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>

Carbon monoxide attenuates amyloidogenesis via down‐regulation of NF‐κB‐mediated BACE1 gene expression

Kim, Hyo Jeong,Joe, Yeonsoo,Chen, Yingqing,Park, Gyu Hwan,Kim, Uh&#x2010,Hyun,Chung, Hun Taeg John Wiley and Sons Inc. 2019 Aging cell Vol.18 No.1

<P><B>Abstract</B></P><P>Amyloid‐β (Aβ) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via β‐secretase (BACE1) and the γ‐secretase complex. It has been proposed that the abnormal secretion and accumulation of Aβ are the initial causative events in the development of Alzheimer's disease (AD). Drugs modulating this pathway could be used for AD treatment. Previous studies indicated that carbon monoxide (CO), a product of heme oxygenase (HO)‐1, protects against Aβ‐induced toxicity and promotes neuroprotection. However, the mechanism underlying the mitigative effect of CO on Aβ levels and BACE1 expression is unclear. Here, we show that CO modulates cleavage of APP and Aβ production by decreasing BACE1 expression in vivo and in vitro. CO reduces Aβ levels and improves memory deficits in AD transgenic mice. The regulation of BACE1 expression by CO is dependent on nuclear factor‐kappa B (NF‐κB). Consistent with the negative role of SIRT1 in the NF‐κB activity, CO fails to evoke significant decrease in BACE1 expression in the presence of the SIRT1 inhibitor. Furthermore, CO attenuates elevation of BACE1 level in brains of 3xTg‐AD mouse model as well as mice fed high‐fat, high‐cholesterol diets. CO reduces the NF‐κB‐mediated transcription of BACE1 induced by the cholesterol oxidation product 27‐hydroxycholesterol or hydrogen peroxide. These data suggest that CO reduces the NF‐κB‐mediated BACE1 transcription and consequently decreases Aβ production. Our study provides novel mechanisms by which CO reduces BACE1 expression and Aβ production and may be an effective agent for AD treatment.</P>

Ascochlorin inhibits growth factor‐induced HIF‐1α activation and tumor‐angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells

Jeong, Ji&#x2010,Hak,Jeong, Yun&#x2010,Jeong,Cho, Hyun‐,Ji,Shin, Jae&#x2010,Moon,Kang, Jeong&#x2010,Han,Park, Kwan&#x2010,Kyu,Park, Yoon&#x2010,Yub,Chung, Il&#x2010,Kyung,Chang, Hyeun&#x2010,Woo Wiley Subscription Services, Inc., A Wiley Company 2012 Journal of cellular biochemistry Vol.113 No.4

<P><B>Abstract</B></P><P>Ascochlorin, a non‐toxic prenylphenol compound derived from the fungus <I>Ascochyta viciae</I>, has been shown recently to have anti‐cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti‐cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia‐inducible factor‐1α (HIF‐1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)‐induced HIF‐1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF‐1α expression in response to EGF stimulation, but not in response to hypoxia (1% O<SUB>2</SUB>) or treatment with a transition metal (CoCl<SUB>2</SUB>). Second, ascochlorin inhibited EGF‐induced ERK‐1/2 activation but not AKT activation, both of which play essential roles in EGF‐induced HIF‐1α protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR‐specific small interfering RNA (siRNA) diminished HIF‐1α expression, which suggested that ascochlorin inhibits HIF‐1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF‐mediated induction of HIF‐1α expression in CaSki cells, providing a potentially new avenue of development of anti‐cancer drugs that target tumor angiogenesis. J. Cell. Biochem. 113: 1302–1313, 2012. © 2011 Wiley Periodicals, Inc.</P>

Analysis of complete genome sequences of swine hepatitis E virus and possible risk factors for transmission of HEV to humans in Korea

Song, Young&#x2010,Jo,Jeong, Hyun‐,Jeong,Kim, Yu&#x2010,Jin,Lee, Sang&#x2010,Won,Lee, Jung&#x2010,Bok,Park, Seung&#x2010,Yong,Song, Chang&#x2010,Seon,Park, Hee&#x2010,Myung,Choi, In&#x2010,Soo Wiley Subscription Services, Inc., A Wiley Company 2010 Journal of Medical Virology Vol.82 No.4

<P><B>Abstract</B></P><P>The hepatitis E virus (HEV) is an emerging zoonotic agent, for which pigs are the most important reservoir. Complete genome sequences of two swine HEV strains, designated swKOR‐1 and swKOR‐2, were determined via RT‐PCR and RACE‐PCR. The strains contained genomes composed of 7,222‐ and 7,221‐bp excluding the poly(A) tails, respectively. The swKOR‐1 and swKOR‐2 strains were classified into subtype 3a of genotype 3 via phylogenetic analysis. These strains formed a distinctive cluster in the phylogenetic tree with human and swine HEVs isolated in the USA and human HEVs isolated in Japan. Anti‐HEV antibodies were identified via ELISA in 8 of 99 (8.1%) cats, whereas, among 115 cattle and 213 dogs, no HEV‐specific antibodies were detected. The conserved RNA‐dependent RNA polymerase (RdRp) gene of HEV could be detected via RT‐PCR in 8.7% of raw oysters collected from coastal regions in Korea. The HEV RNAs detected in oysters were identified as belonging to subtype 3a. The HEV RNAs in oysters most closely resembled that of the swKOR‐2 strain. They also showed a close genetic relationship with the swKOR‐1 strain and the swine and human HEVs isolated in the USA. This is the first report describing the detection in oysters of HEV that may have originated from genotype 3 swine HEV in Korea. Pigs and cats infected with HEV, as well as oysters contaminated with HEV, are potential risk factors for HEV transmission to humans. J. Med. Virol. 82:583–591, 2010. © 2010 Wiley‐Liss, Inc.</P>

Loss of RUNX3 expression promotes cancer‐associated bone destruction by regulating CCL5 , CCL19 and CXCL11 in non‐small cell lung cancer

Kim, Hyun‐,Jeong,Park, Junhee,Lee, Sun Kyoung,Kim, Ki Rim,Park, Kwang&#x2010,Kyun,Chung, Won&#x2010,Yoon John WileySons, Ltd 2015 The Journal of pathology Vol.237 No.4

<P><B>Abstract</B></P><P>Non‐small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre‐invasive lesions. Here, we show that RUNX3 and RUNX3‐regulated chemokines are linked to NSCLC‐mediated bone resorption. Notably, the receptor activator of nuclear factor‐κB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3‐knockdown NSCLC cells. We aimed to identify RUNX3‐regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up‐regulation and down‐regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3‐knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose‐dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL‐treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC‐induced bone destruction. © 2015 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>

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&#x2010,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>

Trend analysis of diabetic prevalence and incidence in a rural area of South Korea between 2003–2008

Jeong, Ji Yun,Kim, Jung&#x2010,Guk,Kim, Bo&#x2010,Wan,Moon, Seong Su,Kim, Hye&#x2010,Soon,Park, Keun&#x2010,Gyu,Won, Kyu Chang,Lee, Hyoung Woo,Yoon, Ji Sung,Shon, Ho&#x2010,Sang,Lee, Ji Hyun,Jung, Eui Blackwell Publishing Ltd 2010 Journal of diabetes investigation Vol.1 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction: </B> This study determined the change in prevalence of diabetes and prediabetes over a period of 5 years in South Korea. The incidence of diabetes and prediabetes and risk factors associated with the development of diabetes were also investigated.</P><P><B>Materials and Methods: </B> The Dalseong population‐based cohort survey recruited 1806 subjects who were over 20‐years‐old in 2003. Five years later, 1287 of the original subjects were re‐evaluated and 187 new subjects were added to the study. All participants completed a questionnaire, were given a physical examination, and provided blood samples for analysis including 2 h oral glucose tolerances.</P><P><B>Results: </B> Age‐adjusted prevalence of diabetes rose from 6.7% in 2003 to 9.1% in 2008. The prevalence of prediabetes also increased from 18.5% in 2003 to 28.4% in 2008. The incidence rates of diabetes and prediabetes were 18.3 per 1000 person‐years and 55.4 per 1000 person‐years, respectively. The development of diabetes was associated with impaired fasting glucose (IFG) (odds ratio [OR] 5.661), impaired glucose tolerance (IGT) (OR: 6.013), age (OR 1.013), and waist‐to‐hip ratio (OR 1.513). After excluding the IFG and IGT, systolic blood pressure (OR 1.023), high‐sensitivity C‐reactive protein (hsCRP; OR 1.097), triglyceride (OR 1.002) and waist‐to‐hip ratio (OR 1.696) were statistically significant risk factors in a multivariate logistic regression analysis.</P><P><B>Conclusions: </B> A significant rise in the prevalence of diabetes and prediabetes was observed between 2003 and 2008. In addition, this study newly demonstrated that waist‐to‐hip ratio and hsCRP were associated with the development of diabetes after adjusting for several confounding factors. <B>(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00045.x, 2010)</B></P>

Suppression of PAI‐1 expression through inhibition of the EGFR‐mediated signaling cascade in rat kidney fibroblast by ascofuranone

Cho, Hyun‐,Ji,Kang, Jeong&#x2010,Han,Kim, Teoan,Park, Kwang&#x2010,Kyun,Kim, Cheorl&#x2010,Ho,Lee, In&#x2010,Seon,Min, Kwan&#x2010,Sik,Magae, Junji,Nakajima, Hiroo,Bae, Young&#x2010,Seuk,Chang, Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of cellular biochemistry Vol.107 No.2

<P><B>Abstract</B></P><P>Fibrosis in glomerulosclerosis causes progressive loss of renal function. Transforming growth factor (TGF)‐β, one of the major profibrotic cytokines, induces the synthesis of plasminogen activator inhibitor (PAI)‐1, a factor that plays a crucial role in the development of fibrosis. Here, we found that an isoprenoid antibiotic, ascofuranone, suppresses expression of profibrotic factors including matrix proteins and PAI‐1 induced by TGF‐β in renal fibroblasts. Ascofuranone selectively inhibits phosphorylation of epidermal growth factor receptor (EGFR), and downstream kinases such as Raf‐1, MEK‐1/2, and ERK‐1/2. PAI‐1 transcription also is suppressed by treatment with kinase inhibitors for MEK‐1/2 or EGFR, and with small interfering RNA for EGFR. Ascofuranone inhibits cellular metalloproteinase activity, and an inhibitor of metalloproteinases suppresses EGFR phosphorylation and PAI‐1 transcription. These results suggest that ascofuranone suppresses expression of profibrotic factors through the inhibition of an EGFR‐dependent signal transduction pathway activated by metalloproteinases. J. Cell. Biochem. 107: 335–344, 2009. © 2009 Wiley‐Liss, Inc.</P>

Feasibility of Bronchial Washing Fluid‐Based Approach to Early‐Stage Lung Cancer Diagnosis

Ryu, Jeong&#x2010,Seon,Lim, Jun Hyeok,Lee, Myoung Kyu,Lee, Seung Jae,Kim, Hyun‐,Jung,Kim, Min Jeong,Park, Mi Hwa,Kim, Jung Soo,Nam, Hae&#x2010,Seong,Park, Nuri,Yong, Seok Joong AlphaMed Press 2019 The oncologist Vol.24 No.7

<P>The potential of circulating tumor DNA (ctDNA) detection in early stage lung cancer is explored. This study investigated whether bronchial washing, a minimally invasive procedure that yields fluids that may contain ctDNA, can reflect genetic profiles of primary tumors using next‐generation sequencing.</P><P>A blood‐based approach such as circulating tumor DNA remains challenging in diagnosis for early‐stage disease. Bronchial washing (BW) is a minimally invasive procedure that yields fluids that may contain tumor DNA. Therefore, we prospectively enrolled 12 patients with early‐stage non‐small cell lung cancer without endoscopically visible tumors. Somatic mutations were analyzed using ultra‐deep next‐generation sequencing in 48 paired specimens (primary tumor tissue, normal tissue, BW supernatant, and BW precipitate). In primary tumors, 130 missense mutations/indels (5–16 per patient) and 20 driver mutations (0–3 per patient) were found. Concordance of driver mutations between BW fluids and primary tumors was 95.0%. The allele frequencies for missense mutations/indels in BW supernatants significantly correlated with those in primary tumors and were higher than those in BW precipitates. These findings suggest that BW supernatants are reflective of tumor‐associated mutations and could be used for early‐stage lung cancer diagnosis.</P>

The restoration of myeloid‐derived suppressor cells as functional antigen‐presenting cells by NKT cell help and all‐<i>trans</i>‐retinoic acid treatment

Lee, Jung&#x2010,Mi,Seo, Jeong&#x2010,Hwan,Kim, Yeon&#x2010,Jeong,Kim, Yun&#x2010,Sun,Ko, Hyun‐,Jeong,Kang, Chang&#x2010,Yuil Wiley Subscription Services, Inc., A Wiley Company 2012 International journal of cancer: Journal internati Vol.131 No.3

<P><B>Abstract</B></P><P>Myeloid‐derived suppressor cells (MDSCs), which accumulate during tumor progression, have been shown to function as important suppressor cells. In a previous study, we showed that immunosuppressive MDSCs could function as immunogenic antigen‐presenting cells (APCs) with the help of activated natural killer T (NKT) cells. In the current study, however, we found that MDSCs harvested at a late time point after tumor injection (late MDSCs) were poorly immunogenic even when stimulated with activated NKT cells. As tumor growth progressed, the expression of MHC and costimulatory molecules on MDSCs was gradually down‐regulated. Late MDSCs also had innate defects in activation and differentiation mediated by cytokine stimuli. Although late MDSCs treated only with all‐<I>trans‐</I>retinoic acid (ATRA), a stimulating agent for MDSC differentiation, could not become immunogenic, NKT ligand‐loaded, ATRA‐treated late MDSCs could be converted into immunogenic APCs to induce incremental immune responses. Furthermore, these effects were mediated by NKT cells secreting IFNγ, and ATRA‐mediated increases in glutathione (GSH) levels. Thus, combined treatment with differentiating and activating agents is a prerequisite for the conversion of late MDSCs into immunogenic APCs. Collectively, these results suggest that combined treatments are required for the differentiation and activation of late MDSCs in late stage cancer.</P>