Current Medicinal Chemistry - Volume 22, Issue 32, 2015

Respiratory diseases including chronic-obstructive-pulmonary-disease (COPD) are globally increasing, with COPD predicted to become the third leading cause of global mortality by 2020. COPD is a heterogeneous disease with COPD-patients displaying different phenotypes as a result of a complex interaction between various genetic, environmental and life-style factors. In recent years, several investigations have been performed to better define such interactions, but the identification of the resulting phenotypes is still somewhat difficult, and may lead to inadequate assessment and management of COPD (usually based solely on the severity of airflow limitation parameter FEV1). In this new scenario, the management of COPD has been driven towards an integrative and holistic approach. The degree of complexity requires analyses based on large datasets (also including advanced functional genomic assays) and novel computational biology approaches (essential to extract information relevant for the clinical decision process and for the development of new drugs). Therefore, according to the emerging “systems/network medicine”, COPD should be re.-evaluated considering multiple network(s) perturbations such as genetic and environmental changes. Systems Medicine (SM) platforms, in which patients are extensively characterized, offer a basis for a more targeted clinical approach, which is predictive, preventive, personalized and participatory (“P4-medicine”). It clearly emerges that in the next future, new opportunities will become available for clinical research on rare COPD patterns and for the identification of new biomarkers of comorbidity, severity, and progression. Herein, we overview the literature discussing the opportunity coming from the adoption of SMapproaches in COPD management, focusing on proteomics and metabolomics, and emphasizing the identification of disease sub-clusters, to improve the development of more effective therapies.

Carriership of coagulation factor V Leiden (FVL) is by far the most common thrombophilia in Western populations. FVL is caused by a single point mutation in the gene coding for coagulation factor V (FV) causing a lifelong procoagulatory state with an increased risk of venous thromboembolism (VTE) which might be fatal. It is believed that the mutation occurred in one person 21,000 years ago and today 3% to 15% of the Western populations are carriers. A potentially dangerous mutation such as FVL ought to be rare and should have been reduced, if not eradicated, by selection during the course of human evolution. Thus, FVL must confer the carriers with an evolutionary advantage in order to be so prevalent. Lower risk of profuse bleeding and increased fecundity might give carriers an advantage. In this paper we give an updated short background and discuss possible evolutionary advantages and disadvantages.

Oxaliplatin is one of the most widely used anticancer drugs representing the cornerstone of the treatment of colorectal cancer. Yet a number of side effects, including oxaliplatin- induced peripheral neurotoxicity (OIPN) which represents a dose-limiting side effect in the clinical use of oxaliplatin, limit its use and a better understanding of its pathogenesis would offer a great opportunity to improve the “quality of survival” of cancer patients. So far, no treatment able to prevent or limit OIPN has been approved, and one of the reasons for this unmet clinical need is the incomplete knowledge of its pathogenesis preventing the development of rationalebased pharmacological interventions. Preclinical and clinical evidence raised the hypothesis that intracellular calcium-related events might play an important role in the onset of OIPN. Yet, the results of mechanistic pre-clinical studies appear inconsistent and, therefore, their relevance in neuroprotective drugs design is still uncertain. Indeed, it is at present unclear whether aberrant calcium signalling is the key pathogenetic moment or whether it just constitutes the mediator of the clinical phenotype. This review will summarize the preclinical results involving calcium-related events and OIPN with the aim to provide an updated overview of the available evidence and highlight the most promising strategies to design effective neuroprotective drugs. In particular, we will focus on the pre-clinical evidence suggesting that TRPV1, TRPM8 or TRPA1 might be involved, as these appear particularly amenable to pharmacological modulation.

Disturbance in the functioning of the gastrointestinal (GI) tract can critically affect the health and even the life of the whole organism. Several factors, both exo- and endogenous may contribute to the dysregulation of homeostasis in the digestive system, including genetic background, ingestion of highly processed food, exposition to environmental pollution or chronic stress, and changes in gut microflora, to name just a few. An important number of these factors rely on metals, which often play a dual, stimulatory and inhibitory role in crucial physiological processes. In this paper, we focus on the structures incorporating silver, copper and other metals as future drugs against GI diseases. We critically review available literature for their effectiveness and potential application, and discuss clinical relevance of these findings.

Coral-derived microorganisms have been a major focus of many research efforts on marine ecology in recent decades. Importantly, research on bioactive compounds from these diverse microorganisms, which include fungi and bacteria, has experienced an explosive growth during the past five years. This has unveiled the ecological roles of these microorganisms, which prevent antifouling, inhibit pathogenic bacteria, and deter predators in ocean ecosystems. Moreover, the structural diversity and pharmacological activity of the compounds produced by these microorganisms have also been studied extensively, leading not only to an understanding their roles within ecosystems, but also the potential value of their use in human health. In this review, 258 marine natural products, including polyketides, terpenoids, meroterpenoids, alkaloids, peptides, shikimates and lipids, all discovered in the past 24 years, are presented. 146 references are cited.