Current Medicinal Chemistry (v.21, #32)

In 2003 Wang described for the first time the properties of the H2S as a gasotransmitter. It is now well established that H2Sexerts beneficial effect on the cardiovascular system including cardioprotection, regulation of the blood pressure and overallantioxidant effects on heart and vessels.In this issue Altaany reviews recent literature about H2S and endothelial dysfunction focusing on the interplay with nitricoxide, the most renown of three gasotransmitters.Endogenous H2S is produced by at least two enzymes involved in the metabolism of cysteine. In his contribution, Pushpakumardescribes how hyperhomocysteinemia is related with increased risk for vascular disease based on endothelial dysfunctionand 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 moleculereacts 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 ofmodulating 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 thepathology 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 administrationof 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 inertin 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 presentreview will investigate the relationship between some metabolic diseases and the endothelial dysfunction and in particularthe mechanisms underlying the effects of metabolic pathologies on the endothelium. Furthermore, it will considerthe possible therapeutic employment of the N-acetilcysteine in such conditions.

Physiological Effect and Therapeutic Application of Alpha Lipoic Acid by Sungmi Park, Udayakumar Karunakaran, Nam Ho Jeoung, Jae-Han Jeon, In-Kyu Lee (3636-3645).
Reactive oxygen species and reactive nitrogen species promote endothelial dysfunction in old ageand contributeto the development of cardiovascular diseases such as atherosclerosis, diabetes, and hypertension. α-lipoic acid wasidentified as a catalytic agent for oxidative decarboxylation of pyruvate and α-ketoglutarate in 1951, and it has been studiedintensively by chemists, biologists, and clinicians who have been interested in its role in energetic metabolism andprotection 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-lipoicacid. The reducing environments inside the cell help to protect from oxidative damage and the reduction-oxidation statusof α-lipoic acid is dependent upon the degree to which the cellular components are found in the oxidized state. Althoughhealthy young humans can synthesize enough α-lipoic acid to scavenge reactive oxygen species and enhance endogenousantioxidants like glutathione and vitamins C and E, the level of α-lipoic acid significantly declines with age and this maylead to endothelial dysfunction. Furthermore, many studies have reported α-lipoic acid can regulate the transcription ofgenes associated with anti-oxidant and anti-inflammatory pathways. In this review, we will discuss recent clinical studiesthat have investigated the beneficial effects of α-lipoic acid on endothelial dysfunction and propose possible mechanismsinvolved.

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide by Zaid Altaany, Francesco Moccia, Luca Munaron, Daniele Mancardi, Rui Wang (3646-3661).
The endothelium is a cellular monolayer that lines the inner surface of blood vessels and plays a central role inthe 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 associatedwith various cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and cardiovascularcomplications of diabetes. Numerous studies have established the anti-inflammatory, anti-apoptotic, and anti-oxidant effectsof hydrogen sulfide (H2S), the latest member to join the gasotransmitter family along with nitric oxide and carbonmonoxide, on vascular endothelium. In addition, H2S may prime endothelial cells (ECs) toward angiogenesis and contributeto wound healing, besides to its well-known ability to relax vascular smooth muscle cells (VSMCs), and thereby reducingblood pressure. Finally, H2S may inhibit VSMC proliferation and platelet aggregation. Consistently, a deficit inH2S 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 endothelialfunction and antagonize the progression of cardiovascular diseases. The present article reviews recent studies on therole of H2S in endothelial homeostasis, under both physiological and pathological conditions, and its putative therapeuticapplications.

Endothelial Dysfunction: The Link Between Homocysteine and Hydrogen Sulfide by Sathnur Pushpakumar, Sourav Kundu, Utpal Sen (3662-3672).
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 homocysteinecauses vascular injury include endothelial injury, DNA dysfunction, proliferation of smooth muscle cells, increasedoxidative stress, reduced activity of glutathione peroxidase and promoting inflammation. HHcy has been shown tocause direct damage to endothelial cells both in vitro and in vivo. Clinically, this manifests as impaired flow-mediatedvasodilation and is mainly due to a reduction in nitric oxide synthesis and bioavailability. The effect of impaired nitric oxiderelease can in turn trigger and potentiate atherothrombogenesis and oxidative stress. Endothelial damage is a crucialaspect of atherosclerosis and precedes overt manifestation of disease. In addition, endothelial dysfunction is also associatedwith hypertension, diabetes, ischemia reperfusion injury and neurodegenerative diseases. Homocysteine is a precursorof 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 cardiovascularhomeostasis. As a potent vasodilator, it plays several roles which include regulation of vessel diameter, protection ofendothelium from redox stress, ischemia reperfusion injury and chronic inflammation. However, the precise mechanismby which it mediates these beneficial effects is complex and still remains unclear. Current evidence indicates H2S modulatescellular functions by a variety of intracellular signaling processes. In this review, we summarize the mechanisms ofHHcy-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 potencyof aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventingtachyphylaxis 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 thatis manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggestingthat the common structural motif is reflected in common binding targets. Second, one common target is the firstextracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observationssuggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinitystate, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptorstructure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. Themechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictionsabout additional compounds that should act as aminergic enhancers.

Thyroglobulin Autoantibodies as Surrogate Biomarkers in the Management of Patients with Differentiated Thyroid Carcinoma by U. Feldt-Rasmussen, F.A. Verburg, M. Luster, C. Cupini, L. Chiovato, L. Duntas, R. Elisei, H. Rimmele, E. Seregni, J.W.A. Smit, C. Theimer, L. Giovanella (3687-3692).
Differentiated thyroid cancer is a rare malignancy, but leaves numerous survivors for life-long follow-up. Thecornerstone 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 inserum, both at diagnosis and after treatment, where follow-up is commenced. These antibodies interfere technically in theimmunological methods for measuring thyroglobulin, and the antithyroglobulin antibody positive patients are thus eliminatedfrom following current guidelines. In recent years studies have indicated that following the concentration of antithyroglobulinantibodies in serum may be a surrogate marker for recurrence of the thyroid carcinoma. This has recently resultedin publication of an expert position paper, providing a flow scheme for these particular patients. The current reviewsummarises the literature which is the basis for the paper.

Spermicidal and Microbicidal Compounds: In Search of an Efficient Multipurpose Strategy by M. Baptista, R. Tavares, J. Ramalho-Santos (3693-3700).
The search for cheap, easy-to-use and effective spermicides and microbicides to help avoid unwanted pregnanciesand the transmission of sexually transmitted diseases has been ongoing for many years. This review takes into accountcompounds designed to act both as microbicides and spermicides for multipurpose prevention, and focuses on therequired methodological studies to evaluate their safety, especially cytotoxicity. A comprehensive literature review wasconducted on the synthesis, development, advantages and disadvantages of vaginal multi-function compounds. The availabledata shows that after several setbacks, there is a current interest in the synthesis and in the activity of novel dualfunctionsubstances.. The study of well-known compounds with distinctive mechanisms of action provides a solid startingpoint to explore the possible development of such strategies. However, a completely safe and efficient compound forcommercialization has yet to be identified.

Nanoparticles in Melanoma by M.A. Berciano-Guerrero, A. Montesa-Pino, G. Castaneda-Penalvo, L. Munoz-Fernandez, J. Rodriguez-Flores (3701-3716).
Malignant melanoma is one of the most common causes of cancer and cancer deaths in young people. Until fewyears ago, scarce drugs have proven efficacy in metastatic setting. However, in the recent years, the treatment of metastaticmalignant melanoma has undergone the incorporation of effective treatment such as immunotherapy, the use of tyrosinekinase inhibitors and the emergence of other cytostatic compounds, like the nanoparticles. This review aims to proposea standardization to classify the different types of nanoparticles, according to chemical aspects, and update the clinicalresearch 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 “IncreasedAkt 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 UJCMwas unfortunately not written completely. To close accounting on this project on each of the presented abstracts from InternationalMeeting - 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: