Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain

Background  

Peripheral tissue inflammation initiates hyperalgesia accompanied by tissue acidosis, nociceptor activation, and inflammation mediators. Recent studies have suggested a significantly increased expression of acid-sensing ion channel 3 (ASIC3) in both carrageenan- and complete Freund's adjuvant (CFA)-induced inflammation. This study tested the hypothesis that acupuncture is curative for mechanical hyperalgesia induced by peripheral inflammation.     

Protein structure similarity from principle component correlation analysis

Background  

Owing to rapid expansion of protein structure databases in recent years, methods of structure comparison are becoming increasingly effective and important in revealing novel information on functional properties of proteins and their roles in the grand scheme of evolutionary biology. Currently, the structural similarity between two proteins is measured by the root-mean-square-deviation (RMSD) in their best-superimposed atomic coordinates. RMSD is the golden rule of measuring structural similarity when the structures are nearly identical; it, however, fails to detect the higher order topological similarities in proteins evolved into different shapes. We propose new algorithms for extracting geometrical invariants of proteins that can be effectively used to identify homologous protein structures or topologies in order to quantify both close and remote structural similarities.     

Conditional random pattern model for copy number aberration detection

Background  

DNA copy number aberration (CNA) is very important in the pathogenesis of tumors and other diseases. For example, CNAs may result in suppression of anti-oncogenes and activation of oncogenes, which would cause certain types of cancers. High density single nucleotide polymorphism (SNP) array data is widely used for the CNA detection. However, it is nontrivial to detect the CNA automatically because the signals obtained from high density SNP arrays often have low signal-to-noise ratio (SNR), which might be caused by whole genome amplification, mixtures of normal and tumor cells, experimental noise or other technical limitations. With the reduction in SNR, many false CNA regions are often detected and the true CNA regions are missed. Thus, more sophisticated statistical models are needed to make the CNAs detection, using the low SNR signals, more robust and reliable.     

Catecholamine-Derived Tetrahydroisoquinolines: O-Methylation Patterns and Regional Brain Distribution Following Intraventricular Administration in Rats

Abstract: The metabolism of 6,7-dihydroxy (catecholic) -1,2,3,4-tetrahydroisoquinoIines (TIQs) is of interest because the heterocyclic substances may form in mammals normally or during certain diseases via condensations of catecholamines (CAs) with aldehydes or α-keto acids. With a specific capillary gas chromatography procedure and confirmatory liquid chromatographic assays, we have determined the structural isomers and relative amounts of mono-O-methylated (phenolic) TIQ metabolites in several rat brain regions 40 min following the acute intracerebroventricular injection of four structurally related catecholic TIQs. In sharp contrast with the established selective m-O-methylation of dopamine (DA) by catechol-O-methyltransferase in brain, the two simple TIQs derived from DA produced predominantly or even exclusively the metabolic isomer arising from methylation of the original p-hydroxyl group (7-O-methylation). In three catecholaminergic brain regions examined, the 7-O-methyl isomer was the only detectable phenolic metabolite of (±) salsolinol-1-carboxylic acid (a condensation product of DA and pyruvic acid) and, as first noted by Bail et al. (1980), constituted 95% of the two possible isomeric mono-O-methyl metabolites of (±) salsolinol (TIQ derivative of DA and acetaldehyde). Though less, the 7-O-methyl isomers still were a significant proportion (40–55%) of the two mono-O-methylated metabolites of (±) 4-hydroxy-desmethylsalsolinol (a TIQ derived from norepinephrine and formaldehyde), or of the DOPA/acetaldehyde-derived TIQ, (cis) salsolinol-3-carboxylic acid. In the time frame of the study, all four administered TIQs showed higher levels in hypothalamus than in striatum or hippocampus, with the two carboxylated alkaloids displaying the greatest differences. However, for a given TIQ, the proportion present as mono-O-methyl metabolite(s) and the O-methyl isomer distribution did not differ across the three brain regions, indicating that O-methylation involved a single homogenous enzyme that was not saturated in vivo at the concentrations attained by the heterocyclic catechols. The most notable findings, that of exclusive methylation on the original p-hydroxyl group of a physiologically relevant CA derivative, and an O-methylation pattern that appeared dependent on the substituents on the heterocyclic ring, are explained on the basis of an important hydrophobic binding site in catechol-O-methyltransferase in vivo.     

Semi-supervised drug-protein interaction prediction from heterogeneous biological spaces

Background

Predicting drug-protein interactions from heterogeneous biological data sources is a key step for in silico drug discovery. The difficulty of this prediction task lies in the rarity of known drug-protein interactions and myriad unknown interactions to be predicted. To meet this challenge, a manifold regularization semi-supervised learning method is presented to tackle this issue by using labeled and unlabeled information which often generates better results than using the labeled data alone. Furthermore, our semi-supervised learning method integrates known drug-protein interaction network information as well as chemical structure and genomic sequence data.

Results

Using the proposed method, we predicted certain drug-protein interactions on the enzyme, ion channel, GPCRs, and nuclear receptor data sets. Some of them are confirmed by the latest publicly available drug targets databases such as KEGG.

Conclusions

We report encouraging results of using our method for drug-protein interaction network reconstruction which may shed light on the molecular interaction inference and new uses of marketed drugs.

     

Inhibition of Catechol-O-Methyltransferase by 6,7-Dihydroxy-3,4-Dihydroisoquinolines Related to Dopamine: Demonstration Using Liquid Chromatography and a Novel Substrate for O-Methylation

We report that 6,7-dihydroxy-3,4-dihydroisoquinolines related to dopamine are potent inhibitors of catechol-O-methyltransferase (COMT), but are not apparent substrates for the enzyme in vitro or in vivo. Three dihydroxy (catecholic) dihydroisoquinolines, including the 1-benzyl (DesDHP) and the 1-methyl (DSAL) analogs, were found to inhibit COMT activity in rat liver supernatant more effectively than the well-known inhibitor, tropolone. Inhibition of O-methylation was uncompetitive with substrate, and O-methylated products of the catecholic dihydroisoquinolines were undetectable. For these in vitro studies, a facile liquid chromatographic assay was developed utilizing as a site-specific substrate, 1-methyl-6,7-dihydroxy-tetrahydroisoquinoline-1-carboxylate (salsolinol-1-carboxylate). This catechol produces only one phenolic product isomer when incubated with liver supernatant and S-adenosylmethionine. Following central injection of DSAL in rats, inhibition of brain COMT in vivo was indicated by the reduced brain levels of homovanillic acid, but not of 3,4-dihydroxyphenylacetic acid. Furthermore, O-methylated DSAL metabolites could not be detected in brain by liquid or gas chromatography. We suggest that 6,7-dihydroxy-dihydroisoquinolines are "nonmethylatable" COMT inhibitors because they exist as quinoidal tautomers resembling pyridones or tropolones rather than as catechols. Quinoid formation is supported by the fluorescence and ultraviolet spectra for DSAL and its O-methyl derivatives. The experiments reveal a new class of COMT inhibitors that may be of pharmacological and mechanistic value. Additionally, 3,4-dihydroisoquinolines could arise endogenously via oxidation of the 1,2,3,4-tetrahydroisoquinolines which are ingested or produced from cellular catecholamine condensations. However, it is unlikely that dihydroisoquinoline (e.g., DSAL) concentrations necessary to inhibit COMT significantly would be attained via endogenous pathways.