Toxicological screening of Euphorbia tirucalli L.: developmental toxicity studies in rats

Euphorbia tirucalli (Euphorbiaceae family), an environmental risk factor for Burkitt's lymphoma, also presents pharmacological activities. In the northeast region of Brazil its latex is used as an antimicrobial, antiparasitic in the treatment of coughs, rheumatism, cancer and other maladies as folk remedy. The present work concerns its developmental toxicity in rats. Wistar rats on the first day post-coitum (dpc) were grouped as control (distilled water) and treated (latex aqueous solution) groups. Animals were treated by oral gavage from the 1st to the 4th (Experiment I) and from the 5th to 7th dpc (Experiment II) and killed on the 5th or 14th dpc, respectively. Maternal variables were: clinical signs of toxicity, body weight, ovaries, liver and kidneys weight and number of corpora lutea. The uterine tubes and cornua were washed for counting and identification of embryos. The embryos and placenta were weighed. Apart from the leucopenia and the higher placental weight observed in treated rats from Experiment II, there were no significant differences between the groups. It is possible to conclude that the latex aqueous solution of Euphorbia tirucalli did not interfere with tubaric embryo development or with implantation, but it seems to alter the placenta morphology.     

Expression and function of epithelial anoctamins

Endogenous Ca(2+)-activated Cl(-) currents (CaCCs) are abundant and present in very different cell types. Very good evidence has been provided that endogenous CaCC is produced by anoctamin 1 (Ano1) and Ano2. Insight into the physiological role of anoctamins has been provided for Ano1, Ano2 and Ano6; however, the physiological role of the other seven members of the anoctamin family remains obscure. Anoctamins 1 and 2 may operate as individual Ca(2+)-sensitive channel proteins or may require accessory subunits for complete function. We find that overexpressed Ano1 has properties resembling all those of endogenous CaCCs, although with some noticeable biophysical and regulatory differences when compared with endogenous channels. Apart from Ano1 and Ano2, expression of Ano6 also produces a Cl(-) conductance. Depending on the cellular background, Ano6 currents may have variable properties. Anoctamins 1 and 6 are frequent in epithelial cells, often coexpressed together with Ano8, Ano9 and Ano10. Most available data on anoctamins were obtained from mouse tissues and from cultured cells, which may not be representative of native human tissues.     

Fetal outcome in autoimmune diseases

The impact on fetal outcome in women with autoimmune diseases is a result of a several conditions. Fetal success depends on early immunological changes in the mother, which rely in modifications of the innate and adaptative immune system, inducing tolerance to the semi-allogenic fetus. Others crucial factors are maternal disease activity, severity of organ damage, circulating antibodies, and drug treatment. Although fetal outcome is becoming better still it has a worse prognosis in comparison with healthy women. Diseases like antiphospholipid syndrome, systemic lupus erythematosus and vasculitis have the higher risk while rheumatoid arthritis and spondiloarthopaties the least. In the majority of the diseases the risk of poor fetal outcome directly correlates with the activity of disease. While there are no pathognomonic autoantibodies for fetal outcome, antiphospholipid and anti-thyroid antibodies have been implicated in unsuccessful pregnancies and anti-Ro and, to a lesser extent, anti-La antibodies may result in neonatal lupus syndrome congenital heart block. There is increasingly the hope that fetal outcome will be good if the disease is well controlled prior to pregnancy, and with a specialized interdisciplinary support.     

The behavior and diagnostic utility of procalcitonin and five other inflammatory molecules in critically ill patients with respiratory distress and suspected 2009 influenza a H1N1 infection

OBJECTIVES:

During the 2009 influenza A H1N1 pandemic, it became difficult to differentiate viral infections from other conditions in patients admitted to the intensive care unit. We sought to evaluate the behavior and diagnostic utility of procalcitonin, C-reactive protein and four other molecules in patients with suspected 2009 Influenza A H1N1 infection.

METHODS:

The serum levels of procalcitonin, C-reactive protein, tumor necrosis factor α, interferon γ, interleukin 1β, and interleukin 10 were tested on admission and on days 3, 5, and 7 in 35 patients with suspected 2009 H1N1 infection who were admitted to two ICUs.

RESULTS:

Twelve patients had confirmed 2009 influenza A H1N1 infections, 6 had seasonal influenza infections, and 17 patients had negative swabs. The procalcitonin levels at inclusion and on day 3, and the C-reactive protein levels on day 3 were higher among subjects with 2009 influenza A H1N1 infections. The baseline levels of interleukin 1β were higher among the 2009 influenza A H1N1 patients compared with the other groups. The C-reactive protein levels on days 3, 5, and 7 and procalcitonin on days 5 and 7 were greater in non-surviving patients.

CONCLUSION:

Higher levels of procalcitonin, C-reactive protein and interleukin-1β might occur in critically ill patients who had a 2009 H1N1 infection. Neither procalcitonin nor CRP were useful in discriminating severe 2009 H1N1 pneumonia. Higher levels of CRP and procalcitonin appeared to identify patients with worse outcomes.     

An isoniazid analogue promotes Mycobacterium tuberculosis-nanoparticle interactions and enhances bacterial killing by macrophages

Nanoenabled drug delivery systems against tuberculosis (TB) are thought to control pathogen replication by targeting antibiotics to infected tissues and phagocytes. However, whether nanoparticle (NP)-based carriers directly interact with Mycobacterium tuberculosis and how such drug delivery systems induce intracellular bacterial killing by macrophages is not defined. In the present study, we demonstrated that a highly hydrophobic citral-derived isoniazid analogue, termed JVA, significantly increases nanoencapsulation and inhibits M. tuberculosis growth by enhancing intracellular drug bioavailability. Importantly, confocal and atomic force microscopy analyses revealed that JVA-NPs associate with both intracellular M. tuberculosis and cell-free bacteria, indicating that NPs directly interact with the bacterium. Taken together, these data reveal a nanotechnology-based strategy that promotes antibiotic targeting into replicating extra- and intracellular mycobacteria, which could actively enhance chemotherapy during active TB.     

Regulation of ENaC biogenesis by the stress response protein SERP1

Cystic fibrosis lung disease is caused by reduced Cl^? secretion along with enhanced Na⁺ absorption, leading to reduced airway surface liquid and compromised mucociliary clearance. Therapeutic strategies have been developed to activate cystic fibrosis transmembrane conductance regulator (CFTR) or to overcome enhanced Na⁺ absorption by the epithelial Na⁺ channel (ENaC). In a split-ubiquitin-based two-hybrid screening, we identified stress-associated ER protein 1 (SERP1)/ribosome-associated membrane protein 4 as a novel interacting partner for the ENaC β-subunit. SERP1 is induced during cell stress and interacts with the molecular chaperone calnexin, thus controlling early biogenesis of membrane proteins. ENaC activity was measured in the human airway epithelial cell lines H441 and A549 and in voltage clamp experiments with ENaC-overexpressing Xenopus oocytes. We found that expression of SERP1 strongly inhibits amiloride-sensitive Na⁺ transport. SERP1 coimmunoprecipitated and colocalized with βENaC in the endoplasmic reticulum, together with the chaperone calnexin. In contrast to the inhibitory effects on ENaC, SERP1 appears to promote expression of CFTR. Taken together, SERP1 is a novel cochaperone and regulator of ENaC expression.     

Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder

The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments. Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6-8 weeks of treatment under double-blind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre- to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern correlated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.     

Acute resistance exercise reduces blood pressure and vascular reactivity, and increases endothelium-dependent relaxation in spontaneously hypertensive rats

The aim of the present study was to assess the effects of acute dynamic resistance exercise on resting blood pressure (BP) and on endothelial function of vascular bed of spontaneously hypertensive rats. Hemodynamic measurements were performed before and after acute dynamic resistance exercise in conscious animals. After exercise, the tail artery was cannulated for mean perfusion pressure with constant flow measurement and for performing concentration–response curves to acetylcholine (ACh) and sodium nitroprusside (SNP) and dose–response curves to phenylephrine (PHE). PHE protocol was also repeated with damaged endothelium and after L-NAME and indomethacin perfusion on the tail. The maximal response (E _max) and sensitivity (pD₂) were evaluated to these drugs. Exercise reduced resting systolic and diastolic BP (Δ −79 ± 1.8; −23 ± 2.3 mmHg, respectively; P < 0.05). ACh-induced relaxation increased in the exercise group (pD₂ = 9.8 ± 0.06, P < 0.05) when compared with control rats (pD₂ = 8.7 ± 0.1). The E _max to PHE with intact endothelium decreased following exercise condition (439 ± 18 mmHg, P < 0.05) when compared with control rats (276 ± 22 mmHg). This response was abolished after L-NAME and indomethacin administration. After damage of the endothelium, PHE responses were not significantly different between the groups; however, E _max and pD₂ increased when compared with responses obtained with intact endothelium. The results demonstrated that acute dynamic resistance exercise decreased resting BP and reactivity to PHE and increased endothelium-dependent relaxation. Nitric oxide and vasodilators prostanoids appear to be involved in post-exercise endothelial and pressor responses.