BackgroundThe genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes.MethodsA pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay.ResultsThree metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype.ConclusionFurther studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12614000851662, date registered: August 8, 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2062-2) contains supplementary material, which is available to authorized users.

A cDNA clone encoding molluscan insulin-related peptide (MIP) I1 was isolated from a cDNA library of the central nervous system (CNS) of the freshwater snail, Lymnaea stagnalis, using a heterologous screening with a previously identified MIP cDNA (renamed MIP-I cDNA). The MIP-I1 cDNA encodes a preprohormone resembling the organization of preproinsulin, with a putative signal sequence, and A and B chains; however, in this case connected by two distinct C peptides, Ca and CP, instead of a single C peptide, a phenomenon which represents a new development in the prohormone organization of peptides belonging to the insulin superfamily. The A and B chains of MIP I1 and I differ remarkably in primary structure; in contrast, the Ca peptide domains are fully identical. MIP I1 has only limited sequence similarity with insulins and related peptides. Both MIP I1 and I exhibit structural features, which make them a unique class of the insulin superfamily. The MIP I and I1 genes are expressed in a single type of neuron: the growth-controlling neuroendocrine light green cells of the Lymnaea CNS. Note. The novel nucleotide sequence data published here have been submitted to the EMBL, GENBANK and BOBJ sequence data bank(s) and are available under accession number(s) X59302. tion, with the exception of an extra C-peptide domain, which is present in preproMIP 11. Although MIP I and I1 differ substantially, they have structural features in common that are absent in other insulins and related peptides. This makes them a unique class of the insulin superfamily. MATERIALS AND METHODS Screening of the Lymnaea cDNA libraryWe screened 20000 clones of an amplified cDNA library in Lgtl0 of the CNS of L. stagnalis [16], using Hybond-N membranes (Amersham International Corporation) at a density of 5000 plaque-forming units/l35-mm filter. Clones were purified by rescreening at a lower plaque density. Plaque lifts were carried out as recommended by the manufacturer. Hybridization of the membranes was performed in 6 x NaCl/Cit (NaCl/Cit: 0.15 M NaCl and 15 mM sodium citrate) for 16 h at 65°C. The filters were washed in NaCl/Cit for 45 min at 65°C. Autoradiography was done on preflashed Kodak X-OMAT using an intensifying screen. MIP-I cDNA radiolabelingRadiolabeled cDNA was synthesized by primer extension on a single-stranded M13 MIP-I cDNA clone [8] using the Klenow fragment of DNA polymerase I. The M13-specific primer 5'-TGACCGGCAGCAAAATG-3' was used. [a-32P]dATP was incorporated during the reaction. A mixture of 0.1 pmol M13 single-stranded DNA and 0.5 pmol primer were heated to 95°C and allowed to cool to 20°C. To the mixture, 10 pCi [E~'P]~ATP and 7 U Klenow enzyme (Boehringer Mannheim) were added and the reaction was carried out for 20 min at 20°C. A chase reaction was performed by adding 0.2 mM dATP for 10 min at 20°C. Next,

The fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, sleep disturbances, fatigue, and cognitive alterations. A limited efficacy of targeted treatment and a high FMS prevalence (2-5% of the adult population) sums up to high morbidity. Although, altered nociception has been explained with the central sensitization hypothesis, which may occur after neuropathy, its molecular mechanism is not understood. The marked female predominance among FMS patients is often attributed to a psychosocial predisposition of the female gender, but here we will focus on sex differences in neurobiological processes, specifically those of the immune system, as various immunological biomarkers are altered in FMS. The activation of innate immune sensors is compatible with a neuropathy or virus-induced autoimmune diseases. Considering sex differences in the immune system and the clustering of FMS with autoimmune diseases, we hypothesize that the female predominance in FMS is due to a neuropathy-induced autoimmune pathophysiology. We invite the scientific community to verify the autoimmune hypothesis for FMS.

Background: Sex bias in immune function has been contributed in part to a preponderance of immune systemrelated genes (ISRG) on the X-chromosome. We verified whether ISRG are more abundant on the X chromosome as compared to autosomal chromosomes and reflected on the impact of our findings. Methods: Consulting freely accessible databases, we performed a comparative study consisting of three complementary strategies. First, among coding X/Y-linked genes, the abundance of ISRG was compared to the abundance of genes dedicated to other systems. Genes were assigned considering three criteria: disease, tissue expression, and function (DEF approach). In addition, we carried out two genome-wide approaches to compare the contribution of sex and autosomal chromosomes to immune genes defined by an elevated expression in lymphatic tissues (LTEEG approach) or annotation to an immune system process, GO:0002376 (GO approach).Results: The X chromosome had less immune genes than the median of the autosomal chromosomes. Among Xlinked genes, ISRG ranked fourth after the reproductive and nervous systems and genes dedicated to development, proliferation and apoptosis. On the Y chromosome, ISRG ranked second, and at the pseudoautosomal region (PAR) first. According to studies on the expression of X-linked genes in a variety of (mostly non-lymphatic) tissues, almost two-thirds of ISRG are expressed without sex bias, and the remaining ISRG presented female and male bias with similar frequency. Various epigenetic controllers, X-linked MSL3 and Y-linked KDM5D and UTY, were preferentially expressed in leukocytes and deserve further attention for a possible role in sex biased expression or its neutralisation. Conclusions: The X chromosome is not enriched for ISRG, though particular X-linked genes may be responsible for sex differences in certain immune responses. So far, there is insufficient information on sex-biased expression of X/ Y-linked ISRG in leukocytes to draw general conclusions on the impact of X/Y-linked ISRG in immune function. More research on the regulation of the expression X-linked genes is required with attention to 1) female and male mechanisms that may either augment or diminish sex biased expression and 2) tissue-specific expression studies.

The objective of this study was to analyze the antitumor activity of a hydrogel loaded with lipophilic bismuth nanoparticles on human cervical, prostate, and colon cancer cell lines. The effect of lipophilic bismuth nanoparticles on the viability of cancer cell lines (HeLa, DU145, and HCT-116) and non-cancer lung fibroblasts (HLF; LL 47[MaDo]) was determined with the MTT cell viability assay and compared with known antineoplastic drugs. The biocompatibility at an organismal level was verified in a murine model by histological examination. A lipophilic bismuth nanoparticle hydrogel at 50 µM time-dependently inhibited the growth of the three cancer cell lines, in a time-dependent way. A 1-hour exposure to 250 µM lipophilic bismuth nanoparticle hydrogel, inhibited the growth of the three cancer cell lines. The in-vitro efficacy of lipophilic bismuth nanoparticle was similar to the one of docetaxel and cisplatin, but without inhibiting the growth of non-cancer control cells. Histology confirmed the biocompatibility of lipophilic bismuth nanoparticles as there were no signs of cytotoxicity or tissue damage in any of the evaluated organs (kidney, liver, brain, cerebellum, heart, and jejunum). In conclusion, a lipophilic bismuth nanoparticle hydrogel is an innovative, low-cost alternative for the topical treatment of cervicouterine, prostate, and colon human cancers.

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Foamy cells have been described in various infectious diseases, for example in actinomycetoma induced by Nocardia brasiliensis. These cells are generally considered to be macrophages, although they present dendritic cell (DC)-specific surface markers. In this study, we determined and confirmed the lineage of possible precursors of foamy cells in vitro and in vivo using an experimental actinomycetoma model in BALB/c mice. Bone marrow-derived macrophages (BMDM) or DC (BMDC) were infected in vitro with N. brasiliensis or labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). Both, macrophages and DC, differentiated into foamy cells after in vitro infection. CFSE-labeled BMDM or BMDC were tested for phagocytosis and CD11c/CD11b receptors markers expression before being transferred into the actinomycetoma lesion site of infected mice. In vivo studies showed that BMDM and BMDC were traced at the site where foamy cells are present in the experimental actinomycetoma. Interestingly, many of the transferred BMDM and BMDC were stained with the lipid-droplet fluorophore Nile Red. In conclusion, macrophages and DC cells can be differentiated into foamy cells in vitro and in vivo during N. brasiliensis infection.