Omega-alkoxy analogues of SAHA (vorinostat) as inhibitors of HDAC: a study of chain-length and stereochemical dependence

A series of omega-alkoxy ethers were prepared with variation of the length of the aliphatic chain of suberoylanilide hydroxamic acid (SAHA, vorinostat). Eight carbon long chain analogues showed the best activity, among which several substituted benzyl ether derivatives exhibited inhibitory activity on HDAC comparable to SAHA, and antiproliferative activity on three human cell lines (NB4, H460, and HCT-116) better than SAHA. However, no significant difference in antiproliferative activity was observed between two enantiomers bearing the benzyl ether moiety.     

Liver enzyme alteration: a guide for clinicians

ISOLATED ALTERATIONS OF BIOCHEMICAL MARKERS OF LIVER DAMAGE in a seemingly healthy patient can present a challenge for the clinician. In this review we provide a guide to interpreting alterations to liver enzyme levels. The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed. Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.Abnormal liver enzyme levels may signal liver damage or alteration in bile flow. Liver enzyme alteration may be either the accompanying biochemical picture in a patient with symptoms or signs suggestive of liver disease or an isolated, unexpected finding in a patient who has undergone a wide range of laboratory tests for a nonhepatic disease or for minor, vague complaints. The latter situation is a common clinical scenario today because of the routine incorporation of hepatic tests in automated blood chemistry panels. Isolated alterations of biochemical markers of liver damage in a seemingly healthy patient often represent a challenge even for the experienced clinician and usually set off a battery of further, costly tests¹ and consultations that may ultimately prove unnecessary. The aim of this review is to provide physicians in general practice with a guide to interpreting liver enzyme alterations.     

T-cell regulator RNF125/TRAC-1 belongs to a novel family of ubiquitin ligases with zinc fingers and a ubiquitin-binding domain

The recently identified RNF125 [RING (really interesting new gene) finger protein 125], or TRAC-1 (T-cell RING protein in activation 1), is unique among ubiquitin ligases in being a positive regulator of T-cell activation. In addition, TRAC-1 has been shown to down-modulate HIV replication and to inhibit pathogen-induced cytokine production. However, apart from the presence of an N-terminal C3HC4 (Cys(3)-His-Cys(4)) RING domain, the TRAC-1 protein remains uncharacterized. In the present paper, we report novel interactions and modifications for TRAC-1, and elucidate its domain organization. Specifically, we determine that TRAC-1 associates with membranes and is excluded from the nucleus through myristoylation. Our data are further consistent with a crucial role for the C-terminus in TRAC-1 function. In this region, novel domains were recognized through the identification of three closely related proteins: RNF114, RNF138 and RNF166. TRAC-1 and its relatives were found to contain, apart from the RING domain, a C2HC (Cys(2)-His-Cys)- and two C2H2 (Cys(2)-His(2))-type zinc fingers, as well as a UIM (ubiquitin-interacting motif). The UIM of TRAC-1 binds Lys(48)-linked polyubiquitin chains and is, together with the RING domain, required for auto-ubiquitination. As a consequence of auto-ubiquitination, the half-life of TRAC-1 is shorter than 30 min. The identification of these novel modifications, interactions, domains and relatives significantly widens the contexts for investigating TRAC-1 activity and regulation.     

Cranial ontogeny of<Emphasis Type="Italic">Lutreolina crassicaudata</Emphasis> (Didelphidae): a comparison with<Emphasis Type="Italic">Didelphis albiventris</Emphasis>

Metatherians experience the greatest developmental changes during extrauterine life. Following previous studies onDidelphis albiventris Lund, 1840, we examined the postweaning cranial allometry of size of the Neotropical marsupialLutreolina crassicaudata (Desmerest, 1804). Our aim was to compare growth patterns of both species to identify traits particular to each species and traits common to both species. This may contribute toward identifying a common developmental plan for didelphids. We measured 15 cranial variables in 32–43 specimens from just-weaned young to old adult. Total length of the skull was the estimator of overall size in least squares and reduced major axis regressions. The skull ofLutreolina crassicaudata grows at a rate slower than the overall change in size in its neurocranial components, palate, and postcanine rows, and it grows relatively faster in the rest of the splanchnocranium. This pattern closely resembles that ofDidelphis albiventris, from which it differs mainly in the allometry of the muzzle. In both species, allometry explains most postweaning changes of the trophic apparatus on functional grounds, in relation to interspecific differences in diet. We hypothesize that most local allometric departures from a generalized didelphid plan would relate to main dietary trends.     

Unbalanced oxidant-antioxidant status and its effects in pediatric diseases

Oxidative stress results from a disparity between the generation of reactive oxygen species and the antioxidant ability of the organism. The alteration of the oxidant-antioxidant system brings in adults an effective state of imbalance, which may influence the pathogenesis of many diseases. Oxidative stress also plays a pivotal role in the progression of various pathologies in childhood, through a manipulation of regulatory proteins. In fact, several studies have demonstrated that an unbalanced oxidant-antioxidant status is able to determine toxic effects even during infancy. Therefore, the aim of this review was to summarize current knowledge about the dynamic relationship between oxidative stress and systemic diseases during childhood. In order to better understand these complex mechanisms, a comprehensive review of the literature was done, focusing mainly on pre-pubertal children. In fact, this age-group offers a unique opportunity to exclude confounding factors, especially those related to the metabolic effects induced by puberty. Early identification of these very young patients should be aimed at minimizing the degree of oxidative damage. Only by achieving early diagnosis, will it be possible to identify those children who could benefit from specific therapeutic approaches targeting oxidative stress.     

Opioid Peptides: Synthesis and Biological Activity of New Endomorphin Analogues

Summary Syntheses are described of new endomorphin 1 and 2 peptoid–peptide hybrids in which Tyr¹ and either one or both Phe³ and Phe⁴ have been replaced by N-substituted-glycine. The preparation is also described of two glycosylated Hyp²-endomorphin 2 analogues in which either 2,3,4,6-tetra-O-acetyl glucose or glucose are β-O-glycosidically linked to the hydroxyproline residue. The Hyp²-endomorphin sequences have also been elongate by adding a C-terminal β-alanine residue and several linear dimers have been prepared by coupling either the native peptides or the modified analogues. The cyclo endomorphin 2 has also been synthesized. Preliminary pharmacological experiments on isolated organ preparations showed that the agonist activities of both endomorphin 1 and 2 are not significantly affected by the Pro/Hyp substitution. Phe⁴/Nphe substitution in the endomorphin 1 reduced the potency on guinea pig ileum (GPI) by about 100 times and abolished the agonist activity on mouse vas deferens (MVD) preparation. The decrease of the agonist activity induced by modification of one phenylalanine residue only, either Phe³ or Phe⁴, is lower on endomorphin 2. Either modification of both Phe³ and Phe⁴ or glycosylation of the Hyp²-endomorphin 2 cancelled any agonist activity on both preparations. The linear peptide dimers [endomorphin 1]₂, [endomorphin 2]₂, [Hyp²-endomorphin 1]₂, [Hyp²-endomorphin 2]₂, [Hyp²-endomorphin 1-Hyp²-endomorphin 2]₂ or [Hyp²-endomorphin 2-Hyp²-endomorphin 1]₂, are 7–19 times less potent than endomorphin 1 on GPI and significantly less active than endomorphins 1 and 2 on MVD. The other afforded modifications significantly affected or abolished the agonist activity of the resulting endomorphin analogues on both GPI and MVD preparations.The α-amino acid residues are of the L-configuration. Standard abbreviations for amino acid derivatives and peptides are according to the suggestions of the IUPAC-IUB Commission on Biochemical Nomenclature (1984) Eur. J. Biochem., 138, 9–37. Abbreviations listed in the guide published in (2003) J. Peptide Sci., 9, 1–8 are used without explanation.     

Elucidation of the opening of the epoxidic ring of the 3beta-acetoxy-14alpha,15alpha-epoxy-5alpha-cholest-8-en-7-one by methanol, using NMR techniques assisted by a conformational study through theoretical calculations

This paper demonstrates that the crystallization of 3beta-acetoxy-14alpha,15alpha-epoxy-5alpha-cholest-8-en-7-one from methanol affords the 3beta-acetoxy-9alpha-methoxy-15alpha-hydroxycholest-8(14)-en-7-one. The structure of this steroid, which shows an apparently anomalous UV absorption maximum, is determined by high field NMR experiments, supporting the coupling constant values assignments and the NOE contacts by a conformational study through theoretical calculations at the B3LYP/6-31G* level. The computational study also justifies the observed UV absorption of the steroid, thus demonstrating the usefulness of computer chemistry in providing support for the identification of unknown compounds.