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Systems biology applied to non-alcoholic fatty liver disease (NAFLD): treatment selection based on the mechanism of action of nutraceuticals

Journal: Nutrafoods, June 2014, Volume 13, Issue 2, pp 61-68

Authors: Perera S, Artigas L, Mulet R, Mas JM, Sardón T

Non-alcoholic fatty liver disease (NAFLD) comprises several liver pathologic states and affects 10%–35% of the population. However, the only known “treatment” for NAFLD is significant weight loss through a lifestyle change, so there is a great need for improvement in the pharmacological management of the disease. As nutraceuticals may alleviate the results of lack of treatment during the first, asymptomatic phase of the disease, we used SIMScells (www.simscells.com) and the Therapeutic Performance Mapping System (TPMS), a proprietary systems biology technology of Anaxomics (www.anaxomics. com), to predict the best nutraceuticals to use against NAFLD. We first performed a reprofiling analysis, which led us to identify 33 potential nutraceuticals that could ameliorate the illness. Next, we found the most probable mechanism of action (MoA) of four selected nutraceuticals. Some of these MoAs feature links that have never before been related to the studied pathophysiological mechanisms, thus providing new testable hypotheses. In addition, the MoAs provide two means of treatment selection, according to disease pathophysiological pathways (“motives”) or to each patient’s response to the nutraceuticals (“cluster MoAs”). In conclusion, we use TPMS to predict the molecular mechanistic explanation of the action of the current top nutraceutical used against NAFLD, L-carnitine, highlighting different response subpopulations. We also mechanistically propose the stratification of patients and usefulness of other nutraceuticals (calcitriol and thiamine) on a par or over L-carnitine according to patients’ pathophysiology.

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The Proton-Pump Inhibitor Lansoprazole Enhances Amyloid Beta Production

Journal: PLoS ONE 2013;8

Authors: Badiola N, Alcalde V, Pujol A, Münter L-M, Multhaup G, Lle&oacute A, Coma M, Soler-L&oacutepez M, Aloy P

A key event in the pathogenesis of Alzheimer’s disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and ?-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

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Unveiling the role of network and systems biology in drug discovery

Journal: Trends Pharmacol Sci 2010 Mar;31(3):115-23

Authors: Pujol A, Mosca R, Farrés J, Aloy P

Network and systems biology offer a novel way of approaching drug discovery by developing models that consider the global physiological environment of protein targets, and the effects of modifying them, without losing the key molecular details. Here we review some recent advances in network and systems biology applied to human health, and discuss how they can have a big impact on some of the most interesting areas of drug discovery. In particular, we claim that network biology will play a central part in the development of novel polypharmacology strategies to fight complex multifactorial diseases, where efficacious therapies will need to center on altering entire pathways rather than single proteins. We briefly present new developments in the two areas where we believe network and system biology strategies are more likely to have an immediate contribution: predictive toxicology and drug repurposing.

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Revealing the molecular relationship between type 2 diabetes and the metabolic changes induced by a very-low-carbohydrate low-fat ketogenic diet

Journal: Nutr Metab (Lond) 2010;7:88

Author: Farrés J, Pujol A, Coma M, Ruiz JL, Naval J, Mas JM, Molins A, Fondevila J, Aloy P

ABSTRACT: BACKGROUND: The prevalence of type 2 diabetes is increasing worldwide, accounting for 85-95% of all diagnosed cases of diabetes. Clinical trials provide evidence of benefits of low-carbohydrate ketogenic diets in terms of clinical outcomes on type 2 diabetes patients. However, the molecular events responsible for these improvements still remain unclear in spite of the high amount of knowledge on the primary mechanisms of both the diabetes and the metabolic state of ketosis. Molecular network analysis of conditions, diseases and treatments might provide new insights and help build a better understanding of clinical, metabolic and molecular relationships among physiological conditions. Accordingly, our aim is to reveal such a relationship between a ketogenic diet and type 2 diabetes through systems biology approaches. METHODS: Our systemic approach is based on the creation and analyses of the cell networks representing the metabolic state in a very-low-carbohydrate low-fat ketogenic diet. This global view might help identify unnoticed relationships often overlooked in molecule or process-centered studies. RESULTS: A strong relationship between the insulin resistance pathway and the ketosis main pathway was identified, providing a possible explanation for the improvement observed in clinical trials. Moreover, the map analyses permit the formulation of some hypothesis on functional relationships between the molecules involved in type 2 diabetes and induced ketosis, suggesting, for instance, a direct implication of glucose transporters or inflammatory processes. The molecular network analysis performed in the ketogenic-diet map, from the diabetes perspective, has provided insights on the potential mechanism of action, but also has opened new possibilities to study the applications of the ketogenic diet in other situations such as CNS or other metabolic dysfunctions.

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Targeting and tinkering with interaction networks

Journal: Nat Chem Biol. 2008/10/22 ed. Volume 4; 2008. p 666-673

Author: Russell RB, Aloy P

Biological interaction networks have been in the scientific limelight for nearly a decade. Increasingly, the concept of network biology and its various applications are becoming more commonplace in the community. Recent years have seen networks move from pretty pictures with limited application to solid concepts that are increasingly used to understand the fundamentals of biology. They are no longer merely results of postgenome analysis projects, but are now the starting point of many of the most exciting new scientific developments. We discuss here recent progress in identifying and understanding interaction networks, new tools that use them in predictive ways in exciting areas of biology, and how they have become the focus of many efforts to study, design and tinker with biological systems, with applications in biomedicine, bioengineering, ecology and beyond.

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Towards a molecular characterisation of pathological pathways

Journal: FEBS Lett 2008;582(8):1259-1265

Authors: Pache RA, Zanzoni A, Naval J, Mas JM, Aloy P

The dominant conceptual reductionism in drug discovery has resulted in many promising drug candidates to fail during the last clinical phases, mainly due to a lack of knowledge about the patho-physiological pathways they are acting on. Consequently, to increase the revenues of the drug discovery process, we need to improve our understanding of the molecular mechanisms underlying complex cellular processes and consider each potential drug target in its full biological context. Here, we review several strategies that combine computational and experimental techniques, and suggest a systems pathology approach that will ultimately lead to a better comprehension of the molecular bases of disease.

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