Exendin‐4 inhibits iNOS expression at the protein level in LPS‐stimulated Raw264.7 macrophage by the activation of cAMP/PKA pathway

Chang, Seo&#x2010,Yoon,Kim, Dong&#x2010,Bin,Ryu, Gyeong Ryul,Ko, Seung&#x2010,Hyun,Jeong, In&#x2010,Kyung,Ahn, Yu&#x2010,Bae,Jo, Yang&#x2010,Hyeok,Kim, Myung‐,Jun Wiley Subscription Services, Inc., A Wiley Company 2013 Journal of cellular biochemistry Vol.114 No.4

<P><B>Abstract</B></P><P>Glucagon‐like peptide‐1 (GLP‐1) and its potent agonists have been widely studied in pancreatic islet β‐cells. However, GLP‐1 receptors are present in many extrapancreatic tissues including macrophages, and thus GLP‐1 may have diverse actions in these tissues and cells. Therefore, we examined the mechanism by which exendin‐4 (EX‐4), a potent GLP‐1 receptor agonist, inhibits lipopolysaccharide (LPS)‐induced iNOS expression in Raw264.7 macrophage cells. EX‐4 significantly inhibited LPS‐induced iNOS protein expression and nitrite production. However, Northern blot and promoter analyses demonstrated that EX‐4 did not inhibit LPS‐induced iNOS mRNA expression and iNOS promoter activity. Electrophoretic mobility shift assay (EMSA) showed that EX‐4 did not alter the binding activity of NF‐κB to the iNOS promoter. Consistent with the result of EMSA, LPS‐induced IκBα phosphorylation and nuclear translocation of p65 were not inhibited by EX‐4. Also, actinomycin D chase study and the promoter assay using the construct containing 3′‐untranslated region of iNOS showed that EX‐4 did not affect iNOS mRNA stability. Meanwhile, cycloheximide chase study demonstrated that EX‐4 significantly accelerated iNOS protein degradation. The EX‐4 inhibition of LPS‐induced iNOS protein was significantly reversed by adenylate cyclase inhibitors (MDL‐12330A and SQ 22536), a PKA inhibitor (H‐89) and PKAα gene silencing. These findings suggest that EX‐4 inhibited LPS‐induced iNOS expression at protein level, but not at transcriptional mechanism of iNOS gene and this inhibitory effect of EX‐4 was mainly dependent on cAMP/PKA system. J. Cell. Biochem. 114: 844–853, 2013. © 2012 Wiley Periodicals, Inc.</P>

Caveolin‐1 deficiency induces premature senescence with mitochondrial dysfunction

Yu, Dong&#x2010,Min,Jung, Seung Hee,An, Hyoung&#x2010,Tae,Lee, Sungsoo,Hong, Jin,Park, Jun Sub,Lee, Hyun,Lee, Hwayeon,Bahn, Myeong&#x2010,Suk,Lee, Hyung Chul,Han, Na&#x2010,Kyung,Ko, Jesang,Lee, Jae&# BLACKWELL PUBLISHING 2017 AGING CELL Vol.16 No.4

<P><B>Summary</B></P><P>Paradoxical observations have been made regarding the role of caveolin‐1 (Cav‐1) during cellular senescence. For example, caveolin‐1 deficiency prevents reactive oxygen species‐induced cellular senescence despite mitochondrial dysfunction, which leads to senescence. To resolve this paradox, we re‐addressed the role of caveolin‐1 in cellular senescence in human diploid fibroblasts, A549, HCT116, and Cav‐1<SUP><I>−/−</I></SUP> mouse embryonic fibroblasts. Cav‐1 deficiency (knockout or knockdown) induced cellular senescence via a p53‐p21‐dependent pathway, downregulating the expression level of the cardiolipin biosynthesis enzymes and then reducing the content of cardiolipin, a critical lipid for mitochondrial respiration. Our results showed that Cav‐1 deficiency decreased mitochondrial respiration, reduced the activity of oxidative phosphorylation complex I (CI), inactivated SIRT1, and decreased the NAD<SUP>+</SUP>/NADH ratio. From these results, we concluded that Cav‐1 deficiency induces premature senescence via mitochondrial dysfunction and silent information regulator 2 homologue 1 (SIRT1) inactivation.</P>

Conditioned media from human palatine tonsil mesenchymal stem cells regulates the interaction between myotubes and fibroblasts by IL ‐1Ra activity

Cho, Kyung‐,Ah,Park, Minhwa,Kim, Yu&#x2010,Hee,Woo, So&#x2010,Youn,Ryu, Kyung‐,Ha John Wiley and Sons Inc. 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.1

<P><B>Abstract</B></P><P>Saturated free fatty acids (FFAs) act as lipid mediators and induce insulin resistance in skeletal muscle. Specifically, in obesity‐related diseases such as type 2 diabetes, FFAs directly reduce insulin sensitivity and glucose uptake in skeletal muscle. However, the knowledge of how FFAs mediate inflammation and subsequent tissue disorders, including fibrosis in skeletal muscle, is limited. FFAs are a natural ligand for toll‐like receptor 2 (TLR2) and TLR4, and induce chronic low‐grade inflammation that directly stimulates skeletal muscle tissue. However, persistent inflammatory stimulation in tissues could induce pro‐fibrogenic processes that ultimately lead to perturbation of the tissue architecture and dysfunction. Therefore, blocking the link between inflammatory primed skeletal muscle tissue and connective tissue might be an efficient therapeutic option for treating obesity‐induced muscle inactivity. In this study, we investigated the impact of conditioned medium obtained from human palatine tonsil‐derived mesenchymal stem cells (T‐MSCs) on the interaction between skeletal muscle cells stimulated with palmitic acid (PA) and fibroblasts. We found that PA‐treated skeletal muscle cells actively secreted interleukin‐1β (IL‐1β) and augmented the migration, proliferation and expression of fibronectin in L929 fibroblasts. Furthermore, T‐CM inhibited the skeletal muscle cell‐derived pro‐fibrogenic effect <I>via</I> the production of the interleukin‐1 receptor antagonist (IL‐1Ra), which is an inhibitor of IL‐1 signalling. Taken together, our data provide novel insights into the therapeutic potential of T‐MSC‐mediated therapy for the treatment of pathophysiological processes that occur in skeletal muscle tissues under chronic inflammatory conditions.</P>

Combining In Situ Synchrotron X‐Ray Diffraction and Absorption Techniques with Transmission Electron Microscopy to Study the Origin of Thermal Instability in Overcharged Cathode Materials for Lithium‐Ion Batteries

Nam, Kyung‐,Wan,Bak, Seong&#x2010,Min,Hu, Enyuan,Yu, Xiqian,Zhou, Youngning,Wang, Xiaojian,Wu, Lijun,Zhu, Yimei,Chung, Kyung‐,Yoon,Yang, Xiao&#x2010,Qing WILEY‐VCH Verlag 2013 Advanced Functional Materials Vol.23 No.8

<P><B>Abstract</B></P><P>The thermal instability of the cathode materials in lithium‐ion batteries is an important safety issue, requiring the incorporation of several approaches to prevent thermal runaway and combustion. Systematic studies, using combined well‐defined in situ techniques, are crucial to obtaining in‐depth understanding of the structural origin of this thermal instability in overcharged cathode materials. Here time‐resolved X‐ray diffraction, X‐ray absorption, mass spectroscopy, and high‐resolution transmission electron microscopy during heating are combined to detail the structural changes in overcharged Li<SUB><I>x</I></SUB>Ni<SUB>0.8</SUB>Co<SUB>0.15</SUB>Al<SUB>0.05</SUB>O<SUB>2</SUB> and Li<SUB><I>x</I></SUB>Ni<SUB>1/3</SUB>Co<SUB>1/3</SUB>Mn<SUB>1/3</SUB>O<SUB>2</SUB> cathode materials. By employing these several techniques in concert, various aspects of the structural changes are investigated in these two materials at an overcharged state; these include differences in phase‐distribution after overcharge, phase nucleation and propagation during heating, the preferred atomic sites and migration paths of Ni, Co, and Mn, and their individual contributions to thermal stability, together with measuring the oxygen release that accompanies these structural changes. These results provide valuable guidance for developing new cathode materials with improved safety characteristics.</P>

AZD1208, a pan‐Pim kinase inhibitor, inhibits adipogenesis and induces lipolysis in 3T3‐L1 adipocytes

Park, Yu&#x2010,Kyoung,Obiang&#x2010,Obounou, Brice Wilfried,Lee, Kyung‐,Bok,Choi, Jong&#x2010,Soon,Jang, Byeong&#x2010,Churl John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.4

<P><B>Abstract</B></P><P>The proviral integration moloney murine leukaemia virus (Pim) kinases, consisting of Pim‐1, Pim‐2 and Pim‐3, are involved in the control of cell growth, metabolism and differentiation. Pim kinases are emerging as important mediators of adipocyte differentiation. AZD1208 is a pan‐Pim kinase inhibitor and is known for its anti‐cancer activity. In this study, we investigated the effect of AZD1208 on adipogenesis and lipolysis in 3T3‐L1 cells, a murine preadipocyte cell line. AZD1208 markedly suppressed lipid accumulation and reduced triglyceride contents in differentiating 3T3‐L1 cells, suggesting the drug's anti‐adipogenic effect. On mechanistic levels, AZD1208 reduced not only the expressions of CCAAT/enhancer‐binding protein‐α (C/EBP‐α), peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), fatty acid synthase (FAS), acetyl‐CoA carboxylase (ACC) and perilipin A but also the phosphorylation of signal transducer and activator of transcription‐3 (STAT‐3) in differentiating 3T3‐L1 cells. Remarkably, AZD1208 increased cAMP‐activated protein kinase (AMPK) and LKB‐1 phosphorylation while decreased intracellular ATP contents in differentiating 3T3‐L1 cells. Furthermore, in differentiated 3T3‐L1 adipocytes, AZD1208 also partially promoted lipolysis and enhanced the phosphorylation of hormone‐sensitive lipase (HSL), a key lipolytic enzyme, indicating the drug's HSL‐dependent lipolysis. In summary, the findings show that AZD1208 has anti‐adipogenic and lipolytic effects on 3T3‐L1 adipocytes. These effects are mediated by the expression and/or phosphorylation levels of C/EBP‐α, PPAR‐γ, FAS, ACC, perilipin A, STAT‐3, AMPK and HSL.</P>

PTEN inhibits replicative senescence‐induced MMP ‐1 expression by regulating NOX 4‐mediated ROS in human dermal fibroblasts

Noh, Eun&#x2010,Mi,Kim, Jeong&#x2010,Mi,Hong, On&#x2010,Yu,Song, Hyun&#x2010,Kyung,Kim, Jong&#x2010,Suk,Kwon, Kang&#x2010,Beom,Lee, Young&#x2010,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>

Delphinidin induces apoptosis and inhibits epithelial‐to‐mesenchymal transition via the ERK/p38 MAPK‐signaling pathway in human osteosarcoma cell lines

Kang, Hae&#x2010,Mi,Park, Bong&#x2010,Soo,Kang, Hyun&#x2010,Kyung,Park, Hae&#x2010,Ryoun,Yu, Su&#x2010,Bin,Kim, In&#x2010,Ryoung John Wiley and Sons Inc. 2018 Environmental toxicology Vol.33 No.6

<P><B>Abstract</B></P><P>Delphinidin is major anthocyanidin that is extracted from many pigmented fruits and vegetables. This substance has anti‐oxidant, anti‐inflammatory, anti‐angiogenic, and anti‐cancer properties. In addition, delphinidin strongly suppresses the migration and invasion of various cancer cells during tumorigenesis. Although delphinidin has anti‐cancer effects, little is known about its functional roles in osteosarcoma (OS). For these reasons, we have demonstrated the effects of delphinidin on OS cell lines. The effects of delphinidin on cell viability and growth of OS cells were assessed using the MTT assay and colony formation assays. Hoechst staining indicated that the delphinidin‐treated OS cells were undergoing apoptosis. Flow cytometry, confocal microscopy, and a western blot analysis also indicated evidence of apoptosis. Inhibition of cell migration and invasion was found to be associated with epithelial‐to‐mesenchymal transition (EMT), observed by using a wound healing assay, an invasion assay, and a western blot analysis. Furthermore, delphinidin treatment resulted in a profound reduction of phosphorylated forms of ERK and p38. These findings demonstrate that delphinidin treatment suppressed EMT through the mitogen‐activated protein kinase (MAPK) signaling pathway in OS cell lines. Taken together, our results suggest that delphinidin strongly inhibits cell proliferation and induces apoptosis. Delphinidin treatment also suppresses cell migration and prevents EMT via the MAPK‐signaling pathway in OS cell lines. For these reasons, delphinidin has anti‐cancer effects and can suppress metastasis in OS cell lines, and it might be worth using as an OS therapeutic agent.</P>

Efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes: A double‐blind randomized controlled trial ( INICOM study)

Lim, Soo,Han, Kyung Ah,Yu, JaeMyung,Chamnan, Parinya,Kim, Eun Sook,Yoon, Kun&#x2010,Ho,Kwon, Sam,Moon, Min Kyong,Lee, Kwan Woo,Kim, Dong&#x2010,Jun,Kim, Mikyung,Wongtanate, Manaj,Kim, Eun Young,Kim, S Blackwell Publishing Ltd 2017 Diabetes, obesity & metabolism Vol.19 No.1

<P><B>Background</B></P><P>Gemigliptin is a new dipeptidyl peptidase‐IV inhibitor. We investigated the efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes (T2D).</P><P><B>Methods</B></P><P>A total of 433 T2D patients with a glycosylated haemoglobin (HbA1c) level of 7.5% to 11.0% and a fasting plasma glucose (FPG) concentration <270 mg/dL were randomly assigned to 3 groups: (1) gemigliptin 50 mg qd + metformin 1000 to 2000 mg qd (titrated individually), (2) gemigliptin 50 mg qd, or (3) metformin 1000 to 2000 mg qd. The primary end‐point was the change in HbA1c level after 24 weeks. Secondary end‐points were the changes in FPG, insulin, proinsulin and C‐peptide levels. The percentages of responders who achieved an HbA1c level <7% (or <6.5%) were compared between treatment groups.</P><P><B>Results</B></P><P>Baseline HbA1c levels were 8.7% in all groups. The mean changes in HbA1c level from baseline to week 24 were −2.06%, −1.24% and −1.47% in the combination, gemigliptin monotherapy and metformin monotherapy groups, respectively. The 95% confidence intervals for between‐group differences in HbA1c changes were −1.02 to −0.63 in the combination group vs the gemigliptin group and −0.82 to −0.41 vs the metformin group, which confirmed the superiority of combination therapy. A significantly higher percentage of patients in the combination therapy group reached the target HbA1c level <7% (or <6.5%) compared with the monotherapy groups. No severe side effects were observed.</P><P><B>Conclusions</B></P><P>In T2D patients, the initial combination of gemigliptin and metformin had superior efficacy without safety concerns compared with monotherapy with either drug.</P>

Structure‐Properties Relationship in Iron Oxide‐Reduced Graphene Oxide Nanostructures for Li‐Ion Batteries

Yu, Seung&#x2010,Ho,Conte, Donato E.,Baek, Seunghwan,Lee, Dong&#x2010,Chan,Park, Seung&#x2010,Keun,Lee, Kyung Jae,Piao, Yuanzhe,Sung, Yung‐,Eun,Pinna, Nicola WILEY‐VCH Verlag 2013 Advanced functional materials Vol.23 No.35

<P><B>Abstract</B></P><P>Non‐aqueous sol‐gel routes involving the reaction of metal oxide precursors in organic solvents (e.g., benzyl alcohol) at moderate temperature and pressure, offer advantages such as high purity, high reproducibility and the ability to control the crystal growth without the need of using additional ligands. In this paper, a study carried out on a series of iron oxide/reduced graphene oxide composites is presented to elucidate a structure‐properties relationship leading to an improved electrochemical performance of such composites. Moreover, it is demonstrated that the easy production of the composites in a variety of temperature and composition ranges, allows a fine control over the final particles size, density and distribution. The materials obtained are remarkable in terms of the particle's size homogeneity and dispersion onto the reduced graphene oxide surface. Moreover, the synthesis method used to obtain the graphene oxide clearly affects the performances of the final composites through the control of the restacking of the reduced graphene oxide sheets. It is shown that a homogeneous and less defective reduced graphene oxide enables good electrochemical performances even at high current densities (over 500 mAh/g delivered at current densities as high as 1600 mA/g). The electrochemical properties of improved samples reach the best compromise between specific capacity, rate capability and cycle stability reported so far.</P>

Evidence of carrier‐mediated transport in the penetration of donepezil into the rat brain

Kim, Mi&#x2010,Hwa,Maeng, Han&#x2010,Joo,Yu, Kyung‐,Ha,Lee, Kyeong&#x2010,Ryoon,Tsuruo, Takashi,Kim, Dae&#x2010,Duk,Shim, Chang&#x2010,Koo,Chung, Suk&#x2010,Jae Wiley Subscription Services, Inc., A Wiley Company 2010 Journal of Pharmaceutical Sciences Vol.99 No.3

<P><B>Abstract</B></P><P>The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CL<SUB>app,br</SUB>) was decreased as a function of the dose of donepezil, suggesting an involvement of a saturable transport process via transporter(s) in the penetration across the blood–brain barrier (BBB). Consistent with <I>in vivo</I> results, the uptake of substrates for organic cation transporters was significantly reduced by donepezil in both MBEC4 cells (i.e., a model for BBB) and HEK 293 cells expressing the transporters found in the brain, indicative of the involvement of organic cation transporters in the transport of the drug. Furthermore, donepezil transport was enhanced (<I>p</I> < 0.01) in HEK 293 cells expressing rOCNT1, rOCTN2, or rCHT1. The CL<SUB>app,br</SUB> was reduced up to 52.8% of the control in rats that had been pretreated with choline, while the CL<SUB>app,br</SUB> was unaffected with pretreatments with organic cations other than choline, suggesting that choline and donepezil share a common transport mechanism in the penetration across the BBB <I>in vivo</I>. Taken together, these observations suggest that the transport of donepezil across the BBB is mediated by organic cation transporters such as choline transport system(s). © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1548–1566, 2010</P>