A Systems Pharmacology Analysis of Major Chemotherapy Combination Regimens Used in Gastric Cancer Treatment: Predicting Potential New Protein Targets and Drugs

Rosado, Joemerson Osório; Henriques, João Antônio Pêgas; Bonatto, Diego

doi:10.2174/156800911796798977

Cited by 16 publications

(16 citation statements)

References 126 publications

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“…Co-targeting of an additional crucial point of drug-affected network pathways is an efficient tool to fight against resistance. Drug combinations and multi-target drugs develop less resistance (Zimmermann et al, 2007; Pujol et al, 2010; Rosado et al, 2011; Savino et al, 2012). Analysis of pathogen interactomes involving random walks or known drug resistance-related proteins plus gene expression changes revealed pathways often involved in resistance development helping co-target determination (Raman & Chandra, 2008; Chen et al, 2012b).…”

Section: Areas Of Drug Design: An Assessment Of Network-related Admentioning

confidence: 99%

Structure and dynamics of molecular networks: A novel paradigm of drug discovery

Csermely

Korcsmáros

Kiss

et al. 2013

Pharmacology & Therapeutics

820

661

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Despite considerable progress in genome- and proteome-based high-throughput screening methods and in rational drug design, the increase in approved drugs in the past decade did not match the increase of drug development costs. Network description and analysis not only gives a systems-level understanding of drug action and disease complexity, but can also help to improve the efficiency of drug design. We give a comprehensive assessment of the analytical tools of network topology and dynamics. The state-of-the-art use of chemical similarity, protein structure, protein-protein interaction, signaling, genetic interaction and metabolic networks in the discovery of drug targets is summarized. We propose that network targeting follows two basic strategies. The “central hit strategy” selectively targets central node/edges of the flexible networks of infectious agents or cancer cells to kill them. The “network influence strategy” works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved. It is shown how network techniques can help in the identification of single-target, edgetic, multi-target and allo-network drug target candidates. We review the recent boom in network methods helping hit identification, lead selection optimizing drug efficacy, as well as minimizing side-effects and drug toxicity. Successful network-based drug development strategies are shown through the examples of infections, cancer, metabolic diseases, neurodegenerative diseases and aging. Summarizing >1200 references we suggest an optimized protocol of network-aided drug development, and provide a list of systems-level hallmarks of drug quality. Finally, we highlight network-related drug development trends helping to achieve these hallmarks by a cohesive, global approach.

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Section: Areas Of Drug Design: An Assessment Of Network-related Admentioning

confidence: 99%

Structure and dynamics of molecular networks: A novel paradigm of drug discovery

Csermely

Korcsmáros

Kiss

et al. 2013

Pharmacology & Therapeutics

820

661

View full text Add to dashboard Cite

show abstract

“…Our group has successfully employed systems chemo-biology to discover potential new anti-tumor drugs for gastric cancer (Rosado et al, 2011) and to understand the molecular pathways underlying fetal malformations associated with tobacco abuse during pregnancy (Feltes et al, 2013).…”

Section: Design Of the Interactome Network Topological Analysis Andmentioning

confidence: 99%

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

Feltes

Poloni

Nunes

et al. 2014

OMICS: A Journal of Integrative Biology

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Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulinassociated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment.

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“…In order to describe the global characteristics of the network, we measured centralities 18 or topological network properties as follows: (i) ‘stress', representing how much a node (gene/protein) is traversed by a high number of ideal routes or short paths in a network. Then, a gene/protein traversed by higher number of short paths will be, by definition, more stressed.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, non-HBs (NH-Bs) are nodes with low connectivity and high betweenness centrality, and non-hub-non-bottlenecks are nodes with both connectivity and betweenness centrality values below the thresholds. 18 …”

Section: Methodsmentioning

confidence: 99%

Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy

et al. 2014

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Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-β precursor protein-α has been shown to be elevated in severe autism, leading to the ‘anabolic hypothesis' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg2+) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.

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A Systems Pharmacology Analysis of Major Chemotherapy Combination Regimens Used in Gastric Cancer Treatment: Predicting Potential New Protein Targets and Drugs

Cited by 16 publications

References 126 publications

Structure and dynamics of molecular networks: A novel paradigm of drug discovery

Structure and dynamics of molecular networks: A novel paradigm of drug discovery

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy

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