The Effect of Trifluoroethanol on Tyrosinase Activity and Conformation: Inhibition Kinetics and Computational Simulations

L체, Z. R.,Shi, L.,Wang, J.,Park, D.,Bhak, J.,Yang, J. M.,Park, Y. D.,Zhou, H. W.,Zou, F. HUMANA PRESS INC 2010 Applied biochemistry and biotechnology Vol.160 No.7

Anti-inflammatory activity of 21(α, β)-methylmelianodiols, novel compounds from Poncirus trifoliata Rafinesque

Zhou, H.Y.,Shin, E.M.,Guo, L.Y.,Zou, L.B.,Xu, G.H.,Lee, S.H.,Ze, K.R.,Kim, E.K.,Kang, S.S.,Kim, Y.S. North-Holland ; Elsevier Science Ltd 2007 european journal of pharmacology Vol.572 No.2

The fruits of Poncirus trifoliata (L.) are widely used in Oriental medicine as a remedy for allergic inflammation. As a part of our program to screen medicinal plants for potential anti-inflammatory compounds, 21α-methylmelianodiol (21α-MMD) and 21β-methylmelianodiol (21β-MMD), which are two isomers of 21-methylmelianodiol isolated from the fruits of P. trifoliata for the first time, were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. 21α-MMD and 21β-MMD attenuated LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expressions as well as the mRNA levels of iNOS, COX-2, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). To investigate the mechanism involved, we examined the effect of 21α-MMD and 21β-MMD on LPS-induced nuclear factor-κB (NF-κB) activation. Both 21α-MMD and 21β-MMD significantly inhibited LPS-induced NF-κB transcriptional activity in RAW 264.7 macrophages. Moreover, the in vivo anti-inflammatory effect of 21α-MMD was examined in two mouse models of acute inflammation. In the carrageenan-induced paw edema model, administration of 21α-MMD (20 and 100 mg/kg, i.p.) dose-dependently reduced paw swelling. In addition, 21α-MMD significantly inhibited the dye leakage in an acetic acid-induced vascular permeability assay. Taken together, our data indicate that 21-methylmelianodiol is an important constituent of the fruit of P. trifoliata, and that the inhibition of iNOS and COX-2 expression by 21α-MMD and 21β-MMD might be one of the mechanisms responsible for their anti-inflammatory effects.

Fabrication and characterization of fluorohydroxyapatite nanocrystals/poly(d,l-lactide) composite scaffolds

L. Cheng,S.M. Zhang,P.P. Chen,S.L. Huang,L. Liu,W. Zhou,J. Liu,H. Gong,Q.M. Luo 한국물리학회 2007 Current Applied Physics Vol.7 No.s1

Poly(D,L-lactide) (PDLLA)/uorohydroxyapatite nanocrystals (nano-F-HA) porous scaolds were successfully fabricated through asolvent-casting and particulate-leaching technique. Nano-HA/PDLLA scaold and PDLLA scaold were prepared by using the sameprocess for comparison. The structure, phase and morphology of the nanocomposite scaolds were observed by SEM. The results indi-cated that F-HA nanocrystals were homogeneously dispersed in the PDLLA matrix. The porosity of the scaolds was up to 90%, andmacropores and micropores coexisted and interconnected throughout the scaolds. Cell culture experiments demonstrated that the nano-F-HA/PDLLA scaffold had the best adhesion tendency to chondrocytes among the scaffolds investigated.

Inhibition of tyrosinase by fumaric acid: Integration of inhibition kinetics with computational docking simulations

Gou, L.,Lee, J.,Yang, J.M.,Park, Y.D.,Zhou, H.M.,Zhan, Y.,Lu, Z.R. Elsevier 2017 International Journal of Biological Macromolecules Vol.105 No.3

Fumaric acid (FA), which is naturally found in organisms, is a well known intermediate of the citric acid cycle. We evaluated the effects of FA on tyrosinase activity and structure via enzyme kinetics and computational simulations. FA was found to be a reversible inhibitor of tyrosinase and its induced mechanism was the parabolic non-competitive inhibition type with IC<SUB>50</SUB>=13.7+/-0.25mM and K<SUB>islope</SUB>=12.64+/-0.75mM. We newly established the equation for the dissociation constant (K<SUB>islope</SUB>) for the parabolic inhibition type in this study. Kinetic measurements and spectrofluorimetry studies showed that FA induced regional changes in the active site of tyrosinase. One possible binding site for FA was identified under the condition without L-DOPA. The computational docking simulations further revealed that FA can interact with HIS263 and HIS85 at the active site. Furthermore, four important hydrogen bonds were found to be involved with the docking of FA on tyrosinase. Our study provides insight into the mechanism by which dicarboxylic acids such as FA inhibit tyrosinase. By inhibiting tyrosinase and its central role in pigment production, FA is a potential natural antipigmentation agent.

Effects of L-malic acid on alpha-glucosidase: inhibition kinetics and computational molecular dynamics simulations.

Gou, Lin,Zhan, Yi,Lee, Jinhyuk,Li, Xuan,Lü,, Zhi-Rong,Zhou, Hai-Meng,Lu, Hang,Wang, Xi-Yao,Park, Yong-Doo,Yang, Jun-Mo Humana Press 2015 Applied biochemistry and biotechnology Vol.175 No.4

<P>The inhibitory effect of L-malic acid (MA) on alpha-glucosidase (EC 3.2.1.20) was investigated by combination study between inhibition kinetics and computational simulations. The results from the serial kinetics demonstrated that MA could directly inactivate the enzyme activity in a dose-dependent manner and a typical non-competitive type, as well as in a fast inactivate process without detectable time course. The tertiary conformation study with an application of spectrofluorimetry showed that MA modulated the tertiary structural conformation of alpha-glucosidase both on the overall and on regional active site pocket, which monitored by red-shift intrinsic fluorescence peak with decreases intensities, and the significant intensity increasing of 1-anilinonaphthalene-8-sulfonate (ANS)-binding fluorescence, respectively. To have more insight, we also adapted the computational molecular dynamics (MD) simulations. The results showed that MA was located in the entrance of active pocket for the catalytic reaction and blocked the passage of substrate. It confirmed that MA inhibits as a non-competitive type, not direct docking to the glucose binding site. Our study provides important molecular mechanisms to figure out alpha-glucosidase inhibition that might associate to development of type 2 diabetes mellitus drug.</P>

High Sustained Virologic Response with Daclatasvir plus Asunaprevir in HCV GT-1b Chinese, Korean and Taiwanese without Baseline NS5A Polymorphisms

( F. Mcphee ),( L. Wei ),( Q. Xie ),( Y. Suzuki ),( J. Toyota ),( Y. Karino ),( K. Chayama ),( Y. Kawakami ),( M. L. Yu ),( S. H. Ahn ),( N. Zhou ),( H. Kumada ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Daclatasvir (DCV) plus asunaprevir (ASV) has demonstrated highsustained virologic response (SVR) in HCV genotype (GT-)1b infection.NS5A-Y93H and NS5A-L31 resistance-associated polymorphisms(RAPs) to DCV are known to impact DCV+ASV response in GT-1b-infectedJapanese. The effect of RAPs on SVR at posttreatment week12 (SVR12) to DCV+ASV was explored in mainland Chinese, Korean,and Taiwanese.Methods: Pooled data from 2 studies of DCV (60 mg daily) + ASV(100 mg capsule, twice-daily) for 24 weeks in GT-1b-infected interferon/ribavirin-naive and -experienced patients from mainland China,Korea, and Taiwan. Similar Japanese data (4 studies; n=445) werepooled for comparison. SVR12 with versus without baseline Y93Hand/or L31 RAPs was compared by age (<65 vs ≥65 years), cirrhosisstatus, and baseline HCV-RNA.Results: SVR12 and baseline NS5A sequences were available for 282patients (126 mainland Chinese [45%〕, 80 Koreans [28%〕, 76Taiwanese [27%〕). NS5A-Y93H and/or -L31 RAPs were observed pretreatmentin 8% mainland Chinese, 14% Korean, and 18%Taiwanese patients, compared with 19% in Japanese. SVR12 in allnon-Japanese patients is shown (Figure); rates were broadly similarbetween countries and with Japanese data (Japanese: 96% overallwithout RAPs, 41% with RAPs). Responses were lower among patientswith baseline RAPs. By contrast, SVR12 in patients without RAPs washigh (92-100%), irrespective of cirrhosis, age, or baseline HCV-RNA.Conclusions: At least 95% of HCV GT-1b-infected patients from mainlandChina, Korea or Taiwan without baseline NS5A-Y93H or -L31polymorphisms who had HCV-RNA ≤7 log10 IU/mL achieved SVR12on DCV+ASV, regardless of cirrhosis status and age.

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

Chen, Han,Li, Chunyan,Peng, Xinxin,Zhou, Zhicheng,Weinstein, John N.,Caesar-Johnson, Samantha J.,Demchok, John A.,Felau, Ina,Kasapi, Melpomeni,Ferguson, Martin L.,Hutter, Carolyn M.,Sofia, Heidi J.,Ta Elsevier 2018 Cell Vol.173 No.2

<P><B>Summary</B></P> <P>The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Systematic analysis of enhancer expression across ∼9,000 samples of 33 cancer types </LI> <LI> Global enhancer activation positively correlates with aneuploidy but not mutations </LI> <LI> A computational method that infers causal enhancer-target-gene relationships </LI> <LI> Enhancers as key regulators of therapeutic targets, including PD-L1 </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Emergence and Persistence of NS5A and NS3 Resistance-Associated Substitutions in HCV Genotype 1b Patients Treated with Daclatasvir and Asunaprevir

( F. Mcphee ),( D. Hernandez ),( N. Zhou ),( F. Yu ),( B. Kienzle ),( Y. Zhao ),( M. Linaberry ),( S. Noviello ),( M. L. Yu ),( S. H. Ahn ),( Y. Karino ),( K. Chayama ),( H. Kumada ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: A pooled analysis of emergent RAS was performed in HCV genotype (GT-)1b-infected patients receiving daclatasvir and asunaprevir (DCV+ASV) and the persistence of DCV- and ASV-resistant substitutions through ≥post-treatment Week (PTWK)192 was assessed to understand the RAS profile and help guide potential retreatment options. Methods: HCV GT-1b-infected patients without a sustained virologic response (SVR) and with HCV RNA ≥1000 IU/mL on or after DCV+ASV treatment were included from 5 Phase 2 and 3 studies. Baseline and post-baseline plasma samples were sequenced at a sensitivity cut-off ł20%. To determine the persistence of emergent RAS, samples at the end of study (up to PTWK48) and/or from a 3-year long-term follow-up rollover study were sequenced (sensitivity cut-off ≥20%, and ≥1% for select samples). Results: 152 DCV+ASV-treated patients without SVR met the resistance testing criteria: 89% (136/152) had NS5A and 95% (145/152) had NS3 sequences at both baseline and virologic failure (VF). NS5A and NS3 RAS emerged in 99% (134/136) and 89% (129/145), respectively, at VF (Table). Overall, 93% (142/152) of patients with VF had both NS5A and NS3 sequence data at failure, of which 77% (109/142) had RAS at L31, Y93 and D168. Emergent NS5A RAS persisted at PTWK96 (92%;24/26) and ≥PTWK192 (100;7/7compared with 22% (6/27) and 14% (1/7), respectively, for emergent NS3 RAS. Replacement of emergent NS5A and NS3 RAS observed at VF occurred in 8% (2/26) of NS5A and 74% (17/23) of NS3 sequences at PTWK96 and in 0% (0/7) of NS5A and 86% (6/7) of NS3 sequences at ≥PTWK192. Conclusions: NS5A and NS3 RAS emerged in most patients treated with DCV+ASV who experienced VF, and NS5A RAS persisted post-treatment. Therapy options for DCV+ASV treatment failures may depend on the timing of retreatment: an NS3 inhibitor-containing regimen may be possible if NS3 RAS are no longer observed, while regimens not impacted by the NS5A-L31+Y93 and NS3-D168 RAS combination would offer an immediate alternative.

Changes in the sorption and rate of 17β-estradiol biodegradation by dissolved organic matter collected from different water sources

Lee, Ji Ho,Zhou, John L.,Lee, Yunho,Oh, Seok-Young,Kim, Sang Don The Royal Society of Chemistry 2012 Journal of environmental monitoring Vol.14 No.2

<P>The potential biodegradation and subsequent transformation of 17β-estradiol (E2) to estrone (E1) were examined in the presence of various dissolved organic matter (DOM) isolated from effluent, river and lake waters. In addition, estrogenicity was estimated in association with the removal of E2 <I>via</I> its sorption onto DOM and biodegradation. The more biodegradable lake-derived DOM promoted more extensive transformation of E2 into E1 than the effluent organic matter through a biodegradation process. Overall, under all conditions, biodegradation dominated the removal of E2 in water. The increased dissolved organic carbon (DOC) concentrations in river and lake-derived DOM (<I>e.g.</I> 6.5 mg C L<SUP>−1</SUP>) reduced the removal of E2 by decreasing its biodegradation due to the moderate sorption of E2 onto DOM. The effluent organic matter showed greater removal of E2 <I>via</I> biodegradation, as well as significantly high sorption. This was associated with a large amount of hydrophobic fulvic acid (FA)- and humic acid (HA)-like organic components, as shown by the small increase in the specific UV absorbance at 254 nm (SUVA<SUB>254</SUB>). An increase in the DOC concentration reduced the removal of E2, resulting in high estrogenicity. The present study suggests that both organic composition and DOC concentration influenced the removal of E2 and, therefore, should be fully considered when assessing estrogenicity and its impacts on the aquatic environment.</P> <P>Graphic Abstract</P><P>The potential biodegradation and subsequent transformation of 17β-estradiol (E2) to estrone (E1) were examined in the presence of various dissolved organic matter isolated from effluent, river and lake waters. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c1em10690b'> </P>

Effects of Fabric Surface Energy on Human Thermophysiological Responses during Exercise and Recovery

Zhou, L.Y.,Li, Y.,Chung, J.,Tokura, H.,Gohel, M.D.I.,Kwok, Y.L.,Feng, X.W. The Korean Fiber Society 2007 Fibers and polymers Vol.8 No.3

The present paper reports a study on influences of fabric surface energy of cotton and polyester garments on clothing microclimates and human thermophysiological responses during intermittent exercise and recovery. Eight healthy males wearing the garments prepared performed exercises and rest according to the following protocol: rest for 30 min, run on treadmill for total 60 min of three sessions with different intensity and duration, and then sit quietly for 30 min for recovery, all at $30^{\circ}C$ and relative humidity of 30 %, while the microclimate humidity ($H_{mc}$) and temperature ($T_{mc}$), the clothing outside surface humidity ($H_{co}$) and temperature ($T_{co}$), the skin temperatures and ear canal temperature ($T_{ear_canal})$ were measured. The garments are made of: (a) hydrophilic and hydrophobic cotton knitted fabrics, and (b) hydrophilic and hydrophobic polyester knitted fabrics. During and after exercise, for cotton, hydrophilic garment resulted in significant lower ${\Delta}H_{mc}$, ${\Delta}H_{co}$, ${\Delta}T_{mc}$, during recovery, higher ${\Delta}{\bar{T}}_{sk}$, lower ${\Delta}T_{ear_canal}$ and ${\Delta}T_{forehead}$. For polyester, hydrophilic garment resulted in significantly lower ${\Delta}H_{co}$, ${\Delta}T_{co}$, higher ${\Delta}T_{forehead}$, during E1, E2 and recovery session but lower during E3. In summary, surface energy of cotton garments had significant influences on human thermophysiological responses during exercise and recovery, and hydrophilic cotton garment was better than hydrophobic one to reduce heat stress. Surface energy of polyester garments had influences of lower significance, and hydrophilic garment appeared better than hydrophobic garment.