Pro‐apoptotic Noxa is involved in ablative focal irradiation‐induced lung injury

Kim, Jee&#x2010,Youn,An, Yong&#x2010,Min,Choi, Won Hoon,Kim, Jin‐,Mo,Cho, Samju,Yoo, Byung Rok,Kang, Jeong Wook,Lee, Yun&#x2010,Sil,Lee, Yoon‐,Jin,Cho, Jaeho CAROL DAVILA UNIVERSITY PRESS 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.4

<P><B>Abstract</B></P><P>Although lung injury including fibrosis is a well‐documented side effect of lung irradiation, the mechanisms underlying its pathology are poorly understood. X‐rays are known to cause apoptosis in the alveolar epithelial cells of irradiated lungs, which results in fibrosis due to the proliferation and differentiation of fibroblasts and the deposition of collagen. Apoptosis and BH3‐only pro‐apoptotic proteins have been implicated in the pathogenesis of pulmonary fibrosis. Recently, we have established a clinically analogous experimental model that reflects focal high‐dose irradiation of the ipsilateral lung. The goal of this study was to elucidate the mechanism underlying radiation‐induced lung injury based on this model. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice for 14 days. About 9 days after irradiation, the mice began to show increased levels of the pro‐apoptotic protein Noxa in the irradiated lung alongside increased apoptosis and fibrosis. Suppression of Noxa expression by small interfering RNA protected cells from radiation‐induced cell death and decreased expression of fibrogenic markers. Furthermore, we showed that reactive oxygen species participate in Noxa‐mediated, radiation‐induced cell death. Taken together, our results show that Noxa is involved in X‐ray‐induced lung injury.</P>

2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation

Yoon, Yae Jin,Kim, Young&#x2010,Hwan,Lee, Yu&#x2010,Jin,Choi, Jiyeon,Kim, Cheol&#x2010,Hee,Han, Dong Cho,Kwon, Byoung&#x2010,Mog John Wiley and Sons Inc. 2019 CANCER SCIENCE Vol.110 No.1

<P>Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway is a novel therapeutic strategy to treat human cancers with constitutively active STAT3. During the screening of natural products to find STAT3 inhibitors, we identified 2′‐hydroxycinnamaldehyde (HCA) as a STAT3 inhibitor, which was isolated from the stem bark of <I>Cinnamomum cassia</I>. In this study, we found that HCA inhibited constitutive and inducible STAT3 activation in STAT3‐activated DU145 prostate cancer cells. HCA selectively inhibited the STAT3 activity by direct binding to STAT3, which was confirmed by biochemical methods, including a pull‐down assay with biotin‐conjugated HCA, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). HCA inhibited STAT3 phosphorylation at the tyrosine 705 residue, dimer formation, and nuclear translocation in DU145 cells, which led to a downregulation of STAT3 target genes. The downregulation of cell cycle progression and antiapoptosis‐related gene expression by HCA induced the accumulation of cells in the G0/G1 phase of the cell cycle and then induced apoptosis. We also found that reactive oxygen species (ROS) were involved in the HCA‐induced inhibition of STAT3 activation and cell proliferation because the suppressed p‐STAT3 level was rescued by glutathione or N‐acetyl‐L‐cysteine treatment, which are general ROS inhibitors. These results suggest that HCA could be a potent anticancer agent targeting STAT3‐activated tumor cells.</P>

Down‐regulation of <i>GIGANTEA</i> ‐ <i>like</i> genes increases plant growth and salt stress tolerance in poplar

Ke, Qingbo,Kim, Ho Soo,Wang, Zhi,Ji, Chang Yoon,Jeong, Jae Cheol,Lee, Haeng&#x2010,Soon,Choi, Young&#x2010,Im,Xu, Bingcheng,Deng, Xiping,Yun, Dae&#x2010,Jin,Kwak, Sang&#x2010,Soo John Wiley and Sons Inc. 2017 Plant biotechnology journal Vol.15 No.3

<P><B>Summary</B></P><P>The flowering time regulator GIGANTEA (GI) connects networks involved in developmental stage transitions and environmental stress responses in <I>Arabidopsis</I>. However, little is known about the role of GI in growth, development and responses to environmental challenges in the perennial plant poplar. Here, we identified and functionally characterized three <I>GI‐like</I> genes (<I>PagGIa</I>,<I> PagGIb</I> and <I>PagGIc)</I> from poplar (<I>Populus alba × Populus glandulosa</I>). <I>PagGIs</I> are predominantly nuclear localized and their transcripts are rhythmically expressed, with a peak around zeitgeber time 12 under long‐day conditions. Overexpressing <I>PagGIs</I> in wild‐type (WT) <I>Arabidopsis</I> induced early flowering and salt sensitivity, while overexpressing <I>PagGIs</I> in the <I>gi‐2</I> mutant completely or partially rescued its delayed flowering and enhanced salt tolerance phenotypes. Furthermore, the PagGIs‐PagSOS2 complexes inhibited PagSOS2‐regulated phosphorylation of PagSOS1 in the absence of stress, whereas these inhibitions were eliminated due to the degradation of PagGIs under salt stress. Down‐regulation of <I>PagGIs</I> by RNA interference led to vigorous growth, higher biomass and enhanced salt stress tolerance in transgenic poplar plants. Taken together, these results indicate that several functions of <I>Arabidopsis GI</I> are conserved in its poplar orthologues, and they lay the foundation for developing new approaches to producing salt‐tolerant trees for sustainable development on marginal lands worldwide.</P>

7‐Methoxy‐luteolin‐8‐C‐<i>β</i>‐6‐deoxy‐xylo‐pyranos‐3‐uloside exactly (mLU8C‐PU) isolated from <i>Arthraxon hispidus</i> inhibits migratory and invasive responses media

Kim, Soo&#x2010,Jin,Pham, Thu&#x2010,Huyen,Bak, Yesol,Ryu, Hyung&#x2010,Won,Oh, Sei&#x2010,Ryang,Yoon, Do&#x2010,Young John Wiley Sons, Inc. 2018 Environmental toxicology Vol.33 No.11

<P><B>Abstract</B></P><P>7‐Methoxy‐luteolin‐8‐C‐<I>β</I>‐6‐deoxy‐xylo‐pyranos‐3‐uloside (mLU8C‐PU) is a glycosylflavone of luteolin isolated from <I>Arthraxon hispidus</I> (Thunb.). Luteolin is known to exert anti‐migratory and anti‐invasive effects on tumor cells. However, there are no reports on the effects of mLU8C‐PU on tumor invasiveness and associated signaling pathways. In this study, we demonstrated the anti‐migratory and anti‐invasive effects of mLU8C‐PU in 12‐<I>O</I>‐tetradecanoylphorbol‐13‐acetate (TPA)‐treated MCF‐7 breast cancer cells. We also investigated the effect of mLU8C‐PU on invasion‐ related signal transducers, including protein kinase Cα (PKCα), c‐Jun N terminal kinase (JNK), activator protein‐1 (AP‐1), and nuclear factor‐kappa B (NF‐ĸB). TPA‐induced membrane translocation of PKCα, phosphorylation of JNK, and the nuclear translocations of AP‐1 and NF‐κB were downregulated by mLU8C‐PU in MCF‐7 cells. In addition, mLU8C‐PU also inhibited matrix metalloproteinase‐9 (MMP‐9) and interleukin‐8 (IL‐8) expression. These results indicate that mLU8C‐PU inhibits migratory and invasive responses in MCF‐7 breast cancer cells by suppressing MMP‐9 and IL‐8 expression through mitigating TPA‐induced PKCα, JNK activation, and the nuclear translocation of AP‐1 and NF‐κB. These results suggest that mLU8C‐PU may be used as an anti‐metastatic agent.</P>

Large‐Deformation Behavior of Honeycomb‐Structured Polymer Sheets as a Function of Polar Angle

Jin, Kwang&#x2010,Yong,Kim, Dae&#x2010,Yoon,Kim, So&#x2010,Eun,Kuo, Shiao&#x2010,Wei,Lee, Joong Hee,Lyu, Min&#x2010,Young,Hwang, Seok&#x2010,Ho,Gent, Alan N.,Nah, Changwoon,Jeong, Kwang&#x2010,Un WILEY‐VCH Verlag 2011 Macromolecular chemistry and physics Vol.212 No.9

<P><B>Abstract</B></P><P>To construct the structure/property relationships of patterned polymer architectures depending on symmetry, the large‐deformation behavior of 2D HSPS with respect to the polar angle was studied. Holes aligned along the HSPS apex were more effective in decreasing tensile force and reducing stress concentration than those located along the plane. On varying the polar angle from 0 to 30°, the tensile force fluctuated up and down like an undamped negative sinusoidal wave with a wavelength of 15°. Additionally, molecular orientations of HSPS were monitored in situ. By comparing experimental measurements with computer simulations, it was concluded that the tensile force depends on the number of holes as well as the orientation of the axes of the honeycomb structure. </P>

NEDD 4‐induced degradative ubiquitination of phosphatidylinositol 4‐phosphate 5‐kinase α and its implication in breast cancer cell proliferation

Tran, Mai Hoang,Seo, Eunjeong,Min, Soohong,Nguyen, Quynh&#x2010,Anh T.,Choi, Juyong,Lee, Uk&#x2010,Jin,Hong, Soon&#x2010,Sun,Kang, Hyuk,Mansukhani, Alka,Jou, Ilo,Lee, Sang Yoon John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.9

<P><B>Abstract</B></P><P>Phosphatidylinositol 4‐phosphate 5‐kinase (PIP5K) family members generate phosphatidylinositol 4,5‐bisphosphate (PIP2), a critical lipid regulator of diverse physiological processes. The PIP5K‐dependent PIP2 generation can also act upstream of the oncogenic phosphatidylinositol 3‐kinase (PI3K)/Akt pathway. Many studies have demonstrated various mechanisms of spatiotemporal regulation of PIP5K catalytic activity. However, there are few studies on regulation of PIP5K protein stability. Here, we examined potential regulation of PIP5Kα, a PIP5K isoform, via ubiquitin‐proteasome system, and its implication for breast cancer. Our results showed that the ubiquitin ligase NEDD4 (neural precursor cell expressed, developmentally down‐regulated gene 4) mediated ubiquitination and proteasomal degradation of PIP5Kα, consequently reducing plasma membrane PIP2 level. NEDD4 interacted with the C‐terminal region and ubiquitinated the N‐terminal lysine 88 in PIP5Kα. In addition, PIP5Kα gene disruption inhibited epidermal growth factor (EGF)‐induced Akt activation and caused significant proliferation defect in breast cancer cells. Notably, PIP5Kα K88R mutant that was resistant to NEDD4‐mediated ubiquitination and degradation showed more potentiating effects on Akt activation by EGF and cell proliferation than wild‐type PIP5Kα. Collectively, these results suggest that PIP5Kα is a novel degradative substrate of NEDD4 and that the PIP5Kα‐dependent PIP2 pool contributing to breast cancer cell proliferation through PI3K/Akt activation is negatively controlled by NEDD4.</P>

Optimal conditioning regimen for haplo‐identical stem cell transplantation in adult patients with acquired severe aplastic anemia: Prospective de‐escalation study of TBI and ATG dose

Lee, Sung&#x2010,Eun,Park, Sung Soo,Jeon, Young&#x2010,Woo,Yoon, Jae&#x2010,Ho,Cho, Byung&#x2010,Sik,Eom, Ki&#x2010,Seong,Kim, Yoo&#x2010,Jin,Lee, Seok,Min, Chang&#x2010,Ki,Kim, Hee&#x2010,Je,Cho, Seo John Wiley Sons, Inc. 2018 American journal of hematology Vol.93 No.11

<P><B>Abstract</B></P><P>This prospective study explored an optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with severe aplastic anemia (SAA) who received haplo‐identical stem cell transplantation from a related mismatched donor (Haplo‐SCT). We explored a safe and sufficient dose of rabbit ATG (Thymoglobulin) in combination with 800 cGy total body irradiation (TBI) and fludarabine (Flu, 30 mg/m<SUP>2</SUP>/day) for 5 days using step‐by‐step dose de‐escalation. The dose of ATG was de‐escalated from 10 mg/kg (group 1), to 7.5 mg/kg (group 2), to 5 mg/kg (group 3), and the TBI dose was reduced to 600 cGy (group 4) beginning in October 2014. If one patient developed transplant‐related mortality (TRM) with engraftment in a group, we moved to the next lower dose group. Thirty‐four patients were enrolled in groups 1‐3 (<I>n</I> = 10) and 4 (<I>n</I> = 24). All patients achieved primary engraftment. The incidence of acute GVHD (grade ≥ 2) and chronic GVHD (≥ moderate) was 29.4% and 14.7%, respectively. With a median follow‐up of 56.6 and 21.8 months in groups 1‐3 and group 4, respectively, the 2‐year probability of overall survival (91.7% in group 4 vs 70% in groups 1‐3, <I>P</I> = 0.155) and GVHD‐free survival (78.4% in group 4 vs 50% in groups 1‐3, <I>P</I> = 0.115) was shown tended to be better in group 4. This study explored an optimal conditioning with step‐by‐step de‐escalation dosage of ATG and TBI to reduce TRM with sustained graft function. TBI‐600 cGy/Flu/intermediate‐dose ATG resulted in feasible outcomes of Haplo‐SCT for adult patients with SAA.</P>

Characterization of the centromere and peri‐centromere retrotransposons in <i>Brassica rapa</i> and their distribution in related <i>Brassica</i> species

Lim, Ki&#x2010,Byung,Yang, Tae&#x2010,Jin,Hwang, Yoon‐,Jung,Kim, Jung Sun,Park, Jee&#x2010,Young,Kwon, Soo&#x2010,Jin,Kim, JinA,Choi, Beom&#x2010,Soon,Lim, Myung&#x2010,Ho,Jin, Mina,Kim, Ho&#x20 Blackwell Publishing Ltd 2007 The Plant journal Vol.49 No.2

<P><B>Summary</B></P><P>We report the identification and characterization of the major repeats in the centromeric and peri‐centromeric heterochromatin of <I>Brassica rapa.</I> The analysis involved the characterization of 88 629 bacterial artificial chromosomes (BAC) end sequences and the complete sequences of two BAC clones. We identified centromere‐specific retrotransposons of <I>Brassica</I> (CRB) and various peri‐centromere‐specific retrotransposons (PCRBr). Three copies of the CRB were identified in one BAC clone as nested insertions within a tandem array of 24 copies of a 176 bp centromeric repeat, CentBr. A complex mosaic structure consisting of nine PCRBr elements and large blocks of 238 bp degenerate tandem repeats (TR238) were found in or near a derivative of 5S–25S rDNA sequences. The chromosomal positions of selected repeats were determined using <I>in situ</I> hybridization. These revealed that CRB is a major component of all centromeres in three diploid <I>Brassica</I> species and their allotetraploid relatives. However, CentBr was not detected in the most distantly related of the diploid species analyzed, <I>B. nigra</I>. PCRBr and TR238 were found to be major components in the peri‐centromeric heterochromatin blocks of four chromosomes of <I>B. rapa.</I> These repetitive elements were not identified in <I>B. oleracea</I> or <I>B. nigra</I>, indicating that they are A‐genome‐specific.</P>

Identifying metabolically obese but normal‐weight (MONW) individuals in a nondiabetic Korean population: the Chungju Metabolic disease Cohort (CMC) study

Lee, Seung&#x2010,Hwan,Ha, Hee&#x2010,Sung,Park, Young&#x2010,Jun,Lee, Jin‐,Hee,Yim, Hyeon&#x2010,Woo,Yoon, Kun&#x2010,Ho,Kang, Moo&#x2010,Il,Lee, Won&#x2010,Chul,Son, Ho&#x2010,Young,Park, Yong Blackwell Publishing Ltd 2011 Clinical endocrinology Vol.75 No.4

<P><B>Summary</B></P><P><B>Objective </B> To investigate the prevalence and identify the phenotype of individuals suspected to be metabolically obese but normal weight (MONW).</P><P><B>Design and subjects </B> Eight thousand nine hundred and eighty‐seven nondiabetic subjects aged over 40 years were selected from the Chungju Metabolic disease Cohort study performed in 2003–2006 in Korea. Those within the highest quartile in the homeostasis model assessment of insulin resistance (HOMA‐IR) with a normal body mass index (BMI) between 18·5 and 23 kg/m<SUP>2</SUP> were classified as MONW.</P><P><B>Measurements </B> Data on anthropometry, lipid profiles and HOMA‐IR values were analysed.</P><P><B>Results </B> The prevalence of MONW was 14·2% for men and 12·9% for women amongst normal‐weight subjects. Multiple logistic regression analysis showed that total cholesterol (TC) levels over 5·17 m<SMALL>m</SMALL> (odds ratio, OR = 1·481; 95% confidence intervals, CI 1·086–2·021), triglyceride (TG) levels over 1·69 m<SMALL>m</SMALL> (OR = 1·507; 95% CI 1·093–2·077) and high‐density lipoprotein‐cholesterol levels lower than 1·03 m<SMALL>m</SMALL> (OR = 1·580; 95% CI 1·053–2·371) independently had higher odds of diagnosing MONW amongst men. For women, a BMI over 21·5 kg/m<SUP>2</SUP> (OR = 1·405; 95% CI 1·034–1·909), TC levels over 5·17 m<SMALL>m</SMALL> (OR = 1·524; 95% CI 1·112–2·090) and TG levels over 1·69 m<SMALL>m</SMALL> (OR = 1·799; 95% CI 1·302–2·487) were independently associated with a diagnosis of MONW.</P><P><B>Conclusions </B> More than 10% of normal‐weight subjects were classed as MONW in this cohort. Identification of these subjects based on lipid profiles could aid in the early detection of a high risk group of developing cardiometabolic diseases.</P>

Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response

Shin, Su&#x2010,Jin,Kim, Sang Yong,Choi, Yoon Young,Son, Taeil,Cheong, Jae&#x2010,Ho,Hyung, Woo Jin,Noh, Sung Hoon,Park, Chung&#x2010,Gyu,Kim, Hyoung&#x2010,Il AlphaMed Press 2019 The oncologist Vol.24 No.9

<P>This article reports on the relationship between microsatellite instability (MSI) status and the antitumor host immune response, focusing on the affect of these factors on prognosis in MSI‐high versus non MSI‐high gastric cancer.</P><P><B>Background.</B></P><P>Microsatellite instability (MSI)‐high (MSI‐H) colorectal cancer is known to be associated with increased tumor‐infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response.</P><P><B>Materials and Methods.</B></P><P>We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti‐CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained.</P><P><B>Results.</B></P><P>Of the 345 patients, 57 demonstrated MSI‐H tumors and 288 demonstrated non‐MSI‐H tumors. MSI‐H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI‐H tumors and those with non‐MSI‐H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence‐free survival (RFS) or overall survival (OS) in the MSI‐H tumor group. In the non‐MSI‐H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS.</P><P><B>Conclusions.</B></P><P>The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response.</P><P><B>Implications for Practice.</B></P><P>This study demonstrates that the density of each subset of tumor‐infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)‐high and non‐MSI‐high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI‐high (MSI‐H) and non‐MSI‐H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI‐high gastric cancer.</P>