In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa

<p>Abstract</p> <p>Background</p> <p>To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. <it>Caesalpinia pluviosa</it>, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity.</p> <p>Methods</p> <p>Crude extract (CE) was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested <it>in vitro </it>against chloroquine-sensitive (3D7) and -resistant (S20) strains of <it>Plasmodium falciparum</it> and <it>in vivo </it>in <it>Plasmodium chabaudi</it>-infected mice. <it>In vitro </it>interaction with artesunate and the active <it>C. pluviosa </it>fractions was assessed, and mass spectrometry analyses were conducted.</p> <p>Results</p> <p>At non-toxic concentrations, the 100% ethanolic (F4) and 50% methanolic (F5) fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to <it>m/z </it>303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of <it>m/z </it>137 and 153.</p> <p>Conclusions</p> <p>The findings show that the F4 fraction of <it>C. pluviosa </it>exhibits anti-malarial activity <it>in vitro </it>at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained <it>in vivo </it>after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.</p

A Small Conductance Calcium-Activated K⁺ Channel in C. elegans, KCNL-2, Plays a Role in the Regulation of the Rate of Egg-Laying

In the nervous system of mice, small conductance calcium-activated potassium (SK) channels function to regulate neuronal excitability through the generation of a component of the medium afterhyperpolarization that follows action potentials. In humans, irregular action potential firing frequency underlies diseases such as ataxia, epilepsy, schizophrenia and Parkinson's disease. Due to the complexity of studying protein function in the mammalian nervous system, we sought to characterize an SK channel homologue, KCNL-2, in C. elegans, a genetically tractable system in which the lineage of individual neurons was mapped from their early developmental stages. Sequence analysis of the KCNL-2 protein reveals that the six transmembrane domains, the potassium-selective pore and the calmodulin binding domain are highly conserved with the mammalian homologues. We used widefield and confocal fluorescent imaging to show that a fusion construct of KCNL-2 with GFP in transgenic lines is expressed in the nervous system of C. elegans. We also show that a KCNL-2 null strain, kcnl-2(tm1885), demonstrates a mild egg-laying defective phenotype, a phenotype that is rescued in a KCNL-2-dependent manner. Conversely, we show that transgenic lines that overexpress KCNL-2 demonstrate a hyperactive egg-laying phenotype. In this study, we show that the vulva of transgenic hermaphrodites is highly innervated by neuronal processes and by the VC4 and VC5 neurons that express GFP-tagged KCNL-2. We propose that KCNL-2 functions in the nervous system of C. elegans to regulate the rate of egg-laying. © 2013 Chotoo et al

Cetuximab plus platinum-based chemotherapy in head and neck Squamous Cell Carcinoma: a retrospective study in a single Comprehensive European Cancer Institution

Background: The use of cetuximab in combination with platinum (P) plus 5-fluorouracil (F) has previously been demonstrated to be effective in the treatment of metastatic squamous cell cancer of head and neck (SCCHN). We investigated the efficacy and outcome of this protocol as a first-line treatment for patients with recurrent or metastatic disease. We evaluated overall-survival (OS), progression-free-survival (PFS), overall response rate (ORR) and the treatment toxicity profile in a retrospective cohort. Patients and Methods: This study enrolled 121 patients with untreated recurrent or metastatic SCCHN. The patients received PF+ cetuximab every 3 weeks for a maximum of 6 cycles. Patients with stable disease who received PF+ cetuximab continued to receive cetuximab until disease progressed or unacceptable toxic effects were experienced, whichever occurred first. Results: The median patient age was 53 (37-78) years. The patient cohort was 86.8% male. The addition of cetuximab to PF in the recurrent or metastatic setting provided an OS of 11 months (Confidential Interval, CI, 95%, 8.684-13.316) and PFS of 8 months (CI 95%, 6.051-9.949). The disease control rate was 48.9%, and the ORR was 23.91%. The most common grade 3 or 4 adverse events in the PF+ cetuximab regimen were febrile neutropenia (5.7%), skin rash (3.8%) and mucosistis (3.8%). Conclusions: The results of this study suggest that cetuximab plus platinum-fluorouracil chemotherapy is a good option for systemic treatment in advanced SSCHN patients. This regimen has a well-tolerated toxicity profile.info:eu-repo/semantics/publishedVersio

A Characterization of Scale Invariant Responses in Enzymatic Networks

An ubiquitous property of biological sensory systems is adaptation: a step increase in stimulus triggers an initial change in a biochemical or physiological response, followed by a more gradual relaxation toward a basal, pre-stimulus level. Adaptation helps maintain essential variables within acceptable bounds and allows organisms to readjust themselves to an optimum and non-saturating sensitivity range when faced with a prolonged change in their environment. Recently, it was shown theoretically and experimentally that many adapting systems, both at the organism and single-cell level, enjoy a remarkable additional feature: scale invariance, meaning that the initial, transient behavior remains (approximately) the same even when the background signal level is scaled. In this work, we set out to investigate under what conditions a broadly used model of biochemical enzymatic networks will exhibit scale-invariant behavior. An exhaustive computational study led us to discover a new property of surprising simplicity and generality, uniform linearizations with fast output (ULFO), whose validity we show is both necessary and sufficient for scale invariance of enzymatic networks. Based on this study, we go on to develop a mathematical explanation of how ULFO results in scale invariance. Our work provides a surprisingly consistent, simple, and general framework for understanding this phenomenon, and results in concrete experimental predictions

First report on dung beetles in intra-Amazonian savannahs in Roraima, Brazil

This is the first study to address the dung beetle (Coleoptera: Scarabaeidae: Scarabaeinae) diversity in intra-Amazonian savannahs in the state of Roraima, Brazil. Our aim was to survey the dung beetle fauna associated with these savannahs (regionally called 'lavrado'), since little is known about the dung beetles from this environment. We conducted three field samples using pitfall traps baited with human dung in savannah areas near the city of Boa Vista during the rainy seasons of 1996, 1997, and 2008. We collected 383 individuals from ten species, wherein six have no previous record in intra-Amazonian savannahs. The most abundant species were Ontherus appendiculatus (Mannerheim, 1829), Canthidium aff. humerale (Germar, 1813), Dichotomius nisus (Olivier, 1789), and Pseudocanthon aff. xanthurus (Blanchard, 1846). We believe that knowing the dung beetles diversity associated with the intra-Amazonian savannahs is ideal for understanding the occurrence and distribution of these organisms in a highly threatened environment, it thus being the first step towards conservation strategy development

Anthropogenic disturbance in tropical forests can double biodiversity loss from deforestation

Concerted political attention has focused on reducing deforestation1,2,3, and this remains the cornerstone of most biodiversity conservation strategies4,5,6. However, maintaining forest cover may not reduce anthropogenic forest disturbances, which are rarely considered in conservation programmes6. These disturbances occur both within forests, including selective logging and wildfires7,8, and at the landscape level, through edge, area and isolation effects9. Until now, the combined effect of anthropogenic disturbance on the conservation value of remnant primary forests has remained unknown, making it impossible to assess the relative importance of forest disturbance and forest loss. Here we address these knowledge gaps using a large data set of plants, birds and dung beetles (1,538, 460 and 156 species, respectively) sampled in 36 catchments in the Brazilian state of Pará. Catchments retaining more than 69–80% forest cover lost more conservation value from disturbance than from forest loss. For example, a 20% loss of primary forest, the maximum level of deforestation allowed on Amazonian properties under Brazil’s Forest Code5, resulted in a 39–54% loss of conservation value: 96–171% more than expected without considering disturbance effects. We extrapolated the disturbance-mediated loss of conservation value throughout Pará, which covers 25% of the Brazilian Amazon. Although disturbed forests retained considerable conservation value compared with deforested areas, the toll of disturbance outside Pará’s strictly protected areas is equivalent to the loss of 92,000–139,000 km2 of primary forest. Even this lowest estimate is greater than the area deforested across the entire Brazilian Amazon between 2006 and 2015 (ref. 10). Species distribution models showed that both landscape and within-forest disturbances contributed to biodiversity loss, with the greatest negative effects on species of high conservation and functional value. These results demonstrate an urgent need for policy interventions that go beyond the maintenance of forest cover to safeguard the hyper-diversity of tropical forest ecosystems