged simulated microgravity (taSMG). In the present study, we investigated whether taSMG produced an anticancer effect. Exposure of human HL cells to taSMG for 2 days increased their reactive oxygen species (ROS) production and NADPH oxidase family gene expression, while mitochondrial mass, ATPase, ATP synthase, and intracellular ATP levels were decreased. Furthermore, human HL cells exposed to taSMG underwent autophagy via AMPK/Akt/mTOR and MAPK pathway modulation; such autophagy was inhibited by the ROS scavenger N-acetylcysteine (NAC). These results suggest an innovative therapeutic approach to HL that is markedly different from conventional chemotherapy and radiotherapy.
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http://dx.doi.org/10.1038/s41598-018-32965-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168562PMC
October 2018

Retinal pigment epithelium-derived transforming growth factor-β2 inhibits the angiogenic response of endothelial cells by decreasing vascular endothelial growth factor receptor-2 expression.

J Cell Physiol 2019 04 7;234(4):3837-3849. Epub 2018 Sep 7.

Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Korea.

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is known to modulate various aspects of endothelial cell (EC) biology. Retinal pigment epithelium (RPE) is important for regulating angiogenesis of choriocapillaris and one of the main cell sources of TGF-β secretion, particularly TGF-β2. However, it is largely unclear whether and how TGF-β2 affects angiogenic responses of ECs. In the current study, we demonstrated that TGF-β2 reduces vascular endothelial growth factor receptor-2 (VEGFR-2) expression in ECs and thereby inhibits vascular endothelial growth factor (VEGF) signaling and VEGF-induced angiogenic responses such as EC migration and tube formation. We also demonstrated that the reduction of VEGFR-2 expression by TGF-β2 is due to the suppression of JNK signaling. In coculture of RPE cells and ECs, RPE cells decreased VEGFR-2 levels in ECs and EC migration. In addition, we showed that TGF-β2 derived from RPE cells is involved in the reduction of VEGFR-2 expression and inhibition of EC migration. These results suggest that TGF-β2 plays an important role in inhibiting the angiogenic responses of ECs during the interaction between RPE cells and ECs and that angiogenic responses of ECs may be amplified by a decrease in TGF-β2 expression in RPE cells under pathologic conditions.
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http://dx.doi.org/10.1002/jcp.27156DOI Listing
April 2019

T Cell-Specific Knockout of STAT3 Ameliorates Dextran Sulfate Sodium-Induced Colitis by Reducing the Inflammatory Response.

Immune Netw 2018 Aug 21;18(4):e30. Epub 2018 Aug 21.

Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.

Signal transducer and activator of transcription 3 (STAT3) has a crucial role in various autoimmune disorders including, inflammatory bowel disease (IBD). Our previous study demonstrated that STAT3 activation by IL-6 in colonic epithelial cells exacerbates experimental ulcerative colitis. Activated T lymphocytes are also found in ulcerative colitis patients with intestinal inflammation, but the role of in T cells remains elusive. To determine the function of T cells in intestinal inflammation, we generated T cell-specific STAT3 knockout (KO) mice and used dextran sulfate sodium (DSS) to induce colitis. In this study, we demonstrated that T cell-specific deletion alleviated DSS-induced colitis in mice, resulting in reduced histological scores and myeloperoxidase (MPO) activity. Importantly, the population of T cells in the spleen and lymph nodes was significantly decreased in the control and DSS-induced groups of STAT3 KO mice. In addition, deficiency in T cells markedly reduced the production of interferon (IFN)-γ, IL-6, and IL-17A, whereas IL-10 secretion was increased. Collectively, the results suggest that in T cells may be a therapeutic target in ulcerative colitis by balancing the immune response through T cell homeostasis.
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http://dx.doi.org/10.4110/in.2018.18.e30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117516PMC
August 2018

Propranolol increases vascular permeability through pericyte apoptosis and exacerbates oxygen-induced retinopathy.

Biochem Biophys Res Commun 2018 09 9;503(4):2792-2799. Epub 2018 Aug 9.

Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea; Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea. Electronic address:

Retinopathy of prematurity (ROP) is an eye disease that causes blindness due to delayed vascular growth, retinal ischemia, and resulting abnormal angiogenesis. Nonselective β-antagonist propranolol is in clinical trials for the treatment of ROP due to its effect of reducing VEGF expression and inhibiting retinal angiogenesis in oxygen-induced ROP models (OIR), but the mechanism by which propranolol acts on ROP vessels is still unclear. In the present study, we have focused on the effect of propranolol on pericyte survival and vascular permeability. We demonstrated that propranolol increases pericyte apoptosis more sensitively than endothelial cells (ECs), thereby weakening EC tight junctions to increase endothelial permeability in co-cultures of pericytes and ECs. Mechanistically, pericyte apoptosis by propranolol was due to the inhibition of Akt signaling pathway. We also demonstrated that propranolol increases pericyte loss and vascular permeability of retinal vessels in a mouse model of OIR. These results suggest that propranolol may be negative for blood vessels in retinas of OIR, and that the efficacy of propranolol for the treatment of ROP needs to be more thoroughly verified.
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http://dx.doi.org/10.1016/j.bbrc.2018.08.041DOI Listing
September 2018

Oleanolic Acids Inhibit Vascular Endothelial Growth Factor Receptor 2 Signaling in Endothelial Cells: Implication for Anti-Angiogenic Therapy.

Mol Cells 2018 Aug 24;41(8):771-780. Epub 2018 Jul 24.

Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Korea.

Angiogenesis must be precisely controlled because uncontrolled angiogenesis is involved in aggravation of disease symptoms. Vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR-2) signaling is a key pathway leading to angiogenic responses in vascular endothelial cells (ECs). Therefore, targeting VEGF/VEGFR-2 signaling may be effective at modulating angiogenesis to alleviate various disease symptoms. Oleanolic acid was verified as a VEGFR-2 binding chemical from anticancer herbs with similar binding affinity as a reference drug in the Protein Data Bank (PDB) entry 3CJG of model A coordination. Oleanolic acid effectively inhibited VEGF-induced VEGFR-2 activation and angiogenesis in HU-VECs without cytotoxicity. We also verified that oleanolic acid inhibits angiogenesis during the development and the course of the retinopathy of prematurity (ROP) model in the mouse retina. Taken together, our results suggest a potential therapeutic benefit of oleanolic acid for inhibiting angiogenesis in proangiogenic diseases, including retinopathy.
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http://dx.doi.org/10.14348/molcells.2018.0207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125422PMC
August 2018

With the greatest care, stromal interaction molecule (STIM) proteins verify what skeletal muscle is doing.

BMB Rep 2018 Aug;51(8):378-387

Department of Physiology, College of Medicine, The Catholic University of Korea; Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, Korea.

Skeletal muscle contracts or relaxes to maintain the body position and locomotion. For the contraction and relaxation of skeletal muscle, Ca2+ in the cytosol of skeletal muscle fibers acts as a switch to turn on and off a series of contractile proteins. The cytosolic Ca2+ level in skeletal muscle fibers is governed mainly by movements of Ca2+ between the cytosol and the sarcoplasmic reticulum (SR). Store-operated Ca2+ entry (SOCE), a Ca2+ entryway from the extracellular space to the cytosol, has gained a significant amount of attention from muscle physiologists. Orai1 and stromal interaction molecule 1 (STIM1) are the main protein identities of SOCE. This mini-review focuses on the roles of STIM proteins and SOCE in the physiological and pathophysiological functions of skeletal muscle and in their correlations with recently identified proteins, as well as historical proteins that are known to mediate skeletal muscle function. [BMB Reports 2018; 51(8): 378-387].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130827PMC
http://dx.doi.org/10.5483/bmbrep.2018.51.8.128DOI Listing
August 2018

Plastid genome analysis of three Nemaliophycidae red algal species suggests environmental adaptation for iron limited habitats.

PLoS One 2018 8;13(5):e0196995. Epub 2018 May 8.

Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.

The red algal subclass Nemaliophycidae includes both marine and freshwater taxa that contribute to more than half of the freshwater species in Rhodophyta. Given that these taxa inhabit diverse habitats, the Nemaliophycidae is a suitable model for studying environmental adaptation. For this purpose, we characterized plastid genomes of two freshwater species, Kumanoa americana (Batrachospermales) and Thorea hispida (Thoreales), and one marine species Palmaria palmata (Palmariales). Comparative genome analysis identified seven genes (ycf34, ycf35, ycf37, ycf46, ycf91, grx, and pbsA) that were different among marine and freshwater species. Among currently available red algal plastid genomes (127), four genes (pbsA, ycf34, ycf35, ycf37) were retained in most of the marine species. Among these, the pbsA gene, known for encoding heme oxygenase, had two additional copies (HMOX1 and HMOX2) that were newly discovered and were reported from previously red algal nuclear genomes. Each type of heme oxygenase had a different evolutionary history and special modifications (e.g., plastid targeting signal peptide). Based on this observation, we suggest that the plastid-encoded pbsA contributes to the iron controlling system in iron-deprived conditions. Thus, we highlight that this functional requirement may have prevented gene loss during the long evolutionary history of red algal plastid genomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940233PMC
August 2018

Epithelial cell-derived cytokines CST3 and GDF15 as potential therapeutics for pulmonary fibrosis.

Cell Death Dis 2018 05 1;9(5):506. Epub 2018 May 1.

Department of Biomedical Sciences, BK21-plus Education Program, Seoul National University College of Medicine, Seoul, Korea.

While wound healing is completed, the epithelium functions to normalize the interstitial context by eliminating fibroblasts excited during matrix reconstruction. If not, tissues undergo pathologic fibrosis. Pulmonary fibrosis is a fatal and hardly curable disorder. We here tried to identify epithelium-derived cytokines capable of ameliorating pulmonary fibrosis. Human lung fibroblasts were inactivated in epithelial cell-conditioned media. Cystatin C (CST3) and growth differentiation factor 15 (GDF15) were found to be enriched in the conditioned media and to inhibit the growth and activation of lung fibroblasts by inactivating the TGF-Smad pathway. In mouse and human lungs with interstitial fibrosis, CST3 and GDF15 expressions were markedly reduced, and the restoration of these cytokines alleviated the fibrotic changes in mouse lungs. These results suggest that CST3 and GDF15 are bona fide regulators to prevent excessive proliferation and activation of fibroblasts in injured lungs. These cytokines could be potential therapeutics for ameliorating interstitial lung fibrosis.
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http://dx.doi.org/10.1038/s41419-018-0530-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938700PMC
May 2018

β-Adrenergic receptor agonists attenuate pericyte loss in diabetic retinas through Akt activation.

FASEB J 2018 05 21;32(5):2324-2338. Epub 2017 Dec 21.

Vascular Microenvironment Laboratory, Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea.

Pericytes (PCs) are crucial in maintaining the quiescence of endothelial cells (ECs) and the integrity of EC tight junctions. Especially in diabetic retinopathy (DR), PC loss is one of the early pathologic changes in capillaries of diabetic retinas. Thus, preventing PC loss is beneficial for attenuating vision impairment in patients with DR. Although many studies have revealed the mechanism of PC loss in retinas, little is known about the mechanisms that increase PC survival. We focused on the effect of β-adrenergic receptor agonists (β-agonists) on PC loss in diabetic retinas. In this study, β-agonists increased the cell viability of PCs by increasing PC survival and proliferation. Mechanistically, β-agonist-induced protein kinase B activation in PCs reduced PC apoptosis in response to various stimuli. β2-agonists more potently increased PC survival than β1-agonists. β2-Agonist reduced vascular leakage and PC loss in retinas of mice with streptozotocin-induced diabetes. In cocultures of PCs and ECs, β2-agonists restored the altered permeability and ZO-1 expression in ECs induced by PC loss. We concluded that β-agonists, especially β2-agonists, increase PC survival, thereby preventing diabetes-induced PC loss in retinas. These results provide a potential therapeutic benefit of β-agonists for preventing PC loss in DR.-Yun, J.-H., Jeong, H.-S., Kim, K.-J., Han, M. H., Lee, E. H., Lee, K., Cho, C.-H. β-Adrenergic receptor agonists attenuate pericyte loss in diabetic retinas through Akt activation.
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http://dx.doi.org/10.1096/fj.201700570RRDOI Listing
May 2018

STIM2 regulates both intracellular Ca distribution and Ca movement in skeletal myotubes.

Sci Rep 2017 12 20;7(1):17936. Epub 2017 Dec 20.

Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea.

Stromal interaction molecule 1 (STIM1) along with Orai1 mediates extracellular Ca entry into the cytosol through a store-operated Ca entry (SOCE) mechanism in various tissues including skeletal muscle. However, the role(s) of STIM2, a homolog of STIM1, in skeletal muscle has not been well addressed. The present study, first, was focused on searching for STIM2-binding proteins from among proteins mediating skeletal muscle functions. This study used a binding assay, quadrupole time-of-flight mass spectrometry, and co-immunoprecipitation assay with bona-fide STIM2- and SERCA1a-expressing rabbit skeletal muscle. The region for amino acids from 453 to 729 of STIM2 binds to sarcoplasmic/endoplasmic reticulum Ca-ATPase 1a (SERCA1a). Next, oxalate-supported Ca-uptake experiments and various single-myotube Ca imaging experiments using STIM2-knockdown mouse primary skeletal myotubes have suggested that STIM2 attenuates SERCA1a activity during skeletal muscle contraction, which contributes to the intracellular Ca distribution between the cytosol and the SR at rest. In addition, STIM2 regulates Ca movement through RyR1 during skeletal muscle contraction as well as SOCE. Therefore, via regulation of SERCA1a activity, STIM2 regulates both intracellular Ca distribution and Ca movement in skeletal muscle, which makes it both similar to, yet different from, STIM1.
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http://dx.doi.org/10.1038/s41598-017-18256-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738411PMC
December 2017

Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia.

Oncotarget 2017 Sep 27;8(37):61592-61603. Epub 2017 Jun 27.

Obstructive Upper Airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul 03080, Korea.

Mounting evidence has revealed a causative role of intermittent hypoxia (IH) in cancer progression in mouse models of obstructive sleep apnea (OSA), but most studies have focused on the effects of IH following tumor implantation using an exposure to single IH frequency. Thus, we aimed to investigate 1) the potential effect of IH on the initial tumor growth in patients with OSA without an interaction with other mechanisms induced by IH in mice and 2) the influence of the IH frequency on tumor growth, which were tested using pre-conditioning with IH (Pre-IH) and 2 different IH frequencies, respectively. Pre-IH was achieved by alternatively maintaining melanoma cells between normoxia (10 min, 21% O) and hypoxia (50 min, 1% O) for 7 days (12 cycles per day) before administering them to mice. The conditions for IH-1 and IH-2 were 90 s of 12% FiO followed by 270s of 21% FiO (10 cycles/h), and 90 s of 12% FiO and 90 s of 21% FiO (20 cycles/h), respectively, for 8 h per day. Tumor growth was significantly higher in the Pre-IH group than in the normoxia group. In addition, the IH-2 group showed more accelerated tumor growth compared to the normoxia and IH-1 groups. Immunohistochemistry and gene-expression results consistently showed the up-regulation of molecules associated with HIF-1α-dependent hypoxic adaptation in tumors of the Pre-IH and IH-2 groups. Our findings reveal that IH increased tumor progression in a frequency-dependent manner, regardless of whether it was introduced before or after tumor cell implantation.
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http://dx.doi.org/10.18632/oncotarget.18644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617448PMC
September 2017

A focus on extracellular Ca entry into skeletal muscle.

Exp Mol Med 2017 09 15;49(9):e378. Epub 2017 Sep 15.

Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

The main task of skeletal muscle is contraction and relaxation for body movement and posture maintenance. During contraction and relaxation, Ca in the cytosol has a critical role in activating and deactivating a series of contractile proteins. In skeletal muscle, the cytosolic Ca level is mainly determined by Ca movements between the cytosol and the sarcoplasmic reticulum. The importance of Ca entry from extracellular spaces to the cytosol has gained significant attention over the past decade. Store-operated Ca entry with a low amplitude and relatively slow kinetics is a main extracellular Ca entryway into skeletal muscle. Herein, recent studies on extracellular Ca entry into skeletal muscle are reviewed along with descriptions of the proteins that are related to extracellular Ca entry and their influences on skeletal muscle function and disease.
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http://dx.doi.org/10.1038/emm.2017.208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628281PMC
September 2017

The complete chloroplast genome sequence of the Japanese Camellia ( L.).

Mitochondrial DNA B Resour 2017 Aug 30;2(2):583-584. Epub 2017 Aug 30.

Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.

The complete chloroplast genome sequence of valuable ornamental tree, L. (Theaceae), was determined. The genome size was 156,971 bp in length, containing a pair of 25,798 bp inverted repeat (IR) regions, which were separated by small and large single copy regions (SSC and LSC) of 18,394 and 86,673 bp, respectively. The cp genome contained 134 genes, including 91 coding genes, six rRNA genes, and 37 tRNA genes. The overall GC content of the chloroplast genome was 37.3%. Phylogenetic analysis revealed the position of being sister to the clade containing and (subgenus ).
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http://dx.doi.org/10.1080/23802359.2017.1372719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800054PMC
August 2017

Differentially Expressed Potassium Channels Are Associated with Function of Human Effector Memory CD8 T Cells.

Front Immunol 2017 24;8:859. Epub 2017 Jul 24.

Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, South Korea.

The voltage-gated potassium channel, Kv1.3, and the Ca-activated potassium channel, KCa3.1, regulate membrane potentials in T cells, thereby controlling T cell activation and cytokine production. However, little is known about the expression and function of potassium channels in human effector memory (EM) CD8 T cells that can be further divided into functionally distinct subsets based on the expression of the interleukin (IL)-7 receptor alpha (IL-7Rα) chain. Herein, we investigated the functional expression and roles of Kv1.3 and KCa3.1 in EM CD8 T cells that express high or low levels of the IL-7 receptor alpha chain (IL-7Rα and IL-7Rα, respectively). In contrast to the significant activity of Kv1.3 and KCa3.1 in IL-7Rα EM CD8 T cells, IL-7Rα EM CD8 T cells showed lower expression of Kv1.3 and insignificant expression of KCa3.1. Kv1.3 was involved in the modulation of cell proliferation and IL-2 production, whereas KCa3.1 affected the motility of EM CD8 T cells. The lower motility of IL-7Rα EM CD8 T cells was demonstrated using transendothelial migration and motility assays with intercellular adhesion molecule 1- and/or chemokine stromal cell-derived factor-1α-coated surfaces. Consistent with the lower migration property, IL-7Rα EM CD8 T cells were found less frequently in human skin. Stimulating IL-7Rα EM CD8 T cells with IL-2 or IL-15 increased their motility and recovery of KCa3.1 activity. Our findings demonstrate that Kv1.3 and KCa3.1 are differentially involved in the functions of EM CD8 T cells. The weak expression of potassium channels in IL-7Rα EM CD8 T cells can be revived by stimulation with IL-2 or IL-15, which restores the associated functions. This study suggests that IL-7Rα EM CD8 T cells with functional potassium channels may serve as a reservoir for effector CD8 T cells during peripheral inflammation.
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http://dx.doi.org/10.3389/fimmu.2017.00859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522836PMC
July 2017

The maintenance ability and Ca availability of skeletal muscle are enhanced by sildenafil.

Exp Mol Med 2016 12 9;48(12):e278. Epub 2016 Dec 9.

Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Sildenafil relaxes vascular smooth muscle cells and is used to treat pulmonary artery hypertension as well as erectile dysfunction. However, the effectiveness of sildenafil on skeletal muscle and the benefit of its clinical use have been controversial, and most studies focus primarily on tissues and organs from disease models without cellular examination. Here, the effects of sildenafil on skeletal muscle at the cellular level were examined using mouse primary skeletal myoblasts (the proliferative form of skeletal muscle stem cells) and myotubes, along with single-cell Ca imaging experiments and cellular and biochemical studies. The proliferation of skeletal myoblasts was enhanced by sildenafil in a dose-independent manner. In skeletal myotubes, sildenafil enhanced the activity of ryanodine receptor 1, an internal Ca channel, and Ca movement that promotes skeletal muscle contraction, possibly due to an increase in the resting cytosolic Ca level and a unique microscopic shape in the myotube membranes. Therefore, these results suggest that the maintenance ability of skeletal muscle mass and the contractility of skeletal muscle could be improved by sildenafil by enhancing the proliferation of skeletal myoblasts and increasing the Ca availability of skeletal myotubes, respectively.
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http://dx.doi.org/10.1038/emm.2016.134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192075PMC
December 2016

STAT3 Potentiates SIAH-1 Mediated Proteasomal Degradation of β-Catenin in Human Embryonic Kidney Cells.

Mol Cells 2016 Nov 18;39(11):821-826. Epub 2016 Nov 18.

Department of Pharmacology, Seoul National University College of Medicine, Seoul 03080, Korea.

The β-catenin functions as an adhesion molecule and a component of the Wnt signaling pathway. In the absence of the Wnt ligand, β-catenin is constantly phosphorylated, which designates it for degradation by the APC complex. This process is one of the key regulatory mechanisms of β-catenin. The level of β-catenin is also controlled by the E3 ubiquitin protein ligase SIAH-1 via a phosphorylation-independent degradation pathway. Similar to β-catenin, STAT3 is responsible for various cellular processes, such as survival, proliferation, and differentiation. However, little is known about how these molecules work together to regulate diverse cellular processes. In this study, we investigated the regulatory relationship between STAT3 and β-catenin in HEK293T cells. To our knowledge, this is the first study to report that β-catenin-TCF-4 transcriptional activity was suppressed by phosphorylated STAT3; furthermore, STAT3 inactivation abolished this effect and elevated activated β-catenin levels. STAT3 also showed a strong interaction with SIAH-1, a regulator of active β-catenin via degradation, which stabilized SIAH-1 and increased its interaction with β-catenin. These results suggest that activated STAT3 regulates active β-catenin protein levels via stabilization of SIAH-1 and the subsequent ubiquitin-dependent proteasomal degradation of β-catenin in HEK293T cells.
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http://dx.doi.org/10.14348/molcells.2016.0212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125938PMC
November 2016

Mitsugumin 53 regulates extracellular Ca entry and intracellular Ca release via Orai1 and RyR1 in skeletal muscle.

Sci Rep 2016 11 14;6:36909. Epub 2016 Nov 14.

Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.

Mitsugumin 53 (MG53) participates in the membrane repair of various cells, and skeletal muscle is the major tissue that expresses MG53. Except for the regulatory effects of MG53 on SERCA1a, the role(s) of MG53 in the unique functions of skeletal muscle such as muscle contraction have not been well examined. Here, a new MG53-interacting protein, Orai1, is identified in skeletal muscle. To examine the functional relevance of the MG53-Orai1 interaction, MG53 was over-expressed in mouse primary or C2C12 skeletal myotubes and the functional properties of the myotubes were examined using cell physiological and biochemical approaches. The PRY-SPRY region of MG53 binds to Orai1, and MG53 and Orai1 are co-localized in the plasma membrane of skeletal myotubes. MG53-Orai1 interaction enhances extracellular Ca entry via a store-operated Ca entry (SOCE) mechanism in skeletal myotubes. Interestingly, skeletal myotubes over-expressing MG53 or PRY-SPRY display a reduced intracellular Ca release in response to K-membrane depolarization or caffeine stimulation, suggesting a reduction in RyR1 channel activity. Expressions of TRPC3, TRPC4, and calmodulin 1 are increased in the myotubes, and MG53 directly binds to TRPC3, which suggests a possibility that TRPC3 also participates in the enhanced extracellular Ca entry. Thus, MG53 could participate in regulating extracellular Ca entry via Orai1 during SOCE and also intracellular Ca release via RyR1 during skeletal muscle contraction.
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http://dx.doi.org/10.1038/srep36909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107933PMC
November 2016

Parallel evolution of highly conserved plastid genome architecture in red seaweeds and seed plants.

BMC Biol 2016 09 2;14:75. Epub 2016 Sep 2.

Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Background: The red algae (Rhodophyta) diverged from the green algae and plants (Viridiplantae) over one billion years ago within the kingdom Archaeplastida. These photosynthetic lineages provide an ideal model to study plastid genome reduction in deep time. To this end, we assembled a large dataset of the plastid genomes that were available, including 48 from the red algae (17 complete and three partial genomes produced for this analysis) to elucidate the evolutionary history of these organelles.

Results: We found extreme conservation of plastid genome architecture in the major lineages of the multicellular Florideophyceae red algae. Only three minor structural types were detected in this group, which are explained by recombination events of the duplicated rDNA operons. A similar high level of structural conservation (although with different gene content) was found in seed plants. Three major plastid genome architectures were identified in representatives of 46 orders of angiosperms and three orders of gymnosperms.

Conclusions: Our results provide a comprehensive account of plastid gene loss and rearrangement events involving genome architecture within Archaeplastida and lead to one over-arching conclusion: from an ancestral pool of highly rearranged plastid genomes in red and green algae, the aquatic (Florideophyceae) and terrestrial (seed plants) multicellular lineages display high conservation in plastid genome architecture. This phenomenon correlates with, and could be explained by, the independent and widely divergent (separated by >400 million years) origins of complex sexual cycles and reproductive structures that led to the rapid diversification of these lineages.
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http://dx.doi.org/10.1186/s12915-016-0299-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010701PMC
September 2016

Endothelial STAT3 Activation Increases Vascular Leakage Through Downregulating Tight Junction Proteins: Implications for Diabetic Retinopathy.

J Cell Physiol 2017 05 21;232(5):1123-1134. Epub 2016 Sep 21.

Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Vascular inflammation is characteristic feature of diabetic retinopathy. In diabetic retina, a variety of the pro-inflammatory cytokines are elevated and involved in endothelial dysfunction. STAT3 transcription factor has been implicated in mediating cytokine signaling during vascular inflammation. However, whether and how STAT3 is involved in the direct regulation of the endothelial permeability is currently undefined. Our studies revealed that IL-6-induced STAT3 activation increases retinal endothelial permeability and vascular leakage in retinas of mice through the reduced expression of the tight junction proteins ZO-1 and occludin. In a co-culture model with microglia and endothelial cells under a high glucose condition, the microglia-derived IL-6 induced STAT3 activation in the retinal endothelial cells, leading to increasing endothelial permeability. In addition, IL-6-induced STAT3 activation was independent of ROS generation in the retinal endothelial cells. Moreover, we demonstrated that STAT3 activation downregulates the ZO-1 and occludin levels and increases the endothelial permeability through the induction of VEGF production in retinal endothelial cells. These results suggest the potential importance of IL-6/STAT3 signaling in regulating endothelial permeability and provide a therapeutic target to prevent the pathology of diabetic retinopathy. J. Cell. Physiol. 232: 1123-1134, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25575DOI Listing
May 2017

Ginsenoside 20(S)-Rh2 exerts anti-cancer activity through targeting IL-6-induced JAK2/STAT3 pathway in human colorectal cancer cells.

J Ethnopharmacol 2016 Dec 23;194:83-90. Epub 2016 Aug 23.

Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Panax ginseng is one of the most well-known medicinal herbs in Korea and China, which has been used for treatment and prevention of cancer, obesity, diabetes, and cardiovascular diseases. Ginsenosides are the major components of P. ginseng, having a wide range of pharmacological activities. Among the ginsenosides, protopanaxadiol (PPD)-types reportedly have potent anti-cancer effects. Rh2 is PPD-type ginsenoside, and two stereoisomeric forms of Rh2 as 20(S)- and 20(R)-Rh2 were selectively isolated recently.

Aim Of The Study: The biological activities of Rh2 ginsenosides are known to depend on their differences in stereochemistry. Colorectal cancer (CRC) is one of the most lethal neoplasm, and cancer-related death is usually associated with metastasis to other organs. We aimed this study to investigate whether 20(S)- and 20(R)-Rh2 can suppress tumor invasion in human CRC cells.

Materials And Methods: 20(S)- and 20(R)-Rh2 were isolated from the roots of ginseng. Human CRC cells were incubated with 20(S)- or 20(R)-Rh2 in the presence or absence of interleukin-6. An MTT assay was used to measure cell viability. Western blot and quantitative real-time PCR analyses were performed to determine levels of expression and phosphorylation. An invasion assay was performed using a Boyden chamber system with the Matrigel-coated membrane to measure cancer cell invasion.

Results: 20(S)- and 20(R)-Rh2 showed differential cytotoxic activity. Only 20(S)-Rh2 decreased cancer cell viability. Additionally, 20(S)-Rh2 effectively inhibited IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of matrix metalloproteinases (MMPs), including MMP-1, -2, and -9, resulting in inhibition of cancer cell invasion. Interestingly, these pharmacological activities of 20(S)-Rh2 were more potent than those of 20(R)-Rh2. Furthermore, combination treatment showed that 20(S)-Rh2 enhanced the sensitization of doxorubicin-treated anti-cancer activities in CRC cells.

Conclusion: Our results demonstrated that ginsenoside 20(S)-Rh2 has therapeutic potential for the treatment with CRC and may be valuable as a combination partner with more classic chemotherapeutic agents, such as doxorubicin, to treat CRC.
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http://dx.doi.org/10.1016/j.jep.2016.08.039DOI Listing
December 2016