Current Medicinal Chemistry - Volume 22, Issue 25, 2015

Tumor necrosis factor (TNF, TNF-α, cachectin) is a pleiotropic, proinflammatory cytokine with multiple biological effects, many of which are not yet fully understood. Although TNF was initially described as an anti-tumor agent more than three decades ago, current knowledge places it central to immune system homeostasis. TNF plays a critical role in host defense against infection, as well as an inhibitory role in autoimmune disease. However, TNF overproduction generates deleterious effects by inducing the transcription of genes involved in acute and chronic inflammatory responses including asthma, rheumatoid arthritis, Crohn´s disease, and psoriasis. Direct inhibition of TNF by biologics, such as monoclonal antibodies and circulating TNF receptor constructs, has produced effective treatments for these disorders and validated the inhibition of this proinflammatory cytokine as an effective therapy. Unfortunately, these biological therapies suffer from several drawbacks, including high cost and the induction of autoantibody production. Thus, the development of small molecules able to modulate TNF production or signaling pathways remains a central challenge in Medicinal Chemistry. Considerable efforts have been made over the past two decades to develop such inhibitors, which could potentially be administered orally and would presumably be cheaper. This review is focused on the recent development of compounds that modulate the activity of this cytokine by acting at different levels, such as TNF expression, processing, binding to its receptors and direct inhibition. These approaches will be compared and discussed.

Melastatin-related Transient Receptor Potential 6 and 7 (TRPM6 and TRPM7) are cation channels with the almost unique trait of each possessing a kinase domain in its C terminus. Both the transmembrane pore and kinase are functional, and have been characterized experimentally, but whether one domain regulates the function of the other, or vice versa has remained largely unsettled. These proteins play important physiological roles in magnesium homeostasis and other cellular processes such as cell death, proliferation, differentiation and migration, and are consequently associated with several types of pathologies. Recently, studies performed in mice expressing a TRPM7 kinase-dead mutant suggest that the enzyme may function as part of a Mg2+ sensor and transducer of signaling pathways during stressful environmental conditions. Additionally, it has been shown that TRPM7's kinase can act on its own in chromatin remodeling processes. Thus, the recent work in this field has provided new insights into the function of these interesting proteins and how they might be involved in human disease.

The increasing prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) worldwide is becoming a challenge for the modern global care system. The lipotoxic process is characterized by an oxidative stress followed by a burst of the inflammatory response, prompting the wound healing process (fibrosis), which can ultimately lead to the development of cirrhosis and the subsequent complications. There is no consensus concerning an effective pharmacological treatment. Therefore, there is a need for effective therapeutic compounds. Silibinin the major active compound of Milk Thistle may be a potential candidate mainly due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties. In spite of the large number of data obtained in experimental models, the translation of the evidence in clinical setting is far to be conclusive. The aim of this paper is to critically review the aspects of the use of the different formulations of Silibinin in several experimental and clinical settings and to provide hints on the needed future studies.

Research on dopamine (DA) and its receptors, and in particular the D2 receptor subclass, has been an intriguing and fast developing scientific field in the past 35 years. Methods of medicinal chemistry, molecular and structural biology as well as computational chemistry were used in the studies of DA receptors (DRs). Early attempts to describe DRs were based on a small amount of experimental data available and produced crude models at best. Once crystal structures of bacteriorhodopsin, rhodopsine, various G-protein coupled receptors, and finally D3 DR receptor became available, better and more detailed D2 DR receptor models emerged. These models gave us an insight into the mechanism of ligand-receptor interactions, and paved the way for the synthesis of new dopaminergic compounds, both agonists and antagonists and possible drugs for the treatment of different imbalances of the dopaminergic system. This review covers the key discoveries on the path to the creation of the D2 DR receptor model.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is one of the most common chronic liver diseases, which may progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD is characterized by the accumulation of lipids in the liver arising from multiple factors: increased fatty acid uptake, increased de novo lipogenesis, reduced fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Most therapeutic approaches for this disease are often directed at reducing body mass index and improving insulin resistance through lifestyle modifications, bariatric surgery and pharmacological treatments. Nevertheless, there is increasing evidence that the use of natural compounds, as polyphenols, exert multiple benefits on the disorders associated with NAFLD. These molecules seem to be able to regulate the expression of genes mainly involved in de novo lipogenesis and fatty acid oxidation, which contributes to their lipid-lowering effect in the liver. Their antioxidant, anti-inflammatory, antifibrogenic and antilipogenic properties seem to confer on them a great potential as strategy for preventing NAFLD progression. In this review, we summarized the effects of these compounds, especially flavonoids, and their mechanisms of action, that have been reported in several studies carried out in in vitro and in vivo models of NAFLD.