Current Medicinal Chemistry - Volume 20, Issue 27, 2013

Estrogens play very important role in opening the transcription event, which is a final step of activation of the first order mediators as receptors or channels in the cell wall by information coming from the outside of the cell. For the long time the exact step by step mechanism of cellular transfer of information to the cell nuclei was not known. Currently many new informations are available. Very important seems the step of phosphorylation and therefore desensitization of the target proteins. All peptide kinases, especially serine and threonine, like protein kinases A and C, RAS and MAP kinases, cycline kinases are potential or confirmed biological targets. Except them elements of the transcription complexes like p160.SRC-1, histon acetyltransferase and histon deacetylase, CBP/p300, TRAP/DRIP, NSD1, PPARγ/PGC-1, NCOR1, SMRT, REA were also found useful. Finally estrogens are able to activate other receptors, namely aryl hydrocarbon receptors (AhR) and estrogen receptor related proteins (ERR). It is well known that many types of cancer are related to the direct or indirect excessive activation of nuclear estrogen receptors, therefore their inhibition could be crucial in many estrogen-related cancers. Understanding the interactions in such complexes would help in developing new and better multi-target cures and finding new ligands with better pharmacological and pharmacokinetic properties.

The present article attempts to provide, on the basis of data emerging from studies carried out in our laboratories, a summary of the chemical and pharmacological properties of the new compound N-[(4-trifluoromethyl)benzyl]4- methoxybutyramide (GET73). Particular emphasis is given to findings obtained in vivo and in vitro suggesting that an allosteric modulation of metabotropic glutamate receptor 5 (mGlu5 receptor) by GET73 may represent the mechanism underlying the effects of the compound produced on rat hippocampal glutamate and GABA transmission. Furthermore, behavioural findings demonstrating how this new compound reduces alcohol intake, displays anxiolytic properties, and influences spatial memory in rats are also summarized. Since mGlu5 receptors play an important role in regulating several central actions of drugs of abuse, and the hippocampus is a crucial brain area involved in addiction, anxiety, and spatial memory, a possible link between mGlu5 receptor allosteric modulation and the profiles of action of GET73 is proposed, although to date no studies have yet explored GET73 binding at the mGlu5 receptor orthosteric and/or allosteric sites. Following a brief overview of glutamatergic neurotransmission, mGlu receptor structures and activation mechanisms, the general properties of mGlu5 receptor and its allosteric modulators are described in the first part of the review.

Studies with breast cancer cells, showed that microRNAs (miRNAs) act as regulators of signaling pathways playing a key role in tumor progression and being targeted in chemotherapy. Deregulation of these pathways by altered miRNA expression or single nucleotide polymorphisms (SNPs) found in certain miRNA genes have been shown to lead tumor growth, metastasis, angiogenesis, and drug resistance. miRNAs have also been indicated to act on stem cell selfrenewal and alter signal transduction in cancer stem-like cells (CSC), which are resistant to many conventional therapies and account for the inability of these therapies to cure cancers. By considering these findings, miRNAs are proposed as potential novel biomarkers as well as therapeutic targets in new anti-cancer strategies. In this review, the miRNAs found to be involved in breast cancer chemoresistance will be covered together with breast CSC and their contribution to chemotherapy resistance.

Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease.

This review examines the biological role of oxidants and antioxidants continuously produced by all living cells. Physiologically, human beings, who have inherited good genes, used to eat moderately a healthy diet and exercised daily, both systems are equally important and essential in maintaining a normal long life. However, the aging process slowly leads to a disequilibrium that is accentuated in pathologies such as diabetes, cardiovascular, degenerative, pulmonary, infective diseases, and cancer. All of these diseases shorten the life span in about 80% of individuals and represent a huge social-economic problem for health authorities. Several factors such as excessive feeding, smoking, alcoholism, and a poor life-style conjure up to their realization. Their progress, initially promoted by some pathogens and a wrong life-style, is deeply accentuated by an excessive and deranged production of deadly oxidants no longer tameable by an inhibited control of the antioxidant defences. Effective orthodox drugs are able to slow down these ailments but they impoverish the quality of life because they cannot reactivate the innate ability to restore the complexity of the antioxidant system. Several potential approaches to renew this system have been discussed and their possible roles to reactivate a valid protection in at least some of the outlined pathologies. It is hoped to evaluate this integrated medical approach because it represents a sheet anchor for many patients.

Leptin is an adipokine with pleiotropic actions that regulates food intake, energy metabolism, inflammation and immunity, and also participates in the complex mechanism that regulates skeleton biology, both at bone and cartilage level. Leptin is increased in obesity and contributes to the “low-grade inflammatory state” of obese subjects causing a cluster of metabolic aberrations that affects joints and bone. In this review, we report the most recent research advances about the role of leptin in bone and cartilage function and its implication in inflammatory and degenerative joint diseases, such as osteoarthritis, rheumatoid arthritis and osteoporosis.