3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Kang, Li&#x2010,Jung,Kwon, Eun&#x2010,Soo,Lee, Kwang Min,Cho, Chanmi,Lee, Jae&#x2010,In,Ryu, Young Bae,Youm, Tae Hyun,Jeon, Jimin,Cho, Mi Ra,Jeong, Seon&#x2010,Yong,Lee, Sang&#x2010,Rae,Kim, Wook,Yang John Wiley and Sons Inc. 2018 British journal of pharmacology Vol.175 No.23

<P><B>Background and Purpose</B></P><P>3′‐Sialyllactose (3′‐SL) is a safe compound that is present in high levels in human milk. Although it has anti‐inflammatory properties and supports immune homeostasis, its effect on collagen‐induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3′‐SL on the progression of rheumatoid arthritis (RA) in <I>in vitro</I> and <I>in vivo</I> models.</P><P><B>Experimental Approach</B></P><P>The anti‐arthritic effect of 3′‐SL was analysed with fibroblast‐like synoviocytes <I>in vitro</I> and an <I>in vivo</I> mouse model of CIA. RT‐PCR, Western blotting and ELISA were performed to evaluate its effects <I>in vitro</I>. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin‐O and haematoxylin staining.</P><P><B>Key Results</B></P><P>3′‐SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3′‐SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro‐inflammatory cytokines, https://en.wikipedia.org/wiki/Matrix_metalloproteinases and osteoclastogenesis <I>via</I> NF‐κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF‐κB signalling pathway, was totally blocked by 3′‐SL in the RA models.</P><P><B>Conclusions and Implications</B></P><P>3′‐SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated <I>via</I> blockade of the NF‐κB signalling pathway. Therefore, 3′‐SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.</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>

Large‐Scale Highly Ordered Chitosan‐Core Au‐Shell Nanopatterns with Plasmonic Tunability: A Top‐Down Approach to Fabricate Core–Shell Nanostructures

Baek, Youn&#x2010,Kyoung,Yoo, Seung Min,Kang, Taejoon,Jeon, Hwan&#x2010,Jin,Kim, Kyounghwan,Lee, Ji&#x2010,Sun,Lee, Sang Yup,Kim, Bongsoo,Jung, Hee&#x2010,Tae WILEY‐VCH Verlag 2010 Advanced functional materials Vol.20 No.24

<P><B>Abstract</B></P><P>A new strategy for fabricating highly ordered chitosan–Au core–shell nano­patterns with tunable surface plasmon resonance (SPR) properties is developed. This strategy combines fabrication of a chitosan nanopattern by using a soft‐nanoimprint technique with selective deposition of Au nanoparticles onto the patterned chitosan surface. The SPR response can be tuned by controlling the features of the resulting Au shell/polymer hybrid pattern, which makes these materials potentially useful in ultrasensitive optical sensors for molecular detection.</P>

Nogo‐A expression in oligodendroglial tumors

Jung, Tae‐,Young,Jung, Shin,Lee, Kyung&#x2010,Hwa,Cao, Van Thang,Jin, Shu&#x2010,Guang,Moon, Kyung&#x2010,Sub,Kim, In&#x2010,Young,Kang, Sam&#x2010,Suk,Kim, Hyung&#x2010,Seok,Lee, Min&#x2010,Che Blackwell Publishing Asia 2011 Neuropathology Vol.31 No.1

<P>Nogo‐A belongs to the reticulon protein family and is expressed in the inner and outer loops of myelin sheaths of oligodendrocytes. We analyzed the patterns of Nogo‐A expression in human gliomas in an effort to identify a useful marker for the characterization of oligodendroglial tumors. We determined the expression of Nogo‐A in a panel of 58 astrocytic and oligodendroglial tumors using immunohistochemistry and compared the expression of Nogo‐A with Olig‐2, a recently identified marker for oligodendrogliomas. To localize Nogo‐A expression, immunofluorescent staining was performed using other glial markers (MAP‐2 and GFAP). We also confirmed the overexpression of the Nogo‐A protein in 53 astrocytic and oligodendroglial tumors using Western blot analysis. Based on immunohistochemical analysis, Nogo‐A and Olig‐2 had specificity in the detection of oligodendroglial tumors from astrocytic tumors (<I>P</I> = 0.001). The level of Nogo‐A staining was highly correlated with Olig‐2 (<I>P</I> = 0.001). The sensitivity and specificity of Nogo‐A for oligodendroglial tumors was 86.9% and 57.1%, respectively. Nogo‐A expression overlapped that of other oligodendroglial markers, but with different patterns of expression. Western blot analysis revealed that Nogo‐A is predominantly expressed in 85.7% of oligodendroglioma cells and 93.7% of anaplastic oligodendroglioma cells. Like other oligodendroglial markers, Nogo‐A is highly expressed in oligodendroglial tumors; however, it does not serve as a definite marker specific for oligodendroglial tumors.</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>

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>

Comparison of VMAT‐SABR treatment plans with flattening filter (FF) and flattening filter‐free (FFF) beam for localized prostate cancer

Chung, Jin&#x2010,Beom,Kim, Jae&#x2010,Sung,Eom, Keun&#x2010,Yong,Kim, In&#x2010,Ah,Kang, Sang&#x2010,Won,Lee, Jeong&#x2010,Woo,Kim, Jin&#x2010,Young,Suh, Tae‐,Suk unknown 2015 Journal of applied clinical medical physics Vol.16 No.6

<P>The purpose of this study is to investigate the feasibility of using a flattening filter‐free (FFF) beam with an endorectal balloon for stereotactic ablative body radiotherapy (SABR) of clinically localized prostate cancer. We assessed plans of SABR with volumetric‐modulated arc therapy (VMAT) that used a flattening filter (FF) beam and an FFF beam and compared the verification results of dosimetric quality assurance for all pretreatment plans. A total of 20 patients with prostate cancer were enrolled in the study. SABR plans using VMAT with two full arcs were optimized in the Eclipse treatment planning system. All plans prescribed 42.7 Gy in 7 fractions of 6.1 Gy each. Four SABR plans were computed for each patient: two with FF beams and two with FFF beams of 6 and 10 MV. For all plans, the cumulative dose‐volume histograms (DVHs) for the target volumes and organs at risk (OARs) were recorded and compared. Pretreatment quality assurance (QA) was performed using the I'm<I>RT</I> MatriXX system and radiochromic EBT3 film to verify treatment delivery, and gamma analysis was used to quantify the agreement between calculations and measurements. In addition, total monitor units (MUs) and delivery time were investigated as technical parameters of delivery. All four plans achieved adequate dose conformity to the target volumes and had comparable dosimetric data. The DVHs of all four plans for each patient were very similar. All plans were highly conformal with CI<1.05 and CN>0.90, and the doses were homogeneous (HI = 0.08–0.15). Sparing for the bladder and rectum was slightly better with the 10 MV FF and FFF plans than with the 6 MV FF and FFF plans, but the difference was negligible. However, there was no significant difference in sparing for the other OARs. The mean agreement with the 3%/3% mm criterion was higher than 97% for verifying all plans. For the 2%/2% mm criterion, the corresponding agreement values were more than 90%, which showed that the plans were acceptable. The mean MUs and delivery time used were 1701±101 and 3.02±0.17 min for 6 MV FF, 1870±116 and 2.01±0.01 min for 6 MV FFF, 1471±86 and 2.68±0.14 min for 10 MV FF, and 1619±101 and 2.00±0.00 min for 10 MV FFF, respectively. In the current study, the dose distributions of the prostate SABR plans using 6 and 10 MV FFF beams were similar to those using 6 and 10 MV FF beams. However, this study confirmed that SABR treatment using an FFF beam had an advantage with respect to delivery time. In addition, all pretreatment plans were verified as acceptable and their results were comparable. Therefore, the results of this study suggest that the use of an FFF beam for prostate SABR is a feasible and efficient technique, if carefully applied.</P><P>PACS numbers: 87.55.D, 87.55.dk</P>

Retinoic acid receptor–related orphan receptor α–induced activation of adenosine monophosphate–activated protein kinase results in attenuation of hepatic steatosis

Kim, Eun&#x2010,Jin,Yoon, Young&#x2010,Sil,Hong, Suckchang,Son, Ho&#x2010,Young,Na, Tae‐,Young,Lee, Min&#x2010,Ho,Kang, Hyun&#x2010,Jin,Park, Jinyoung,Cho, Won&#x2010,Jea,Kim, Sang&#x2010,Gun,Ko Wiley Subscription Services, Inc., A Wiley Company 2012 Hepatology Vol.55 No.5

<P><B>Abstract</B></P><P>There is increasing evidence that the retinoic acid receptor–related orphan receptor α (RORα) plays an important role in the regulation of metabolic pathways, particularly of fatty acid and cholesterol metabolism; however, the role of RORα in the regulation of hepatic lipogenesis has not been studied. Here, we report that RORα attenuates hepatic steatosis, probably via activation of the adenosine monophosphate (AMP)‐activated protein kinase (AMPK) and repression of the liver X receptor α (LXRα). First, RORα and its activator, cholesterol sulfate (CS), induced phosphorylation of AMPK, which was accompanied by the activation of serine–threonine kinase liver kinase B1 (LKB1). Second, the activation of RORα, either by transient transfection or CS treatment, decreased the TO901317‐induced transcriptional expression of LXRα and its downstream target genes, such as the sterol regulatory element binding protein‐1 (SREBP‐1) and fatty acid synthase. RORα interacted physically with LXRα and inhibited the LXRα response element in the promoter of LXRα, indicating that RORα interrupts the autoregulatory activation loop of LXRα. Third, infection with adenovirus encoding RORα suppressed the lipid accumulation that had been induced by a free‐fatty–acid mixture in cultured cells. Furthermore, we observed that the level of expression of the RORα protein was decreased in the liver of mice that were fed a high‐fat diet. Restoration of RORα via tail‐vein injection of adenovirus (Ad)‐RORα decreased the high‐fat‐diet–induced hepatic steatosis. Finally, we synthesized thiourea derivatives that activated RORα, thereby inducing activation of AMPK and repression of LXRα. These compounds decreased hepatic triglyceride levels and lipid droplets in the high‐fat‐diet–fed mice. <I>Conclusion</I>: We found that RORα induced activation of AMPK and inhibition of the lipogenic function of LXRα, which may be key phenomena that provide the beneficial effects of RORα against hepatic steatosis. (H<SMALL>EPATOLOGY</SMALL> 2012;)</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>

Up‐regulation and clinical significance of serine protease kallikrein 6 in colon cancer

Kim, Jong&#x2010,Tae,Song, Eun Young,Chung, Kyung&#x2010,Sook,Kang, Min Ah,Kim, Jae Wha,Kim, Sang Jick,Yeom, Young Il,Kim, Joo Heon,Kim, Kyo Hyun,Lee, Hee Gu Wiley Subscription Services, Inc., A Wiley Company 2011 Cancer Vol.117 No.12

<P><B>Abstract</B></P><P><B>BACKGROUND:</B></P><P>Kallikrein‐related peptidase 6 (KLK6) encodes a trypsin‐like serine protease that is up‐regulated in several cancers, although the putative functions of KLK6 in cancer have not been elucidated. In the current study, overexpression of KLK6 was identified in colon cancer, and the possibility that KLK6 may be a suitable candidate as a tumor marker was examined.</P><P><B>METHODS:</B></P><P>Messenger RNA (mRNA) transcript levels and protein up‐regulation of KLK6 in colon cancer tissues was examined using reverse transcriptase‐polymerase chain reaction, immunohistochemistry, and clinicopathologic analyses. Cell proliferation, invasiveness, and antiapoptotic activity were determined in colon cancer cells that were transfected with small‐interfering RNA (siRNA) of <I>KLK6</I>.</P><P><B>RESULTS:</B></P><P><I>KLK6</I> mRNA was up‐regulated significantly in tumor tissues compared with nontumor regions. KLK6 protein was strongly expressed in adenocarcinomas but was not expressed in normal mucosa or in premalignant dysplastic lesions. Sera from patients with colon cancer revealed an increase in KLK6 secretion (0.25 μg/mL; <I>P</I> = .031) compared with noncancer cells (0.19 μg/mL). Clinicopathologic and immunohistochemical studies of 143 patients with colon cancer revealed a significant correlation between KLK6 expression and Dukes disease stage (<I>P</I> = .005). High KLK6 expression was associated significantly with shorter overall (<I>P</I> = .001) and recurrence‐free survival (<I>P</I> = .001). The rates of proliferation and invasiveness were decreased by 50% in cells that were transfected with <I>KLK6</I> siRNA. The overexpression of KLK6 led to decreased activity of the E‐cadherin promoter.</P><P><B>CONCLUSIONS:</B></P><P>KLK6 was up‐regulated significantly in tissues and sera from patients with colon cancer and was associated closely with a poor prognosis, suggesting that KLK6 may be used as a potential biomarker and a therapeutic target for colon cancer. Cancer 2011;. © 2010 American Cancer Society.</P>