Moracin M inhibits airway inflammation by interrupting the JNK/c-Jun and NF-κB pathways in vitro and in vivo

Lee, J.H.,Ko, H.J.,Woo, E.R.,Lee, S.K.,Moon, B.S.,Lee, C.W.,Mandava, S.,Samala, M.,Lee, J.,Kim, H.P. North-Holland ; Elsevier Science Ltd 2016 european journal of pharmacology Vol.783 No.-

<P>The therapeutic effectiveness of moracins as 2-arylbenzofuran derivatives against airway inflammation was examined. Moracin M, O, and R were isolated from the root barks of Morus alba, and they inhibited interleukin (IL)-6 production from IL-1 beta-treated lung epithelial cells (A549) at 101-00 mu M. Among them, moracin M showed the strongest inhibitory effect (IC50=8.1 mu M). Downregulation of IL-6 expression by moracin M was mediated by interrupting the c-Jun N-terminal kinase (JNK)/c-Jun pathway. Moracin derivatives inhibited inducible nitric oxide synthase (iNOS)-catalyzed NO production from lipopolysaccharide (LPS)-treated alveolar macrophages (MH-S) at 50-100 mu M. In particular, moracin M inhibited NO production by downregulating iNOS. When orally administered, moracin M (20-60mg/kg) showed comparable inhibitory action with dexamethasone (30mg/kg) against LPS-induced lung inflammation, acute lung injury, in mice with that of dexamethasone (30mg/kg). The action mechanism included interfering with the activation of nuclear transcription factor-kB in inflamed lungs. Therefore, it is concluded that moracin M inhibited airway inflammation in vitro and in vivo, and it has therapeutic potential for treating lung inflammatory disorders. (C) 2016 Elsevier B.V. All rights reserved.</P>

Microneedle patch delivery to the skin of virus-like particles containing heterologous M2e extracellular domains of influenza virus induces broad heterosubtypic cross-protection

Kim, M.C.,Lee, J.W.,Choi, H.J.,Lee, Y.N.,Hwang, H.S.,Lee, J.,Kim, C.,Lee, J.S.,Montemagno, C.,Prausnitz, M.R.,Kang, S.M. Elsevier Science Publishers 2015 Journal of controlled release Vol.210 No.-

A broadly cross-protective influenza vaccine that can be administrated by a painless self-immunization method would be a value as a potential universal mass vaccination strategy. This study developed a minimally-invasive microneedle (MN) patch for skin vaccination with virus-like particles containing influenza virus heterologous M2 extracellular (M2e) domains (M2e5x VLPs) as a universal vaccine candidate without adjuvants. The stability of M2e5x VLP-coated microneedles was maintained for 8weeks at room temperature without losing M2e antigenicity and immunogenicity. MN skin immunization induced strong humoral and mucosal M2e antibody responses and conferred cross-protection against heterosubtypic H1N1, H3N2, and H5N1 influenza virus challenges. In addition, M2e5x VLP MN skin vaccination induced T-helper type 1 responses such as IgG2a isotype antibodies and IFN-γ producing cells at higher levels than those by conventional intramuscular injection. These potential immunological and logistic advantages for skin delivery of M2e5x VLP MN vaccines could offer a promising approach to develop an easy-to-administer universal influenza vaccine.

Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection

Kim, M.C.,Lee, J.S.,Kwon, Y.M.,O, E.,Lee, Y.J.,Choi, J.G.,Wang, B.Z.,Compans, R.W.,Kang, S.M. Elsevier/North-Holland 2013 Antiviral research Vol.99 No.3

The influenza M2 ectodomain (M2e) is poorly immunogenic and has some amino acid changes among isolates from different host species. We expressed a tandem repeat construct of heterologous M2e sequences (M2e5x) derived from human, swine, and avian origin influenza A viruses on virus-like particles (M2e5x VLPs) in a membrane-anchored form. Immunization of mice with M2e5x VLPs induced protective antibodies cross-reactive to antigenically different influenza A viruses and conferred cross protection. Anti-M2e antibodies induced by heterologous M2e5x VLPs showed a wider range of cross reactivity to influenza A viruses at higher levels than those by live virus infection, homologous M2e VLPs, or M2e monoclonal antibody 14C2. Fc receptors were found to be important for mediating protection by immune sera from M2e5x VLP vaccination. The present study provides evidence that heterologous recombinant M2e5x VLPs can be more effective in inducing protective M2e immunity than natural virus infection and further supports an approach for developing an effective universal influenza vaccine.

Predicting temporal shifts in the spring occurrence of overwintered Scotinophara lurida (Hemiptera: Pentatomidae) and rice phenology in Korea with climate change

Lee, H.,Kang, W. S.,Ahn, M. I.,Cho, K.,Lee, J. H. Springer Science + Business Media 2016 International journal of biometeorology Vol.60 No.1

<P>Climate change could shift the phenology of insects and plants and alter their linkage in space and time. We examined the synchrony of rice and its insect pest, Scotinophara lurida (Burmeister), under the representative concentration pathways (RCP) 8.5 climate change scenario by comparing the mean spring immigration time of overwintered S. lurida with the mean rice transplanting times in Korea. The immigration time of S. lurida was estimated using an overwintered adult flight model. The rice transplanting time of three cultivars (early, medium, and medium-late maturing) was estimated by forecasting the optimal cultivation period using leaf appearance and final leaf number models. A temperature increase significantly advanced the 99 % immigration time of S. lurida from Julian day 192.1 in the 2000s to 178.4 in the 2050s and 163.1 in the 2090s. In contrast, rice transplanting time was significantly delayed in the early-maturing cultivar from day 141.2 in the 2000s to 166.7 in the 2050s and 190.6 in the 2090s, in the medium-maturing cultivar from day 130.6 in the 2000s to 156.6 in the 2050s and 184.7 in the 2090s, and in the medium-late maturing cultivar from day 128.5 in 2000s to 152.9 in the 2050s and 182.3 in the 2090s. These simulation results predict a significant future phenological asynchrony between S. lurida and rice in Korea.</P>

A novel chimeric promoter that is highly responsive to hypoxia and metals

Lee, J-Y,Lee, Y-S,Kim, J-M,Kim, K L,Lee, J-S,Jang, H-S,Shin, I-S,Suh, W,Jeon, E-S,Byun, J,Kim, D-K Nature Publishing Group 2006 Gene Therapy Vol.13 No.10

To develop a potent hypoxia-inducible promoter, we evaluated the usefulness of chimeric combinations of the (Egr-1)-binding site (EBS) from the Egr-1 gene, the metal-response element (MRE) from the metallothionein gene, and the hypoxia-response element (HRE) from the phosphoglycerate kinase 1 gene. In transient transfection assays, combining three copies of HRE (3 × HRE) with either EBS or MRE significantly increased hypoxia responsiveness. When a three-enhancer combination was tested, the EBS–MRE-3 × HRE (E–M–H) gave a hypoxia induction ratio of 69. The expression induced from E–M–H-pGL3 was 2.4-fold higher than that induced from H-pGL3 and even surpassed the expression from a human cytomegalovirus promoter-driven vector. The high inducibility of E–M–H was confirmed by validation studies in different cells and by expressing other cDNAs. Gel shift assays together with functional overexpression studies suggested that increased levels of hypoxia-inducible factor 1α, metal transcription factor-1 and Egr-1 may be associated with the high inducibility of the E–M–H chimeric promoter. E–M–H was also induced by hypoxia mimetics such as Co<SUP>2+</SUP> and deferoxamine (DFX) and by hydrogen peroxide. Gene expression from the E–M–H was reversible as shown by the reduced expression of the transgene upon removal of inducers such as hypoxia and DFX. In vivo evaluation of the E–M–H in ischemic muscle revealed that erythropoietin secretion and luciferase and LacZ expression were significantly higher in the E–M–H group than in a control or H group. With its high induction capacity and versatile means of modulation, this novel chimeric promoter should find wide application in the treatment of ischemic diseases and cancer.Gene Therapy (2006) 13, 857–868. doi:10.1038/sj.gt.3302728; published online 9 February 2006

논문 : 생물생산시설 및 환경공학 ; 소규모 복도-더그매 예열 음압환기방식 무창자돈사의 최적 환기 요건에 관한 연구

이승주 ( S. J. Lee ),장동일 ( D. I. Chang ),황선호 ( S. H. Hwang ),( W. M. Gutierrez ),장홍희 ( H. H. Chang ) 한국농업기계학회 2010 바이오시스템공학 Vol.35 No.6

This study was carried out to determine necessary conditions for optimal ventilation of small windowless piglet house (4.0 (W) × 11.0 (L) × 2.6(H) m) with corridor and attic for preheating using CFD (Computational Fluid Dynamics) simulation. The experimental weaning piglet house was consisted of a corridor, an attic, 4 rooms (3.0 (W) × 2.75(L) m), 3 fences (0.7(H) m), 5 air inlets and 2 exhaust fans (0.4 (D) m) and simulated using CFD code, FLUENT. The simulation results for the experimental weaning piglet house showed that each room was uniformly ventilated under all the experimental conditions and air velocities at 0.1 m above floor are less than 0.15 m/s for 0.75 m/s and 1.0 m/s of air inlet velocity but 0.61 m/s for 1.25 m/s. The simulation results are similar to the measured results. Considering the air flow pattern, ventilating efficiency, air velocity at 0.1 m above floor and cold stress of weaning piglets and so on, the optimum velocity of air inlet might be 1.0 m/s.

Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects

Oh, M.J.,Hwang, H.H.,Kim, H.G.,Lee, G.H.,Cho, Y.S.,Lee, S.Y.,Kang, S.Y.,Cho, K.H.,Lee, Y.Y.,Lee, Y.J.,Jang, C.G.,Lee, S.Y. Excerpta Medica] ; Elsevier Science Ltd 2017 Clinical therapeutics Vol.39 No.7

Purpose: A fixed-dose combination (FDC) pill of amlodipine (relatively old calcium channel blocker as dihydropyridine) and olmesartan (relatively new angiotensin II receptor blocker) is used for hypertension that is not adequately controlled with a single-formulation drug. Because the FDC is a one-pill formulation, and amlodipine and olmesartan have different mechanisms of action, it is expected to improve patients' medication compliance and have an increased blood pressure-lowering efficacy. The purpose of this study was to assess the safety profile and the bioequivalence of two different FDC formulations [amlodipine besylate/olmesartan medoxomil 10/40 mg (reference product) and S-amlodipine nicotinate/olmesartan medoxomil 5/40 mg (test product)]. Methods: A randomized, open-label, single-dose, 2-treatment, 2-way, and 2-period crossover study, including a 3-week washout period, was performed in 32 healthy Korean male volunteers. To analyze the concentration of S-amlodipine or olmesartan, plasma samples were collected up to 144 hours after the dose for S-amlodipine and 48 hours after the dose for olmesartan. Pharmacokinetic parameters, including the C<SUB>max</SUB> and the area under the curve from time 0 to the last measurable concentration (AUC<SUB>0-last</SUB>) for the time versus concentration plot, were calculated. Analysis of variance for bioequivalence was conducted using C<SUB>max</SUB> and AUC<SUB>0-last</SUB> converted to log scale, and the mean ratios and 90% CIs were determined. Safety data included analysis of adverse events (AEs), vital signs, physical examinations, clinical laboratory test, and 12-lead ECGs. Findings: Of the 32 enrolled participants, 29 healthy volunteers completed the study. For both S-amlodipine and olmesartan, the main pharmacokinetic parameters were all within the acceptable range for regulatory bioequivalence. The 90% CIs for the geometric mean ratios of C<SUB>max</SUB> and AUC<SUB>0-last</SUB> were 0.8766 to 0.9760 and 0.8288 to 0.9224, respectively, for S-amlodipine and 0.9097 to 1.1229 and 0.8904 to 1.0407, respectively, for olmesartan. Hypotension was the most frequent AE, and it was observed in 4 volunteers with the test product and 7 volunteers with the reference product. Both the test and reference formulations were well tolerated. Implications: The present study demonstrates that the newly developed FDC product (test drug) and the conventional FDC product (reference drug) have comparable pharmacokinetic characteristics in healthy adult male volunteers. Both the test and reference products indicated good tolerance in this population, and no serious AEs were observed.

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer

Han, S-W,Oh, D-Y,Im, S-A,Park, S R,Lee, K-W,Song, H S,Lee, N-S,Lee, K H,Choi, I S,Lee, M H,Kim, M A,Kim, W H,Bang, Y-J,Kim, T-Y Nature Publishing Group 2009 The British journal of cancer Vol.100 No.2

<P>This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m<SUP>−2</SUP> at week 1 and 250 mg m<SUP>−2</SUP> weekly thereafter until disease progression. Oxaliplatin (100 mg m<SUP>−2</SUP>) and leucovorin (100 mg m<SUP>−2</SUP>) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m<SUP>−2</SUP>) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1–65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5–6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-<I>α</I> levels showed a 100% RR compared to 37.0% in the remaining 27 patients (<I>P</I><0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.</P>

Phase I/II study of S-1 combined with weekly docetaxel in patients with metastatic gastric carcinoma

Park, S R,Kim, H K,Kim, C G,Choi, I J,Lee, J S,Lee, J H,Ryu, K W,Kim, Y-W,Bae, J-M,Kim, N K Cancer Research UK 2008 The British journal of cancer Vol.98 No.8

We designed a phase I/II trial of S-1 combined with weekly docetaxel to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in metastatic gastric carcinoma (MGC). Patients with measurable disease received S-1 orally b.i.d. on days 1–14 and docetaxel intravenously on days 1 and 8 every 3 weeks. In phase I (n=30), each cohort received escalating doses of S-1 (30–45 mg m<SUP>−2</SUP> b.i.d.) and docetaxel (25–40 mg m<SUP>−2</SUP>); MTD was 45 mg m<SUP>−2</SUP> b.i.d. S-1/35 mg m<SUP>−2</SUP> docetaxel and RD was 40 mg m<SUP>−2</SUP> b.i.d. S-1/35 mg m<SUP>−2</SUP> docetaxel. Dose-limiting toxicities included grade 3 elevated liver enzymes, gastric perforation, grade 3 diarrhoea/fatigue, febrile neutropenia with grade 3 anorexia/fatigue, and neutropenic infection with grade 3 stomatitis/anorexia. In phase II (n=52), the overall response rate was 66.7% (95% confidence interval (CI): 53.8–79.6%) and the median time to progression and overall survival were 6.5 months (95% CI: 4.9–8.1) and 13.7 months (95% CI: 9.9–17.5), respectively. The most common grade 3/4 toxicity was neutropenia (29.4%), and febrile neutropenia/neutropenic infection occurred in 19.6% of patients. Non-haematological toxicities were generally mild. There was one treatment-related death due to pneumonitis. S-1 combined with weekly docetaxel is active in MGC with moderate toxicities.British Journal of Cancer (2008) 98, 1305–1311. doi:10.1038/sj.bjc.6604312 www.bjcancer.com Published online 25 March 2008

Supplemented vaccination with tandem repeat M2e virus-like particles enhances protection against homologous and heterologous HPAI H5 viruses in chickens

Song, B.M.,Kang, H.M.,Lee, E.K.,Jung, S.C.,Kim, M.C.,Lee, Y.N.,Kang, S.M.,Lee, Y.J. Butterworths ; Elsevier Science Ltd 2016 Vaccine Vol.34 No.5

Highly pathogenic avian influenza (HPAI) H5 viruses derived from A/Goose/Guangdong/1/96 have been continuously circulating globally, severely affecting the public health and poultry industries. The matrix 2 protein ectodomain (M2e) is considered a promising candidate for a universal cross-protective influenza vaccine that provides more effective control over HPAI H5 viruses harboring variant hemagglutinin (HA)-antigens. Here, we evaluated the protective efficacy of a tandem repeat construct of heterologous M2e presented on virus-like particles (M2e5x VLPs) either alone or as a supplement against HPAI H5 viruses in a chicken model. Chickens immunized with M2e5x VLPs alone induced M2e-specific antibodies but were not protected against HPAI H5. The homo- and cross-protective efficacy of M2e5x VLP-supplemented vaccination of chickens was also examined. Importantly, supplementation with M2e5x VLPs induced significantly higher levels of antibodies specific for M2e and different viruses as well as provided improved protection against homologous and heterologous HPAI H5 viruses. Considering the limited efficacy of inactivated vaccines, supplement vaccination with M2e5x VLPs may be an effective measure for preventing outbreaks of HPAI viruses that have the ability to constantly change their antigenic properties in poultry.