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>

Identification and metabolite profiling of alkaloids in aerial parts of <i>Papaver rhoeas</i> by liquid chromatography coupled with quadrupole time‐of‐flight tandem mass spectrometry

Oh, Jae&#x2010,Hyeon,Ha, In Jin,Lee, Min Young,Kim, Eun&#x2010,Ok,Park, Dain,Lee, Jun&#x2010,Hee,Lee, Seok&#x2010,Geun,Kim, Do&#x2010,Wan,Lee, Tae‐,Ho,Lee, Eui&#x2010,Ju,Kim, Chang&#x2010,Kug John Wiley and Sons Inc. 2018 Journal of Separation Science Vol.41 No.12

<P><B>Abstract</B></P><P><I>Papaver</I> plants can produce diverse bioactive alkaloids. <I>Papaver rhoeas</I> Linnaeus (common poppy or corn poppy) is an annual flowering medicinal plant used for treating cough, sleep disorder, and as a sedative, pain reliever, and food. It contains various powerful alkaloids like rhoeadine, benzylisoquinoline, and proaporphine. To investigate and identify alkaloids in the aerial parts of <I>P. rhoeas</I>, samples were collected at different growth stages and analyzed using liquid chromatography coupled with quadrupole time‐of‐flight tandem mass spectrometry. A liquid chromatography with mass spectrometry method was developed for the identification and metabolite profiling of alkaloids for <I>P. rhoeas</I> by comparing with <I>Papaver somniferum</I>. Eighteen alkaloids involved in benzylisoquinoline alkaloid biosynthesis were used to optimize the liquid chromatography gradient and mass spectrometry conditions. Fifty‐five alkaloids, including protoberberine, benzylisoquinoline, aporphine, benzophenanthridine, and rhoeadine‐type alkaloids, were identified authentically or tentatively by liquid chromatography coupled with quadrupole time‐of‐flight tandem mass spectrometry in samples taken during various growth stages. Rhoeadine alkaloids were observed only in <I>P. rhoeas</I> samples, and codeine and morphine were tentatively identified in <I>P. somniferum</I>. The liquid chromatography coupled with quadrupole time‐of‐flight tandem mass spectrometry method can be a powerful tool for the identification of diverse metabolites in the genus <I>Papaver</I>. These results may help understand the biosynthesis of alkaloids in <I>P. rhoeas</I> and evaluate the quality of this plant for possible medicinal applications.</P>

Hypoxia‐inducible transgelin 2 selects epithelial‐to‐mesenchymal transition and γ‐radiation‐resistant subtypes by focal adhesion kinase‐associated insulin‐like growth factor 1 receptor activation in non&#

Kim, In&#x2010,Gyu,Lee, Jei&#x2010,Ha,Kim, Seo&#x2010,Yeon,Hwang, Hai&#x2010,Min,Kim, Tae‐,Rim,Cho, Eun&#x2010,Wie John Wiley and Sons Inc. 2018 Cancer Science Vol.109 No.11

<P>Microenvironment, such as hypoxia common to cancer, plays a critical role in the epithelial‐to‐mesenchymal transition (EMT) program, which is a major route of cancer metastasis and confers γ‐radiation resistance to cells. Herein, we showed that transgelin 2 (TAGLN2), an actin‐binding protein, is significantly induced in hypoxic lung cancer cells and that Snail1 is simultaneously increased, which induces EMT by downregulating <I>E‐cadherin</I> expression. Forced <I>TAGLN2</I> expression induced severe cell death; however, a small population of cells surviving after forced <I>TAGLN2</I> overexpression showed γ‐radiation resistance, which might promote tumor relapse and recurrence. These surviving cells showed high metastatic activity with an increase of EMT markers including Snail1. In these cells, TAGLN2 activated the insulin‐like growth factor 1 receptor β (IGF1Rβ)/PI3K/AKT pathway by recruitment of focal adhesion kinase to the IGF1R signaling complex. Activation of the IGF1Rβ/PI3K/AKT pathway also induced inactivation of glycogen synthase kinase 3β (GSK3β), which is involved in Snail1 stabilization. Therefore, both the IGF1Rβ inhibitor (AG1024) and the PI3K inhibitor (LY294002) or AKT inactivation with MK2206 lower the cellular level of Snail1. Involvement of GSK3β was also confirmed by treatment with lithium chloride, the inducer of GSK3β phosphorylation, or MG132, the 26S proteasomal inhibitor, which also stabilized Snail1. In conclusion, the present study provides important evidence that hypoxia‐inducible TAGLN2 is involved in the selection of cancer cells with enhanced EMT properties to overcome the detrimental environment of cancer cells.</P>

3′‐Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis

Jeon, Jimin,Kang, Li&#x2010,Jung,Lee, Kwang Min,Cho, Chanmi,Song, Eun Kyung,Kim, Wook,Park, Tae Joo,Yang, Siyoung John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.1

<P><B>Abstract</B></P><P>3′‐Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3′‐sialyllactose on osteoarthritic cartilage destruction. <I>In vitro</I> and <I>ex vivo</I>, biochemical and histological analysis demonstrated that 3′‐sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL‐1β, IL‐6, IL‐17 and TNF‐α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3′‐sialyllactose, whereas the direct binding of NF‐κB to the <I>Mmp3</I>,<I> Mmp13</I> and <I>Cox2</I> promoters was reduced by 3′‐sialyllactose in IL‐1β‐treated chondrocytes. Additionally, IL‐1β induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3′‐sialyllactose in a dose‐dependent manner. <I>In vivo</I>, 3′‐sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3′‐sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration <I>via</I> promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3′‐sialyllactose could be attributed in part to its regulation of Sox9 or NF‐κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3′‐sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.</P>

The lack of histological changes of CDMA cellular phone‐based radio frequency on rat testis

Lee, Hae&#x2010,June,Pack, Jeong&#x2010,Ki,Kim, Tae‐,Hong,Kim, Nam,Choi, Soo&#x2010,Yong,Lee, Jae&#x2010,Seon,Kim, Sung&#x2010,Ho,Lee, Yun&#x2010,Sil Wiley Subscription Services, Inc., A Wiley Company 2010 Bioelectromagnetics Vol.31 No.7

<P><B>Abstract</B></P><P>We examined the histological changes by radiofrequency (RF) fields on rat testis, specifically with respect to sensitive processes such as spermatogenesis. Male rats were exposed to 848.5 MHz RF for 12 weeks. The RF exposure schedule consisted of two 45‐min RF exposure periods, separated by a 15‐min interval. The whole‐body average specific absorption rate (SAR) of RF was 2.0 W/kg. We then investigated correlates of testicular function such as sperm counts in the cauda epididymis, malondialdehyde concentrations in the testes and epididymis, frequency of spermatogenesis stages, germ cell counts, and appearance of apoptotic cells in the testes. We also performed p53, bcl‐2, caspase 3, p21, and PARP immunoblotting of the testes in sham‐ and RF‐exposed animals. Based on these results, we concluded that subchronic exposure to 848.5 MHz with 2.0 W/kg SAR RF did not have any observable adverse effects on rat spermatogenesis. Bioelectromagnetics 31:528–534, 2010. © 2010 Wiley‐Liss, Inc.</P>

Highly Efficient p‐i‐n and Tandem Organic Light‐Emitting Devices Using an Air‐Stable and Low‐Temperature‐Evaporable Metal Azide as an n‐Dopant

Yook, Kyoung Soo,Jeon, Soon Ok,Min, Sung&#x2010,Yong,Lee, Jun Yeob,Yang, Ha&#x2010,Jin,Noh, Taeyong,Kang, Sung&#x2010,Kee,Lee, Tae‐,Woo WILEY‐VCH Verlag 2010 Advanced Functional Materials Vol.20 No.11

<P><B>Abstract</B></P><P>Cesium azide (CsN<SUB>3</SUB>) is employed as a novel n‐dopant because of its air stability and low deposition temperature. CsN<SUB>3</SUB> is easily co‐deposited with the electron transporting materials in an organic molecular beam deposition chamber so that it works well as an n‐dopant in the electron transport layer because its evaporation temperature is similar to that of common organic materials. The driving voltage of the p‐i‐n device with the CsN<SUB>3</SUB>‐doped n‐type layer and a MoO<SUB>3</SUB>‐doped p‐type layer is greatly reduced, and this device exhibits a very high power efficiency (57 lm W<SUP>−1</SUP>). Additionally, an n‐doping mechanism study reveals that CsN<SUB>3</SUB> was decomposed into Cs and N<SUB>2</SUB> during the evaporation. The charge injection mechanism was investigated using transient electroluminescence and capacitance–voltage measurements. A very highly efficient tandem organic light‐emitting diodes (OLED; 84 cd A<SUP>−1</SUP>) is also created using an n–p junction that is composed of the CsN<SUB>3</SUB>‐doped n‐type organic layer/MoO<SUB>3</SUB> p‐type inorganic layer as the interconnecting unit. This work demonstrates that an air‐stable and low‐temperature‐evaporable inorganic n‐dopant can very effectively enhance the device performance in p‐i‐n and tandem OLEDs, as well as simplify the material handling for the vacuum deposition process.</P>

Nutrikinetics of Isoflavone Metabolites After Fermented Soybean Product (Cheonggukjang) Ingestion in Ovariectomized Mice

Lee, Da&#x2010,Hye,Kim, Min Jung,Ahn, Jiyun,Lee, Sang Hee,Lee, Hyunjung,Kim, Jin Hee,Park, So&#x2010,Hyun,Jang, Young&#x2010,Jin,Ha, Tae‐,Youl,Jung, Chang Hwa John Wiley and Sons Inc. 2017 Molecular Nutrition & Food Research (Print) Vol.61 No.12

<P><B>Scope</B></P><P>Cheonggukjang (CGJ) is a soybean‐based quick‐fermented food popular in Korea that contains a variety of biologically active compounds including isoflavones and saponins. Isoflavone bioavailability may be important for the bone health of postmenopausal women; therefore, the aim of this study is to evaluate the influence of fermentation on the isoflavone metabolite nutrikinetic profile after single dose CGJ or unfermented soybean administration in ovariectomized (OVX) and sham mice.</P><P><B>Methods and results</B></P><P>We identify 34 isoflavone metabolites using UPLC–QTOF‐MS and analyze their nutrikinetics at different time points (0.25, 0.5, 1, 2, 4, 8, 16, and 24 h) to understand their fermentation‐ and OVX‐mediated time‐dependent concentration changes. Nutrikinetics analysis shows that genistein, daidzein, genistein 4′‐sulfate, dihydrodaidzein sulfate, equol 4′‐sulfate, and equol‐7‐glucuronide are present at high concentrations in all groups based on area‐under‐the‐curve analysis. OVX mice appear to show lower isoflavone bioavailability than mice in the sham group. CGJ enhances various isoflavone metabolite bioavailability including genistein, 3‐hydroxygenistein, and equol 7‐glucuronide, compared to the unfermented soybean‐treated group. Among these metabolites, intact isoflavones, 3‐hydroxygenistein, genistein 4′‐sulfate, and equol 7‐glucuronide promote osteoblastogenesis and inhibit osteoclast formation.</P><P><B>Conclusions</B></P><P>CGJ has good isoflavone bioavailability and may be beneficial for the bone health of postmenopausal women.</P>

Stretching‐Induced Growth of PEDOT‐Rich Cores: A New Mechanism for Strain‐Dependent Resistivity Change in PEDOT:PSS Films

Lee, Yoo&#x2010,Yong,Lee, Ji&#x2010,Hoon,Cho, Ju&#x2010,Young,Kim, Na&#x2010,Rae,Nam, Dae&#x2010,Hyun,Choi, In&#x2010,Suk,Nam, Ki Tae,Joo, Young&#x2010,Chang WILEY‐VCH Verlag 2013 Advanced functional materials Vol.23 No.32

<P><B>Abstract</B></P><P>It remains a fundamental challenge in the development of stretchable electronics to understand how mechanical strain changes the electrical properties of materials. Although the piezoresistive behavior of poly(3,4‐ethylene‐ dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been observed, its intrinsic origin is not yet fully understood because there are many extrinsic contributing factors and an experimental platform with which to assess such behavior has not been established. Here, systematic analysis shows that the matching Poisson's ratio and elastic modulus between PEDOT:PSS films and their underlying substrates is important in decoupling the factors that affect the material's piezoresistivity, allowing for tunable resistivity. Based on such a fundamental understanding, the conductivity of PEDOT:PSS can be controlled to be invariant and decrease as a function of applied tensile stress. Furthermore, a linear response of the resistivity with respect to mechanical strains of up to 60%, which has never before been realized, is shown. The irreversible conductivity enhancement is primarily caused by the coalescence‐induced growth of conductive PEDOT‐rich cores.</P>

Structure and function of the N‐terminal domain of the human mitochondrial calcium uniporter

Lee, Youngjin,Min, Choon Kee,Kim, Tae Gyun,Song, Hong Ki,Lim, Yunki,Kim, Dongwook,Shin, Kahee,Kang, Moonkyung,Kang, Jung Youn,Youn, Hyung&#x2010,Seop,Lee, Jung&#x2010,Gyu,An, Jun Yop,Park, Kyoung Ryou John Wiley and Sons Inc. 2015 EMBO reports Vol.16 No.10

<P><B>Abstract</B></P><P>The mitochondrial calcium uniporter (MCU) is responsible for mitochondrial calcium uptake and homeostasis. It is also a target for the regulation of cellular anti‐/pro‐apoptosis and necrosis by several oncogenes and tumour suppressors. Herein, we report the crystal structure of the MCU N‐terminal domain (NTD) at a resolution of 1.50 Å in a novel fold and the S92A MCU mutant at 2.75 Å resolution; the residue S92 is a predicted CaMKII phosphorylation site. The assembly of the mitochondrial calcium uniporter complex (uniplex) and the interaction with the MCU regulators such as the mitochondrial calcium uptake‐1 and mitochondrial calcium uptake‐2 proteins (MICU1 and MICU2) are not affected by the deletion of MCU NTD. However, the expression of the S92A mutant or a NTD deletion mutant failed to restore mitochondrial Ca<SUP>2+</SUP> uptake in a stable MCU knockdown HeLa cell line and exerted dominant‐negative effects in the wild‐type MCU‐expressing cell line. These results suggest that the NTD of MCU is essential for the modulation of MCU function, although it does not affect the uniplex formation.</P>

22‐ S ‐Hydroxycholesterol protects against ethanol‐induced liver injury by blocking the auto/paracrine activation of MCP ‐1 mediated by LXRα

Na, Tae‐,Young,Han, Young&#x2010,Hyun,Ka, Na&#x2010,Lee,Park, Han&#x2010,Su,Kang, Yun Pyo,Kwon, Sung Won,Lee, Byung&#x2010,Hoon,Lee, Mi&#x2010,Ock John WileySons, Ltd 2015 The Journal of pathology Vol.235 No.5

<P><B>Abstract</B></P><P>Chronic ethanol consumption causes hepatic steatosis and inflammation, which are associated with liver hypoxia. Monocyte chemoattractant protein‐1 (MCP‐1) is a hypoxia response factor that determines recruitment and activation of monocytes to the site of tissue injury. The level of MCP‐1 is elevated in the serum and liver of patients with alcoholic liver disease (ALD); however, the molecular details regarding the regulation of MCP‐1 expression are not yet understood completely. Here, we show the role of liver X receptor α (LXRα) in the regulation of MCP‐1 expression during the development of ethanol‐induced fatty liver injury, using an antagonist, 22‐S‐hydroxycholesterol (22‐S‐HC). First, administration of 22‐S‐HC attenuated the signs of liver injury with decreased levels of MCP‐1 and its receptor CCR2 in ethanol‐fed mice. Second, hypoxic conditions or treatment with the LXRα agonist GW3965 significantly induced the expression of MCP‐1, which was completely blocked by treatment with 22‐S‐HC or infection by shLXRα lentivirus in the primary hepatocytes. Third, over‐expression of LXRα or GW3965 treatment increased MCP‐1 promoter activity by increasing the binding of hypoxia‐inducible factor‐1α to the hypoxia response elements, together with LXRα. Finally, treatment with recombinant MCP‐1 increased the level of expression of LXRα and LXRα‐dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXRα and its ligand‐induced up‐regulation of MCP‐1 and MCP‐1‐induced LXRα‐dependent lipogenesis play a key role in the autocrine and paracrine activation of MCP‐1 in the pathogenesis of alcoholic fatty liver disease, and that this activation may provide a promising new target for ALD therapy.Copyright © 2014 The Authors. <I>The Journal of Pathology</I> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</P>