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Suh, Dong‐,Hyeon,Trinh, Hoang Kim Tu,Liu, Jing‐,Nan,Pham, Le Duy,Park, Sang Myun,Park, Hae‐,Sim,Shin, Yoo Seob CAROL DAVILA UNIVERSITY PRESS 2016 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.20 No.2
<P><B>Abstract</B></P><P>Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty‐eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA‐sensitized and ‐challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus‐containing goblet cells were reduced in clopidogrel‐administered mice compared to vehicle‐treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL‐1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.</P>
Pro‐apoptotic Noxa is involved in ablative focal irradiation‐induced lung injury
Kim, Jee‐,Youn,An, Yong‐,Min,Choi, Won Hoon,Kim, Jin‐,Mo,Cho, Samju,Yoo, Byung Rok,Kang, Jeong Wook,Lee, Yun‐,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>
Noh, Eun‐,Mi,Kim, Jeong‐,Mi,Hong, On‐,Yu,Song, Hyun‐,Kyung,Kim, Jong‐,Suk,Kwon, Kang‐,Beom,Lee, Young‐,Rae CAROL DAVILA UNIVERSITY PRESS 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.11
<P><B>Abstract</B></P><P>The biological function of NADPH oxidase (NOX) is the generation of reactive oxygen species (ROS). ROS, primarily arising from oxidative cell metabolism, play a major role in both chronological ageing and photoageing. ROS in extrinsic and intrinsic skin ageing may be assumed to induce the expression of matrix metalloproteinases. NADPH oxidase is closely linked with phosphatidylinositol 3‐OH kinase (PI3K) signalling. Protein kinase C (PKC), a downstream molecule of PI3K, is essential for superoxide generation by NADPH oxidase. However, the effect of PTEN and NOX4 in replicative‐aged MMPs expression has not been determined. In this study, we confirmed that inhibition of the PI3K signalling pathway by PTEN gene transfer abolished the NOX‐4 and MMP‐1 expression. Also, NOX‐4 down‐expression of replicative‐aged skin cells abolished the MMP‐1 expression and ROS generation. These results suggest that increase of MMP‐1 expression by replicative‐induced ROS is related to the change in the PTEN and NOX expression.</P>
Class I HDAC s specifically regulate E‐cadherin expression in human renal epithelial cells
Choi, Sin Y.,Kee, Hae J.,Kurz, Thomas,Hansen, Finn K.,Ryu, Yuhee,Kim, Gwi R.,Lin, Ming Q.,Jin, Li,Piao, Zhe H.,Jeong, Myung H. CAROL DAVILA UNIVERSITY PRESS 2016 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.20 No.12
<P><B>Abstract</B></P><P>Epithelial‐mesenchymal transition (EMT) and renal fibrosis are closely involved in chronic kidney disease. Inhibition of histone deacetylase (HDAC) has an anti‐fibrotic effect in various diseases. However, the pathophysiological role of isoform‐specific HDACs or class‐selective HDACs in renal fibrosis remains unknown. Here, we investigated EMT markers and extracellular matrix (ECM) proteins in a human proximal tubular cell line (HK‐2) by using HDAC inhibitors or by knockdown of class I HDACs (HDAC1, 2, 3 and 8). Trichostatin A (TSA), MS275, PCI34051 and LMK235 inhibited ECM proteins such as collagen type I or fibronectin in transforming growth factor β1 (TGF‐β1)‐induced HK2 cells. However, restoration of TGF‐β1‐induced E‐cadherin down‐regulation was only seen in HK‐2 cells treated with TSA or MS275, but not with PCI34051, whereas TGF‐β1‐induced N‐cadherin expression was not affected by the inhibitors. ECM protein and EMT marker levels were prevented or restored by small interfering RNA transfection against HDAC8, but not against other class I HDACs (HDAC1, 2 and 3). E‐cadherin regulation is mediated by HDAC8 expression, but not by HDAC8 enzyme activity. Thus, class I HDACs (HDAC1, 2, 3 and 8) play a major role in regulating ECM and EMT, whereas class IIa HDACs (HDAC4 and 5) are less effective.</P>
Tannic acid inhibits EGFR / STAT 1/3 and enhances p38/ STAT 1 signalling axis in breast cancer cells
Darvin, Pramod,Joung, Youn Hee,Kang, Dong Young,Sp, Nipin,Byun, Hyo Joo,Hwang, Tae Sook,Sasidharakurup, Hema,Lee, Chi Ho,Cho, Kwang Hyun,Park, Kyung Do,Lee, Hak Kyo,Yang, Young Mok CAROL DAVILA UNIVERSITY PRESS 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.4
<P><B>Abstract</B></P><P>Tannic acid (TA), a naturally occurring polyphenol, is a potent anti‐oxidant with anti‐proliferative effects on multiple cancers. However, its ability to modulate gene‐specific expression of tumour suppressor genes and oncogenes has not been assessed. This work investigates the mechanism of TA to regulate canonical and non‐canonical STAT pathways to impose the gene‐specific induction of G1‐arrest and apoptosis. Regardless of the p53 status and membrane receptors, TA induced G1‐arrest and apoptosis in breast cancer cells. Tannic acid distinctly modulated both canonical and non‐canonical STAT pathways, each with a specific role in TA‐induced anti‐cancer effects. Tannic acid enhanced STAT1 ser727 phosphorylation <I>via</I> upstream serine kinase p38. This STAT1 ser727 phosphorylation enhanced the DNA‐binding activity of STAT1 and in turn enhanced expression of p21<SUP>Waf1/Cip1</SUP>. However, TA binds to EGF‐R and inhibits the tyrosine phosphorylation of both STAT1 and STAT3. This inhibition leads to the inhibition of STAT3/BCL‐2 DNA‐binding activity. As a result, the expression and mitochondrial localization of BCl‐2 are declined. This altered expression and localization of mitochondrial anti‐pore factors resulted in the release of cytochrome c and the activation of intrinsic apoptosis cascade involving caspases. Taken together, our results suggest that TA modulates EGF‐R/Jak2/STAT1/3 and P38/STAT1/p21<SUP>Waf1/Cip1</SUP> pathways and induce G1‐arrest and intrinsic apoptosis in breast carcinomas.</P>
Kim, Doyun,Chung, Sena,Lee, Seung‐,Hyun,Choi, Se‐,Young,Kim, Soung‐,Min,Koo, JaeHyung,Lee, Jong‐,Ho,Jahng, Jeong Won CAROL DAVILA UNIVERSITY PRESS 2017 Journal of Cellular and Molecular Medicine Vol.21 No.12
<P><B>Abstract</B></P><P>The hypoglossal nerve controls tongue movements, and damages of it result in difficulty in mastication and food intake. Mastication has been reported to maintain hippocampus‐dependent cognitive function. This study was conducted to examine the effect of tongue motor loss on the hippocampus‐dependent cognitive function and its underlying mechanism. Male Sprague Dawley rats were subjected to the initial training of Morris water maze task before or after the bilateral transection of hypoglossal nerves (Hx). When the initial training was given before the surgery, the target quadrant dwelling time during the probe test performed at a week after the surgery was significantly reduced in Hx rats relative to sham‐operated controls. When the initial training was given after the surgery, Hx affected the initial and reversal trainings and probe tests. Brain‐derived neurotrophic factor (BDNF) expression, cell numbers and long‐term potentiation (LTP) were examined in the hippocampus on the 10<SUP>th</SUP> day, and BrdU and doublecortin staining on the 14<SUP>th</SUP> day, after the surgery. Hx decreased the hippocampal BDNF and cells in the CA1/CA3 regions and impaired LTP. BrdU and doublecortin staining was decreased in the dentate gyrus of Hx rats. Results suggest that tongue motor loss impairs hippocampus‐dependent cognitive function, and decreased BDNF expression in the hippocampus may be implicated in its underlying molecular mechanism in relation with decreased neurogenesis/proliferation and impaired LTP.</P>