Current Medicinal Chemistry - Volume 21, Issue 32, 2014

In 2003 Wang described for the first time the properties of the H2S as a gasotransmitter. It is now well established that H2S exerts beneficial effect on the cardiovascular system including cardioprotection, regulation of the blood pressure and overall antioxidant effects on heart and vessels. In this issue Altaany reviews recent literature about H2S and endothelial dysfunction focusing on the interplay with nitric oxide, the most renown of three gasotransmitters. Endogenous H2S is produced by at least two enzymes involved in the metabolism of cysteine. In his contribution, Pushpakumar describes how hyperhomocysteinemia is related with increased risk for vascular disease based on endothelial dysfunction and emphasizing on the physiological role of H2S as a protective agent. It is known that the endothelial cells in physiological conditions account for the reduced glutathione pool and this molecule reacts with NO activating soluble guanylate cyclase. Bioavailability of reduced compounds, such as sulfur bound hydrogen, represents a redox-state balancing buffer. Depletion of such a buffer leads to a shift toward an oxidative intracellular environment. One of the inevitable effects of this pro-oxidative mechanism is aging. Along with aging, several pathological conditions (i.e. inflammation, obesity, diabetes mellitus, metabolic syndrome, etc.) contribute to the impaired ability of hydrogen to maintain the normal redox state. As suggested by the contributions of Masha and Park, thiols administration is able to restore the hydrogen capacity of modulating ox-reductive balance and to partially reverse the above mentioned pathological conditions. This effect is peculiar of thiols that are the only antioxidant able to reverse the endothelial dysfunction after the onset of the pathology while other antioxidants are effective only in primary prevention. The current issue, with different contribution, points to the opportunity to establish clinical trials based on the administration of thiols for the treatment of endothelial dysfunction.

Several metabolic diseases present a high cardiovascular mortality due to endothelial dysfunction consequences. In the last years of the past century, it has come to light that the endothelial cells, previously considered as inert in what regards an eventual secretion activity, play a pivotal role in regulating different aspects of the vascular function (endothelial function). It was clearly demonstrated that the endothelium acts as a real active organ, owning endocrine, paracrine and autocrine modulation activities by means of which it is able to regulate the vascular homeostasis. The present review will investigate the relationship between some metabolic diseases and the endothelial dysfunction and in particular the mechanisms underlying the effects of metabolic pathologies on the endothelium. Furthermore, it will consider the possible therapeutic employment of the N-acetilcysteine in such conditions.

Reactive oxygen species and reactive nitrogen species promote endothelial dysfunction in old ageand contribute to the development of cardiovascular diseases such as atherosclerosis, diabetes, and hypertension. α-lipoic acid was identified as a catalytic agent for oxidative decarboxylation of pyruvate and α-ketoglutarate in 1951, and it has been studied intensively by chemists, biologists, and clinicians who have been interested in its role in energetic metabolism and protection from reactive oxygen species-induced mitochondrial dysfunction. Consequently, many biological effects of α- lipoic acid supplementation can be attributed to the potent antioxidant properties of α-lipoic acid and dihydro α-lipoic acid. The reducing environments inside the cell help to protect from oxidative damage and the reduction-oxidation status of α-lipoic acid is dependent upon the degree to which the cellular components are found in the oxidized state. Although healthy young humans can synthesize enough α-lipoic acid to scavenge reactive oxygen species and enhance endogenous antioxidants like glutathione and vitamins C and E, the level of α-lipoic acid significantly declines with age and this may lead to endothelial dysfunction. Furthermore, many studies have reported α-lipoic acid can regulate the transcription of genes associated with anti-oxidant and anti-inflammatory pathways. In this review, we will discuss recent clinical studies that have investigated the beneficial effects of α-lipoic acid on endothelial dysfunction and propose possible mechanisms involved.

The endothelium is a cellular monolayer that lines the inner surface of blood vessels and plays a central role in the maintenance of cardiovascular homeostasis by controlling platelet aggregation, vascular tone, blood fluidity and fibrinolysis, adhesion and transmigration of inflammatory cells, and angiogenesis. Endothelial dysfunctions are associated with various cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and cardiovascular complications of diabetes. Numerous studies have established the anti-inflammatory, anti-apoptotic, and anti-oxidant effects of hydrogen sulfide (H2S), the latest member to join the gasotransmitter family along with nitric oxide and carbon monoxide, on vascular endothelium. In addition, H2S may prime endothelial cells (ECs) toward angiogenesis and contribute to wound healing, besides to its well-known ability to relax vascular smooth muscle cells (VSMCs), and thereby reducing blood pressure. Finally, H2S may inhibit VSMC proliferation and platelet aggregation. Consistently, a deficit in H2S homeostasis is involved in the pathogenesis of atherosclerosis and of hyperglycaemic endothelial injury. Therefore, the application of H2S-releasing drugs or using gene therapy to increase endogenous H2S level may help restore endothelial function and antagonize the progression of cardiovascular diseases. The present article reviews recent studies on the role of H2S in endothelial homeostasis, under both physiological and pathological conditions, and its putative therapeutic applications.

High level of homocysteine (hyperhomocysteinemia, HHcy) is associated with increased risk for vascular disease. Evidence for this emerges from epidemiological studies which show that HHcy is associated with premature peripheral, coronary artery and cerebrovascular disease independent of other risk factors. Possible mechanisms by which homocysteine causes vascular injury include endothelial injury, DNA dysfunction, proliferation of smooth muscle cells, increased oxidative stress, reduced activity of glutathione peroxidase and promoting inflammation. HHcy has been shown to cause direct damage to endothelial cells both in vitro and in vivo. Clinically, this manifests as impaired flow-mediated vasodilation and is mainly due to a reduction in nitric oxide synthesis and bioavailability. The effect of impaired nitric oxide release can in turn trigger and potentiate atherothrombogenesis and oxidative stress. Endothelial damage is a crucial aspect of atherosclerosis and precedes overt manifestation of disease. In addition, endothelial dysfunction is also associated with hypertension, diabetes, ischemia reperfusion injury and neurodegenerative diseases. Homocysteine is a precursor of hydrogen sulfide (H2S) which is formed by transulfuration process catalyzed by the enzymes, cystathionine β- synthase and cystathionine γ-lyase. H2S is a gasotransmitter that has emerged recently as a novel mediator in cardiovascular homeostasis. As a potent vasodilator, it plays several roles which include regulation of vessel diameter, protection of endothelium from redox stress, ischemia reperfusion injury and chronic inflammation. However, the precise mechanism by which it mediates these beneficial effects is complex and still remains unclear. Current evidence indicates H2S modulates cellular functions by a variety of intracellular signaling processes. In this review, we summarize the mechanisms of HHcy-induced endothelial dysfunction and the metabolism and physiological functions of H2S as a protective agent.

Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, corticosteroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, inobvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers.

Differentiated thyroid cancer is a rare malignancy, but leaves numerous survivors for life-long follow-up. The cornerstone in current guidelines for follow-up is by measuring the thyroid specific tumour marker, thyroglobulin in serum. Most patients can be followed by this method, but some thyroid cancer patients have antithyroglobulin antibodies in serum, both at diagnosis and after treatment, where follow-up is commenced. These antibodies interfere technically in the immunological methods for measuring thyroglobulin, and the antithyroglobulin antibody positive patients are thus eliminated from following current guidelines. In recent years studies have indicated that following the concentration of antithyroglobulin antibodies in serum may be a surrogate marker for recurrence of the thyroid carcinoma. This has recently resulted in publication of an expert position paper, providing a flow scheme for these particular patients. The current review summarises the literature which is the basis for the paper.

The search for cheap, easy-to-use and effective spermicides and microbicides to help avoid unwanted pregnancies and the transmission of sexually transmitted diseases has been ongoing for many years. This review takes into account compounds designed to act both as microbicides and spermicides for multipurpose prevention, and focuses on the required methodological studies to evaluate their safety, especially cytotoxicity. A comprehensive literature review was conducted on the synthesis, development, advantages and disadvantages of vaginal multi-function compounds. The available data shows that after several setbacks, there is a current interest in the synthesis and in the activity of novel dualfunction substances.. The study of well-known compounds with distinctive mechanisms of action provides a solid starting point to explore the possible development of such strategies. However, a completely safe and efficient compound for commercialization has yet to be identified.

Malignant melanoma is one of the most common causes of cancer and cancer deaths in young people. Until few years ago, scarce drugs have proven efficacy in metastatic setting. However, in the recent years, the treatment of metastatic malignant melanoma has undergone the incorporation of effective treatment such as immunotherapy, the use of tyrosine kinase inhibitors and the emergence of other cytostatic compounds, like the nanoparticles. This review aims to propose a standardization to classify the different types of nanoparticles, according to chemical aspects, and update the clinical research with nanoparticles and their use in melanoma field.

Due to an oversight on the part of the authors in Current Medicinal Chemistry, 2013, 20(1), 144-157 of article entitled “Increased Akt signaling resulting from the loss of androgen responsiveness in prostate cancer” by Dulinska-Litewka J, McCubrey JA and Laidler P, one slip-up was encountered. The project number assigned by the Commission to research UJCM was unfortunately not written completely. To close accounting on this project on each of the presented abstracts from International Meeting - Conferences, publications and chapters in books, the number assigned by the NCN must be given. The number which was published was K/PBW/ 000561 but it should have been K/PBW/ 000561 - N N401 125638 (1256/B/P01/2010/38). The correct acknowledgement section of my manuscript should be as follows: