Permeability of Gemcitabine and PBPK Modeling to Assess Oral Administration

Gemcitabine is a nucleoside analog effective against several solid tumors. Standard treatment consists of an intravenous infusion over 30 min. This is an invasive, uncomfortable and often painful method, involving recurring visits to the hospital and costs associated with medical staff and equipment. Gemcitabine’s activity is significantly limited by numerous factors, including metabolic inactivation, rapid systemic clearance of gemcitabine and transporter deficiency-associated resistance. As such, there have been research efforts to improve gemcitabine-based therapy efficacy, as well as strategies to enhance its oral bioavailability. In this work, gemcitabine in vitro and clinical data were analyzed and in silico tools were used to study the pharmacokinetics of gemcitabine after oral administration following different regimens. Several physiologically based pharmacokinetic (PBPK) models were developed using simulation software GastroPlus™, predicting the PK parameters and plasma concentration–time profiles. The integrative biomedical data analyses presented here are promising, with some regimens of oral administration reaching higher AUC in comparison to the traditional IV infusion, supporting this route of administration as a viable alternative to IV infusions. This study further contributes to personalized health care based on potential new formulations for oral administration of gemcitabine, as well nanotechnology-based drug delivery systems.     

Fluorescent Labeling of Oligonucleotide Probes for Double Indicator Microarray Hybridization Analysis

Russian Journal of Bioorganic Chemistry - Herein, we present a synthesis of a molecular construct based on the polysulfonated indocarbocyanine dye and the lysine. The chemical structure of the...     

Neural Correlates of Sexual Cue Reactivity in Individuals with and without Compulsive Sexual Behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a “behavioural” addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions.     

Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A2A and A3 receptors

Inosine, a naturally occurring purine formed from the breakdown of adenosine, is associated with immunoregulatory effects. Evidence shows that inosine modulates lung inflammation and regulates cytokine generation. However, its role in controlling allergen-induced lung inflammation has yet to be identified. In this study, we aimed to investigate the role of inosine and adenosine receptors in a murine model of lung allergy induced by ovalbumin (OVA). Intraperitoneal administration of inosine (0.001–10 mg/kg, 30 min before OVA challenge) significantly reduced the number of leukocytes, macrophages, lymphocytes and eosinophils recovered in the bronchoalveolar lavage fluid of sensitized mice compared with controls. Interestingly, our results showed that pre-treatment with the selective A_2A receptor antagonist (ZM241385), but not with the selective A_2B receptor antagonist (alloxazine), reduced the inhibitory effects of inosine against macrophage count, suggesting that A_2A receptors mediate monocyte recruitment into the lungs. In addition, the pre-treatment of mice with selective A₃ antagonist (MRS3777) also prevented inosine effects against macrophages, lymphocytes and eosinophils. Histological analysis confirmed the effects of inosine and A_2A adenosine receptors on cell recruitment and demonstrated that the treatment with ZM241385 and alloxazine reverted inosine effects against mast cell migration into the lungs. Accordingly, the treatment with inosine reduced lung elastance, an effect related to A₂ receptors. Moreover, inosine reduced the levels of Th₂-cytokines, interleukin-4 and interleukin-5, an effect that was not reversed by A_2A or A_2B selective antagonists. Our data show that inosine acting on A_2A or A₃ adenosine receptors can regulate OVA-induced allergic lung inflammation and also implicate inosine as an endogenous modulator of inflammatory processes observed in the lungs of asthmatic patients.     

Association of CD209 and CD209L polymorphisms with tuberculosis infection in a Northeastern Brazilian population

Tuberculosis (TB) caused by Mycobacterium tuberculosis, is major cause of morbidity and mortality worldwide. So far, many candidate genes have been investigated for their possible association with TB. Dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3) grabbing non-integrin (DC-SIGN) and Liver/lymph node-specific intercellular adhesion molecule-grabbing non-integrin (L-SIGN), encoded by CD209 and CD209L genes respectively, are known for binding to M. tuberculosis on human dendritic cells and macrophages. We screened 4 single nucleotide polymorphisms (SNPs) in the promoter region of CD209, namely ?939G>A (rs735240), ?871A>G (rs735239), ?336A>G (rs4804803) and ?139G>A (rs2287886) and tandem repeat polymorphisms in exon 4 of CD209 and CD209L genes looking for association with TB in a Northeastern Brazilian population (295 subjects, 131 TB patients and 164 healthy controls). The ?139G>A and ?939G>A SNPs were associated with susceptibility to TB, and in particular with pulmonary and extra-pulmonary forms respectively. The ?871A>G and ?336A>G SNPs were associated, the first with protection to both pulmonary and extra-pulmonary TB, the latter only with the pulmonary form. An association between GGAG haplotype and protection to TB infection was also found. Also tandem repeat polymorphism in CD209L exon 4 was associated with TB infection. This study provides evidence of an association between CD209 and CD209L polymorphisms and TB development in a Brazilian population, suggesting that variations in these genes may influence the protection and susceptibility to infection caused by M. tuberculosis.     

Enhanced Attentional Bias towards Sexually Explicit Cues in Individuals with and without Compulsive Sexual Behaviours

Compulsive sexual behaviour (CSB) is relatively common and has been associated with significant distress and psychosocial impairments. CSB has been conceptualized as either an impulse control disorder or a non-substance ‘behavioural’ addiction. Substance use disorders are commonly associated with attentional biases to drug cues which are believed to reflect processes of incentive salience. Here we assess male CSB subjects compared to age-matched male healthy controls using a dot probe task to assess attentional bias to sexually explicit cues. We show that compared to healthy volunteers, CSB subjects have enhanced attentional bias to explicit cues but not neutral cues particularly for early stimuli latency. Our findings suggest enhanced attentional bias to explicit cues possibly related to an early orienting attentional response. This finding dovetails with our recent observation that sexually explicit videos were associated with greater activity in a neural network similar to that observed in drug-cue-reactivity studies. Greater desire or wanting rather than liking was further associated with activity in this neural network. These studies together provide support for an incentive motivation theory of addiction underlying the aberrant response towards sexual cues in CSB.     

Polyhydroxyalkanoates and pigments coproduction by Arthrospira (Spirulina) platensis cultivated in crude glycerol

Journal of Applied Phycology - Valorization of industrial waste as an alternative carbon source for microalgae mixotrophic cultivation and co-production of high-value compounds are strategies to...     

Cyanine-dye-modified 2′-deoxyuridine-5′-triphosphates: Synthesis,applications, and linker effect on substrate properties for Taq DNA polymerase

A number of fluorescently labeled nucleoside triphosphates containing electroneutral indodicarbocyanine dye (Cy) have been synthesized. The dye has been attached to the C5 position of pyrimidine through the transalkene linkers of different structure. The synthesized labeled nucleoside triphosphates have been tested as substrates for Taq polymerase in PCR using the “TB-biochip” test system.     

Molecular phylogenetics of the Brazilian giant bromeliads (Alcantarea, Bromeliaceae): implications for morphological evolution and biogeography

The genus Alcantarea comprises near 30 species endemic to rocky outcrops from eastern Brazil. Most species are ornamental and several are threatened due to habitat loss and over collection. In this paper we examine the phylogenetics of Alcantarea and its relationship with the Brazilian members of Vriesea, a genus of which Alcantarea has been treated as a subgenus. We discuss the morphological evolution of the stamen position and its implication for pollination and the occurrence of Alcantarea in the Espinha?o mountain range rocky savanna-like habitat vegetation. DNA sequence data derived from two plastid markers (trnK-rps16, trnC-petN) and from a low copy nuclear gene (Floricaula/Leafy) together with 20 nuclear microsatellite loci were the data source to perform analyses and construct phylogenetic and Neighbor Joining trees for the genus. Alcantarea is well supported as monophyletic in both Bayesian and parsimony analyses, but sections of Vriesea, represented by the eastern Brazilian species, appear paraphyletic. Microsatellites delimit geographically isolated species groups. Nevertheless individuals belonging to a single species may appear related to distinct clusters of species, suggesting that hybridization and/or homoplasy and/or incomplete lineage sorting are also influencing the analysis based on such markers and may be the reasons for some unexpected results. Alcantarea brasiliana is hypothesized as putative hybrid between A. imperialis and A. geniculata. Spreading stamens, a morphological floral characteristic assumed to be related to Chiropterophily, apparently evolved multiple times within the genus, and invasion of rocky savanna-like habitat vegetation by Atlantic rainforest ancestors seems to have occurred multiple times as well.     

Multiplex on-Chip PCR with Direct Detection of Immobilized Primer Elongation

Russian Journal of Bioorganic Chemistry - A variant of multiplex PCR on a chip with direct detection of immobilized primer elongation has been developed. Detection is performed by determining the...