Description

Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each bi-weekly issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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Bentham Science Publishers

Publications in this journal

• Cancer Regulator MicroRNA: Potential Relevance in Diagnosis, Prognosis and Treatment of Cancer.

  Authors: G Fiorucci, M V Chiantore, G Mangino, Z A Percario, E Affabris, G Romeo

  Current medicinal chemistry. 19(4):461-74.

  MicroRNAs (miRNAs) are small (typically 22 nucleotides) non-coding, endogenous, single-stranded RNAs. MiRNA genes are evolutionarily conserved and are located within the introns or exons ofMicroRNAs (miRNAs) are small (typically 22 nucleotides) non-coding, endogenous, single-stranded RNAs. MiRNA genes are evolutionarily conserved and are located within the introns or exons of protein-coding genes, as well as in intergenic areas. Before the discovery of miRNAs, it had been known that a large part of the genome is not translated into proteins. This so called "junk" DNA was thought to be evolution debris with no function. Recently, the explosive research in this area has established miRNAs as powerful regulators of gene expression. While only about 1,424 human miRNA sequences have been identified so far, genomic computational analysis indicates that as many as 50,000 miRNAs may exist in the human genome, and each may have multiple targets based on similar sequences in the 3'-UTR of mRNA. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and others and it is impressive the list of diseases which have recently been found to be associated with abnormal miRNA expression. Here, we focus our attention on the importance of cancer regulator miRNAs. They are divided into oncomiRs and anti-oncomiRs that negatively regulate tumor suppressor genes and oncogenes, respectively. Importantly, the association of miRNAs with cancer has prompted additional functional classification of these short RNAs and their potential relevance in cancer diagnosis, prognosis and treatment.

• Disulfide Linkage: A Potent Strategy in Tumor-Targeting Drug Discovery.

  Authors: J Wang, S Li, T Luo, C Wang, J Zhao

  Current medicinal chemistry.

  Targeted drug delivery has attracted much attention in improving the curative effect of existing chemotherapy drugs, and many published studies have suggested the disulfide linkage for key unit inTargeted drug delivery has attracted much attention in improving the curative effect of existing chemotherapy drugs, and many published studies have suggested the disulfide linkage for key unit in constructing a targeting conjugate. An appropriate disulfide bond, through which cytotoxic agents and drug carriers were linked together, would guarantee the conjugate stable during circulation in vivo and, readily cleavable to release the drug. The aim of this article is to review various design strategies based on disulfide linkage which have been used to assemble a tumor-targeting conjugate, with the goal of presenting a promising avenue in the field of targeted drug delivery.

• Discovery of Selective Small Molecular TACE Inhibitors for the Treatment of Rheumatoid Arthritis.

  Authors: N-G Li, Z-H Shi, Y-P Tang, Wei-Li, Lian-Yin, J-A Duan

  Current medicinal chemistry.

  Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction,Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. The treatment goals of RA should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Current treatment can be divided into four classes, namely general analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and biological agents (tumor-necrosis factor modifiers). However, gastrointestinal (GI) side effects of NSAIDs cannot be neglected, direct joint injections of glucocorticoids cannot be injected more than once every 3 months, synthetic DMARDs is far from optimal and only minority of patients achieved longterm remission, the biologics are very expensive to manufacture, need to be injected, and can cause allergic reactions. An alternative and good approach to the treatment of this disease is to lower the levels of tumour necrosis factor-α (TNF-α) in RA, which can be achieved by selectively inhibiting the tumour necrosis factor-α converting enzyme (TACE) that generate these cytokines using cheaper small molecules. This review focuses on the current status of selective small molecule inhibitors of TACE, with respect to lead compound search, inhibitors design approach, structure-activity relationship (SAR) and pharmacological studies in animals and humans. Through these methods, new hope is emerging for the treatment of RA through selective inhibition of TACE.

• Recent Advances in the Medicinal Chemistry of Aurones.

  Authors: R Haudecoeur, A Boumendjel

  Current medicinal chemistry.

  The first review regarding the potential of aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeuticalThe first review regarding the potential of aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeutical activities of aurones. In this regard, many biological areas were concerned, including major pathological, such as cancer and neurodegenerative disorders. The aim of the present report is to highlight the progress made during the last ten years on the medicinal chemistry of aurones. A special focus will be made on the structure-activity relationship aspects among aurones and especially in case where aurones were found highly active than the corresponding flavones and chalcones.

• Recent Progress and Future Potential for Metal Complexes as Anticancer Drugs Targeting G-quadruplex DNA.

  Authors: J Zhang, F Zhang, H Li, C Liu, J Xia, L Ma, W Chu, Z Zhang, C Chen, S Li, S Wang

  Current medicinal chemistry.

  Now cisplatin and its analogs are some of the most effective chemotherapeutic agents in clinical use as the first line of treatment in testicular and ovarian cancers. Unfortunately, they have severalNow cisplatin and its analogs are some of the most effective chemotherapeutic agents in clinical use as the first line of treatment in testicular and ovarian cancers. Unfortunately, they have several major drawbacks, such as cumulative toxicities of nephrotoxicity and ototoxicity, inherent or treatment-induced resistance. This has provided the motivation for developing novel metal complexes as anticancer agents with different mechanism of action. In recent years, significant attention has been devoted to the role of G-quadruplexes in cancer. It was found that the stabilization of G-quadruplexes by small molecules has been shown to inhibit the transcriptional activity of some oncogenes. Thus, the G-quadruplex motif has emerged as a promising target for the design of selective anticancer drugs. Apart from the purely organic heteroaromatic compounds reported as G-quadruplex binders, it has recently been shown that metal complexes can also interact strongly and selectively with quadruplex DNA and have potential anticancer activity. This review will highlight recent progress of the metal complexes as anticancer drugs targeting G-quadruplex DNA, and discuss their future potential in the medical fields. Considering the significant roles of the metal ions, the metal complexes will be discussed as follows: (1) Ruthenium(II) complexes; (2) Nickel(II) complexes; (3) Zinc(II) complexes; (4) Manganese(III) complexes; (5) Copper(II) complexes; (6) Palladium(II)/Platinum(II); (7) Other metal complexes.

• Screening of 64 Tryptamines at NMDA, 5-HT1A, and 5-HT2A Receptors: A Comparative Binding and Modeling Study.

  Authors: M L Berger, R Palangsuntikul, P Rebernik, P Wolschann, H Berner

  Current medicinal chemistry.

  Tryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet beenTryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet been subjected to a detailed SAR study. Here, 64 Ts have been tested as inhibitors of [3H]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [3H]8-OHDPAT binding to 5-HT1A and of [3H]ketanserin binding to 5-HT2A receptors. Since most of these Ts have not been tested before at any of these receptors, we start with a review of the effects of Ts on 5-HT1A and 5-HT2A binding sites. NRs were inhibited with IC50s from 2 to 7 μM by Ts with alkyl or halogen at positions 2, 5, and/or 7. Inhibition by some Ts was attenuated more than 10-fold by 30 μM spermine. The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 μM) and serotonin (0.0016 μM), at 5-HT2A receptors 2-Me-4,7-Cl2-T (1.2 μM) and 2,7-Me2-4-Cl-T (2.0 μM). Fujita-Ban modified Free-Wilson analyses pointed to the individual significance of particular substituents. Also QSARs based on molecular operating environment descriptors resulted in sound correlations at all 4 targets. No similarities between the NR and 5-HT receptors could be found. At the NR, only L-Trp-NH2 bound 10 times better than at both 5-HT receptors studied. L-Trp-NH2 may be a structural lead to endogenous non-competitive NR antagonists.

• Some Recent Approaches of Biologically Active Substituted Pyridazine and Phthalazine Drugs.

  Authors: M Asif

  Current medicinal chemistry.

  Nitrogen atom containing heterocyclic compounds, pyridazines, pyridazinones and phthalazines are important structural feature of many biologically active compounds and show diverse pharmacologicalNitrogen atom containing heterocyclic compounds, pyridazines, pyridazinones and phthalazines are important structural feature of many biologically active compounds and show diverse pharmacological properties. Pyridazines and phthalazines hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds. On the basis of literature, pyridazines, pyridazinone and phthalazines further focus our attention because of their easy fictionalization at various ring positions, which makes them attractive synthetic compounds for designing and development of the novel pyridazines and phthalazines drugs in future.

• Protocatechuic Acid and Human Disease Prevention: Biological Activities and Molecular Mechanisms.

  Authors: R Masella, C Santangelo, M D'Archivio, G Li Volti, C Giovannini, F Galvano

  Current medicinal chemistry.

  Epidemiological evidence has shown that a high dietary intake of vegetables and fruit rich in polyphenols is associated with a reduction of cancer incidence and mortality from coronary heart disease.Epidemiological evidence has shown that a high dietary intake of vegetables and fruit rich in polyphenols is associated with a reduction of cancer incidence and mortality from coronary heart disease. The healthy effects associated with polyphenol consumption have made the study of the mechanisms of action a matter of great importance. In particular, the hydroxybenzoic acid protocatechuic acid (PCA) has been eliciting a growing interest for several reasons. Firstly, PCA is one of the main metabolites of complex polyphenols such as anthocyanins and procyanidins that are normally found at high concentrations in vegetables and fruit, and are absorbed by animals and humans. Since the daily intake of anthocyanins has been estimated to be much higher than that of other polyphenols, the nutritional value of PCA is increasingly recognized. Secondly, a growing body of evidence supports the concept that PCA can exert a variety of biological effects by acting on different molecular targets. It has been shown that PCA possesses antioxidant, anti-inflammatory as well as antihyperglycemic and neuroprotective activities. Furthermore, PCA seems to have chemopreventive potential because it inhibits the in vitro chemical carcinogenesis and exerts pro-apoptotic and anti-proliferative effects in different tissues. This review is aimed at providing an up-dated and comprehensive report on PCA giving a special emphasis on its biological activities and the molecular mechanisms of action most likely responsible for a beneficial role in human disease prevention.

• Mechanisms Involved in the Protective Effects of Metformin Against Nonalcoholic Fatty Liver Disease.

  Authors: V J Barbero-Becerra, J J Santiago-Hernandez, F A Villegas-Lopez, N Mendez-Sanchez, M Uribe, N C Chavez-Tapia

  Current medicinal chemistry.

  Metformin is an antidiabetic drug used widely in clinical practice. Its main clinical effect is to reduce blood glucose levels by improving insulin resistance. Nonalcoholic fatty liver disease isMetformin is an antidiabetic drug used widely in clinical practice. Its main clinical effect is to reduce blood glucose levels by improving insulin resistance. Nonalcoholic fatty liver disease is characterized by chronic liver damage and can develop into liver cirrhosis. Nonalcoholic fatty liver disease is associated with obesity and contributes to insulin resistance, and metformin is used to treat individuals with these conditions. The mechanisms underlying the clinical effects of metformin in treating nonalcoholic fatty liver disease are unclear. This article summarizes the literature on the mechanisms associated with liver glucose metabolism and the beneficial effects of metformin on this common liver disease.

• Intracellular Signaling Pathways Modulated by Phenolic Compounds: Application for New Anti-Inflammatory Drugs Discovery.

  Authors: G Costa, V Francisco, M C Lopes, M T Cruz, M T Batista

  Current medicinal chemistry.

  Extensive research within the last two decades revealed that most chronic illnesses, including cancer, neurological, autoimmune and cardiovascular diseases are mediated through chronic inflammation.Extensive research within the last two decades revealed that most chronic illnesses, including cancer, neurological, autoimmune and cardiovascular diseases are mediated through chronic inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and treat those diseases. However, side effects and high costs of current anti-inflammatory drugs force the development of new drugs. Natural products represent an important source of new bioactive compounds. Among them, phenolic compounds, which are widely distributed in plants, have been described as having many therapeutic effects. Several reviews have addressed the anti-inflammatory activity of phenols, attributing their properties not only to the antioxidant capacity, but also to inflammatory mediators' modulation, namely cytokines and pro-inflammatory proteins, such as inducible nitric oxide synthase and cyclooxygenase-2. Signal transduction pathways precede changes in inflammatory mediators' expression. However, only a restricted number of studies have addressed the effect of phenols on a specific signal transduction pathway. The present review attempts to summarize and highlight a broad range of inflammation-associated signaling pathways modulated by phenols namely: nuclear factor (NF)-κB, activator protein (AP)-1, peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factors; mitogen-activated protein kinases (MAPKs); protein tyrosine kinases (PTKs); tyrosine phosphatidylinositol 3-kinase (PI3K)/Akt and ubiquitin-proteasome system. As a consequence of phenols effect on signaling pathways, described above, their action on inflammatory mediators' production is mentioned. Finally, it is established that the structure-activity relationships of phenolic compounds are a valuable information source on the development of new anti-inflammatory drugs from natural products.

• Extraction, Characterization and In Vivo Neuromodulatory Activity of Phytosterols from Microalga Dunaliella Tertiolecta.

  Authors: M Francavilla, M Colaianna, M Zotti, M G Morgese, P Trotta, P Tucci, S Schiavone, V Cuomo, L Trabace

  Current medicinal chemistry.

  In recent years, a great deal of research has been devoted to identify new natural sources of phytosterols and to improve methods for their recovery and purification. In this regard, unexploredIn recent years, a great deal of research has been devoted to identify new natural sources of phytosterols and to improve methods for their recovery and purification. In this regard, unexplored natural sources of bioactive ingredients are gaining much attention since they can lead to the isolation of new compounds or bioactivities. The field of available natural sources has been further increased by including algae and, even more interestingly, microalgae. In the present study, a multidisciplinary approach has been used considering, in an integrated view, extraction, chemical composition and bioactivity of phytosterols from the microalga Dunaliella tertiolecta. A novel methodology to extract, separate and characterize microalgal-derived phytosterols has been developed. In addition, recoverable and reusable eluents have been selected in order to reduce the quantities of employed organic solvents. Finally, we addressed the question whether orally administered phytosterols reach the brain and if those interfere with the major neurotransmitter systems, such as the dopaminergic, serotoninergic and noradrenergic ones, in several brain areas of rats. Flash Liquid Chromatography has been used to separate the Total Sterol (TS) fraction, composed of twelve sterols, with a purity of 97.87% and a recovery percentage of 98%, while the "flash version" of Silver Ion Liquid Chromatography has been used to purify the most abundant phytosterols in TS, (22E,24R)-methylcholesta-5,7,22-trien-3β-ol (ergosterol) and (22E,24R)-ethylcholesta-5,7,22-trien-3β-ol (7-dehydroporiferasterol), with a purity of 97.4%. These two combined methods did not need sophisticated technologies but only cheap laboratory supplies. Moreover, the possibility of recovering and recycling the solvents used as eluents made it a cleaner process. Finally, for the first time, a neuromodulatory action of Dunaliella tertiolecta-derived phytosterols has been found in selective brain areas of rats.

• Pitfalls in Lung Cancer Molecular Pathology: How to Limit them in Routine Practice?

  Authors: M Ilie, P Hofman

  Current medicinal chemistry.

  New treatment options in advanced non-small cell lung carcinoma (NSCLC) targeting activating epidermal growth factor receptor (EGFR) gene mutations and other genetic alterations demonstrated theNew treatment options in advanced non-small cell lung carcinoma (NSCLC) targeting activating epidermal growth factor receptor (EGFR) gene mutations and other genetic alterations demonstrated the clinical significance of the molecular features of specific subsets of tumors. Therefore, the development of personalized medicine has stimulated the routine integration into pathology departments of somatic mutation testing. However, clinical mutation testing must be optimized and standardized with regard to histological profile, type of samples, pre-analytical steps, methodology and result reporting. Routine molecular testing in NSCLC is currently moving beyond EGFR mutational analysis. Recent progress of targeted therapies will require molecular testing for a wide panel of mutations for a personalized molecular diagnosis. As a consequence, efficient testing of multiple molecular abnormalities is an urgent requirement in thoracic oncology. Moreover, increasingly limited tumor sample becomes a major challenge for molecular pathology. Continuous efforts should be made for safe, effective and specific molecular analyses. This must be based on close collaboration between the departments involved in the management of lung cancer. In this review we explored the practical issues and pitfalls surrounding the routine implementation of molecular testing in NSCLC in a pathology laboratory.

• The Chemistry and Biology of the Bryostatins: Potential PKC Inhibitors in Clinical Development.

  Authors: B F Ruan, H L Zhu

  Current medicinal chemistry.

  The bryostatins, powerful protein kinase C (PKC) agonists, are a family of complex macrolactone natural products. They are originally isolated from the marine bryozoan Bugula neritina. So far tweentyThe bryostatins, powerful protein kinase C (PKC) agonists, are a family of complex macrolactone natural products. They are originally isolated from the marine bryozoan Bugula neritina. So far tweenty bryostatins have been obtained naturally and exhibit a remarkable range of biological activities, including antineoplastic activity, synergistic chemotheoreputic activity, cognition and memory enhancement, etc. Of the 20 known members, the most extensively studied is bryostatin 1. The effects of bryostatin 1 are mainly linked to its ability of selectively modulating the function of various individual protein kinase C (PKC) isozymes. Moreover, bryostatin 1, or in combination with other agents, has been proposed for phase I and phase II clinical trials. The bryostatins have excellent biological properties, but are scarce in nature. Therefore, it has attracted considerable interests in structural modification over the past two decades. In this review, we will attempt to summarize the main developments that have occurred in the structure-activity relationship and biology of bryostatins over the period 1982-2011.

• The Progress of Selective Fluorescent Chemosensors by Boronic Acid.

  Authors: S Huang, M Jia, Y Xie, J Wang, W Xu, H Fang

  Current medicinal chemistry.

  As a cutting-edge scientific research field, the detection of biological active substance is very important for the prevention, diagnosis and treatment of diseases. Boronic acid interacts withAs a cutting-edge scientific research field, the detection of biological active substance is very important for the prevention, diagnosis and treatment of diseases. Boronic acid interacts with cis-1,2-or 1,3-diol to form five- or six-membered ring which could be used as the reporter of fluorescent sensors to probe carbohydrates and bioactive substance. This review summarizes the recent progress of boronic acid sensors for carbohydrates, L-dopamine, fluoride, copper ion, mercury ion and hydrogen peroxide. In this article, we will briefly introduce the chemistry of boronic acid, and then give a description of the fluorescence properties of each boronic acid sensor, such as fluorescence intensity change, excitation and emission wavelengths, quantum yields and water solubility. In addition, we summarize the mechanisms of fluorescent signal output for some representative sensors and discuss the strategies for developing new fluorescent probes.

• Clinical utility of biomarkers in premature atherosclerosis.

  Authors: Anna-Maria Kampoli, Dimitris Tousoulis, Nikolaos Papageorgiou, Zoi Pallatza, Georgia Vogiatzi, Alexandros Briasoulis, Emmanouel Androulakis, Costas Toutouzas, Pavlos Stougianos, Costas Tentolouris, Christodoulos Stefanadis

  Current medicinal chemistry.

  Atherosclerosis is a very complex procedure responsible for the development of coronary artery disease which is the leading cause of death in the civilized world. The obvious pandemic character ofAtherosclerosis is a very complex procedure responsible for the development of coronary artery disease which is the leading cause of death in the civilized world. The obvious pandemic character of atherosclerosis augments the need to discover an ideal biomarker, which will be able to facilitate the clinical diagnosis of the atherosclerosis from the physicians especially in the early stages of the atherosclerotic process. Among the biomarkers that are already used there are classical ones, such as c-reactive protein, interleukins, tumour necrosis factor, apolipoproteins, fibrinogen, homocysteine, and novel promising ones such as lipoprotein-associated phospholipase, asymmetric dimethylarginine, myeloperoxidase, cathepsins and cystatin C. The possibility of combining circulating biomarkers with other methods such as non-invasive and invasive imaging is clinically attractive because this could contribute to improved diagnosis and understanding of premature atherosclerosis pathogenesis.

• Assessment of Acute Coronary Syndromes: Focus on Novel Biomarkers.

  Authors: Dimitris Tousoulis, George Hatzis, Nikolaos Papageorgiou, Emmanuel Androulakis, George Bouras, Anastasios Giolis, Constantinos Bakogiannis, Gerasimos Siasos, George Latsios, Charalambos Antoniades, Christodoulos Stefanadis

  Current medicinal chemistry.

  Coronary artery disease (CAD) is the leading cause of mortality in Western Societies and several developing countries. Recent evidence suggests that most detrimental clinical manifestations of CAD,Coronary artery disease (CAD) is the leading cause of mortality in Western Societies and several developing countries. Recent evidence suggests that most detrimental clinical manifestations of CAD, such as acute coronary syndromes (ACS), are the outcome of inflammatory processes that lead to plaque formation and rupture and eventually to ischemia and potentially myocardial necrosis. Neither of the traditionally used biomarkers is thought to be the gold standard in detection of myocardial ischemia or necrosis. A biomarker that could detect quite early the ischemic myocardium as well as define the risk of a future event with high sensitivity and specificity is still lacking. Several biomarkers, implicated in the pathogenesis and clinical evolution of atherosclerosis, have emerged as potent biomarkers for early detection of myocardial ischemia. In the current review, we summarize recent evidence of the most promising biomarkers and discuss their potential role in clinical practice in patients suffering from ACS.

• Monitoring Calcific Aortic Valve Disease: The Role of Biomarkers.

  Authors: George Latsios, Dimitris Tousoulis, Emmanuel Androulakis, Nikolaos Papageorgiou, Andreas Synetos, Costas Tsioufis, Kostas Toutouzas, Christodoulos Stefanadis

  Current medicinal chemistry.

  Calcific aortic valve disease is a common disease in the elderly associated with significant morbidity and mortality. It was once described as a passive degenerative process during which serumCalcific aortic valve disease is a common disease in the elderly associated with significant morbidity and mortality. It was once described as a passive degenerative process during which serum calcium attaches to the valve surface and binds to the leaflet. However, during the last decade mounting evidence demonstrated that this disease has an active biologic process with numerous signaling pathways. The histological hallmarks seem to be inflammation, oxidized lipids-also detectable in aortic valve lesions-and a remodeling of the extracellular matrix leading to bone formation. Over the years, growing evidence has indicated the risk factors for calcific aortic stenosis including lipids, hypertension, male gender, renal failure, and diabetes. Additional monitoring tools, such as molecular imaging, could improve risk stratification, while assessment of severity and prognosis of patients with chronic aortic regurgitation, is desirable. Also, several studies have investigated the role of biomarkers regarding their utility in the screening of calcific aortic valve disease and their putative clinical value, though their role still remains undetermined.

• Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes.

  Authors: Constantinos Bakogiannis, Dimitris Tousoulis, Emmanuel Androulakis, Alexandros Briasoulis, Nikolaos Papageorgiou, Georgia Vogiatzi, Anna-Maria Kampoli, Marietta Charakida, Gerasimos Siasos, George Latsios, Charalambos Antoniades, Christodoulos Stefanadis

  Current medicinal chemistry.

  Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulatingExperimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.

• Functional, Genetic and Biochemical Biomarkers of Peripheral Arterial Disease.

  Authors: Marietta Charakida, Stefano Masi, Dimitris Tousoulis

  Current medicinal chemistry.

  Patients with peripheral arterial disease (PAD) suffer from increased cardiovascular morbidity and mortality. The ankle brachial index has been widely used as an easy tool to identify and stratifyPatients with peripheral arterial disease (PAD) suffer from increased cardiovascular morbidity and mortality. The ankle brachial index has been widely used as an easy tool to identify and stratify patients with PAD, however its predictive value remains limited. Higher levels of inflammatory and prothrombotic biomarkers have been associated with the development and progression of PAD and recent data suggest that may provide additional information for cardiovascular risk stratification of these patients. The current review will present available information on functional, genetic and biochemical biomarkers which have been associated with PAD in cross sectional and large prospective studies and highlight their additive value for risk stratification of these patients.

• Biomarkers associated with vulnerable atheromatous plaque.

  Authors: Toshio Imanishi, Takashi Akasaka

  Current medicinal chemistry.

  Atherogenesis progresses through lipid core expansion and macrophage accumulation at the plaque, leading to fibrous cap rupture. Plaque rupture occurs in the plaque fissuring at one point, whichAtherogenesis progresses through lipid core expansion and macrophage accumulation at the plaque, leading to fibrous cap rupture. Plaque rupture occurs in the plaque fissuring at one point, which ultimately brings the platelets into contact with the content of the lipid core, and the blood coagulation factors together with tissue factor. The transition from stable atherosclerotic plaques to vulnerable plaques finally resulting in the plaque rupture is the consequence of an inflammatory reaction. This process involves complex cellular interactions engaging many mediators, chemokines, and cytokines which can be measured in serum and plasma and thus serve as biomarkers that differentiate the pathophysiologic phases of disease progression. Pathological studies support the risk of inflammation in high-risk patients to a greater extent than the degree of vessel stenosis. It is therefore important to identify reliable biomarkers allowing us to monitor vascular inflammatory state. In clinical investigations, several new biomarkers have been identified that provide increasing diagnostic and prognostic significance. However, more confirmatory studies are required to clinical use. Furthermore, assays for automated use need to be developed, and cut-off levels need to be defined. Further technological advances will likely facilitate the use of multimarker profiling to identify with coronary vulnerable plaque.

• Chelating agents for neurodegenerative diseases.

  Authors: Roberta J Ward, David T Dexter, Robert R Crichton

  Current medicinal chemistry.

  It has become apparent in the last years that metal ion homeostasis and its dysfunction which results in increased accumulation in brain, notably of copper, iron and zinc, may be associated with aIt has become apparent in the last years that metal ion homeostasis and its dysfunction which results in increased accumulation in brain, notably of copper, iron and zinc, may be associated with a number of neurodegenerative diseases, such that chelation therapy may be one therapeutic option. We briefly outline chelators currently available together with strategies to develop new chelators capable of crossing the blood-brain-barrier. The homeostasis of iron in brain together with changes in brain iron with ageing are reviewed as well as the role of iron in Parkinson's disease, and the potential of chelation therapy in PD. Copper and zinc homeostasis in brain and age associated changes are then outlined, along with a discussion of the possible involvement of Zn, Cu and Fe in Alzheimer's disease. We conclude with a brief summary of chelation therapy in AD.

• New therapeutic approaches by using microorganism-derived compounds.

  Authors: Amedeo Amedei, Mario Milco D'Elios

  Current medicinal chemistry.

  It has become apparent in the last years that metal ion homeostasis and its dysfunction which results in increased accumulation in brain, notably of copper, iron and zinc, may be associated with aIt has become apparent in the last years that metal ion homeostasis and its dysfunction which results in increased accumulation in brain, notably of copper, iron and zinc, may be associated with a number of neurodegenerative diseases, such that chelation therapy may be one therapeutic option. We briefly outline chelators currently available together with strategies to develop new chelators capable of crossing the blood-brain-barrier. The homeostasis of iron in brain together with changes in brain iron with ageing are reviewed as well as the role of iron in Parkinson's disease, and the potential of chelation therapy in PD. Copper and zinc homeostasis in brain and age associated changes are then outlined, along with a discussion of the possible involvement of Zn, Cu and Fe in Alzheimer's disease. We conclude with a brief summary of chelation therapy in AD.

• Evaluating oxidative stress in human cardiovascular disease: Methodological aspects and considerations.

  Authors: Regent Lee, Marios Margaritis, Keith M Channon, Charalambos Antoniades

  Current medicinal chemistry.

  Oxidative stress is a key feature in atherogenesis, since reactive oxygen species (ROS) are involved in all stages of the disease, from endothelial dysfunction to atheromatic plaque formation andOxidative stress is a key feature in atherogenesis, since reactive oxygen species (ROS) are involved in all stages of the disease, from endothelial dysfunction to atheromatic plaque formation and rupture. It is therefore important to identify reliable biomarkers allowing us to monitor vascular oxidative stress status. These may lead to improved understanding of disease pathogenesis and development of new therapeutic strategies. Measurement of circulating biomarkers of oxidative stress is challenging, since circulation usually behaves as a separate compartment than the individual structures of the vascular wall. However, measurement of stable products released by the reaction of ROS and vascular/circulating molecular structures is a particularly popular approach. Serum lipid hydroperoxides , plasma malondialdehyde or urine F2-isoprostanes are widely used and have a prognostic value in cardiovascular disease. Quantification of oxidative stress at a tissue level is much more accurate. Various chemiluminescence and high performance liquid chromatography assays have been developed over the last few years, and some of them are extremely accurate and specific. Electron spin resonance spectroscopy and micro-electrode assays able to detect ROS directly, are also widely used. In conclusion, measurement of circulating biomarkers of oxidative stress is valuable, and some of them appear to have predictive value in cardiovascular disease. However, these biomarkers do not reflect intravascular oxidative stress and therefore cannot be used as therapeutic targets or markers to monitor pharmacological treatments in clinical settings. Measurement of vascular oxidative stress status is still the only reliable way to evaluate the involvement of oxidative stress in atherogenesis.

• Predictive Value of Biomarkers in Patients with Heart Failure.

  Authors: Dimitris Tousoulis, Evangelos Oikonomou, Gerasimos Siasos, Evangelos D Papadimitriou, Maria Limperi, Christina Chrysohoou, Marietta Charakida, Athanasios Trikas, Athanasios G Papavassiliou, Christodoulos Stefanadis

  Current medicinal chemistry.

  Heart failure (HF) is a complex syndrome with high morbidity and mortality while, myocardial injury, hemodynamic overload, genetic, neurohormonal, inflammatory and biochemical factors are implicatedHeart failure (HF) is a complex syndrome with high morbidity and mortality while, myocardial injury, hemodynamic overload, genetic, neurohormonal, inflammatory and biochemical factors are implicated in the development and progression of the disease. Interestingly, despite the development of several diagnostic tests, HF diagnosis remains clinical, based on symptoms and signs, while there is a poor relationship between symptoms and the prognosis of HF. Several biomarkers have recently been examined for their efficacy to predict outcome and assess prognosis of HF patients. The best study sub-group is the neurohormones including the natriuretic peptides, the components of the renin-angiotensin-aldosterone system and the catecholamines. Others sub-groups of biomarkers include inflammatory and oxidative stress markers, extracellular matrix remodeling markers and myocardial injury markers (such as troponins I and T). Nevertheless, it is difficult to access a single biomarker fulfilling our need to evaluate prognosis and guiding treatment in acute or chronic HF patients, thus the predictive ability of combined biomarkers is recently under research. Therefore, further studies are needed to elucidate the clinical significance of these biomarkers.

• Biomarkers Determining Cardiovascular Risk in Patients with Kidney Disease.

  Authors: Gerasimos Siasos, Dimitris Tousoulis, Stavroula Michalea, Evangelos Oikonomou, Christina Kolia, Stamatis Kioufis, Andreas Synetos, Athanasios G Papavassiliou, Christodoulos Stefanadis

  Current medicinal chemistry.

  Cardiovascular disease (CVD) remains the leading cause of premature death in patients with chronic kidney disease (CKD). Recent evidence suggests that the interaction of ''classic'' andCardiovascular disease (CVD) remains the leading cause of premature death in patients with chronic kidney disease (CKD). Recent evidence suggests that the interaction of ''classic'' and ''non-classic" cardiovascular risk factors is an important contributor in excessive and accelerated CVD in patients with CKD. Indeed, the imposing cardiovascular morbidity and mortality of CKD patients corresponds to a significant extent in endothelial dysfunction, inflammation, oxidative stress, vascular calcification and volume overload. In addition, the kidney's function decline is independently associated with CVD in patients with kidney disease. Currently, there is a growing interest in the role of new biomarkers that are closely correlated with the aforementioned novel risk factors in CKD population. In current review, we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors and new biomarkers of CVD in CKD patients, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population.

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