Current Medicinal Chemistry - Volume 21, Issue 24, 2014

Alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Cancer cells esterify fatty acids predominantly to phospholipids, an essential component of cell membranes. The main pathway along which proliferating cells gain lipids for membrane synthesis is the endogenous mevalonate pathway. Increased synthesis of mevalonate and mevalonate-derived isoprenoids supports increased cell proliferation through activating growthregulatory proteins and oncoproteins and promoting DNA synthesis. The importance of a better knowledge of metabolic changes in lipogenic enzymes pathways, as well as of the role of each biochemical pathway in carcinogenesis, provides the rationale for in-depth study of the oncogenic signaling important for the initiation and progression of tumors. The dependence of tumor cells on a dysregulated lipid metabolism suggests that the proteins involved in this process may be excellent chemotherapeutic targets for cancer treatment. Here, we confirm the vital link between lipogenesis and cell proliferation, and our recent findings suggest that nutritional intervention is an effective and safe way to reduce cell proliferation in experimental models of carcinogenesis. The olive oil diet significantly reduces the protein activities of lipogenic enzymes associated with cell growth. The use of natural dietary components could potentially assist in the management of subjects with metabolic disorders-related tumors.

Natural selection clearly favors the accumulation and storage of lipids in humans, predisposing women to store excess fat in gluteal regions and predisposing males to store excess fat in visceral regions. In addition, gender differences are reported with respect to the concentrations of circulating lipids and lipoproteins, with lower concentrations of total cholesterol and low density lipoprotein (LDL)-cholesterol in premenopausal women than in men. This latter evidence renders gender differences in fat distribution and whole-body lipid metabolism of particular interest with respect to the incidence and prevalence of human diseases. Although the mechanisms underlying gender-related differences in body fat distribution and lipid homeostasis remain to be fully determined, the reported differences appear to principally reflect the actions of the sex steroid hormone estrogen on whole-body lipid metabolism. In the present review, we dissect the role played by 17β-estradiol, the most active between estrogens, and by its receptors in regulating lipid homeostasis in adipose tissue, liver, and brain, evaluating the potential impact of this hormone in preventing lipid abnormalities.

In multi-target drug design (MTD) medicinal chemistry aims to integrate multiple pharmacophores into a single drug molecule in order to make it active on several molecular biological mechanisms simultaneously. Given the fact that most diseases are multifactorial in nature, MTD is being pursued with increasing intensity, which has resulted in improved outcomes in disease models and several compounds have entered clinical trials. In a wide range of examples we illustrate how various functionalities have been combined within single structures and how this has affected their (pre)clinical outcome. This review describes the successful application of MTD for disorders such as neurodegenerative, cardiovascular, diabetes, metabolic and inflammatory diseases, especially focusing on the field of atherosclerosis where multi-target strategies are a promising alternative to the classical “one target-one drug” design approach.

Cholesterol is one of the most important molecules in cell physiology because of its involvement in several biological processes: for instance, it determines both physical and biochemical properties of cell membranes and proteins. Disruption to cholesterol homeostasis leads to coronary heart disease, atherosclerosis and metabolic syndrome. Strong evidence suggests that cholesterol also has a crucial role in the brain as various neurological and neurodegenerative disorders, including Alzheimer’s, Huntington’s and Parkinson diseases are associated with disruptions to cholesterol homeostasis. Here, we summarize the current knowledge about the role cholesterol plays at synaptic junctions and the pathological consequences caused by disruptions in the homeostatic maintenance of this compound.

Signalling lipids are known to control a wide array of cellular processes, including cell proliferation, apoptosis, migration, and energy metabolism. Fatty acids and their derivatives, eicosanoids, phosphoinositides, sphingolipids, some cannabinoid-like molecules bind and activate nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). This subfamily of transcription factors comprises three isotypes - PPARα (NR1C1), PPAR β/δ (NR1C2), PPARγ (NR1C3) - which bind to specific DNA response elements, as heterodimers with retinoid X receptors. PPAR activity is modulated by post-translational modifications and cofactors, towards which they show differential affinity. The three PPARs mutually interact, being integrated in a complex system, leading to the concept of a "PPAR triad". Nevertheless, the isotypes also show distinct actions on cellular physiology and partially different tissue, ligand and target gene specificities. In the brain, while the functions of PPARγ and its ligands are being thoroughly investigated, the actual and potential roles of PPARα and β/δ are far from being clarified. PPARα appears especially intriguing, since it is selectively expressed in certain brain areas and neuronal/glial populations, and modulates antioxidant responses, neurotransmission, neuroinflammation, neurogenesis, and glial cell proliferation/differentiation. This receptor and its endogenous ligands, including oleoylethanoloamide (OEA) and palmitoylethanolamide (PEA), are involved in physiological and pathological responses, such as satiety, memory consolidation, and modulation of pain perception. The protective role of PPARα agonists in neurodegenerative diseases and in neuropsychiatric disorders makes manipulation of this pathway highly attractive as therapeutic strategy for neuropathological conditions. In this review, we focus on the pleiotropic functions of PPARα and its lipid ligands in the nervous tissue, devoting special attention to neuroprotection.

In the last decade, it became clear that bile acids, in addition to their role in intestinal absorption of lipids and fat-soluble vitamins, are major regulators of metabolism. They activate signal transduction pathways through binding to the specific bile acid receptors TGR5 and FXR. Indirectly, bile acids influence metabolism via modification of the gut microbiota ecosystem. The relation between bile acid metabolism and gut microbiota composition is very complex whereas gut microbiota modulates bile acid structure, creating a complex bile acid pool consisting of a mixture of differentially structured species, bile acids alter gut microbiota by disturbing bacterial membrane integrity. In addition, to the effects on glucose and energy homeostasis, recent literature ascribed a role for bile acid signaling in control of inflammation and regulation of the nervous system. In this review, we discuss a selection of recent published studies describing the effects of intestinal bile acid signaling on health and disease.

Interest in Central Nervous System (CNS) inflammation has rapidly grown over the past decade driven by the increasing evidence indicating that chronic inflammation and neuroinflammation in the brain may play an important role in the progressive neuronal cell death in many chronic CNS diseases, such as Alzheimer and Parkinson’s diseases, traumatic brain injury, spinal cord injury (SCI), as well as pathologies associated with CNS infections. In peripheral tissues, generally inflammation has a protective role limiting the survival and proliferation of invading pathogens, promoting tissue repair and recovery. This innate response normally resolves over a few weeks, accompanyied by tissue repair aided by macrophages recruited to the site. However, when the inflammatory response does not undergo resolution, it might turn into chronic inflammation. Any chronic inflammatory process can damage healthy tissue and the brain may be particularly vulnerable, since destroyed neurons can not be replaced. Recently, several reports have suggested that phosphodiesterases (PDEs) are new targets for central nervous system (CNS) diseases. All the PDEs are expressed in the CNS, making this gene family a particularly attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders. Significantly, all neurons express multiple PDEs, which differ in cyclic nucleotide specificity, affinity, regulatory control and subcellular compartmentalization. Therefore, PDEs inhibition represents a mechanism through which it could be possible to precisely modulate neuronal activity. In this article, we review the current state of art of PDEs in the CNS diseases associated with neuroinflammation.

Synthesis and research of pharmacological properties of polyfunctional “hybrid” compounds containing fragments of nitroxyl radicals (NR) in a molecule (spin-labeled conjugates) is a rapidly developing area of medicinal chemistry. Many examples of various classes of natural compounds have shown that the introduction of nitroxyl fragment into a molecule leads to either strengthening of biological activity or its modification, decrease of general toxicity, or increase of selective cytotoxicity. The review of the published data on spin-labeled biologically active natural compounds has revealed that various classes of natural compounds, such as anthracycline antibiotics, lignans, triterpene acids, chromanes, flavonoids, stilbenoids, alkaloids, amino acids, etc. are used for obtaining conjugates with nitroxyl radicals. Some spinlabeled derivatives of natural compounds are used for the treatment and prevention of the most dangerous diseases. Conjugates of nitroxyl radicals with “molecular compasses” (e.g. folic acid, fragments of gramicidin, heparin) may well serve as drug delivery systems to pathological areas of a body for diagnostics and treatment of diseases. We have summarized the results of the last decade on the synthesis and study of biological activity of conjugates with nitroxyl radicals.