Current Medicinal Chemistry - Volume 19, Issue 16, 2012

Cardiovascular disease (CVD) is a multifactorial one consisting of several disorders and represents the leading cause of mortality and morbidity in the western societies. Further to our wide knowledge of CVD, the role of atherosclerosis is well known [1]. Several underlying processes including inflammation, oxidative stress, thrombosis and importantly endothelial dysfunction are responsible for the initiation and progression of atherosclerosis and its clinical manifestations. Thus, multiple biomarkers related to the aforementioned processes have been proposed in order to monitor CVD [2]. Despite the role of biomarkers at a pathophysiological level, their importance is far more. Recent studies aim to investigate whether a biomarker that could detect quite early the ischemic myocardium as well as define the risk of future events with high sensitivity and specificity. In addition, the ability to monitor coronary plaque progression before the onset of an acute coronary syndrome (ACS) is a major goal for the management of ischemic heart disease [3]. Over the years, growing evidence has indicated the risk factors for calcific aortic stenosis. Additional monitoring tools, such as molecular imaging, could improve risk stratification, while assessment of severity and prognosis of patients with chronic aortic regurgitation, are desirable. Importantly, CVD remains the leading cause of premature death in patients with chronic kidney disease (CKD). Recent evidence suggests that the interaction of “classic” and “nonclassic” cardiovascular risk factors is important contributor in excessive and accelerated CVD in patients with CKD. 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. Furthermore, recent research focuses on the investigation of biomarkers monitoring peripheral artery disease, strongly associated to CVD, as well as biomarkers predicting CVD. Finally, during the last few years there are data regarding to the role of microRNAs (miRNAs) in CVD. miRNAs are expressed in the cardiovascular system and could have crucial roles in normal development and physiology, as well as in disease development. Also, they have been found to participate in cardiovascular disease pathogenesis including atherosclerosis, coronary artery disease, myocardial infarction, heart failure and cardiac arrhythmias.....

There is increasing interest in utilizing novel markers of cardiovascular disease risk and consequently, there is a need to assess the value of their use. In this paper, we will review the role of biomarkers in acute coronary syndromes, heart failure and risk stratification for cardiovascular events as guide for treatment scribing. In particular, high sensitivity assays for troponin evaluation detect with greater precision patients with elevated troponin. Therefore, direct and appropriate management is succeeded in these patients with reduction of complications due to earlier treatment, as well. Regarding heart failure, randomized trials that have evaluated biomarker guided treatment approach have not succeeded in establishing specific results for natriuretic peptides (BNP, NT-proBNP) use in terms of therapy guidance. Apart from them, a variety of novel or already used biomarkers, have been tested by small trials for heart failure management, without however, managing to dominate in every day care. Finally, as far as risk stratification for cardiovascular events is concerned, hsCRP has proved to be a strong but doubted biomarker. Therefore, lifestyle and behavioral modification remain the cornerstone of primary prevention.

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 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.

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 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 to 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 necessarily 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.

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 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 the improved diagnosis and understanding of premature atherosclerosis pathogenesis.

Heart 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 studied for its prognostic ability sub-group of biomarkers 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. In the present review, we will discuss the usefulness and significance of potentials or established biomarkers in HF patients focusing on their ability to predict adverse events, morbidity and mortality.

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 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.

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” 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 chronic kidney disease. Currently, there is a growing interest in the role of new biomarkers that are closely correlated with CVD 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.

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 ACSs.

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, 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.

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 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.

Cardiovascular disease, which is multifactorial and can be influenced by a multitude of environmental and heritable risk factors, remains a major health problem, even though its pathophysiology is far from been elucidated. Discovered just over a decade ago, microRNAs comprise short, non-coding RNAs, which have evoked a great deal of interest, due to their importance for many aspects of homeostasis and disease. Hundreds of different microRNAs are constantly being reported in various organisms. According to a growing body of literature, they have been implicated in the regulation of human physiological processes. More specifically, miRNAs are expressed in the cardiovascular system and could have crucial roles in normal development and physiology, as well as in disease development. Furthermore, they have been shown to participate in cardiovascular disease pathogenesis including atherosclerosis, coronary artery disease, myocardial infarction, heart failure and cardiac arrhythmias. In contrast to our original thought, miRNAs exist in circulating blood and are relatively stable, thus, they could be proved useful as biomarkers in that state. Understanding the underlying mechanisms, in which these major regulatory gene families are implicated, will provide novel opportunities for diagnosis and therapy of cardiovascular diseases.

Cadmium (Cd) is a toxic, nonessential transition metal and contributes a health risk to humans, including various cancers and cardiovascular diseases; however, underlying molecular mechanisms remain largely unknown. Cells transmit information to the next generation via two distinct ways: genetic and epigenetic. Chemical modifications to DNA or histone that alters the structure of chromatin without change of DNA nucleotide sequence are known as epigenetics. These heritable epigenetic changes include DNA methylation, post-translational modifications of histone tails (acetylation, methylation, phosphorylation, etc), and higher order packaging of DNA around nucleosomes. Apart from DNA methyltransferases, histone modification enzymes such as histone acetyltransferase, histone deacetylase, and methyltransferase, and microRNAs (miRNAs) all involve in these epigenetic changes. Recent studies indicate that Cd is able to induce various epigenetic changes in plant and mammalian cells in vitro and in vivo. Since aberrant epigenetics plays a critical role in the development of various cancers and chronic diseases, Cd may cause the above-mentioned pathogenic risks via epigenetic mechanisms. Here we review the in vitro and in vivo evidence of epigenetic effects of Cd. The available findings indicate that epigenetics occurred in association with Cd induction of malignant transformation of cells and pathological proliferation of tissues, suggesting that epigenetic effects may play a role in Cd toxic, particularly carcinogenic effects. The future of environmental epigenomic research on Cd should include the role of epigenetics in determining long-term and late-onset health effects following Cd exposure.

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 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.

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 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 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.