Huang CH

References (20)

Title : Protective effect of Ganoderma lucidum-fermented crop extracts against hydrogen peroxide- or beta-amyloid-induced damage in human neuronal SH-SY5Y cells - Huang_2024_BMC.Complement.Med.Ther_24_148
Author(s) : Huang CH , Liao YT , Chen CL , Tsai GJ
Ref : BMC Complement Med Ther , 24 :148 , 2024
Abstract : BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of stacked beta-amyloid peptides in the brain and associated with the generation of oxidative stress. So far, there is no cure for AD or a way to stop its progression. Although the neuroprotective effects of Ganoderma lucidum aqueous extract and G. lucidum-derived triterpenoids and polysaccharides have been reported, the influence of G. lucidum-fermented crops on AD still lacks clarity. METHODS: This study aimed to investigate the protective effect of G. lucidum-fermented crop extracts against hydrogen peroxide- or beta-amyloid peptide (Abeta(25-35))-induced damage in human neuroblastoma SH-SY5Y cells. RESULTS: Various extracts of G. lucidum-fermented crops, including extract A: 10% ethanol extraction using microwave, extract B: 70C water extraction, and extract C: 100C water extraction followed by ethanol precipitation, were prepared and analyzed. Extract B had the highest triterpenoid content. Extract C had the highest total glucan content, while extract A had the highest gamma-aminobutyric acid (GABA) content. The median inhibitory concentration (IC(50), mg/g) for DPPH and ABTS scavenging activity of the fermented crop extracts was significantly lower than that of the unfermented extract. Pretreatment with these extracts significantly increased the cell viability of SH-SY5Y cells damaged by H(2)O(2) or Abeta(25-35), possibly by reducing cellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. Moreover, extract B markedly alleviated the activity of acetylcholinesterase (AChE), which is crucial in the pathogenesis of AD. CONCLUSION: These results clearly confirmed the effects of G. lucidum-fermented crop extracts on preventing against H(2)O(2)- or Abeta(25-35)-induced neuronal cell death and inhibiting AChE activity, revealing their potential in management of AD.
ESTHER : Huang_2024_BMC.Complement.Med.Ther_24_148
PubMedSearch : Huang_2024_BMC.Complement.Med.Ther_24_148
PubMedID: 38580956

Title : Manipulating Diastereomeric Bicyclononynes to Sensitively Determine Enzyme Activity and Facilitate Macromolecule Conjugations - Huang_2023_ACS.Omega_8_46073
Author(s) : Huang CH , Hou SY , Severance S , Hwang CC , Fang BK , Gong MM , Yu SL , Weng YC , Wang LF , Dai CY , Wang SH , Kuo HT , Wang JJ , Wang TP
Ref : ACS Omega , 8 :46073 , 2023
Abstract : Bicyclo[6.1.0]nonyne (BCN) is one of the most commonly used cycloalkynes in strain-promoted azide-alkyne cycloaddition (SPAAC). The synthesis of BCN produces two diastereomers, exo-BCN and endo-BCN. The potential significance of the different steric structures of the tricyclic fused rings in SPAAC products synthesized from the BCN diastereomers has not been previously studied. We first demonstrated that only endo-BCN could reduce the level of fluorescence quenching in SPAAC reaction products. The reduction was likely due to the presence of extended tricyclic fused ring systems. This hypothesis was supported by the synthesis of a fluorescence always-on construct by substituting endo-BCN for exo-BCN in a previously reported chemical probe that was characterized with good contact fluorescence quenching. We also synthesized bis-BCN derivatives to enhance the steric structural differences in the corresponding SPAAC products. A constitutional isomer of the azido-derivatized 5(6)-carboxyfluorescein [5(6)-FAM] was reacted with both bis-exo-BCN and bis-endo-BCN compounds. However, one form of the bis-exo-BCN-based product did not augment contact fluorescence quenching, while a second bis-exo-BCN product could not further reduce contact fluorescence quenching. Nevertheless, a new fluorescence turn-on chemical probe was employed to determine the activities of two serum biomarkers, butyrylcholinesterase and paraoxonase 1. Moreover, bis-endo-BCN was exploited to successfully conjugate BSA with a 5-FAM derivative compound.
ESTHER : Huang_2023_ACS.Omega_8_46073
PubMedSearch : Huang_2023_ACS.Omega_8_46073
PubMedID: 38075741

Title : Time-dependent effects of storage at -80 C on the stability of butyrylcholinesterase activity in human serum - Huang_2022_Pract.Lab.Med_31_e00298
Author(s) : Huang CH , Chang YT , Severance S , Feng JY , Hou SY , Gong MM , Hwang CC , Dai CY , Wang JJ , Wang TP
Ref : Pract Lab Med , 31 :e00298 , 2022
Abstract : OBJECTIVES: Butyrylcholinesterase (BChE) is an important biomarker in serum, and aberrant BChE activity indicates onset and progression of human diseases. The duration of serum storage at -80 degreesC may introduce variability into and compromise the reproducibility of BChE activity measurements. DESIGN AND METHODS: We collected serum samples from eight healthy volunteers and determined serum BChE activity in these samples using a sensitive fluorescence assay at various time points during a six-month storage period at -80 degreesC. Changes in averaged BChE activity over storage time were assessed by repeated measures analysis of variance (ANOVA). Sidak multiple comparisons test was also used to perform post-hoc analysis. RESULTS: Almost all determined BChE activity values lay within the normal physiological range of BChE activity. However, repeated measures ANOVA using mean BChE activity vs. storage time showed that BChE activity values from two time points were significantly different. Analysis by Sidak multiple comparisons test provided no substantial change of BChE activity during the first 90 days of storage, but BChE activity noticeably decreased after 90 days. CONCLUSIONS: Serum samples stored in -80 degreesC for up to 90 days can be exploited to accurately determine BChE activity.
ESTHER : Huang_2022_Pract.Lab.Med_31_e00298
PubMedSearch : Huang_2022_Pract.Lab.Med_31_e00298
PubMedID: 35880118

Title : Naja atra cardiotoxins enhance the protease activity of chymotrypsin - Shi_2019_Int.J.Biol.Macromol_136_512
Author(s) : Shi YJ , Huang CH , Lee YC , Wang LJ , Chiou JT , Chang LS
Ref : Int J Biol Macromol , 136 :512 , 2019
Abstract : Snake venom cardiotoxins (CTXs) present diverse pharmacological functions. Previous studies have reported that CTXs affect the activity of some serine proteases, namely, chymotrypsin, subtilisin, trypsin, and acetylcholinesterase. To elucidate the mode of action of CTXs, the interaction of CTXs with chymotrypsin was thus investigated. It was found that Naja atra CTX isotoxins concentration-dependently enhanced chymotrypsin activity. The capability of CTX1 and CTX5 in increasing chymotrypsin activity was higher than that of CTX2, CTX3, and CTX4. Removal of the molecular beacon-bound CTXs by chymotrypsin, circular dichroism measurement, and acrylamide quenching of Trp fluorescence indicated that CTXs bound to chymotrypsin. Chemical modification of Lys, Arg, or Met residues of CTX1 attenuated its capability to enhance chymotrypsin activity without impairing their bond with chymotrypsin. Catalytically inactive chymotrypsin retained the binding affinity for native and modified CTX1. CTX1 and chemically modified CTX1 differently altered the global conformation of chymotrypsin and inactivated chymotrypsin. Moreover, CTX1 did not reduce the interaction of 2-(p-toluidino)-naphthalene-6-sulfonate (TNS) with chymotrypsin and inactivated chymotrypsin. Together with previous results revealing that TNS can bind at the hydrophobic region of active site in chymotrypsin, our data suggest that CTXs can enhance chymotrypsin activity by binding to the region outside the enzyme's active site.
ESTHER : Shi_2019_Int.J.Biol.Macromol_136_512
PubMedSearch : Shi_2019_Int.J.Biol.Macromol_136_512
PubMedID: 31199971

Title : Structural insights into enzymatic degradation of oxidized polyvinyl alcohol - Yang_2014_Chembiochem_15_1882
Author(s) : Yang Y , Ko TP , Liu L , Li J , Huang CH , Chan HC , Ren F , Jia D , Wang AH , Guo RT , Chen J , Du G
Ref : Chembiochem , 15 :1882 , 2014
Abstract : The ever-increasing production and use of polyvinyl alcohol (PVA) threaten our environment. Yet PVA can be assimilated by microbes in two steps: oxidation and cleavage. Here we report novel alpha/beta-hydrolase structures of oxidized PVA hydrolase (OPH) from two known PVA-degrading organisms, Sphingopyxis sp. 113P3 and Pseudomonas sp. VM15C, including complexes with substrate analogues, acetylacetone and caprylate. The active site is covered by a lid-like beta-ribbon. Unlike other esterase and amidase, OPH is unique in cleaving the CC bond of beta-diketone, although it has a catalytic triad similar to that of most alpha/beta-hydrolases. Analysis of the crystal structures suggests a double-oxyanion-hole mechanism, previously only found in thiolase cleaving beta-ketoacyl-CoA. Three mutations in the lid region showed enhanced activity, with potential in industrial applications.
ESTHER : Yang_2014_Chembiochem_15_1882
PubMedSearch : Yang_2014_Chembiochem_15_1882
PubMedID: 25044912
Gene_locus related to this paper: psesp-OPH , sphs1-OPH

Title : Roles of tryptophan residue and disulfide bond in the variable lid region of oxidized polyvinyl alcohol hydrolase - Yang_2014_Biochem.Biophys.Res.Commun_452_509
Author(s) : Yang Y , Ko TP , Liu L , Li J , Huang CH , Chen J , Guo RT , Du G
Ref : Biochemical & Biophysical Research Communications , 452 :509 , 2014
Abstract : Oxidized polyvinyl alcohol hydrolase (OPH) catalyzes the cleavage of C-C bond in beta-diketone. It belongs to the alpha/beta-hydrolase family and contains a unique lid region that covers the active site. The lid is the most variable region when pOPH from Pseudomonas sp. VM15C and sOPH from Sphingopyxis sp. 113P3 are compared. The wild-type enzymes and the pOPH mutants W255A, W255Y and W255F were analyzed for lipase activity by using p-nitrophenyl (pNP) esters as the substrates. The wild-type enzymes showed increased Km and decreased kcat/Km with the acyl chain length, and the mutants showed reduced kcat/Km for pNP acetate, indicating the importance of Trp255 in sequestering the active site from solvent. The significantly lower activity for pNP butyrate can be a result of product inhibition, as suggested by the complex crystal structures, in which butyric acid, DMSO or PEG occupied the same substrate-binding cleft. The mutant activity was retained with pNP caprylate and pNP laurate as the substrates, reflecting the amphipathic nature of the cleft. Moreover, the disulfide bond formation of Cys257/267 is important for the activity of pOPH, but it is not essential for sOPH, which has a shorter lid structure.
ESTHER : Yang_2014_Biochem.Biophys.Res.Commun_452_509
PubMedSearch : Yang_2014_Biochem.Biophys.Res.Commun_452_509
PubMedID: 25173935
Gene_locus related to this paper: sphs1-OPH

Title : Crystal structure and substrate-binding mode of the mycoestrogen-detoxifying lactonase ZHD from Clonostachys rosea - Peng_2014_RSC.Adv_4_62321
Author(s) : Peng W , Ko TP , Yang YY , Zheng YY , Chen CC , Zhu Z , Huang CH , Zeng YF , Huang JW , Wang AHJ , Liu JR , Guo RT
Ref : RSC Advances , 4 :62321 , 2014
Abstract : The mycotoxin zearalenone has been contaminating maize and other grains. It can be hydrolyzed and inactivated by the lactonase ZHD, which belongs to the alpha/beta-hydrolase family. Besides the catalytic core domain, the enzyme comprises an alpha-helical cap domain. Zearalenone differs from other quorum-sensing lactones in its chemical structure. As revealed by the complex structure, the substrate binds into a deep pocket between the core and cap domains, adjacent to the catalytic triad Ser102-His242-Glu126. The enzyme-substrate interactions include three direct hydrogen bonds and several nonpolar contacts. In particular, the Trp183 side chain is engaged in both hydrogen bonding and T-stacking interactions with the benzoate ring. The central role of Trp183 in substrate binding was verified by the mutants W183A, W183H and W183F. Several mutants were also produced to investigate the roles of nearby amino-acid residues. Interestingly, mutants that destabilize the dimer had adverse functional effects on ZHD.
ESTHER : Peng_2014_RSC.Adv_4_62321
PubMedSearch : Peng_2014_RSC.Adv_4_62321
PubMedID:
Gene_locus related to this paper: biooc-ZHD101

Title : Discrimination between Alzheimer's Disease and Mild Cognitive Impairment Using SOM and PSO-SVM - Yang_2013_Comput.Math.Methods.Med_2013_253670
Author(s) : Yang ST , Lee JD , Chang TC , Huang CH , Wang JJ , Hsu WC , Chan HL , Wai YY , Li KY
Ref : Comput Math Methods Med , 2013 :253670 , 2013
Abstract : In this study, an MRI-based classification framework was proposed to distinguish the patients with AD and MCI from normal participants by using multiple features and different classifiers. First, we extracted features (volume and shape) from MRI data by using a series of image processing steps. Subsequently, we applied principal component analysis (PCA) to convert a set of features of possibly correlated variables into a smaller set of values of linearly uncorrelated variables, decreasing the dimensions of feature space. Finally, we developed a novel data mining framework in combination with support vector machine (SVM) and particle swarm optimization (PSO) for the AD/MCI classification. In order to compare the hybrid method with traditional classifier, two kinds of classifiers, that is, SVM and a self-organizing map (SOM), were trained for patient classification. With the proposed framework, the classification accuracy is improved up to 82.35% and 77.78% in patients with AD and MCI. The result achieved up to 94.12% and 88.89% in AD and MCI by combining the volumetric features and shape features and using PCA. The present results suggest that novel multivariate methods of pattern matching reach a clinically relevant accuracy for the a priori prediction of the progression from MCI to AD.
ESTHER : Yang_2013_Comput.Math.Methods.Med_2013_253670
PubMedSearch : Yang_2013_Comput.Math.Methods.Med_2013_253670
PubMedID: 23737859

Title : MRI\/SPECT-based diagnosis and CT-guided high-intensity focused-ultrasound treatment system in MPTP mouse model of Parkinson's disease - Lee_2013_Med.Eng.Phys_35_222
Author(s) : Lee JD , Huang CH , Yang ST , Chu YH , Shieh YY , Chen JW , Lin KJ
Ref : Med Eng Phys , 35 :222 , 2013
Abstract : Single-photon emission computed tomography (SPECT) of dopamine transporters with (99m)Tc-TRODAT-1 has recently been proposed to offer valuable information for the diagnosis of Parkinson's disease (PD). Furthermore, High-intensity focused ultrasound (HIFU) is a newly developed technique in which the energy of ultrasound wave is directed to a focused spot for the purpose treatment of PD. This study presents a diagnosis and image-guided system using HIFU to treat the mouse with PD under a designed stereotactic frame. The system comprises two key components: an automatic atlas-based SPECT/MRI image registration module for diagnosis and a stereotactic CT-guided module for HIFU treatment. The SPECT/MR image registration here is important in the non-invasive examination of the dopamine concentration in vivo. From the experimental results, the image registration module proves to have comparable performance to that derived from manual drawing by experts. In addition, the stereotactic CT-guided module achieved a positioning accuracy to within 2mm on the average, which is acceptable for the purpose of HIFU treatment.
ESTHER : Lee_2013_Med.Eng.Phys_35_222
PubMedSearch : Lee_2013_Med.Eng.Phys_35_222
PubMedID: 22377520

Title : Secondary Metabolites of a Mangrove Endophytic Fungus Aspergillus terreus (No. GX7-3B) from the South China Sea - Deng_2013_Mar.Drugs_11_2616
Author(s) : Deng CM , Liu SX , Huang CH , Pang JY , Lin YC
Ref : Mar Drugs , 11 :2616 , 2013
Abstract : The mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) was cultivated in potato dextrose liquid medium, and one rare thiophene compound (1), together with anhydrojavanicin (2), 8-O-methylbostrycoidin (3), 8-O-methyljavanicin (4), botryosphaerone D (5), 6-ethyl-5-hydroxy-3,7-dimethoxynaphthoquinone (6), 3beta,5alpha-dihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (7), 3beta,5alpha,14alpha-trihydroxy-(22E,24R)-ergosta-7, 22-dien-6-one (8), NGA0187 (9) and beauvericin (10), were isolated. Their structures were elucidated by analysis of spectroscopic data. This is the first report of a natural origin for compound 6. Moreover, compounds 3, 4, 5, 7, 8 and 10 were obtained from marine microorganism for the first time. In the bioactive assays in vitro, compounds 2, 3, 9 and 10 displayed remarkable inhibiting actions against alpha-acetylcholinesterase (AChE) with IC50 values 2.01, 6.71, 1.89, and 3.09 muM, respectively. Furthermore, in the cytotoxicity assays, compounds 7 and 10 exhibited strong or moderate cytotoxic activities against MCF-7, A549, Hela and KB cell lines with IC50 values 4.98 and 2.02 (MCF-7), 1.95 and 0.82 (A549), 0.68 and 1.14 (Hela), and 1.50 and 1.10 muM (KB), respectively; compound 8 had weak inhibitory activities against these tumor cell lines; compounds 1, 2, 3, 4, 5, 6 and 9 exhibited no inhibitory activities against them.
ESTHER : Deng_2013_Mar.Drugs_11_2616
PubMedSearch : Deng_2013_Mar.Drugs_11_2616
PubMedID: 23877026

Title : (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-p yrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV - Yeh_2010_Bioorg.Med.Chem.Lett_20_3596
Author(s) : Yeh TK , Tsai TY , Hsu T , Cheng JH , Chen X , Song JS , Shy HS , Chiou MC , Chien CH , Tseng YJ , Huang CY , Yeh KC , Huang YL , Huang CH , Huang YW , Wang MH , Tang HK , Chao YS , Chen CT , Jiaang WT
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :3596 , 2010
Abstract : A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
ESTHER : Yeh_2010_Bioorg.Med.Chem.Lett_20_3596
PubMedSearch : Yeh_2010_Bioorg.Med.Chem.Lett_20_3596
PubMedID: 20483603

Title : Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein - Tsai_2010_J.Med.Chem_53_6572
Author(s) : Tsai TY , Yeh TK , Chen X , Hsu T , Jao YC , Huang CH , Song JS , Huang YC , Chien CH , Chiu JH , Yen SC , Tang HK , Chao YS , Jiaang WT
Ref : Journal of Medicinal Chemistry , 53 :6572 , 2010
Abstract : Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC(50) of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC(50) > 100 muM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.
ESTHER : Tsai_2010_J.Med.Chem_53_6572
PubMedSearch : Tsai_2010_J.Med.Chem_53_6572
PubMedID: 20718420

Title : The dimeric transmembrane domain of prolyl dipeptidase DPP-IV contributes to its quaternary structure and enzymatic activities - Chung_2010_Protein.Sci_19_1627
Author(s) : Chung KM , Cheng JH , Suen CS , Huang CH , Tsai CH , Huang LH , Chen YR , Wang AH , Jiaang WT , Hwang MJ , Chen X
Ref : Protein Science , 19 :1627 , 2010
Abstract : Dipeptidyl peptidase IV (DPP-IV) is a drug target in the treatment of human type II diabetes. It is a type II membrane protein with a single transmembrane domain (TMD) anchoring the extracellular catalytic domain to the membrane. DPP-IV is active as a dimer, with two dimer interacting surfaces located extracellularly. In this study, we demonstrate that the TM of DPP-IV promotes DPP-IV dimerization and rescues monomeric DPP-IV mutants into partial dimers, which is specific and irreplaceable by TMs of other type II membrane proteins. By bioluminescence resonance energy transfer (BRET) and peptide electrophoresis, we found that the TM domain of DPP-IV is dimerized in mammalian cells and in vitro. The TM dimer interaction is very stable, based on our results with TM site-directed mutagenesis. None of the mutations, including the introduction of two prolines, resulted in their complete disruption to monomers. However, these TM proline mutations result in a significant reduction of DPP-IV enzymatic activity, comparable to what is found with mutations near the active site. A systematic analysis of TM structures deposited in the Protein Data Bank showed that prolines in the TM generally produce much bigger kinking angles than occur in nonproline-containing TMs. Thus, the proline-dependent reduction in enzyme activity may result from propagated conformational changes from the TM to the extracellular active site. Our results demonstrate that TM dimerization and conformation contribute significantly to the structure and activity of DPP-IV. Optimal enzymatic activity of DPP-IV requires an optimal interaction of all three dimer interfaces, including its TM.
ESTHER : Chung_2010_Protein.Sci_19_1627
PubMedSearch : Chung_2010_Protein.Sci_19_1627
PubMedID: 20572019

Title : Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors - Tsai_2009_Bioorg.Med.Chem.Lett_19_1908
Author(s) : Tsai TY , Hsu T , Chen CT , Cheng JH , Chiou MC , Huang CH , Tseng YJ , Yeh TK , Huang CY , Yeh KC , Huang YW , Wu SH , Wang MH , Chen X , Chao YS , Jiaang WT
Ref : Bioorganic & Medicinal Chemistry Lett , 19 :1908 , 2009
Abstract : A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.
ESTHER : Tsai_2009_Bioorg.Med.Chem.Lett_19_1908
PubMedSearch : Tsai_2009_Bioorg.Med.Chem.Lett_19_1908
PubMedID: 19269819

Title : Novel trans-2-aryl-cyclopropylamine analogues as potent and selective dipeptidyl peptidase IV inhibitors - Tsai_2009_Bioorg.Med.Chem_17_2388
Author(s) : Tsai TY , Hsu T , Chen CT , Cheng JH , Yeh TK , Chen X , Huang CY , Chang CN , Yeh KC , Hsieh SH , Chien CH , Chang YW , Huang CH , Huang YW , Huang CL , Wu SH , Wang MH , Lu CT , Chao YS , Jiaang WT
Ref : Bioorganic & Medicinal Chemistry , 17 :2388 , 2009
Abstract : A series of trans-2-aryl-cyclopropylamine derived compounds were synthesized and evaluated their biological activities against DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance in lean mice and diet induced obese mice.
ESTHER : Tsai_2009_Bioorg.Med.Chem_17_2388
PubMedSearch : Tsai_2009_Bioorg.Med.Chem_17_2388
PubMedID: 19261480

Title : Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8\/9 inhibitor - Wu_2009_Biochem.Pharmacol_78_203
Author(s) : Wu JJ , Tang HK , Yeh TK , Chen CM , Shy HS , Chu YR , Chien CH , Tsai TY , Huang YC , Huang YL , Huang CH , Tseng HY , Jiaang WT , Chao YS , Chen X
Ref : Biochemical Pharmacology , 78 :203 , 2009
Abstract : DPP-IV (EC 3.4.14.5) is a validated drug target for human type II diabetes. DPP-IV inhibitors without DPP8/9 inhibitory activity have been sought because a possible association has been reported between a "DPP8/9 inhibitor" and severe toxicity in animals. However, at present, it is not known whether the observed toxicity is associated with DPP8/9 inhibition, or an off-target effect induced by the compound. We investigated whether the inhibition of DPP8/9 is the cause of the severe toxicity in animals using a very potent and selective DPP8/9 inhibitor with different pharmacophore, 1G244. By Ki measurement, 1G244 is 15- and 8-fold more potent against DPP8 and DPP9, respectively, than the "DPP8/9 inhibitor". Strikingly, the "DPP8/9 inhibitor" does not penetrate the plasma membrane but remains outside the cells, whereas 1G244 readily enters the cells, even at low doses. By repeatedly exposing Sprague-Dawley rats to 1G244 by intravenous injection for a period of 14 days, we observed no significant toxicological symptoms associated with 1G244. Blood and serum chemistry parameters were all within the normal ranges for the treated animals. Because of the high potency, good membrane penetration and adequate tissue distribution of 1G244, the mild symptoms observed are probably associated with DPP8/9 inhibition.
ESTHER : Wu_2009_Biochem.Pharmacol_78_203
PubMedSearch : Wu_2009_Biochem.Pharmacol_78_203
PubMedID: 19439267

Title : Six new mutations of the thyroglobulin gene discovered in taiwanese children presenting with thyroid dyshormonogenesis - Niu_2009_J.Clin.Endocrinol.Metab_94_5045
Author(s) : Niu DM , Hsu JH , Chong KW , Huang CH , Lu YH , Kao CH , Yu HC , Lo MY , Jap TS
Ref : J Clinical Endocrinology Metab , 94 :5045 , 2009
Abstract : BACKGROUND: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis. STUDY OBJECTIVE: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein. PATIENTS AND
RESULTS: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues.
CONCLUSIONS: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T(4) withdrawal, plasma T(4) < or = 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.
ESTHER : Niu_2009_J.Clin.Endocrinol.Metab_94_5045
PubMedSearch : Niu_2009_J.Clin.Endocrinol.Metab_94_5045
PubMedID: 19837936
Gene_locus related to this paper: human-TG

Title : Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2) - Bentley_2002_Nature_417_141
Author(s) : Bentley SD , Chater KF , Cerdeno-Tarraga AM , Challis GL , Thomson NR , James KD , Harris DE , Quail MA , Kieser H , Harper D , Bateman A , Brown S , Chandra G , Chen CW , Collins M , Cronin A , Fraser A , Goble A , Hidalgo J , Hornsby T , Howarth S , Huang CH , Kieser T , Larke L , Murphy L , Oliver K , O'Neil S , Rabbinowitsch E , Rajandream MA , Rutherford K , Rutter S , Seeger K , Saunders D , Sharp S , Squares R , Squares S , Taylor K , Warren T , Wietzorrek A , Woodward J , Barrell BG , Parkhill J , Hopwood DA
Ref : Nature , 417 :141 , 2002
Abstract : Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.
ESTHER : Bentley_2002_Nature_417_141
PubMedSearch : Bentley_2002_Nature_417_141
PubMedID: 12000953
Gene_locus related to this paper: strco-cxest , strco-cxest2 , strco-ester , strco-estli , strco-MMYT , strco-ORF3 , strco-q9f2m1 , strco-q9rdq9 , strco-q9x8r0 , strco-SC1A6.21 , strco-SC3F7.14 , strco-SC4C2.18 , strco-SC10F4.23 , strco-SCBAC20F6.10 , strco-SCD95A , strco-SCE8.12C , strco-SCE63.01 , strco-SCF43.16C , strco-SCJ9A.33C , strco-SCO0047 , strco-SCO0135 , strco-SCO0490 , strco-SCO0503 , strco-SCO0556.1 , strco-SCO0556.2 , strco-SCO1265 , strco-SCO2123 , strco-SCO2516 , strco-SCO2723 , strco-SCO2761 , strco-SCO3396 , strco-SCO3772 , strco-SCO4160 , strco-SCO4900 , strco-SCO5215 , strco-SCO5986 , strco-SCO6351 , strco-SCO6488 , strco-SCO7057 , strco-SCO7121 , strco-SCO7396 , strco-SCO7609 , strco-SCOT , strco-SLPD , strco-TAP

Title : Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning - Hu_2000_Proc.Natl.Acad.Sci.U.S.A_97_9543
Author(s) : Hu RM , Han ZG , Song HD , Peng YD , Huang QH , Ren SX , Gu YJ , Huang CH , Li YB , Jiang CL , Fu G , Zhang QH , Gu BW , Dai M , Mao YF , Gao GF , Rong R , Ye M , Zhou J , Xu SH , Gu J , Shi JX , Jin WR , Zhang CK , Wu TM , Huang GY , Chen Z , Chen MD , Chen JL
Ref : Proc Natl Acad Sci U S A , 97 :9543 , 2000
Abstract : The primary neuroendocrine interface, hypothalamus and pituitary, together with adrenals, constitute the major axis responsible for the maintenance of homeostasis and the response to the perturbations in the environment. The gene expression profiling in the human hypothalamus-pituitary-adrenal axis was catalogued by generating a large amount of expressed sequence tags (ESTs), followed by bioinformatics analysis (http://www.chgc.sh.cn/ database). Totally, 25,973 sequences of good quality were obtained from 31,130 clones (83.4%) from cDNA libraries of the hypothalamus, pituitary, and adrenal glands. After eliminating 5,347 sequences corresponding to repetitive elements and mtDNA, 20,626 ESTs could be assembled into 9, 175 clusters (3,979, 3,074, and 4,116 clusters in hypothalamus, pituitary, and adrenal glands, respectively) when overlapping ESTs were integrated. Of these clusters, 2,777 (30.3%) corresponded to known genes, 4,165 (44.8%) to dbESTs, and 2,233 (24.3%) to novel ESTs. The gene expression profiles reflected well the functional characteristics of the three levels in the hypothalamus-pituitary-adrenal axis, because most of the 20 genes with highest expression showed statistical difference in terms of tissue distribution, including a group of tissue-specific functional markers. Meanwhile, some findings were made with regard to the physiology of the axis, and 200 full-length cDNAs of novel genes were cloned and sequenced. All of these data may contribute to the understanding of the neuroendocrine regulation of human life.
ESTHER : Hu_2000_Proc.Natl.Acad.Sci.U.S.A_97_9543
PubMedSearch : Hu_2000_Proc.Natl.Acad.Sci.U.S.A_97_9543
PubMedID: 10931946
Gene_locus related to this paper: human-ESD

Title : Biochemical and behavioral effects of intraseptal microinjection of fasciculin, an irreversible acetylcholinesterase inhibitor - Quillfeldt_1991_Braz.J.Med.Biol.Res_24_499
Author(s) : Quillfeldt J , Bolioli B , Dalmaz C , Rascovsky S , Huang CH , Dias M , Ferreira MB , Schneider F , Izquierdo I , Medina JH , Dajas F
Ref : Brazilian Journal of Medical & Biological Research , 24 :499 , 1991
Abstract : 1. We examined the effect, in rats, of an intraseptal microinjection of fasciculin (FAS), an irreversible peptide acetylcholinesterase (AChE) inhibitor, on a) AChE activity measured in septum and hippocampus, b) 3H-quinuclidinyl benzylate (3H-QNB) and 3H-oxotremorine (3H-OXO) binding to hippocampal cholinergic muscarinic receptors, c) 3H-flunitrazepam (3H-FNZ) binding to hippocampal benzodiazepine receptors as a control for QNB and OXO binding, d) acquisition and retention in three different behavioral paradigms, i.e., water-finding (in which there is concomitant habituation to the apparatus), step-down inhibitory avoidance, and shuttle avoidance. 2. AChE activity in septum decreased 2 days (-66%) and 5 days (-48%) after FAS microinjection; a slight reduction (-35%) occurred in the dorsal hippocampus on day 2 (P less than 0.05; N = 6 per group); no changes in AChE activity were observed in ventral hippocampus on day 2 or day 5. 3. No changes in 3H-QNB, 3H-OXO, or 3H-FNZ binding constants were demonstrable in the hippocampus either 2 or 5 days after intraseptal FAS administration. 4. No changes in training or test session performance in any of the three behavioral situations were observed 2-3 days after the intraseptal microinjection of FAS. 5. The persistent inhibition of septal AChE caused by FAS microinjection into the septum is not sufficient to induce major changes either in hippocampal cholinergic muscarinic receptors, or in the learning or retention of behaviors regulated by the septum and/or hippocampus.
ESTHER : Quillfeldt_1991_Braz.J.Med.Biol.Res_24_499
PubMedSearch : Quillfeldt_1991_Braz.J.Med.Biol.Res_24_499
PubMedID: 1823265