Current Medicinal Chemistry - Volume 23, Issue 11, 2016

The current lifestyle of “western societies” is based on excessive consumption of high-energy diets and physical inactivity. Such behavior has pressured biological systems towards the development of metabolic diseases. This increased incidence of metabolic disorders is also accompanied by a decline in male reproductive health, particularly among young males. Male fertility is sensitive to metabolic dysfunctions, such as diabetes mellitus, which disrupt the link between energy metabolism and reproduction. Evidences showed that compromised sperm parameters induced by diabetes are associated with impaired testicular metabolism, suggesting that deficient testicular bioenergetics contributes to a decline in spermatogenesis. Energy metabolism is a well-coordinated process that involves a network of carbohydrate, lipid and protein metabolic pathways. This intricate process is an act of balance between mitochondria and nucleus, governed by metabolic sensors, such as sirtuins. The emerging role of sirtuins in the control of metabolism has been highlighted, specially in cancer metabolism. Little attention has been given to their role in non-cancerous cells that exhibit a “Warburg-like metabolism”, such as Sertoli cells. Spermatogenesis is highly dependent on glycolytic metabolism, since the lactate produced by Sertoli cells is the major substrate of germ cells. The regulation of sirtuins in the glycolytic metabolism not only increases their physiological relevance to the testicular environment, but also suggests that these proteins may control male fertility. This review will discuss the recent findings in the role of sirtuins in testicular metabolism and will address the concept that sirtuins can be a potential target to counteract subfertility/infertility promoted by diabetes mellitus.

Antimitotics binding at the colchicine site of tubulin are important antitumour and vascular disrupting agents. Pyridines and azines are privileged scaffolds in medicinal chemistry and in recent years many colchicine site ligands (CSL) have incorporated them into their structures with the aim of improving their pharmacokinetic and pharmacodynamics properties. CSL have been classified according to their chemical structures and the chemical structures of the pyridine and azine containing antimitotic compounds are described. The designed principles behind the structural modifications and the achieved effect on the biological activity upon inclusion of these heterocycles are also discussed. Lessons from the achievements and failures have been extracted and future perspectives delineated.

The arachidonic acid metabolizing enzymes, cyclooxygenase-2 (COX-2) and 5- lipoxygenase (5-LOX), are both highly expressed during the carcinogenesis in colons. Cigarette smoking promotes these carcinogenic processes at the early stage during adenoma formation. In this article, the involvement of COX-2 and 5-LOX, alongside with the dual COX/5-LOX inhibitors in colorectal cancer development is introduced. The co-regulation of 5-LOX and COX-2 in colon cancer growth and its relationship with cigarette smoke and hyaluronic acid-CD44v6 is also described. It is envisaged that dual inhibition of 5-LOX/COX could be the most promising therapeutic option for the treatment of colorectal cancer in humans.

Osteoarthritis is a disabling affliction expected to increase in the coming decades, and disease- modifying osteoarthritis drugs (DMOADs) would be highly desirable adjuncts to symptomatic relief and structure reconstruction as they may delay the disease process. Chondroitin sulfate and glucosamine have been observed to exert beneficial effects on the metabolism of various cells involved in osteoarthritis as well as in animal models and clinical trials. Clinical trials have reported beneficial effects of both these biological agents, alone or in combination, on pain and functions as well as their structure-modifying capacity reported and analyzed in recent meta-analyses. Nonetheless, the effectiveness of these bioactive (macro)molecules as DMOADs reported from randomized trials is mismatched. Current studies with varying levels of evidence suggest that chondroitin sulfate and glucosamine can modify the disease progression but at the same time there are not absolute certainties on their efficacy in modifying the course of the disease. This comprehensive review aims to clarify the role of these compounds in the therapeutic molecules/ drugs useful to patients affected by osteoarthritis.

Multiple sclerosis (MS) is the most prevalent autoimmune disease affecting the central nervous system (CNS). Its pathophysiology is centered on neuron myelin sheath destruction in a manner largely dependent upon CD4+/CD8+ T-cell autoreactivity against myelin antigens, inducing Th1/Th17 pathogenic responses with the resulting production of free radicals and soluble mediators that exhibit the effector mechanisms of neurodegeneration. The immune response responsible for this disease is complex and challenges modern medicine. Consequently, many experimental therapies have been proposed in addition to the classical array of immunoregulatory/ immunosuppressive drugs that are normally used to treat MS. In this review, we will describe the effects and mechanisms of action of widely used disease-modifying MS drugs as well as those of select treatments that are currently in the experimental phase. Special emphasis is placed on helminth-derived immunoregulators, as some of them have shown promising results. Additionally, we will compare the mechanisms of action of both the MS drugs and the helminth-derived treatments to discuss the potential importance of some signaling pathways in the control of MS.

Background: Verteporfin is a porphyrinic photosensitizer clinically used for the photodynamic treatment of age-related macular degeneration. It has been identified almost simultaneously as a YAP/TEAD and an autophagosome inhibitor. Over the last few years, YAP (TAZ), the downstream effectors of the Hippo pathway, have emerged as promising anticancer targets, as shown by several experimental lines of evidence, showing the overproduction of YAP in several cancers. However, YAP was also found to be closely connected to autophagy, mitochondria and reactive oxygen/nitrogen species. We herein, review the recent studies where VP was used without photoactivation as a YAP/TEAD inhibitor or protein oligomerization promoter, focusing on its effects on the YAP/TEAD gene targets and other biomarkers related to autophagy. Results: Since the identification of VP as YAP/TEAD inhibitor, several in vitro and in vivo studies have revealed the new potential of this molecule in different cancers, where YAP is overexpressed. However, detailed structural information about its interaction with YAP is still lacking. Concomitantly, VP was identified as autophagosome inhibitor by promoting oligomerization of p62. Moreover, VP proves to be tumor-selective proteotoxic (by oligomerization of p62, STAT3) in colorectal cancer. Knowledge on the biological properties of the only YAP inhibitor available to date is vital for its pharmacological use on cellular and animal models. Conclusion: VP is a multi-target drug interacting with several proteins implicated in major cellular processes. Although this does not impact its clinical use, VP does not seem to be the ideal drug for pharmacological inhibitions of YAP/TEAD.