Current Pharmaceutical Biotechnology - Volume 13, Issue 5, 2012

In the last few years we have observed a revolution in several branches of science, with many new areas of study being born. In this issue we will have insights in some hot topics in the area of -OMICS and their contribution in translational medicine and human health. Cardiovascular disorders constitute the leading health problem and cause of death in developed countries. In the past few years, the use soy and its derivatives as an approach to prevent and control the onset of the disease has been increasingly popular and, for this reason, epidemiological, clinical and -omics perspectives on soy isoflavones and cardiovascular disease will be reviewed by Gil-izquierdo et al. Next to cardiovascular disorders, cancer is the second most prevalent health condition and is frequently is associated with high mortality. The work by Pereira et al. will discuss the contribution of metabolomics in drug discovery by reviewing the major classes of drugs from vegetable origin in clinical practice. Unfortunately, the area of cancer chemotherapy is well aware of the problem of drugs resistance and, in this regard, Rodrigues et al. will review the contribution of genomics to cancer drug resistance, an area of knowledge that may be vastly important in a near future with the onset of personalized medicine. Central nervous system disorders constitute the third problem of health in developed countries, after the above-referred ones. Given the alarming abuse of psychotropic drugs, as well as the inappropriate response of most patients, new approaches are urgent. In this matter, the seminal work by Cacabelos et al., will address the genomics and pharmacogenomics of brain disorders. Apart from the traditional areas of OMICS, namely genomics, transcriptomics, proteomics and metabolomics, several new areas of research have been paving their way in the last few years. Such is the case of lipidomics, the study of lipidome (the totality of lipids in cells, organs or organisms). In this area, we count with two most important contributions. Cecile and co-workers will address non-alcoholic steatohepatitis, the most common liver pathology characterized by fat accumulation in a context of metabolic syndrome or insulin resistence. This area has been subjected to several studies in the past few years and the major conclusions and future directions are presented. Still in the area of lipidomics, Quinn et al contribute with an unavoidable work that reviews the application of lipidomics to assess lipogenesis in drug development as well as pre-clinical trials, covering all topics from the methodological steps to data handling and interpretation. Serino and colleagues will review the contribution of “-omics ”to the assessment of gut microbiota-driven metabolic modifications of the host. In their work on Microbiomics, they will discuss how new methodologies can help to understand the complex interactions between host and gut microbes. Overall, I hope this special issue constitutes an elucidative state of the art for some hot topics in the ever growing areas of – OMICS sciences.

Cardiovascular disease (CVD) mortality rates are lower in Asian countries where dietary patterns are very different from Western diet. A number of studies have linked these lower rates to the inclusion of soy products as a staple food in those countries. Soy is the richest dietary source of isoflavones, a type of phytoestrogen associated with many potentially beneficial effects. Isoflavone-containing soy protein consumption has been linked to reduced levels of LDL cholesterol in hypercholesterolemic patients. This effect is increased with the concomitant administration of isoflavones, and seems to be also complemented by the isoflavone capacity to restore the endothelial function in patients with weak and moderated endothelial dysfunction. The effects are variable depending on individuals’ metabolism and in particular to their ability to convert daidzein to equol that seems to be restricted to approximately 1/3 of the population. Equol production has been indeed linked to a decreased arterial stiffness and antiatherosclerotic effects via NO production. Because the relevance of isoflavones consumption on the modulation of cardiovascular risk still remains unclear, this paper aims to review the existing knowledge on the biological activity of the isoflavones on the human cardiovascular system from an epidemiological, clinical and -omics point of view.

Nowadays we have a number of chemical and biological agents at our disposal to treat chronic pathologies such as cancer. Although most drugs display significant activity, thus improving the clinical outcome, side-effects and emergence of resistances cannot be looked down. From an historical point of view, higher plants have been very important in the search of new therapeutic agents and they were in the origin of the first medicines used in human health. The contribute of plants to treat pathologies such as cancer is far from being over, mainly due to the high number of new drugs that are currently being evaluated in clinical trials. Metabolomics-based studies have rendered several new chemical entities, some of them with remarkable complex chemistry, which sometimes results in novel mechanisms of action, higher potency and lower toxicity. In this review, we will focus the most important plant-derived classes of compounds in clinical use, as well as those currently in clinical trials, with special focus on vinca alkaloids, taxanes, combretastatins, podophylotoxins and camptothecins. The molecular mechanism of action and spectrum of activity will also be discussed.

Cellular drug resistance is a major obstacle in cancer therapy. Mechanisms of resistance can be associated with altered expression of ATP-binding cassette (ABC) family of transporters on cell membrane transporters, the most common cause of multi-drug resistance (MDR), but can also include alterations of DNA repair pathways, resistance to apoptosis and target modifications. Anti-cancer treatments may be divided into different categories based on their purpose and action: chemotherapeutic agents damage and kill dividing cells; hormonal treatments prevent cancer cells from receiving signals essential for their growth; targeted drugs are a relatively new cancer treatment that targets specific proteins and pathways that are limited primarily to cancer cells or that are much more prevalent in cancer cells; and antibodies function by either depriving the cancer cells of necessary signals or by causing their direct death. In any case, resistance to anticancer therapies leads to poor prognosis of patients. Thus, identification of novel molecular targets is critical in development of new, efficient and specific cancer drugs. The aim of this review is to describe the impact of genomics in studying some of the most critical pathways involved in cancer drug resistance and in improving drug development. We shall also focus on the emerging role of microRNAs, as key gene expression regulators, in drug resistance. Finally, we shall address the specific mechanisms involved in resistance to tyrosine kinase inhibitors in chronic myeloid leukemia.

CNS disorders are the third major problem of health in developed countries, with approximately 10% of direct costs associated with a pharmacological treatment of doubtful cost-effectiveness. There is an alarming abuse of psychotropic drugs worldwide and only 20-30% of patients with CNS disorders appropriately respond to conventional drugs. The pathogenesis of most CNS disorders is the result of the interplay of genetic and epigenetic factors with environmental factors leading to post-transcriptional changes and proteomic and metabolomic dysfunctions. It is estimated that genetics accounts for 20% to 95% of variability in drug disposition and pharmacodynamics, and about 25-60% of the Western population is defective in genes responsible for drug metabolism. In the European population only 25% of subjects are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6, CYP2C19 and CYP2C9 genes. About 50% of adverse drug events in CNS disorders might be attributed to pharmacogenomic factors. The rationale for practical pharmacogenomics and personalized therapeutics based on individual genomic profiles implies the management of different types of genes and their products including (i) genes associated with the mechanism of action of psychotropic drugs (neurotransmitters, receptors, transporters), (ii) genes encoding enzymes responsible for drug metabolism (phase I, phase II reactions), (iii) disease-specific genes associated with a particular pathogenic cascade, and (iv) pleiotropic genes with multilocative effects in metabolomic networks. The incorporation of genomic medicine procedures and pharmacogenomics into clinical practice, together with educational programs for the correct use of medication, must help to optimize therapeutics in CNS disorders.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver pathology characterized by fat accumulation in a context of metabolic syndrome or insulin resistance. It can be associated with obesity, diabetes, hyperinsulinemia, dyslipidemia as well as hypertension. NAFLD consists of a large spectrum of hepatic lesions including benign steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma. Upon chronic stress, NASH would occur via at least “two-hits” process involving modulation of a high number of genes and proteins. Firstly, the accumulation of fat, either due to the increased inflow of free fatty acids or de novo lipogenesis, leads to steatosis. Secondly, when adaptive mechanisms for stress tolerance are overwhelmed, lipotoxicity and chronic inflammation trigger major hepatic damages, mainly via oxidative and inflammatory stress, lipid peroxidation and cell death. As a consequence, all these processes concur to favor steatohepatitis, fibrosis and cancer. Recently, the elucidation of physiopathological signaling cascades controlling NAFLD and NASH benefited from large-scale studies, namely the omics, such as transcriptomics, genomics, proteomics, and lipidomics. The advent of lipidomics would allow shedding light upon the respective roles of triglyceride and fatty acid metabolites in the lipotoxic liver injury hypothesis for the pathogenesis of NASH. In this review, the contribution of the omics to the understanding of the molecular basis of NASH is discussed that could offer perspectives for novel biomarkers discovery.

The rising incidence of cardiovascular and metabolic diseases in industrialized countries has led the pharmaceutical industry to make them key areas of drug development. These diseases imply a clustering of metabolic factors where lipid metabolites play a relevant role. Measurement of pharmacodynamic endpoints of drugs on lipid metabolism pathways and downstream biological processes appear crucial for a rational drug discovery/development. Fortunately, recent mass spectrometers with an enhanced sensitivity and resolution in combination with multivariate statistical analysis provide the practical possibility to analyze and measure wide portions of the lipidome. The final goal is to identify lipid signatures which fit with specific pharmacologic responses to therapeutic intervention. Focusing on applications of lipidomics for drug development this review outlines the methodological steps, from analytical measurements to data processing and to graphical representation, for an efficient implementation of informative lipid signatures.

Over the last five years an increasing effort has been made to understand the role of intestinal microbiota in health and disease, resulting in regarding to it as a new organ actively involved in the control of host metabolism, both in humans and mice. Amongst hundreds (up to thousand) germ species inhabiting the intestine, few of them are cultivable. Nevertheless, next-generation sequencing-based molecular technologies have been developed, allowing to overcome this problem and shed light on the way the gut microbiota undergoes dramatic changes during (patho)-physiological modifications of the host. Hence, the study of the overall gut germ genome (metagenome) and transcriptome (microbiome) has been launched. Thus, Genomics and Transcriptomics have begun to be increasingly used, opening the so called “Omics” era, including Proteomics and Metabolomics techniques as well. Taken together, the “Omics” allow the study of gut microbiota impact on whole host metabolism, resulting in the definition of new metabolic profiles (i.e. the presence of metabolites within the blood defines a metabolomic profile), others than those based on nucleic acid analyses only. Once demonstrated the involvement of gut microbiota within metabolic diseases, “Omics” analyses has allowed the identification of the obesity-induced gut microbiota imbalance, characterized by increased Firmicutes to Bacteroidetes ratio (metagenomics) and of the so called "core microbiome", focusing on the gut microbiota at a gene- rather than, solely, at a taxonomic-level. In addition, metabolomics studies revealed, for instance, the implication of gut microbiota to nonalcoholic fatty liver disease in insulin-resistant mice. Additionally, the use of germ-free (axenic) mice has made possible the microflora transfer to investigate the mechanisms through which gut microbes modulate host metabolism, albeit the molecular actors of the host–gut-microbiota interplay remain to be fully determined. Here, we report the role of “Omics” in the multiple analyses of gut microbiota-driven metabolic modifications of the host, proposing also to focus on lipopolysaccharides (LPS), the Gram negative proinflammatory molecules we already showed to be the initiators of metabolic diseases.