Lucrative antioxidant effect of metformin against cyclophosphamide induced nephrotoxicity

Cyclophosphamide is anticancer drug with a well-Known nephrotoxicity. This work was applied to study the lucrative antioxidant influence of metformin as co-therapy on the nephrotoxicity induced by cyclophosphamide in the treatment of different cancer diseases. Four groups of male Sprague Dawley rats were used; Control group (C) received single I.P. injection of 0.2 ml saline, Metformin (MET) group received daily gavage of 200 mg/kg metformin for two weeks, Cyclophosphamide (CP) group received single I.P. injection of 200 mg/kg CP, Protector group (CP.MET) received daily gavage of 200 mg/kg metformin for two weeks and single I.P. injection of 200 mg/kg CP at day 7. By day 14 rats were euthanized. Samples were collected from kidney tissues and blood for kidney function evaluation, histopathological and assessment of oxidative stress markers. The results disclosed that CP yields many functional and structural damage to the kidney, worsened oxidative stress markers and kidney function indicators. The protector group displayed better kidney tissue morphology, acceptable kidney function indicators as well as satisfactory oxidative stress markers.In assumption, metformin could be combined with CP owing to its lucrative effect counter to CP persuaded nephrotoxicity.     

Sepsis impairs alveolar epithelial function by downregulating Na-K-ATPase pump

Widespread vascular endothelial injury is the major mechanism for multiorgan dysfunction in sepsis. Following this process, the permeability of the alveolar capillaries is augmented with subsequent increase in water content and acute respiratory distress syndrome (ARDS). Nevertheless, the role of alveolar epithelium is less known. Therefore, we examined alveolar fluid clearance (AFC) using isolated perfused rat lung model in septic rats without ARDS. Sepsis was induced by ligating and puncturing the cecum with a 21-gauge needle. AFC was examined 24 and 48 h later. The expression of Na-K-ATPase proteins was examined in type II alveolar epithelial cells (ATII) and basolateral membrane (BLM). The rate of AFC in control rats was 0.51 ± 0.02 ml/h (means ± SE) and decreased to 0.3 ± 0.02 and 0.33 ± 0.03 ml/h in 24 and 48 h after sepsis induction, respectively (P < 0.0001). Amiloride, significantly decreased AFC in sepsis; conversely, isoproterenol reversed the inhibitory effect of sepsis. The alveolar-capillary barrier in septic rats was intact; therefore the finding of increased extravascular lung water in early sepsis could be attributed to accumulation of protein-poor fluid. The expression of epithelial sodium channel and Na-K-ATPase proteins in whole ATII cells was not different in both cecal ligation and puncture and control groups; however, the abundance of Na-K-ATPase proteins was significantly decreased in BLMs of ATII cells in sepsis. Early decrease in AFC in remote sepsis is probably related to endocytosis of the Na-K-ATPase proteins from the cell plasma membrane into intracellular pools, with resultant inhibition of active sodium transport in ATII cells.     

Comparison of 2 cell-based phosphoprotein assays to support screening and development of an ALK inhibitor

Anaplastic lymphoma kinase (ALK) when expressed as a fusion protein with nucleophosmin (NPM) has been implicated as a driving oncogene in a subset of lymphomas. Recent reports of ALK expression in a number of other cancers have raised the possibility that an ALK inhibitor may benefit patients with these diseases as well. In a campaign to identify and develop a selective ALK inhibitor, 2 assays were devised to measure the phosphorylation of tyrosine residue 1604 of ALK (pY(1604) ALK). Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen(?)) and phosflow platforms were used to detect modulation of pY(1604) ALK to determine the relative potency of a set of small-molecule inhibitors. Prior to making use of these assays in diverse settings, the authors attempted to ensure their equivalence with a direct comparison of their performance. The pY(1604) ALK assays correlated well both with each other and with assays of ALK enzyme activity or ALK-dependent cell proliferation. The AlphaScreen(?) assay was amenable to automation and enabled rapid, high-throughput compound assessment in an NPM-ALK-driven cell line, whereas the phosflow assay enabled the authors to characterize the activity of compounds with respect to their impact on targeted enzymes and pathways. Results show that both AlphaScreen(?) and phosflow ALK assays exhibited diverse characteristics that made them desirable for different applications but were determined to be equally sensitive and robust in the detection of inhibition of pY(1604) ALK.     

Steering vaccinomics innovations with anticipatory governance and participatory foresight

Vaccinomics is the convergence of vaccinology and population-based omics sciences. The success of knowledge-based innovations such as vaccinomics is not only contingent on access to new biotechnologies. It also requires new ways of governance of science, knowledge production, and management. This article presents a conceptual analysis of the anticipatory and adaptive approaches that are crucial for the responsible design and sustainable transition of vaccinomics to public health practice. Anticipatory governance is a new approach to manage the uncertainties embedded on an innovation trajectory with participatory foresight, in order to devise governance instruments for collective "steering" of science and technology. As a contrast to hitherto narrowly framed "downstream impact assessments" for emerging technologies, anticipatory governance adopts a broader and interventionist approach that recognizes the social construction of technology design and innovation. It includes in its process explicit mechanisms to understand the factors upstream to the innovation trajectory such as deliberation and cocultivation of the aims, motives, funding, design, and direction of science and technology, both by experts and publics. This upstream shift from a consumer "product uptake" focus to "participatory technology design" on the innovation trajectory is an appropriately radical and necessary departure in the field of technology assessment, especially given that considerable public funds are dedicated to innovations. Recent examples of demands by research funding agencies to anticipate the broad impacts of proposed research--at a very upstream stage at the time of research funding application--suggest that anticipatory governance with foresight may be one way how postgenomics scientific practice might transform in the future toward responsible innovation. Moreover, the present context of knowledge production in vaccinomics is such that policy making for vaccines of the 21st century is occurring in the face of uncertainties where the "facts are uncertain, values in dispute, stakes high and decisions urgent and where no single one of these dimensions can be managed in isolation from the rest." This article concludes, however, that uncertainty is not an accident of the scientific method, but its very substance. Anticipatory governance with participatory foresight offers a mechanism to respond to such inherent sociotechnical uncertainties in the emerging field of vaccinomics by making the coproduction of scientific knowledge by technology and the social systems explicit. Ultimately, this serves to integrate scientific and social knowledge thereby steering innovations to coproduce results and outputs that are socially robust and context sensitive.     

Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Currently there are several dozen human polymorphisms that have been loosely associated with cancer risk. Correlating such variants with cancer risk has been challenging, primarily due to factors such as genetic heterogeneity, contributions of diet and environmental factors, and the difficulty in obtaining large sample sizes for analysis. Such difficulties can be circumvented with the establishment of mouse models for human variants. Recently, several groups have modeled human cancer susceptibility polymorphisms in the mouse. Remarkably, in each case these mouse models have accurately reflected human phenotypes, and clarified the contribution of these variants to cancer risk. We recently reported on a mouse model for the codon 72 polymorphism in p53, and found that this polymorphism regulates the ability to cooperate with NFκB and induce apoptosis. Here-in we present evidence that this polymorphism impacts the apoptotic function of p53 in a tissue-specific manner; such tissue-specific effects of polymorphic variants represent an added challenge to human cancer risk association studies. The data presented here support the premise that modeling human polymorphisms in the mouse represents a powerful tool to assess the impact of these variants on cancer risk, progression and therapy.Key words: p53, polymorphism, apoptosis, codon 72, NFκB     

Imidacloprid‐induced transference effect on some elements in rice plants and the brown planthopper Nilaparvata lugens (Hemiptera: Delphacidae)

Abstract The widespread use of imidacloprid against insect pests has not only increased the rate of the development of target pest resistance but has also resulted in various negative effects on rice plants and Nilaparvata lugens resurgence. However, the effect of imidacloprid on elements in rice plants and the transference of these element changes between rice and N. lugens are currently poorly understood. The present study investigated changes of Cu, Fe, Mn, Zn, Ca, K, Mg and Na contents in rice plants following imidacloprid foliar sprays in the adult female of N. lugens that develops from nymphs that feed on treated plants and honeydew produced by females. The results indicated that imidacloprid foliar spray significantly increased Fe and K contents in leaf sheaths. Generally, Fe, Mn, K and Na contents in leaf blades were noticeably decreased, but Ca contents in leaf blades for 10 and 30 mg/kg imidacloprid treatments were significantly increased. The contents of most elements except K and Mg in the adult females and honeydew were significantly elevated. Multivariate statistical analysis showed that Fe, Mn and Na in leaf blades and Fe and Mn in leaf sheaths could be proportionally transferred to N. lugens. The relationship between most elements in adult female bodies and in the honeydew showed a positive correlation coefficient. There were significant differences in the contents of some elements in rice plants and N. lugens from different regions.     

Characterizing asymmetry across the whole sit to stand movement in healthy participants

Sit-to-stand transfer (STS) is a common yet critical prerequisite for many daily tasks. Literature conducted on healthy STS often assume the body to behave symmetrically across the left and right side; yet only a few studies have been conducted to investigate this supposition. These studies have focused on a single numerical indicator such as peak joint moment (JM) values to describe symmetricity; however, STS is a dynamic and time dependent movement. This study addresses the validity of peak value analyses through the introduction of a time based peak-offset measure and proposes two time-dependent techniques to further characterize asymmetry and assesses their feasibility in ten (10) healthy male participants. JM and joint power (JP) over the whole STS movement was determined using motion capture and inverse dynamics. Using a paired one-tailed t-test differences were found in the time at which the left and right side reached peak values in all lower extremity joints (p<0.05) with exception of the hip JM. Using a measure of JM and JP straight-difference it was determined that the ankle joint displayed the largest number of JM and JP development strategies of all the lower extremity joints. Finally, through numerical integration of the JM and JP data with respect to time, it was found that the longer one side spends dominating the movement, the larger the excess angular impulse and work that can be expected from that side. The results suggest that when analyzing STS movements, one must be aware of the potential asymmetry present even in healthy movements. Furthermore, a simple peak JM or JP analysis may not fully describe the extent of these asymmetries.