Current Medicinal Chemistry - Volume 26, Issue 1, 2019

Background: The development of effective screening methods for early cancer detection is one of the foremost challenges facing modern cancer research. Urinary metabolomics has recently emerged as a potentially transformative approach to cancer biomarker discovery owing to its noninvasive sampling characteristics and robust analytical feasibility. Objective: To provide an overview of new developments in urinary metabolomics, cover the most promising aspects of hyphenated techniques in untargeted and targeted metabolomics, and to discuss technical and clinical limitations in addition to the emerging challenges in the field of urinary metabolomics and its application to cancer biomarker discovery. Methods: A systematic review of research conducted in the past five years on the application of urinary metabolomics to cancer biomarker discovery was performed. Given the breadth of this topic, our review focused on the five most widely studied cancers employing urinary metabolomics approaches, including lung, breast, bladder, prostate, and ovarian cancers. Results: As an extension of conventional metabolomics, urinary metabolomics has benefitted from recent technological developments in nuclear magnetic resonance, mass spectrometry, gas and liquid chromatography, and capillary electrophoresis that have improved urine metabolome coverage and analytical reproducibility. Extensive metabolic profiling in urine has revealed a significant number of altered metabolic pathways and putative biomarkers, including pteridines, modified nucleosides, and acylcarnitines, that have been associated with cancer development and progression. Conclusion: Urinary metabolomics presents a transformative new approach toward cancer biomarker discovery with high translational capacity to early cancer screening.

Background: Steroid hormones belong to a group of low-molecular weight compounds which are responsible for maintenance of various body functions, thus, their accurate assessment is crucial for evaluation of biosynthetic defects. The development of reliable methods allowing disease diagnosis is essential to improve early detection of various disorders connected with altered steroidogenesis. Currently, the field of metabolomics offers several improvements in terms of sensitivity and specificity of the diagnostic methods when opposed to classical diagnostic approaches. The combination of hyphenated techniques and pattern recognition methods allows to carry out a comprehensive assessment of the slightest alterations in steroid metabolic pathways and can be applied as a tool for biomarker discovery. Methods: We have performed an extensive literature search applying various bibliographic databases for peer-reviewed articles concentrating on the applications of hyphenated techniques and pattern recognition methods incorporated into the steroid metabolomic approach for biomarker discovery. Results: The review discusses strengths, challenges and recent developments in steroidbased metabolomics. We present methods of sample collection and preparation, methods of separation and detection of steroid hormones in biological material, data analysis, and interpretation as well as examples of applications of steroid metabolomics for biomarker discovery (cancer, mental and central nervous system disorders, endocrine diseases, monitoring of drug therapy and doping control). Conclusion: Information presented in this review will be valuable to anyone interested in the application of metabolomics for biomarker discovery with a special emphasis on disorders of steroid hormone synthesis and metabolism.

Background: The field of metabolomics has been steadily increasing in size for the last 15 years. Advances in analytical and statistical methods have allowed metabolomics to flourish in various areas of medicine. Cardiovascular diseases are some of the main research targets in metabolomics, due to their social and medical relevance, and also to the important role metabolic alterations play in their pathogenesis and evolution. Metabolomics has been applied to the full spectrum of cardiovascular diseases: from patient risk stratification to myocardial infarction and heart failure. However - despite the many proof-ofconcept studies describing the applicability of metabolomics in the diagnosis, prognosis and treatment evaluation in cardiovascular diseases - it is not yet used in routine clinical practice. Recently, large phenome centers have been established in clinical environments, and it is expected that they will provide definitive proof of the applicability of metabolomics in clinical practice. But there is also room for small and medium size centers to work on uncommon pathologies or to resolve specific but relevant clinical questions. Objectives: In this review, we will introduce metabolomics, cover the metabolomic work done so far in the area of cardiovascular diseases. Conclusion: The cardiovascular field has been at the forefront of metabolomics application and it should lead the transfer to the clinic in the not so distant future.

Background: Obesity, insulin resistance, diabetes, and metabolic syndrome are associated with lipid alterations, and they affect the risk of long-term cardiovascular disease. A reliable analytical instrument to detect changes in the composition or structures of lipids and the tools allowing to connect changes in a specific group of lipids with a specific disease and its progress, is constantly lacking. Lipidomics is a new field of medicine based on the research and identification of lipids and lipid metabolites present in human organism. The primary aim of lipidomics is to search for new biomarkers of different diseases, mainly civilization diseases. Objective: We aimed to review studies reporting the application of mass spectrometry for lipid analysis in metabolic diseases. Method: Following an extensive search of peer-reviewed articles on the mass spectrometry analysis of lipids the literature has been discussed in this review article. Results: The lipid group contains around 1.7 million species; they are totally different, in terms of the length of aliphatic chain, amount of rings, additional functional groups. Some of them are so complex that their complex analyses are a challenge for analysts. Their qualitative and quantitative analysis of is based mainly on mass spectrometry. Conclusion: Mass spectrometry techniques are excellent tools for lipid profiling in complex biological samples and the combination with multivariate statistical analysis enables the identification of potential diagnostic biomarkers.

Amyloidoses are a group of diseases caused by the extracellular deposition of proteins forming amyloid fibrils. The amyloidosis is classified according to the main protein or peptide that constitutes the amyloid fibrils. The most effective methods for the diagnosis of amyloidosis are based on mass spectrometry. Mass spectrometry enables confirmation of the identity of the protein precursor of amyloid fibrils in biological samples with very high sensitivity and specificity, which is crucial for proper amyloid typing. Due to the fact that biological samples are very complex, mass spectrometry is usually connected with techniques such as liquid chromatography or capillary electrophoresis, which enable the separation of proteins before MS analysis. Therefore mass spectrometry constitutes an important part of the so called “hyphenated techniques” combining, preferentially in-line, different analytical methods to provide comprehensive information about the studied problem. Hyphenated methods are very useful in the discovery of biomarkers in different types of amyloidosis. In systemic forms of amyloidosis, the analysis of aggregated proteins is usually performed based on the tissues obtained during a biopsy of an affected organ or a subcutaneous adipose tissue. In some cases, when the diagnostic biopsy is not possible due to the fact that amyloid fibrils are formed in organs like the brain (Alzheimer’s disease), the study of biomarkers presented in body fluids can be carried out. Currently, large-scale studies are performed to find and validate more effective biomarkers, which can be used in diagnostic procedures. We would like to present the methods connected with mass spectrometry which are used in the diagnosis of amyloidosis based on the analysis of proteins occurring in tissues, blood and cerebrospinal fluid.

Background: Analytical chemistry and biotechnology as an interdisciplinary fields of science have been developed during many years and are experiencing significant growth, to cover a wide range of microorganisms separation techniques and methods, utilized for medical therapeutic and diagnostic purposes. Currently scientific reports contribute by introducing electrophoretical and immunological methods and formation of devices applied in food protection (avoiding epidemiological diseases) and healthcare (safety ensuring in hospitals). Methods: Electrophoretic as well as nucleic-acid-based or specific immunological methods have contributed tremendously to the advance of analyses in recent three decades, particularly in relation to bacteria, viruses and fungi identifications, especially in medical in vitro diagnostics, as well as in environmental or food protection. Results: The paper presents the pathogen detection competitiveness of these methods against conventional ones, which are still too time consuming and also labor intensive. The review is presented in several parts following the current trends in improved pathogens separation and detection methods and their subsequent use in medical diagnosis. Discussion: Part one, consists of elemental knowledge about microorganisms as an introduction to their characterization: descriptions of divisions, sizes, membranes (cells) components. Second section includes the development, new technological and practical solution descriptions used in electrophoretical procedures during microbes analyses, with special attention paid to bio-samples analyses like blood, urine, lymph or wastewater. Third part covers biomolecular areas that have created a basis needed to identify the progress, limitations and challenges of nucleic-acid-based and immunological techniques discussed to emphasize the advantages of new separative techniques in selective fractionating of microorganisms.

The general function of anticoagulants is to prevent blood clotting and growing of the existing clots in blood vessels. In recent years, there has been a significant improvement in developing methods of prevention as well as pharmacologic and surgical treatment of thrombosis. For over the last two decades, low molecular weight heparins (LMWHs) have found their application in the antithrombotic diseases treatment. These types of drugs are widely used in clinical therapy. Despite the biological and medical importance of LMWHs, they have not been completely characterized in terms of their chemical structure. Due to both, the structural complexity of these anticoagulants and the presence of impurities, their structural characterization requires the employment of advanced analytical techniques. Since separation techniques play the key role in these endeavors, this review will focus on the presentation of recent developments in the separation of LMWH anticoagulants.

Background: Ethyl alcohol is the most popular legal drug, but its excessive consumption causes social problems. Despite many public campaigns against alcohol use, car accidents, instances of aggressive behaviour, sexual assaults and deterioration in labor productivity caused by inebriated people is still commonplace. Fast and easy diagnosis of alcohol consumption is required in order to introduce proper and effective therapy, and is crucial in forensic toxicology analysis. The easiest method to prove alcohol intake is determination of ethanol in body fluids or in breath. However, since ethanol is rapidly metabolized in the human organism, only recent consumption can be detected using this method. Because of that, the determination of alcohol biomarkers was introduced for monitoring alcohol consumption over a wider range of time. Objective: The objective of this study was to review published studies focusing on the sample preparation methods and chromatographic or biochemical techniques for the determination of alcohol biomarkers in whole blood, plasma, serum and urine. Methods: An electronic literature search was performed to discuss possibilities and limitations of application of alcohol biomarkers in toxicological analysis. Results: Authors described the markers of alcohol consumption such as: ethanol, its nonoxidative metabolites (ethyl glucuronide, ethyl sulfate, phosphatidylethanol, ethyl phosphate, fatty acid ethyl esters) and oxidative metabolites (acetaldehyde and acetaldehyde adducts). We also discussed issues concerning the detection window of these biomarkers, and possibilities and limitations of their use in routine analytical toxicology for monitoring alcohol consumption or sobriety during alcohol therapy.

Background: Electronic nose technology is being developed in order to analyse complex mixtures of volatiles in a way parallel to biologic olfaction. When applied in the field of medicine, the use of such devices should enable the identification and discrimination between different diseases. In this review, a comprehensive summary of research in medical diagnostics using electronic noses is presented. A special attention has been paid to the application of these devices and sensor technologies, in response to current trends in medicine. Methods: Peer-reviewed research literature pertaining to the subject matter was identified based on a search of bibliographic databases. The quality and relevance of retrieved papers was assessed using standard tools. Their content was critically reviewed and certain information contained therein was compiled in tabularized form. Results: The majority of reviewed studies show promising results, often surpassing the accuracy and sensitivity of established diagnostic methods. However, only a relatively small number of devices have been field tested. The methods used for sample collection and data processing in various studies were listed in a table, together with electronic nose models used in these investigations. Conclusion: Despite the fact that devices equipped with arrays of chemical sensors are not routinely used in everyday medical practice, their prospective use would solve some established issues in medical diagnostics, as well as lead to developments in prophylactics by facilitating a widespread use of non-invasive screening tests.

Background: In regard to urogenital tract cancer studies, an estimated 340,650 new cases and 58,360 deaths from genital system cancer and about 141,140 new cases and 29330 deaths from urinary system were projected to occur in the United States in 2012. The main drawbacks of currently available diagnostic tests constitute the low specificity, costliness and quite high invasiveness. Objective: The main goal of this pilot study was to determine and compare urine metabolic fingerprints in urogenital tract cancer patients and healthy controls. Method: A comparative analysis of the metabolic profile of urine from 30 patients with cancer of the genitourinary system (bladder (n=10), kidney (n=10) and prostate (n=10)) and 30 healthy volunteers as a control group was provided by LC-TOF/MS and GCQqQ/ MS. The data analysis was performed by the use of U-Mann Whitney test or Student’s t-test, principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA). Results: As a result, 33, 43, and 22 compounds were identified as statistically significant in bladder, prostate and kidney cancer, respectively, compared to healthy groups. Conclusion: Diverse compounds such as purine, sugars, amino acids, nucleosides, organic acids which play a role in purine metabolism, in tricarboxylic acid cycle, in amino acid metabolism or in gut microbiota metabolism were identified. Only two metabolites namely glucocaffeic acid and lactic acid were found to be in common in studied three types of cancer.

Background: Resistant hypertension (RH) affects about 15-20% of treated hypertensive patients worldwide. RH increases the risk of cardiovascular events such as myocardial infarction and stroke by 50%. The pathological mechanisms underlying resistance to treatment are still poorly understood. Objective: The main goal of this pilot study was to determine and compare plasma metabolomic profiles in resistant and non-resistant hypertensive patients. Methods: We applied untargeted metabolomic profiling in plasma samples collected from 69 subjects with RH and 81 subjects with controlled hypertension. To confirm patients’ compliance to antihypertensive treatment, levels of selected drugs and their metabolites were determined in plasma samples with the LC-ESI-TOF/MS technique. Results: The results showed no statistically significant differences in the administration of antihypertensive drug in the compared groups. We identified 19 up-regulated and 13 downregulated metabolites in the RH. Conclusion: The metabolites altered in RH are linked to oxidative stress and inflammation, endothelium dysfunction, vasoconstriction and cell proliferation. Our results may generate new hypothesis about RH development and progression.