The anticancer properties of dietary polyphenols and its relation with apoptosis

Aberrantly regulated apoptosis is involved in the pathogenesis of several diseases and defective apoptosis leads to uncontrolled cell proliferation and tumorigenesis. Cancer is an example of a pathologic condition where the normal mechanisms of cell cycle regulation are dysfunctional either by excessive cell proliferation, inhibited/suppressed apoptosis or both. Dietary habits are estimated to contribute to, at least, one third of all human cancers, showing that dietary components can exacerbate or interfere with carcinogenesis. However, several epidemiological studies have revealed that some dietary factors can decrease the risk of different types of cancer. Apoptosis is suggested to be a crucial mechanism for the chemopreventive properties associated with several dietary factors by eliminating potentially deleterious (damaged/mutated) cells. Food, a readily available item, contains several promising chemopreventive agents. Polyphenols are serious candidates since they are responsible for the cancer protective properties of a diet rich in vegetables and fruits: numerous phenolic compounds showed antiproliferative and cytotoxic effects, and more specifically pro-apoptotic activities, in several cancer cells lines and animal tumor models. The aim of the present review is to analyze and summarize several aspects related to the molecular mechanisms of apoptosis induced by dietary factors with particular emphasis on polyphenols. Dietary factors that can activate cell death signals and induce apoptosis, preferentially in precancerous or malignant cells, and the study of their apoptotic inducing targets can represent a mean to devise new strategies for cancer prevention in the future

Vancomycin therapeutic drug monitoring and population pharmacokinetic models in special patient subpopulations

Vancomycin is a fundamental antibiotic in the management of severe Gram-positive infections. Inappropriate vancomycin dosing is associated with therapeutic failure, bacterial resistance and toxicity. Therapeutic drug monitoring (TDM) is acknowledged as an important part of the vancomycin therapy management, at least in specific patient subpopulations, but implementation in clinical practice has been difficult because there are no consensus and agglutinator documents. The aims of the present work are to present an overview of the current knowledge on vancomycin TDM and population pharmacokinetic (PPK) models relevant to specific patient subpopulations. Based on three published international guidelines (American, Japanese and Chinese) on vancomycin TDM and a bibliographic review on available PPK models for vancomycin in distinct subpopulations, an analysis of evidence was carried out and the current knowledge on this topic was summarized. The results of this work can be useful to redirect research efforts to address the detected knowledge gaps. Currently, TDM of vancomycin presents a moderate level of evidence and practical recommendations with great robustness in neonates, pediatric and patients with renal impairment. However, it is important to investigate in other subpopulations known to present altered vancomycin pharmacokinetics (eg neurosurgical, oncological and cystic fibrosis patients), where evidence is still unsufficient

The systematicity challenge to anti-representational dynamicism

After more than twenty years of representational debate in the cognitive sciences, anti-representational dynamicism may be seen as offering a rival and radically new kind of explanation of systematicity phenomena. In this paper, I argue that, on the contrary, anti-representational dynamicism must face a version of the old systematicity challenge: either it does not explain systematicity, or else, it is just an implementation of representational theories. To show this, I present a purely behavioral and representation-free account of systematicity. I then consider a case of insect sensorimotor systematic behavior: communicating behavior in honey bees. I conclude that anti-representational dynamicism fails to capture the fundamental trait of systematic behaviors qua systematic, i.e., their involving exercises of the same behavioral capacities. I suggest, finally, a collaborative strategy in pursuit of a rich and powerful account of this central phenomenon of high cognition at all levels of explanation, including the representational level

Amino acids in the development of Prodrugs

Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable pharmacological and pharmaceutical properties. Most of the drugs have low bioavailability, lack of sensitivity, and do not target only the damaged cells, thus also affecting normal cells. Moreover, there is the risk of developing resistance against drugs upon chronic treatment. Consequently, their potential clinical applications might be limited and therefore, it is mandatory to find strategies that improve those properties of therapeutic agents. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. Herein, we provide an overview of models currently in use of prodrug design with amino acids. Furthermore, we review the challenges related to the permeability of poorly absorbed drugs and transport and deliver on target organs.NV acknowledges support from Fundação para a Ciência e Tecnologia (FCT, Lisbon, Portugal) and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004. NV also thanks FCT for the IF position and Fundação Manuel António da Mota (FMAM, Porto, Portugal) and Pfizer (Portugal) for support for the Nuno Vale Research Group. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT, FMAM and Pfizer

The molecular organization and function of paranodal septate junctions

Close communication between axons and glial cells is required and necessary for maturation, organization and maintenance of the nervous system. The axon provides signals to promote differentiation, survival and proliferation of both oligodendrocytes and Schwann cells in the central and peripheral nervous systems respectively, while providing instructions to regulate myelin thickness. Conversely, glial cells provide reciprocal signals that regulate and control axonal mechanisms such as axonal thickness and transport. The combined efforts of glial and axonal signals result in a mature myelinated fiber that has a structural organization optimal for a maximum conduction velocity. One characteristic feature of myelinated fibers is their ability to organize specialized domains with distinctive molecular and structural characteristics. The myelinated domains include the node of Ranvier, the paranodal junction, the juxtaparanodal junction and the internodal region. This domain organization is a result of the fine bi-directional communication between the axon and the overlying glial cell. The paranodal axo-glial junction is a complex of proteins including: NCP1, Contactin (CN), Neurofascin 155 (NF155) and band 4.1B. NF155 is expressed by the overlying glial cell while the others are clustered on the axonal membrane. All proteins are necessary for the maintenance and establishment of the paranodal domain and provide a link to the axonal cytoskeleton. We and others have previously characterized two knockout mice (NCP1 and CGT) that display several signs of cerebellar deficits, including abnormal motor coordination, tremors at rest and ataxia. These knockouts share the same phenotypes one of which is their inability to form paranodal junctions properly. Interestingly NCP1 is an axonal protein and CGT is a glial protein suggesting a common mechanism of action by both cell types and the importance of axo-glial interactions in proper axonal development and organization. The goal of this project is to further understand the role, molecular composition and organization of axo-glial junctions in vertebrate systems, in particular the paranodal junction of myelinated nerve fibers. We will use these two knockout mouse model systems to identify new key components that play a role in establishing a link between the axon and glial cells

Antifungal, anti-inflammatory and cytotoxicity activities of three varieties of Labisia pumila benth : from microwave obtained extracts.

Background: Labisia pumila, locally known as Kacip Fatimah, is a forest-floor plant that has tremendous potential in the herbal industry. It is one of the five herbal plants identified by the government as one of the national key economic areas to be developed for commercial purposes. There are three varieties of L. pumila namely, L. pumila var. pumila, L. pumila var. alata and L. pumila var. lanceolata and each has its own use.Methods: The leaves and roots of the three varieties of L. pumila Benth. were extracted using microwave assisted extraction (MAE). Antifungal activity of all plant extracts were characterized against Fusarium sp., Candida sp. and Mucor using the agar diffusion disc. Anti-inflammatory assays were performed using NO production by macrophage RAW 264.7 cell lines induced by LPS/IFN-g and cytotoxic activity was determined using several cancer cell lines and one normal cell line.Results: The overall result demonstrated that leaf and root extracts of all three varieties of L. pumila exhibited moderate to appreciable antifungal activity against Fusarium sp., Candida sp. and Mucor compared to streptomycin used as positive control. Leaf and root extracts of all varieties significantly decreased NO release. However, the root extracts showed higher activity compared to the leaf extracts. Cytotoxic activity against MCF-7, MDA-MB-231 and Chang cell lines were observed with all extracts.Conclusions: These findings suggest the potential use of L. pumila Benth. as a natural medicine and indicated the possible application of this medicinal plant such anti inflammatory activity and cytotoxic agents

On malfunctioning software

Artefacts do not always do what they are supposed to, due to a variety of reasons, including manufacturing problems, poor maintenance, and normal wear-and-tear. Since software is an artefact, it should be subject to malfunctioning in the same sense in which other artefacts can malfunction. Yet, whether software is on a par with other artefacts when it comes to malfunctioning crucially depends on the abstraction used in the analysis. We distinguish between “negative” and “positive” notions of malfunction. A negative malfunction, or dysfunction, occurs when an artefact token either does not (sometimes) or cannot (ever) do what it is supposed to. A positive malfunction, or misfunction, occurs when an artefact token may do what is supposed to but, at least occasionally, it also yields some unintended and undesirable effects. We argue that software, understood as type, may misfunction in some limited sense, but cannot dysfunction. Accordingly, one should distinguish software from other technical artefacts, in view of their design that makes dysfunction impossible for the former, while possible for the latter