Secondary lymphoid tissue chemokine (CCL21) is upregulated in allergic contact dermatitis

Chemokines are important players in the development of allergic contact dermatitis (ACD). The participation of secondary lymphoid tissue chemokine (CCL21) is essential in the induction of the disease due to its expression in lymphatic vessels and in secondary lymphoid organs. Since there is no information about its participation during the effector phase of ACD, we studied this chemokine in patients already diagnosed with ACD, who were challenged with the relevant positive and negative (control) antigens. All patients showed a specific antigen-induced immune response characterized by early expression of inflammatory markers in blood endothelial cells followed by dermal accumulation of mononuclear cells with an important increase in infiltration of CXCR3+ but not of CCR7+ cells. In situ hybridization and immunohistochemistry showed low levels of CCL21 in lymphatic vessels at 2 h, whereas they were significantly increased at 10 and 48 h in all positive patch tests. In contrast, very low expression of this chemokine was observed in skin biopsies from the control site at 48 h. In addition, Langerin+ cells, which were present in dermis from positive patch tests at 2 h, were diminished in number at 10 and 48 h, but a significant number of those cells was still present in dermal areas of the control site at 48 h. We demonstrate for the first time that CCL21, a constitutively expressed chemokine, is strongly upregulated in human lymphatic vessels during a Th1/Tc1 allergic inflammatory response. This can provide the signal required for CCR7+ cells to leave the skin through CCL21-positive lymphatic vessels.     

Transepithelial transport of biperiden hydrochloride in Caco-2 cell monolayers

The aim of this research has been to determine the biperiden hydrochloride permeability in Caco-2 model, in order to classify it based on the Biopharmaceutics Classification System (BCS). The World Health Organization (WHO) as well as many other authors have provisionally assigned the drug as BCS class I (high solubility-high permeability) or III (high solubility-low permeability), based on different methods. We determined biperiden BCS class by comparing its permeability to 5 pre-defined compounds: atenolol and ranitidine hydrochloride (low permeability group) and metoprolol tartrate, sodium naproxen and theophylline (high permeability group). Since biperiden permeability was higher than those obtained for high permeability drugs, we classified it as a BCS class I compound. On the other hand, as no differences were obtained for permeability values when apical to basolateral and basolateral to apical fluxes were studied, this drug cannot act as a substrate of efflux transporters. As a consequence of our results, we suggest that the widely used antiparkinsonian drug, biperiden, should be candidate for a waiver of in vivo bioequivalence studies.     

Cytokine polymorphisms in patients with pemphigus

The aim of this study was to assess whether tumor necrosis factor (TNF-), transforming growth factor 1 (TGF-1) and interleukin-10 (IL-10) polymorphisms are among the factors influencing the development of pemphigus. Whole blood from 20 patients with pemphigus and 24 control subjects was taken. Genomic DNA was obtained and cytokine genotyping for IL-10 (–1082 G/A; –819 C/T), TGFB1 (codon 10 C/T, codon 25 G/C) and TNFA (–308 G/A) was performed using the ARMS-PCR method. The distribution of IL-10 (–819) alleles was significantly different between the pemphigus and control groups (P=0.009). In particular, allele T was associated with the disease (OR 3.291, 95% CI 1.350–8.020). Similar results were observed when only pemphigus vulgaris (PV) patients were analyzed (P=0.012, OR 3.410, 95% CI 1.346–8.639). An increased frequency of the low producer IL-10 haplotype (–1082/–819 A/T) in patients with pemphigus compared with controls was observed (OR 2.714, 95% CI 1.102–6.685) and this association was also significant when only PV patients were considered (OR 2.667, 95% CI 1.043–6.816). There were no differences between patients and controls in the frequency of any other gene polymorphism analyzed. The increased frequency of the low producer IL-10 haplotype (–1082 /–819 A/T) suggest that the carriage of this haplotype might predispose to pemphigus or the high and intermediate producer haplotypes may be protective factors. The prevalence of the allele IL-10 (–819 T) in pemphigus patients cannot be explained by the current hypothesis, according to which a particular allele of the gene is associated with a different level of cytokine production and therefore affects the predisposition to a particular disease. However, this cytokine polymorphism might be linked to an unknown susceptibility factor.     

Vitamin B12, demyelination, remyelination and repair in multiple sclerosis

Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.     

Design,synthesis and cytotoxic evaluation of a library of oxadiazole-containing hybrids

The development of hybrid compounds led to the discovery of new pharmacologically active agents for some of the most critical diseases, including cancer. Herein, we describe a new series of oxadiazole-containing structures designed by a molecular hybridization approach. Penicillin derivatives and amino acids were linked to amino acid and aromatic moieties through the formation of a 1,2,4-oxadiazole ring. Alternatively, condensation between amino acid-derived hydrazides and an activated penicillanic acid led to a series of 1,3,4-oxadiazole penicillin-containing hybrids and non-cyclized diacylhydrazides. From the cytotoxicity assays it is highlighted that two 1,2,4-oxadiazoles and one 1,3,4-oxadiazole connecting a penicillin and aliphatic amino acids displayed a high degree of cytotoxic selectivity, ranging between being three and four times more potent against tumor cells than normal cells. The results give a very interesting perspective suggesting that these hybrid compounds can offer a novel antitumor scaffold with promising cytotoxicity profiles.

Synthesized hybrids of 1,2,4-oxadiazole and 1,3,4-oxadiazole connecting a penicillin and aliphatic amino acids displayed a high degree of cytotoxic selectivity.     

Polyfluoroalkylated antipyrines in Pd-catalyzed transformations

In the direct C–H arylation with arylhalogenides in the presence of Pd(OAc)₂, trifluoromethyl-containing antipyrine reacts very slowly and incompletely owing to the low nucleophilicity of its C4 center. However, it was effective in modifying polyfluoroalkyl-substituted 4-bromo- and 4-iodo antipyrines by the Suzuki and Sonogashira reactions. It was established that using Pd₂(dba)₃ as catalyst and XPhos as phosphine ligand was the optimal catalytic system for the synthesis of 4-aryl- and 4-phenylethynyl-3-polyfluoroalkyl-antipyrines. Moreover, iodo-derivatives as the initial reagents were found to be more advantageous compared to bromo-containing analogs. It was found that 4-phenylethynyl-5-CF₃-antipyrine has a moderate activity against the influenza virus A/Puerto Rico/8/34 (H1N1) and 4-iodo-5-CF₃-antipyrine reveals a weak activity against the vaccine virus (strain Copenhagen) and bovine diarrhea virus (strain VC-1).

Peculiarities of heterocyclic systems with electron-withdrawing groups (polyfluoroalkyl-containing antipyrines) in Pd-catalyzed C–H arylation and cross-coupling reactions.     

Vascular Cryografts Offer Better Biomechanical Properties in Chronically Hemodialyzed Patients: Role of Cryograft Type,Arterial Pathway,and Diabetic Nephropathy as Matching Determinants

This study aimed to characterize the following: (i) in chronically hemodialyzed subjects (CHDSs), with and without diabetic nephropathy (DN), and in healthy subjects (non‐CHDSs) different arterial pathways stiffness to determine potential pathology‐dependent, etiology‐ and/or pathway‐dependent differences; and (ii) the biomechanical mismatch (BM) between arteries from non‐CHDSs or CHDSs (with and without DN) and arterial cryografts, venous cryografts, and synthetic prosthesis to determine arterial pathway, pathology, and/or etiology‐related differences in the substitute of election in terms of BM. Carotid–femoral and carotid–brachial pulse wave velocity (PWV) were measured in 30 non‐CHDSs and 71 CHDSs (11 with DN). In addition, PWV was measured in arterial (elastic and muscular) and venous cryografts and in expanded polytetrafluorethylene prosthesis. The arterial pathways regional differences and the subjects' arterial pathways‐substitutes BM were calculated. Arterial stiffness levels and regional differences were higher in CHDS than in non‐CHDS. Among CHDS, those with DN showed higher stiffness in the aorto–femoral pathway and larger regional differences. Cryografts showed always the least BM. Non‐CHDS and CHDS differed in the cryograft of election. In CHDS, the BM was related with the cryograft type, arterial pathway, and renal disease etiology. The BM could be minimized, selecting the most adequate cryograft type, taking into account the recipient specific characteristic (i.e., arterial pathway and renal disease etiology).