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 GISSI Story (1983–1996): A Comprehensive Review

n/

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

The Left Ventricular Dysfunction Questionnaire: Italian translation and validation.

Patients affected by heart failure have a compromised quality of life (QOL) and in the last few years "health related quality of life" has become an important outcome indicator for the evaluation of heart failure treatment. Methods: Translation into Italian of the Left Ventricular Dysfunction Questionnaire (LVD-36), a new, 36-item, disease-specific health status instrument for patients with congestive heart failure, and its subsequent validation by administration to 50 consecutive patients in our heart failure outpatient clinic. The Italian LVD-36 was compared to the "The Minnesota Living with Heart Failure Questionnaire" (MLHF). Results: The Italian version of the LVD-36 correlates well with MLHF for ejection fraction (EF), NYHA class I and II, etiology and therapy. Since, however, the LVD-36 has only one domain, it may be able to offer more synthetic information than MLHF about patients' status. Conclusions: The Italian version of the LVD-36 appears to be a reliable instrument for assessing patients' QOL and the degree of limitations imposed on them by the disease. It is short, clear and easy to complete. In patients with heart failure the LVD-36 correlates well with the MLHF and may be considered a new disease- specific instrument to estimate changes in health status, and an useful support in optimizing therapeutic options

Training experts in inclusive practices for an equity on access to culture in Europe

Access to cultural content should be offered by several services available by default. If access services are thought, and budgeted, in the production phase, they are better integrated, and cultural content can be enjoyed by all patrons. How to integrate access services in the production of any cultural good relays on education. Until accessibility enters the syllabus in primary and secondary education curricula, and also in higher education, much work needs to be done. Until such a time when accessibility is normalized as a must-carry requirement, the work of experts in media accessibility will be needed to add accessibility in postproduction stages. The main focus of the chapter is training in postproduction accessibility. The enterprise is looked from many angles, but in all cases putting the end user at the center to understand their needs and expectations. To illustrate our approach to the subject, three European projects funded under the Erasmus + scheme will be used as examples: ACT (Accessible Culture and Training), ADLAB PRO (field of audio description), and ILSA (Interlingual Live Subtitling for Access

Carbidopa Alters Tryptophan Metabolism in Breast Cancer and Melanoma Cells Leading to the Formation of Indole-3-Acetonitrile, a Pro-Proliferative Metabolite

Carbidopa is used for the treatment of Parkinson's disease (PD) as an inhibitor of DOPA decarboxylase, and PD patients taking carbidopa have a lower incidence of various tumors, except for breast cancer and melanoma. Recently, it was shown that carbidopa inhibits tryptophan-2,3-dioxygenase (TDO) and kynureninase enzymes. In the present study, the effect of carbidopa on the viability and metabolic profile of breast cancer MCF-7 and melanoma A375 cells was investigated. Carbidopa was not effective in inhibiting MCF-7 and A375 proliferation. Liquid chromatography and mass spectrometry revealed a new compound, identified as indole-3-acetonitrile (IAN), which promoted a concentration-dependent increase in the viability of both cell lines. The results suggest that treatment with carbidopa may alter tryptophan (Trp) metabolism in breast cancer and melanoma leading to the formation of a pro-proliferative Trp metabolite, which may contribute to its failure in reducing breast cancers and melanoma incidence in PD patients taking carbidopa.This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT, in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274).” NV thanks FCT for IF position, Fundação Manuel António da Mota (FMAM, Portugal) for support. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT and FMAMinfo:eu-repo/semantics/publishedVersio

Europe’s Farm to Fork Strategy and Its Commitment to Biotechnology and Organic Farming: Conflicting or Complementary Goals?

The European Commission's Farm to Fork (F2F) strategy, under the European Green Deal, acknowledges that innovative techniques, including biotechnology, may play a role in increasing sustainability. At the same time, organic farming will be promoted, and at least 25% of the EU's agricultural land shall be under organic farming by 2030. How can both biotechnology and organic farming be developed and promoted simultaneously to contribute to achieving the Sustainable Development Goals (SDGs)? We illustrate that achieving the SDGs benefits from the inclusion of recent innovations in biotechnology in organic farming. This requires a change in the law. Otherwise, the planned increase of organic production in the F2F strategy may result in less sustainable, not more sustainable, food systems