Vitamin C deficiency attenuates liver fibrosis by way of up‐regulated peroxisome proliferator‐activated receptor‐gamma expression in senescence marker protein 30 knockout mice

Park, Jin&#x2010,Kyu,Ki, Mi&#x2010,Ran,Lee, Hye&#x2010,Rim,Hong, Il‐,Hwa,Ji, Ae&#x2010,Ri,Ishigami, Akihito,Park, Se&#x2010,Il,Kim, Ji&#x2010,Min,Chung, Hae&#x2010,Young,Yoo, Sung&#x2010,Eun,Jeo Wiley Subscription Services, Inc., A Wiley Company 2010 Hepatology Vol.51 No.5

<P><B>Abstract</B></P><P>Senescence marker protein 30 (SMP30), an important aging marker molecule that is highly expressed in the liver, has been known to protect hepatocytes from apoptosis by the synthesis of vitamin C. To explore the function of SMP30 in liver fibrosis, the effect of SMP30 deficiency on liver fibrosis was investigated in SMP30 knockout (KO) mice. Moreover, the <I>in vivo</I> results were further confirmed by way of hepatic stellate cell (HSC) isolation. We demonstrated that carbon tetrachloride (CCl<SUB>4</SUB>)‐induced liver fibrosis and the nuclear translocation of p‐Smad2/3, the immediate downstream of transforming growth factor beta (TGF‐β), were significantly inhibited in the liver of SMP30 KO mice compared with wildtype (WT) mice. We also confirmed that both WT and SMP30 KO HSCs did not express SMP30. Finally, we further confirmed that up‐regulation of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) caused by a lack of vitamin C was the pivotal factor in the mechanisms for attenuated liver fibrosis of SMP30 KO mice, and feeding with vitamin C restored CCl<SUB>4</SUB>‐induced liver fibrosis in SMP30 KO mice. <I>Conclusion:</I> Vitamin C deficiency by SMP30 depletion attenuated liver fibrosis by way of up‐regulated PPAR‐γ expression in SMP30 KO mice. Our results provide, for the first time, the possible mechanisms underlying inhibition of HSC activation associated with vitamin C and PPAR‐γ up‐regulation in liver fibrosis of SMP30 KO mice. (H<SMALL>EPATOLOGY</SMALL> 2010.)</P>

Biocompatible Poly(2‐hydroxyethyl methacrylate)‐<i>b</i>‐poly(<small>L</small>‐histidine) Hybrid Materials for pH‐Sensitive Intracellular Anticancer Drug Delivery

Johnson, Renjith P.,Jeong, Young&#x2010,Il,Choi, Eunji,Chung, Chung&#x2010,Wook,Kang, Dae Hwan,Oh, Sae&#x2010,Ock,Suh, Hongsuk,Kim, Il WILEY‐VCH Verlag 2012 Advanced Functional Materials Vol.22 No.5

<P><B>Abstract</B></P><P>A series of synthetic polymer bioconjugate hybrid materials consisting of poly(2‐hydroxyethyl methacrylate) (p(HEMA)) and poly(<SMALL>l‐</SMALL>histidine) (p(His)) are synthesized by combining atom transfer radical polymerization of HEMA with ring opening polymerization of benzyl‐<I>N</I>‐carboxy‐<SMALL>L</SMALL>‐histidine anhydride. The resulting biocompatible and membranolytic p(HEMA)<SUB>25</SUB>‐<I>b</I>‐p(His)<SUB><I>n</I></SUB> (<I>n</I> = 15, 25, 35, and 45) polymers are investigated for their use as pH‐sensitive drug‐carrier for tumor targeting. Doxorubicin (Dox) is encapsulated in nanosized micelles fabricated by a self‐assembly process and delivered under different pH conditions. Micelle size is characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM) observations. Dox release is investigated according to pH, demonstrating the release is sensitive to pH. Antitumor activity of the released Dox is assessed using the HCT 116 human colon carcinoma cell line. Dox released from the p(HEMA)‐<I>b</I>‐p(His) micelles remains biologically active and has the dose‐dependent capability to kill cancer cells at acidic pH. The p(HEMA)‐<I>b</I>‐p(His) hybrid materials are capable of self‐assembling into nanomicelles and effectively encapsulating the chemotherapeutic agent Dox, which allows them to serve as suitable carriers of drug molecules for tumor targeting.</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&#x2010,Ji,Shin, Jae&#x2010,Moon,Kang, Jeong&#x2010,Han,Park, Kwan&#x2010,Kyu,Park, Yoon&#x2010,Yub,Chung, Il‐,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>

Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response

Shin, Su&#x2010,Jin,Kim, Sang Yong,Choi, Yoon Young,Son, Taeil,Cheong, Jae&#x2010,Ho,Hyung, Woo Jin,Noh, Sung Hoon,Park, Chung&#x2010,Gyu,Kim, Hyoung&#x2010,Il AlphaMed Press 2019 The oncologist Vol.24 No.9

<P>This article reports on the relationship between microsatellite instability (MSI) status and the antitumor host immune response, focusing on the affect of these factors on prognosis in MSI‐high versus non MSI‐high gastric cancer.</P><P><B>Background.</B></P><P>Microsatellite instability (MSI)‐high (MSI‐H) colorectal cancer is known to be associated with increased tumor‐infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response.</P><P><B>Materials and Methods.</B></P><P>We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti‐CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained.</P><P><B>Results.</B></P><P>Of the 345 patients, 57 demonstrated MSI‐H tumors and 288 demonstrated non‐MSI‐H tumors. MSI‐H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI‐H tumors and those with non‐MSI‐H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence‐free survival (RFS) or overall survival (OS) in the MSI‐H tumor group. In the non‐MSI‐H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS.</P><P><B>Conclusions.</B></P><P>The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response.</P><P><B>Implications for Practice.</B></P><P>This study demonstrates that the density of each subset of tumor‐infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)‐high and non‐MSI‐high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI‐high (MSI‐H) and non‐MSI‐H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI‐high gastric cancer.</P>

Pleural or pericardial metastasis: A significant factor affecting efficacy and adverse events in lung cancer patients treated with PD‐1/PD‐L1 inhibitors

Kang, Da Hyun,Chung, Chaeuk,Kim, Ju&#x2010,Ock,Jung, Sung Soo,Park, Hee Sun,Park, Dong Il,Jung, Sun Young,Park, Myoungrin,Lee, Jeong Eun John WileySons Australia, Ltd 2018 Thoracic cancer Vol.9 No.11

<P><B>Background</B></P><P>Immunotherapy is a new paradigm for the treatment of non‐small‐cell lung cancer (NSCLC), and targeting the PD‐1 or PD‐L1 pathway is a promising therapeutic option. Although PD‐1/PD‐L1 inhibitors are more effective than standard chemotherapy in lung cancer, clinicians are afraid to actively use them because of hyperprogression and pseudoprogression. The aim of this study was to investigate the factors associated with tumor response and serious outcomes.</P><P><B>Methods</B></P><P>We retrospectively collected the medical records of 51 patients with advanced NSCLC who received PD‐1/PD‐L1 inhibitors between January 2016 and February 2018.</P><P><B>Results</B></P><P>The mean patient age was 63.9 years, and 72.5% (37/51) were male. Most (92.2%, 47/51) had received previous systemic treatment. The overall response rate was 21.6% (11/51). The response rate was significantly lower in patients with pleural or pericardial metastasis than in patients without pleural or pericardial metastasis (4.3% vs. 35.7%; <I>P</I> = 0.007). Patients with pleural or pericardial metastasis had a significantly higher rate of adverse events of any grade (91.3% vs. 50.0%; <I>P</I> = 0.002) and grade 3–5 adverse events (52.2% vs. 25.0%; <I>P</I> = 0.046).</P><P><B>Conclusion</B></P><P>Pleural or pericardial metastasis is a significant factor affecting the efficacy and rate of adverse events in advanced NSCLC patients treated with PD‐1/PD‐L1 inhibitors. Clinicians should pay attention to the use of immune checkpoint inhibitors in lung cancer patients with pleural or pericardial metastasis.</P>

Clinical trial: Inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects

Kim, Hyung&#x2010,Keun,Park, Soo&#x2010,Heon,Cheung, Dae&#x2010,Young,Cho, Young&#x2010,Seok,Kim, Jin&#x2010,Il,Kim, Sung&#x2010,Soo,Chae, Hiun&#x2010,Suk,Kim, Jae&#x2010,Kwang,Chung, In&#x2010,Sik Blackwell Publishing Asia 2010 Journal of gastroenterology and hepatology Vol.25 No.10

<P><B>Abstract</B></P><P><B>Background and Aim: </B> Revaprazan is a novel acid pump antagonist. The aim of this study was to investigate the inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects.</P><P><B>Methods: </B> In a double‐blind, three‐way cross‐over study, 30 healthy male volunteers were randomized to 100, 150 or 200 mg of oral revaprazan daily for 7 days. Serum gastrin concentration was measured, and 24‐h intragastric pH was recorded at baseline and on days 1 and 7 of each administration period. Serial blood samples were processed for pharmacokinetics.</P><P><B>Results: </B> Median intragastric pH over 24 h and mean percentage time that pH was > 4 increased in a dose‐dependent manner and were significantly higher on days 1 and 7 compared with baseline in all groups (<I>P</I> < 0.05). The antisecretory effect of revaprazan was rapid and nearly maximal on day 1 in all groups. Serum gastrin levels were rapidly normalized by 100 and 150 mg/day of revaprazan on days 1 and 7, but were significantly higher in the 200 mg/day revaprazan group. The pharmacokinetic effect was rapidly absorbed and eliminated on days 1 and 7 in all groups.</P><P><B>Conclusions: </B> Revaprazan rapidly and effectively inhibits gastric acid secretion in healthy male subjects. Therefore, revaprazan can be used as an effective drug for acid‐related disease.</P>

PPAR<i>γ</i> inhibits inflammatory reaction in oxidative stress induced human diploid fibloblast

Lee, Young&#x2010,Hee,Lee, Nan&#x2010,Hee,Bhattarai, Govinda,Yun, Ji&#x2010,Soo,Kim, Tae&#x2010,Il,Jhee, Eun&#x2010,Chung,Yi, Ho&#x2010,Keun John Wiley Sons, Ltd. 2010 CELL BIOCHEMISTRY AND FUNCTION Vol.28 No.6

<P><B>Abstract</B></P>10.1002/cbf.1681.abs<P>The ageing of an inevitable life function is an unavoidable regressive physical process. Peroxisome proliferator‐activated receptors (PPARs) are members of the nuclear hormone receptor family. PPAR<I>γ</I> plays an important role in regulating several metabolic pathways. Recently, PPAR<I>γ</I> has been implicated in inflammatory responses and age‐related diseases. The aim of this study was to determine the anti‐inflammatory reaction of PPAR<I>γ</I> in an induced ageing progress. The late passage of human diploid fibroblasts (HDF), an <I>in vitro</I> ageing model, reveals the biological index materials of ageing. Aged cells showed decreased PPAR<I>γ</I> expression and elevated levels of intracellular adhesion molecule‐1 (ICAM‐1), an inflammatory molecule. To induce the aged cell phenotype, the middle stage of HDF cells (PD31) were induced stress induced premature senescence (SIPS) with 200 µM H<SUB>2</SUB>O<SUB>2</SUB> for 2 h. SIPS‐HDF cells showed high levels of ICAM‐1, extracellular signal regulated kinase (ERK1/2) activity and matrix metallomatrix protease (MMP‐2, ‐9) activity, and low levels of PPAR<I>γ</I> expression. A reconstitution of SIPS HDF cells with Ad/PPAR<I>γ</I> resulted in the downregulation of ICAM‐1, ERK1/2, MMP‐2 and ‐9, and normalized growth of SIPS‐HDF cells. Moreover, PPAR<I>γ</I> in aged HDF cells reduced pro‐inflammatory molecules and eliminated the formation of reactive oxygen species (ROS) through the ERK1/2 pathway. These results strongly suggest that PPAR<I>γ</I> plays a key role in age‐related inflammation and may have clinical applications as a molecular target in the treatment of age‐related inflammation. Copyright © 2010 John Wiley & Sons, Ltd.</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>

Distribution of human papillomavirus type 16 E6 and E7 gene variants in the progression of cervical dysplasia in Korean women

Lee, Chung&#x2010,Won,Bae, Jeong&#x2010,Hoon,Lee, Sung&#x2010,Jong,Ho, Eun&#x2010,Mi,Lee, Il‐,Han,Park, Yong&#x2010,Gyu,Park, Jong&#x2010,Sup Blackwell Publishing Asia 2011 JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH -TO Vol.37 No.10

<P><B>Abstract</B></P><P><B>Aim: </B> This cross‐sectional, hospital‐based study examined the distribution of human papillomavirus 16 E6 and E7 gene variants in Korean women with cervical lesions of varying degrees.</P><P><B>Material & Methods: </B> One hundred and forty‐one Korean women (median age 43 years; range 22–65 years) with human papillomavirus 16 single infections were included. The human papillomavirus 16 E6/E7 sequences were amplified from cytology specimens. The distribution of human papillomavirus 16 variations with respect to cervical lesion was examined by the exact Mantel–Haenszel linear trend test (<I>P</I><SUB>trend</SUB>) and Fisher's exact test (<I>P</I>).</P><P><B>Results: </B> Human papillomavirus 16 E6 and E7 gene variants were identified in a total of 100 women (70.9%). The most prevalent human papillomavirus 16 variants were E6 Thymine178Guanine (number = 70, 49.6%) and E7 Adenine647Guanine (number = 75, 53.2%). Human papillomavirus 16 E6 Thymine178Guanine and E7 Adenine647Guanine were significantly related to the degree of cervical neoplasia (<I>P</I><SUB>trend</SUB> = 0.0002, <I>P</I> < 0.0001; <I>P</I><SUB>trend</SUB> < 0.0001, <I>P</I> < 0.0001, respectively). The odds ratio of human papillomavirus 16 E6 Thymine178Guanine to predict progression to cervical intraepithelial neoplasia 2‐3 and invasive cancer was 2.37 (95% confidence interval 1.03–5.45) and 9.07 (95% confidence interval 2.86–28.72), respectively. The odds ratio of E7 Adenine647Guanine to predict progression to cervical intraepithelial neoplasia 2‐3 and invasive cancer was 3.65 (95% confidence interval 1.16–8.51) and 9.07 (95% confidence interval 2.86–28.72), respectively.</P><P><B>Conclusion: </B> The distribution of HPV variants appears to be related to geographic difference. Human papillomavirus 16 E6 Thymine178Guanine and E7 Adenine647Guanine can be used as the candidate marker for the progression of the cervical neoplasia.</P>

Effect of Selenophene in a DPP Copolymer Incorporating a Vinyl Group for High‐Performance Organic Field‐Effect Transistors

Kang, Il,An, Tae Kyu,Hong, Jung&#x2010,a,Yun, Hui&#x2010,Jun,Kim, Ran,Chung, Dae Sung,Park, Chan Eon,Kim, Yun&#x2010,Hi,Kwon, Soon&#x2010,Ki WILEY‐VCH Verlag 2013 Advanced Materials Vol.25 No.4

<P><B>A new polymeric semiconductor, PDPPDTSE,</B> is reported which is composed of a diketopyrrolopyrrole moiety and selenophenylene vinylene selenophene, with a high field‐effect mobility achieved through intermolecular donor–acceptor interactions. The field‐effect mobility of OFET devices based on PDPPDTSE by spin‐casting is 4.97 cm<SUP>2</SUP> V<SUP>−1</SUP> s<SUP>−1</SUP>, which is higher than predecessor polymeric semiconductors.</P>