Protective mechanism of curcumin against Vibrio vulnificus infection.

Na, Hee Sam,Cha, Mi Hye,Oh, Dool-Ri,Cho, Cheong-Weon,Rhee, Joon Haeng,Kim, Young Ran Elsevier Science Publishers, B.V. on behalf of the 2011 FEMS immunology and medical microbiology Vol.63 No.3

<P>Curcumin, a natural polyphenolic flavonoid extracted from the rhizome of Curcuma longa L., has many beneficial biological activities. However, there are relatively few reports of the effects of curcumin on pathogen infections. This study examined the effect of curcumin on a Vibrio vulnificus infection. The cytotoxicity of V. vulnificus to HeLa cells was significantly inhibited by curcumin (at 10 or 30?μM). To further examine the inhibitory mechanism of curcumin against V. vulnificus-mediated cytotoxicity, the level of bacterial growth, bacterial motility, cell adhesion, RTX toxin expression and host cell reactions were evaluated. Curcumin inhibited V. vulnificus growth in HI broth. Curcumin inhibited both bacterial adhesion and RTX toxin binding to the host cells, which can be considered the major protective mechanisms for the decrease in V. vulnificus cytotoxicity. Curcumin also inhibited host cell rounding and actin aggregation, which are the early features of cell death caused by V. vulnificus. In addition, curcumin decreased the V. vulnificus-induced NF-κB translocation in HeLa cells. Finally, curcumin protected mice from V. vulnificus-induced septicemia. In conclusion, curcumin may be an alternative antimicrobial agent against fatal bacterial infections.</P>

Up-regulation of human bradykinin B1 receptor by secreted components of Pseudomonas aeruginosa via a NF-κB pathway in epithelial cells.

Shin, Hee-Sung,Ha, Un-Hwan Elsevier Science Publishers, B.V. on behalf of the 2011 FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY Vol.63 No.3

<P>Pulmonary epithelial cells produce neutrophil chemotactic activity in response to pathogenic bacterial infections, resulting in neutrophil migration to infection sites. Elicited neutrophils in the inflamed tissues were found to be dependent on bradykinin B1 receptor (B1R), which shows high affinity for the active metabolites derived from bradykinin. Thus, the up-regulation of bradykinin and B1R expression represents an important host defense response against invading microbes such as Pseudomonas aeruginosa. However, the effect of P.?aeruginosa on the expression of B1R remains unclear, while P.?aeruginosa infection is known to stimulate the production of bradykinin. Here, we report that human B1R (hB1R) transcription is up-regulated in host cells co-cultured with P.?aeruginosa. Components secreted from P.?aeruginosa play a major role in the up-regulation, and the secretion of the components is not controlled by either type III secretion system or quorum sensing. Moreover, the B1R induction is mediated by a NF-κB signaling pathway in human lung epithelial cells. Taken together, this study demonstrates that P.?aeruginosa is capable of up-regulating hB1R expression via the NF-κB signaling pathway.</P>

Exploring preferred amino acid mutations in cancer genes: Applications to identify potential drug targets

Anoosha, P.,Sakthivel, R.,Michael Gromiha, M. Elsevier Science Publishers B.V 2016 Biochimica et biophysica acta Vol.1862 No.2

Somatic mutations developed with missense, silent, insertions and deletions have varying effects on the resulting protein and are one of the important reasons for cancer development. In this study, we have systematically analysed the effect of these mutations at protein level in 41 different cancer types from COSMIC database on different perspectives: (i) Preference of residues at the mutant positions, (ii) probability of substitutions, (iii) influence of neighbouring residues in driver and passenger mutations, (iv) distribution of driver and passenger mutations around hotspot site in five typical genes and (v) distribution of silent and missense substitutions. We observed that R→H substitution is dominant in drivers followed by R→Q and R→C whereas E→K has the highest preference in passenger mutations. A set of 17 mutations including R→Y, W→A and V→R are specific to driver mutations and 31 preferred substitutions are observed only in passenger mutations. These frequencies of driver mutations vary across different cancer types and are selective to specific tissues. Further, driver missense mutations are mainly surrounded with silent driver mutations whereas the passenger missense mutations are surrounded with silent passenger mutations. This study reveals the variation of mutations at protein level in different cancer types and their preferences in cancer genes and provides new insights for understanding cancer mutations and drug development.

Routine angiographic follow-up versus clinical follow-up in patients with diabetes following percutaneous coronary intervention with drug-eluting stents in Korean population

Kim, Yong Hoon,Her, Ae-Young,Choi, Byoung Geol,Choi, Se Yeon,Byun, Jae Kyeong,Park, Yoonjee,Baek, Man Jong,Ryu, Yang Gi,Mashaly, Ahmed,Jang, Won Young,Kim, Woohyeun,Park, Eun Jin,Choi, Jah Yeon,Na, Ji Elsevier Science Publishers B.V 2018 Diabetes research and clinical practice Vol.138 No.-

<P><B>Abstract</B></P> <P><B>Aims</B></P> <P>The usefulness of routine angiographic follow-up (RAF) and clinical follow-up (CF) after percutaneous coronary intervention (PCI) in patients with diabetes is not well understood. We compare 3-year clinical outcomes of RAF and CF in diabetic patients underwent PCI with drug-eluting stents (DES).</P> <P><B>Methods</B></P> <P>A total of 843 patients with diabetes who underwent PCI with DES were enrolled. RAF was performed at 6–9 months after PCI (n = 426). Rest of patients were medically managed and clinically followed (n = 417); symptom-driven events were captured. After propensity score matched analysis, 2 propensity-matched groups (262 pairs, n = 524, C-statistic = 0.750) were generated. The primary endpoint was major adverse cardiac events (MACE), the composite of total death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), non-target vessel revascularization (Non-TVR).</P> <P><B>Results</B></P> <P>During the 3-year follow-up period, the cumulative incidence of target lesion revascularization [TLR: hazard ratio (HR), 4.07; 95% confidence interval (CI), 1.18–9.34; p = 0.001], target vessel revascularization (TVR: HR, 4.02; 95% CI, 1.93–8.40; p < 0.001), non-TVR (HR, 4.92; 95% CI, 1.68–14.4; p = 0.004) and major adverse cardiac events (MACE: HR, 2.53; 95% CI, 1.60–4.01, p < 0.001) were significantly higher in the RAF group. However, the incidence of total death, non-fatal MI were similar between the two groups.</P> <P><B>Conclusions</B></P> <P>RAF following index PCI with DES in patients with diabetes was associated with increased incidence of revascularization and MACE without changes of death or re-infarction rates and increased TLR and TVR rates in both first- and second-generation DES.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Usefulness of routine angiographic follow-up (RAF) in diabetes is less well known. </LI> <LI> RAF cause increased incidence of revascularization and major adverse cardiac events. </LI> <LI> Target lesion revascularization also higher in second-generation drug-eluting stents. </LI> </UL> </P>

Development of ssDNA aptamers as potent inhibitors of Mycobacterium tuberculosis acetohydroxyacid synthase.

Baig, Irshad Ahmed,Moon, Ji-Young,Lee, Sang-Choon,Ryoo, Sung-Weon,Yoon, Moon-Young Elsevier Science Publishers B.V 2015 Biochimica et biophysica acta. Proteins and proteo Vol.1854 No.10

<P>Acetohydroxyacid synthase (AHAS) from Mycobacterium tuberculosis (Mtb) is a promising potential drug target for an emerging class of new anti-tuberculosis agents. In this study, we identify short (30-mer) single-stranded DNA aptamers as a novel class of potent inhibitors of Mtb-AHAS through an in vitro DNA-SELEX method. Among all tested aptamers, two candidate aptamers (Mtb-Apt1 and Mtb-Apt6) demonstrated the greatest inhibitory potential against Mtb-AHAS activity with IC50 values in the low nanomolar range (28.940.002 and 22.350.001nM respectively). Interestingly, inhibition kinetics analysis of these aptamers showed different modes of enzyme inhibition (competitive and mixed type of inhibition respectively). Secondary structure-guided mutational modification analysis of Mtb-Apt1 and Mtb-Apt6 identified the minimal region responsible for their inhibitory action and consequently led to 17-mer and 20-mer shortened aptamers that retained equivalent or greater inhibitory potential. Notably, a modeling and docking exercise investigated the binding site of these two potent inhibitory aptamers on the target protein and showed possible involvement of some key catalytic dimer interface residues of AHAS in the DNA-protein interactions that lead to its potent inhibition. Importantly, these two short candidate aptamers, Mtb-Apt1 (17-mer) and Mtb-Apt6 (20-mer), also demonstrated significant growth inhibition against multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains of tuberculosis with very low MIC of 5.36μg/ml and 6.24μg/ml, respectively and no significant cytotoxicity against mammalian cell line. This is the first report of functional inhibitory aptamers against Mtb-AHAS and provides the basis for development of these aptamers as novel and strong anti-tuberculosis agents.</P>

Rise of latecomers and catch-up cycles in the world steel industry

Lee, K.,Ki, J.h. Elsevier Science Publishers B.V. (North-Holland) 2017 RESEARCH POLICY Vol.46 No.2

This study analyzes the sources of changes in industrial leadership and catch-up by latecomers in the world steel industry since World War II. The shift of leadership from the United States to Japan in 1980 and the subsequent rise of Korea, with POSCO's output surpassing that of Nippon Steel in 1998, is explained on the basis of a single theoretical framework. We rely on the neo-Schumpeterian concepts of sectoral innovation systems and windows of opportunity for latecomers in catching up with leading countries. These windows include changing generations of technologies, business cycles and demand shifts, and government regulations and other interventions. Japan realized a path-creating catch-up by taking advantage of the opportunity window associated with the emergence of new technologies. Entering as a state-owned enterprise, POSCO engaged in stage-skipping catch-up by utilizing the downturn as a window of opportunity to pay low prices for expanding its facilities and updating its technologies.

Hepatic ischemia/reperfusion injury disrupts the homeostasis of kidney primary cilia via oxidative stress

Han, S.J.,Jang, H.S.,Seu, S.Y.,Cho, H.J.,Hwang, Y.J.,Kim, J.I.,Park, K.M. Elsevier Science Publishers B.V 2017 Biochimica et biophysica acta. Molecular basis of Vol.1863 No.7

Acute kidney injury (AKI) is a major complication of hepatic surgeries. The primary cilium protrudes to the lumen of kidney tubules and plays an important role in renal functions. Disruption of primary cilia homeostasis is highly associated with human diseases including AKI. Here, we investigated whether transient hepatic ischemia induces length change and deciliation of kidney primary cilia, and if so, whether reactive oxygen species (ROS)/oxidative stress regulates those. HIR induced damages to the liver and kidney with increases in ROS/oxidative stress. HIR shortened the cilia of kidney epithelial cells and caused them to shed into the urine. This shortening and shedding of cilia was prevented by Mn(III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP, an antioxidant). The urine of patient undergone liver resection contained ciliary proteins. These findings indicate that HIR induces shortening and deciliation of kidney primary cilia into the urine via ROS/oxidative stress, suggesting that primary cilia is associated with HIR-induced AKI and that the presence of ciliary proteins in the urine could be a potential indication of kidney injury.

BMP-9 enhances fibroblast growth factor 21 expression and suppresses obesity

Kim, S.,Choe, S.,Lee, D.K. Elsevier Science Publishers B.V 2016 Biochimica et biophysica acta. Molecular basis of Vol.1862 No.7

Although BMP-9 has been reported to induce browning of white adipose tissues (WATs) and suppress high fat diet-induced obesity, detailed molecular mechanism needs to be further elucidated. We report here that administration of MB109, a recombinant derivative of human BMP-9, into obese mice enhanced gene expression of fibroblast growth factor 21 (FGF21), a metabolic regulator, and alleviates a spectrum of pathological symptoms due to high fat diet-induced obesity. In addition, periodical injection of MB109 (500μg/kg/week) reduced an amount of lipid droplets in the liver, serum levels of alanine aminotransferase (ALT), and total cholesterol. These results indicate that MB109 is also effective to treat obesity-mediated non-alcoholic fatty liver disease (NAFLD).

Catch-up cycles and changes in industrial leadership:Windows of opportunity and responses of firms and countries in the evolution of sectoral systems

Lee, K.,Malerba, F. Elsevier Science Publishers B.V. (North-Holland) 2017 RESEARCH POLICY Vol.46 No.2

This study proposes a framework that aims to explain why successive changes in industry leadership (called also the catch-up cycle) occur over time in a sector. In catch-up cycles, latecomer firms and countries emerge as international leaders, whereas incumbents lose their previous positions. New leaders are then dethroned by newcomers. To identify factors at the base of catch-up cycles, this article adopts a sectoral system framework and identifies windows of opportunity that may emerge during the long-run evolution of an industry. This study proposes three windows related to the specific dimensions of a sectoral system. One dimension is related to changes in knowledge and technology. The second dimension pertains to changes in demand, and the third includes changes in institutions and public policy. The combination of the opening of a window (technological, demand, or institutional/policy) and the responses of firms and other components of the sectoral system of the latecomer and incumbent countries determines changes in industrial leadership and catch-up. Sectors differ according to the type of windows that may open and the responses of firms and other components of systems. Empirical evidence of catch-up cycles is presented from six sectors, namely mobile phones, cameras, semiconductors, steel, mid-sized jets, and wines.

Horizon problem and firm innovation: The influence of CEO career horizon, exploitation and exploration on breakthrough innovations

Cho, S.Y.,Kim, S.K. Elsevier Science Publishers B.V. (North-Holland) 2017 RESEARCH POLICY Vol.46 No.10

Building on labor market evaluations and legacy conservation motivation perspectives, we propose a mechanism to explain the relationship between CEO career horizons and breakthrough innovations. Using 10-year panel data from 681 U.S. firms, we find that firms that have a CEO with a short career horizon tend to produce fewer breakthrough innovations. We also find that the relationship between CEO career horizon and breakthrough innovation is partially mediated by R&D spending, and also moderated by organizational learning behavior (exploration vs. exploitation). This study highlights how a CEO's motivation to protect success in the short term affects the firm's innovativeness.