Naringenin targets ERK 2 and suppresses UVB ‐induced photoaging

Jung, Sung Keun,Ha, Su Jeong,Jung, Chang Hwa,Kim, Yun Tai,Lee, Hoo&#x2010,Keun,Kim, Myoung Ok,Lee, Mee&#x2010,Hyun,Mottamal, Madhusoodanan,Bode, Ann M.,Lee, Ki Won,Dong, Zigang John Wiley and Sons Inc. 2016 Journal of Cellular and Molecular Medicine Vol.20 No.5

<P><B>Abstract</B></P><P>A number of natural phytochemicals have anti‐photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase‐1 (MMP‐1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB‐induced MMP‐1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3‐dimensional (3‐D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm<SUP>2</SUP>) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB‐induced MMP‐1 expression and AP‐1 activity, and strongly suppressed UVB‐induced phosphorylation of Fos‐related antigen (FRA)‐1 at Ser265. Importantly, UVB irradiation‐induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen‐activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB‐induced extracellular signal‐regulated kinase 2 (ERK2) activity and subsequently attenuated UVB‐induced phosphorylation of p90<SUP>RSK</SUP> by competitively binding with ATP. Constitutively active MEK (CA‐MEK) increased FRA1 phosphorylation and expression and also induced MMP‐1 expression, whereas dominant‐negative ERK2 (DN‐ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP‐1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB‐induced wrinkle formation, trans‐epidermal water loss and MMP‐13 expression. Naringenin exerts potent anti‐photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down‐regulation of AP‐1 transactivation and MMP‐1 expression.</P>

Anti‐inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide‐stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase‐1 expression

Jung, Ji&#x2010,Sun,Shin, Jin A.,Park, Eun&#x2010,Mi,Lee, Jung&#x2010,Eun,Kang, Young&#x2010,Sook,Min, Sung&#x2010,Won,Kim, Dong&#x2010,Hyun,Hyun, Jin&#x2010,Won,Shin, Chan&#x2010,Young,Kim, Hee&#x201 Blackwell Publishing Ltd 2010 Journal of Neurochemistry Vol.115 No.6

<P> <I>J. Neurochem.</I> (2010) <B>115,</B> 1668–1680.</P><P><B>Abstract</B></P><P>Microglia activation plays a pivotal role in neurodegenerative diseases, and thus controlling microglial activation has been suggested as a promising therapeutic strategy for neurodegenerative diseases. In the present study, we showed that ginsenoside Rh1 inhibited inducible nitric oxide synthase, cyclooxygenase‐2, and pro‐inflammatory cytokine expression in lipopolysaccharide (LPS)‐stimulated microglia, while Rh1 increased anti‐inflammatory IL‐10 and hemeoxygenase‐1 (HO‐1) expression. Suppression of microglial activation by Rh1 was also observed in the mouse brain following treatment with LPS. Subsequent mechanistic studies revealed that Rh1 inhibited LPS‐induced MAPK phosphorylation and nuclear factor‐κB (NF‐κB)‐mediated transcription without affecting NF‐κB DNA binding. As the increase of pCREB (cAMP responsive element‐binding protein) is known to result in suppression of NF‐κB‐mediated transcription, we examined whether Rh1 increased pCREB levels. As expected, Rh1 increased pCREB, which was shown to be related to the anti‐inflammatory effect of Rh1 because pre‐treatment with protein kinase A inhibitors attenuated the Rh1‐mediated inhibition of nitric oxide production and the up‐regulation of IL‐10 and HO‐1. Furthermore, treatment of HO‐1 shRNA attenuated Rh1‐mediated inhibition of nitric oxide and reactive oxygen species production. Through this study, we have demonstrated that protein kinase A and its downstream effector, HO‐1, play a critical role in the anti‐inflammatory mechanism of Rh1 by modulating pro‐ and anti‐inflammatory molecules in activated microglia.</P>

Trend analysis of diabetic prevalence and incidence in a rural area of South Korea between 2003–2008

Jeong, Ji Yun,Kim, Jung&#x2010,Guk,Kim, Bo&#x2010,Wan,Moon, Seong Su,Kim, Hye&#x2010,Soon,Park, Keun&#x2010,Gyu,Won, Kyu Chang,Lee, Hyoung Woo,Yoon, Ji Sung,Shon, Ho&#x2010,Sang,Lee, Ji Hyun,Jung, Eui Blackwell Publishing Ltd 2010 Journal of diabetes investigation Vol.1 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction: </B> This study determined the change in prevalence of diabetes and prediabetes over a period of 5 years in South Korea. The incidence of diabetes and prediabetes and risk factors associated with the development of diabetes were also investigated.</P><P><B>Materials and Methods: </B> The Dalseong population‐based cohort survey recruited 1806 subjects who were over 20‐years‐old in 2003. Five years later, 1287 of the original subjects were re‐evaluated and 187 new subjects were added to the study. All participants completed a questionnaire, were given a physical examination, and provided blood samples for analysis including 2 h oral glucose tolerances.</P><P><B>Results: </B> Age‐adjusted prevalence of diabetes rose from 6.7% in 2003 to 9.1% in 2008. The prevalence of prediabetes also increased from 18.5% in 2003 to 28.4% in 2008. The incidence rates of diabetes and prediabetes were 18.3 per 1000 person‐years and 55.4 per 1000 person‐years, respectively. The development of diabetes was associated with impaired fasting glucose (IFG) (odds ratio [OR] 5.661), impaired glucose tolerance (IGT) (OR: 6.013), age (OR 1.013), and waist‐to‐hip ratio (OR 1.513). After excluding the IFG and IGT, systolic blood pressure (OR 1.023), high‐sensitivity C‐reactive protein (hsCRP; OR 1.097), triglyceride (OR 1.002) and waist‐to‐hip ratio (OR 1.696) were statistically significant risk factors in a multivariate logistic regression analysis.</P><P><B>Conclusions: </B> A significant rise in the prevalence of diabetes and prediabetes was observed between 2003 and 2008. In addition, this study newly demonstrated that waist‐to‐hip ratio and hsCRP were associated with the development of diabetes after adjusting for several confounding factors. <B>(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00045.x, 2010)</B></P>

Overexpression of <i>OsERF48</i> causes regulation of <i>OsCML16</i> , a calmodulin‐like protein gene that enhances root growth and drought tolerance

Jung, Harin,Chung, Pil Joong,Park, Su&#x2010,Hyun,Redillas, Mark Christian Felipe Reveche,Kim, Youn Shic,Suh, Joo&#x2010,Won,Kim, Ju&#x2010,Kon BLACKWELL 2017 PLANT BIOTECHNOLOGY JOURNAL Vol.15 No.10

<P><B>Summary</B></P><P>The AP2/ERF family is a plant‐specific transcription factor family whose members have been associated with various developmental processes and stress tolerance. Here, we functionally characterized the drought‐inducible <I>OsERF48</I>, a group Ib member of the rice ERF family with four conserved motifs, CMI‐1, ‐2, ‐3 and ‐4. A transactivation assay in yeast revealed that the C‐terminal CMI‐1 motif was essential for OsERF48 transcriptional activity. When <I>OsERF48</I> was overexpressed in an either a root‐specific (ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP>) or whole‐body (OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP>) manner, transgenic plants showed a longer and denser root phenotype compared to the nontransgenic (NT) controls. When plants were grown on a 40% polyethylene glycol‐infused medium under <I>in vitro</I> drought conditions, ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> plants showed a more vigorous root growth than OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> and NT plants. In addition, the ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> plants exhibited higher grain yield than OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> and NT plants under field‐drought conditions. We constructed a putative <I>OsERF48</I> regulatory network by cross‐referencing ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> root‐specific RNA‐seq data with a co‐expression network database, from which we inferred the involvement of 20 drought‐related genes in <I>OsERF48</I>‐mediated responses. These included genes annotated as being involved in stress signalling, carbohydrate metabolism, cell‐wall proteins and drought responses. They included, <I>OsCML16</I>, a key gene in calcium signalling during abiotic stress, which was shown to be a direct target of OsERF48 by chromatin immunoprecipitation‐qPCR analysis and a transient protoplast expression assay. Our results demonstrated that OsERF48 regulates <I>OsCML16</I>, a calmodulin‐like protein gene that enhances root growth and drought tolerance.</P>

Signal transducer and activator of transcription 3‐mediated CD133 up‐regulation contributes to promotion of hepatocellular carcinoma

Won, Cheolhee,Kim, Byung&#x2010,Hak,Yi, Eun Hee,Choi, Kyung&#x2010,Ju,Kim, Eun&#x2010,Kyung,Jeong, Jong&#x2010,Min,Lee, Jae&#x2010,Ho,Jang, Ja&#x2010,June,Yoon, Jung&#x2010,Hwan,Jeong, Won‐,Il,P John Wiley and Sons Inc. 2015 Hepatology Vol.62 No.4

<P>Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin‐6/signal transducer and activator of transcription 3 (IL‐6/STAT3) signaling up‐regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL‐6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL‐6, with a concomitant decrease of hypoxia‐inducible factor 1 alpha (HIF‐1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF‐κB) p65 subunit to positively regulate the transcription of HIF‐1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF‐1α and CD133 expression were not observed in Toll‐like receptor 4/IL‐6 double‐knockout mice. Long‐term silencing of CD133 by a lentiviral‐based approach inhibited cancer cell‐cycle progression and suppressed <I>in vivo</I> tumorigenicity by down‐regulating expression of cytokinesis‐related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF‐1α proteins. <I>Conclusion</I>: IL‐6/STAT3 signaling induces expression of CD133 through functional cooperation with NF‐κB and HIF‐1α during liver carcinogenesis. Targeting STAT3‐mediated CD133 up‐regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment. (H<SMALL>EPATOLOGY</SMALL> 2015;62:1160‐1173)</P>

Confidence limits for patient‐specific IMRT dose QA: a multi‐institutional study in Korea

Kim, Jung&#x2010,in,Chung, Jin&#x2010,Beom,Song, Ju&#x2010,Young,Kim, Sung Kyu,Choi, Yunseok,Choi, Chang Heon,Choi, Won Hoon,Cho, Byungchul,Kim, Jin Sung,Kim, Sung Jin,Ye, Sung&#x2010,Joon John Wiley and Sons Inc. 2016 Journal of applied clinical medical physics Vol.17 No.1

<P>This study aims to investigate tolerance levels for patient‐specific IMRT dose QA (DQA) using the confidence limits (CL) determined by a multi‐institutional study. Eleven institutions participated in the multi‐institutional study in Korea. A total of 155 DQA measurements, consisting of point‐dose differences (high‐ and low‐dose regions) and gamma passing rates (composite and per‐field) for IMRT patients with brain, head and neck (H&N), abdomen, and prostate cancers were examined. The Shapiro‐Wilk test was used to evaluate the normality of data grouped by the treatment sites and the DQA methods. The confidence limit coefficients in cases of the normal distribution, and the two‐sided Student's <I>t</I>‐distribution were applied to determine the confidence limits for the grouped data. The Spearman's test was applied to assess the sensitivity of DQA results within the limited groups. The differences in CLs between the two confidence coefficients based on the normal and <I>t</I>‐distributions were negligible for the point‐dose data and the gamma passing rates with 3%/3 criteria. However, with 2%/2 criteria, the difference in CLs were 1.6% and 2.2% for composite and per‐field measurements, respectively. This resulted from the large standard deviation and the more sensitive criteria of 2%/2. There was no noticeable correlation among the different QA methods. Our multi‐institutional study suggested that the CL was not a suitable metric for defining the tolerance level when the statistics of the sample group did not follow the normality and had a large standard deviation.</P><P>PACS number: 87.55.Qr</P>

Radiosynthesis and <i>in vitro</i> evaluation of 1‐(tetrahydro‐5‐hydroxy‐6‐(hydroxymethyl)‐2H‐pyran‐3‐yl)‐5‐[¹²⁵I]iodouracil: A new potential agent for HSV1‐tk

Jo, Nam Hyun,Kim, Jung Young,El&#x2010,Gamal, Mohammed I.,Choi, Won‐,Kyoung,Park, Jin&#x2010,Hun,Kim, Eun Jung,Cho, Jung&#x2010,Hyuck,Ha, Hyun&#x2010,Joon,Choi, Tae Hyun,Oh, Chang&#x2010,Hyun John Wiley Sons, Ltd. 2011 Journal of labelled compounds & radiopharmaceutica Vol.54 No.2

<P><B>Abstract</B></P><P>Synthesis, radiolabelling, and <I>in vitro</I> evaluation of a new <SUP>125</SUP>I‐labelled iodouracil hexitol nucleoside analogue are reported. The target compound was successfully synthesized by an iodination–destannylation method and then purified by reverse phase HPLC. The radiochemical purity of the product was >99% with decay‐corrected yields of 48±3%. <I>In vitro</I> cellular uptake testing was carried out using MCA and MCA‐tk cell lines for comparison of compound 1 with [<SUP>18</SUP>F]FHBG. The newly synthesized compound 1 showed higher accumulation in herpex simplex virus type 1 thymidine kinase (HSV1‐tk) gene expression cell line (MCA‐tk cell line) than in the wild type MCA cell line compared with [<SUP>18</SUP>F]FHBG. The MCA‐tk to MCA cellular uptake ratio for compound 1 was higher than that of [<SUP>18</SUP>F]FHBG from 2 h after incubation. The radioiodine‐labelled compound 1 (I‐125, <I>t</I><SUB>1/2</SUB>=59.37 days) has a longer physical half‐life than F‐18‐(<I>t</I><SUB>1/2</SUB>=110 min) labelled FHBG. Radioiodine‐labelled compound 1 could be used for monitoring gene expression for a long time. The selectivity for MCA‐tk cell line makes compound 1 a promising imaging agent for HSV1‐tk expression. Copyright © 2010 John Wiley & Sons, Ltd.</P>

Role of CXCR2 in the Ac‐PGP‐Induced Mobilization of Circulating Angiogenic Cells and its Therapeutic Implications

Kwon, Yang Woo,Lee, Seung Jun,Heo, Soon Chul,Lee, Tae Wook,Park, Gyu Tae,Yoon, Jung Won,Kim, Seung&#x2010,Chul,Shin, Ho Jin,Lee, Sang Chul,Kim, Jae Ho unknown 2018 Stem cells translational medicine Vol.8 No.3

<P><B>Abstract</B></P><P>Circulating angiogenic cells (CACs) have been implicated in the repair of ischemic tissues, and their mobilization from bone marrow is known to be regulated by the activations of chemokine receptors, including CXCR2 and CXCR4. This study was conducted to investigate the role of N‐acetylated proline‐glycine‐proline (Ac‐PGP; a collagen‐derived chemotactic tripeptide) on CAC mobilization and its therapeutic potential for the treatment of peripheral artery diseases. Ac‐PGP was administered daily to a murine hind limb ischemia model, and the effects of Ac‐PGP on blood perfusion and CAC mobilization (Sca1<SUP>+</SUP>Flk1<SUP>+</SUP> cells) into peripheral blood were assessed. Intramuscular administration of Ac‐PGP significantly improved ischemic limb perfusion and increased limb salvage rate by increasing blood vessel formation, whereas Ac‐PGP‐induced blood perfusion and angiogenesis in ischemic limbs were not observed in CXCR2‐knockout mice. In addition, Ac‐PGP‐induced CAC mobilization was found to occur in wild‐type mice but not in CXCR2‐knockout mice. Transplantation of bone marrow from green fluorescent protein (GFP) transgenic mice to wild‐type mice showed bone marrow‐derived cells homed to ischemic limbs after Ac‐PGP administration and that GFP‐positive cells contributed to the formation of ILB4‐positive capillaries and α smooth muscle actin (α‐SMA)‐positive arteries. These results suggest CXCR2 activation in bone marrow after Ac‐PGP administration improves blood perfusion and reduces tissue necrosis by inducing CAC mobilization. These findings suggest a new pharmaceutical basis for the treatment of critical limb ischemia. <SMALL>STEM CELLS TRANSLATIONAL MEDICINE</SMALL><I>2019;8:236&246</I></P>

Cross‐resistance of <i>Echinochloa</i> species to acetolactate synthase inhibitor herbicides

Song, Jong&#x2010,Seok,Lim, Soo&#x2010,Hyun,Yook, Min&#x2010,Jung,Kim, Jin&#x2010,Won,Kim, Do&#x2010,Soon John Wiley Sons Australia, Ltd 2017 Weed Biology and Management Vol.17 No.2

<P>This study was conducted to evaluate the cross‐resistance of acetolactate synthase (ALS) inhibitors with different chemistries, specifically azimsulfuron (sulfonylurea), penoxsulam (triazolopyrimidine sulfonanilide) and bispyribac‐sodium (pyrimidinyl thio benzoate), in <I>Echinochloa oryzicola</I> and <I>Echinochloa crus‐galli</I> that had been collected in South Korea and to investigate their herbicide resistance mechanism. Both <I>Echinochloa</I> spp. showed cross‐resistance to the ALS inhibitors belonging to the above three different chemistries. In a whole plant assay with herbicides alone, the resistant/susceptible ratios for azimsulfuron, penoxsulam and bispyribac‐sodium were 12.6, 28.1 and 1.9 in <I>E. oryzicola</I> and 21.1, 13.7 and 1.8 in <I>E. crus‐galli</I>, respectively. An <I>in vitro</I> ALS enzyme assay with herbicides showed that the I<SUB>50</SUB>‐values of the resistant accessions were approximately two‐to‐three times higher than the susceptible accessions, with no statistical difference, suggesting that the difference in ALS sensitivity cannot explain ALS inhibitor resistance in <I>Echinochloa</I> spp. for azimsulfuron, penoxsulam and bispyribac‐sodium. A whole plant assay with fenitrothion showed that the GR<SUB>50</SUB>‐values significantly decreased in both the resistant <I>E. oryzicola</I> and <I>E. crus‐galli</I> accessions when azimsulfuron, penoxsulam and bispyribac‐sodium were applied with the P450 inhibitor, while no significant decrease was observed in the susceptible accessions when the P450 inhibitor was used. Thus, these results suggest that ALS inhibitor cross‐resistance for azimsulfuron, penoxsulam and bispyribac‐sodium is related to enhanced herbicide metabolism.</P>

Solar Cells: Performance Optimization of Polymer Solar Cells Using Electrostatically Sprayed Photoactive Layers (Adv. Funct. Mater. 20/2010)

Kim, Joon&#x2010,Sung,Chung, Won‐,Suk,Kim, Kyungkon,Kim, Dong Young,Paeng, Ki&#x2010,Jung,Jo, Seong Mu,Jang, Sung&#x2010,Yeon WILEY‐VCH Verlag 2010 Advanced Functional Materials Vol.20 No.20

<P><B>Abstract</B></P><P>Polymer solar cells (PSCs) are fabricated using a novel film deposition method, the electrostatic spray (e‐spray) technique. Stable atomization and uniform deposition of the polymer blend by e‐spray are achieved by manipulating the solution concentration, the solvent composition, and the electric field. The performance of PSCs is primarily influenced by the inherent film morphology of the e‐sprayed polymer‐blend active layers, which is significantly different from that of the conventional films that are formed using the spin‐coating (SC) method. The intrinsically formed interfacial boundaries between the e‐sprayed blend pancakes resist charge transport, which unfavorably influences device efficiency. The internal series resistance (<I>R</I><SUB>S</SUB>) of the PSCs that are formed using the e‐spray method (e‐spray‐PSC) is significantly reduced by a solvent vapor soaking (SVS) treatment in addition to the conventional thermodynamic nanomorphology controls. The detailed relationship between the morphologies (film morphology and internal nanomorphology) and the <I>R</I><SUB>S</SUB> is revealed using impedance spectroscopy. The performance of the e‐spray‐PSCs is comparable to those of the PSCs that are fabricated using the SC method under identical conditions. Therefore, the e‐spray method can be used to fabricate ultralow‐cost PSCs, because of the performance results combined with the intrinsic advantages that the e‐spray method is simple and has a low materials loss.</P>