Current Medicinal Chemistry - Volume 23, Issue 26, 2016

The microglia, once thought only to be supporting cells of the central nervous system (CNS), are now recognized to play essential roles in many pathologies. Many studies within the last decades indicated that the neuro-immune interaction underlies the generation and maintenance of neuropathic pain. Through a large number of receptors and signaling pathways, the microglial cells communicate with neurons, astrocytes and other cells, including those of the immune system. A disturbance or loss of CNS homeostasis causes rapid responses of the microglia, which undergo a multistage activation process. The activated microglia change their cell shapes and gene expression profiles, which induce proliferation, migration, and the production of pro- or antinociceptive factors. The cells release a large number of mediators that can act in a manner detrimental or beneficial to the surrounding cells and can indirectly alter the nociceptive signals. This review discusses the most important microglial intracellular signaling cascades (MAPKs, NF-ΚB, JAK/STAT, PI3K/Akt) that are essential for neuropathic pain development and maintenance. Our objective was to identify new molecular targets that may result in the development of powerful tools to control the signaling associated with neuropathic pain.

Background: Increased consumer´s interest in health has driven the development of foods that offer specific beneficial effects. The list of foods and ingredients includes essential and non-essential nutrients, plant and marine components, whole foods, microorganisms, microalgae and technological approaches. Traditionally, health outcomes focussed on the prevention of chronic diseases but health targets have expanded to cover areas such as brain health, inflammation, eye health, women´s health, healthy ageing and beauty. Objective: This review highlights, from a nutritional biochemistry perspective, differential aspects on designing and interpreting human studies to support the health effects of functional foods. Results: Despite the available evidence from in vitro, animal and observational studies, welldesigned human studies are necessary to support the health effects of functional foods. Intervention trials with foods are complex as they imply limitations due to methodological, food-related and host-related factors. The use of responsive, validated and clinically relevant markers becomes essential even though there is a lack of reliable biomarkers of exposure for many bioactives. Furthermore, the effect of modulating factors such as subclinical inflammation, gut microbiota and genetic variability should be taken into account. Multiple indicators may provide a more reliable alternative to assess physiological processes while emerging biomarkers (microRNAs, epigenetic changes) constitute a promising approach. Additionally, the magnitude of the change is critical to support any health effect although interventions may have a limited clinical impact but be epidemiologically relevant. Also, based on the available data, the premise that bioactivescontaining foods are safe may be questionable. Conclusion: An integrated approach including multiple biomarkers, genetic variability, effect of gut microbiota and risk/benefit assessment should be used to support the potential health effects of functional foods.

Background: Atherosclerosis, a chronic inflammatory disease of the blood vessel wall, is the most common cause of cardiovascular pathologies. Hyaluronan, the major polysaccharide involved in this process, plays a pivotal role acting as a modulator of all inflammatory stages, affecting the behavior of both endothelial and smooth muscle cells. Objective: The inflammatory condition is the main reason of the increased deposition of extracellular matrix, that in turn, traps lipoproteins and inflammatory/growth factors from the circulation within the vessel wall and thicken the arterial wall. Therefore, this chronic condition that continuously affects the arterial walls in a specific area causes a severe remodeling of the tissue architecture and a drastic change in the resident cell behavior. Methods: Because of the great complexity of the extracellular matrix in the arterial wall, we investigate the modification in the different layers of the vessels with a particular attention to hyaluronan and proteoglycans and to the events that affects their normal turnover. Results: Hyaluronan, the major polysaccharide involved in this process, plays a pivotal role acting as a modulator of all inflammatory stages, affecting the behavior of both endothelial and smooth muscle cells. Moreover, glycosaminoglycans and proteoglycans had been shown to change during the lesion progression, and to possess the chemical features essential for lipid retention, immune system activation, smooth cells proliferation and macrophages recruitment. Conclusion: The ECM characteristics should be investigated in order to understand their prevention potentials as well as their negative impact on the onset of the disease.

Phenoxazines are an important class of heterocycles, which are emerging in the field of medicinal chemistry. They exhibit numerous biological activities, including antiviral, anticancer, anti-Alzheimer, antidiabetic, antioxidant, anti-inflammatory, antibiotic and many more. The present review focuses on the chemistry along with the medicinal applications of the phenoxazine moiety, in order to provide a greater insight for the development of future phenoxazine therapeutics.

An innovative approach to analyze the complexity of translating novel molecular entities and nanomaterials into pharmaceutical alternatives (i.e., knowledge translation, KT) is discussed. First, some key concepts on the organization and translation of the biomedical knowledge (paradigms, homophily, power law distributions, hierarchy, modularity, and research fronts) are reviewed. Then, we propose a model for the knowledge translation (KT) in Drug Discovery that considers the complexity of interdisciplinary communication. Specifically, we address two highly relevant aspects: 1) A successful KT requires the emergence of organized bodies of inter-and transdisciplinary research, and 2) The hierarchical and modular topological organization of these bodies of knowledge. We focused on a set of previously-published studies on KT which rely on a combination of network analysis and computer-assisted analysis of the contents of scientific literature and patents. The selected studies provide a duo of complementary perspectives: the demand of knowledge (cervical cancer and Ebola hemorrhagic fever) and the supply of knowledge (liposomes and nanoparticles to treat cancer and the paradigmatic Doxil, the first nano- drug to be approved).