Cause-effect relationships in medicine: a protein network perspective

Fliri, Anton; Loging, William; Volkmann, Robert A.

doi:10.1016/j.tips.2010.07.005

Cited by 33 publications

(27 citation statements)

References 89 publications

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“…We might identify key molecules within PRN structure (integrators or otherwise) that facilitate or constrain evolutionary change. Such approaches are being used in pharmacology to identify key targets for drug discovery [51] and their potential side-effects [52]. An ecological example would be to ask what bird lineages were able to successfully diversify from tropical habitat into temperate.…”

Section: How To Study Prnsmentioning

confidence: 99%

Physiological regulatory networks: ecological roles and evolutionary constraints

Cohen

Martin

Wingfield

et al. 2012

Trends in Ecology & Evolution

180

160

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Ecological and evolutionary physiology has traditionally focused on aspects of physiology one at a time. Here, we discuss the implications of considering physiological regulatory networks (PRNs) as integrated wholes, a perspective that reveals novel roles for physiology in organismal ecology and evolution. For example, evolutionary response to changes in resource abundance might be constrained by the role of dietary micronutrients in immune response regulation, given a particular pathogen environment. Because many physiological components impact more than one process, organismal homeostasis is maintained, individual fitness is determined, and evolutionary change is constrained (or facilitated) by interactions within PRNs. We discuss how PRN structure and its system-level properties could determine both individual performance and patterns of physiological evolution. GlossaryAlternative physiological structures -Different PRN structures that would produce equivalent functional and fitness outcomes for a given species in a given environment. Which structure evolves might be largely random, but might have consequences for long-term evolution of PRN structure.Cytokines -Small cell-signalling proteins involved in intercellular communication. Regulatory cascades of cytokines are particularly critical in the immune system. Dysregulation -A breakdown over time in the ability of an individual's PRN to maintain homeostasis; possibly in response to chronic stress or infection, and possibly a root cause of aging.3 Homeostasis -A state of healthy physiological equilibrium, including appropriate anticipation of and responses to changing conditions.Integrator -A PRN molecule that has a particularly crucial role in synthesizing information (internal or external) and thereby determining multiple aspects of PRN functioning (e.g., a 'hub' or 'keystone' PRN molecule) Physiological Regulatory Network (PRN) -The network of molecules and their regulatory relationships that maintain and adjust homeostasis and facilitate performance at the wholeorganism level.PRN Molecule -PRN molecules are the subset of molecules that maintain homeostasis at the organism level via their regulatory relationships with other molecules. In most cases, these molecules are the nodes (vertices) in a PRN, and regulatory relationships between them are the links (edges). In some cases, several related molecules (e.g., circulating steroid, receptors, binding globulins) may be grouped together as a single node for measurement purposes, or gene activation may be a node in some contexts. Flexibility of node definition is common in other biological networks-for example, nodes in ecological networks can be species, groups of species, life stages, or other categories (e.g., detritus). PRN state -The concentrations of all PRN molecules at a given moment for a given individual in a particular context (e.g. age, time of year, life history stage). More generally, "changes in PRN state" describe joint adjustments in molecule concentrations in anticipation of or respo...

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Section: How To Study Prnsmentioning

confidence: 99%

Physiological regulatory networks: ecological roles and evolutionary constraints

Cohen

Martin

Wingfield

et al. 2012

Trends in Ecology & Evolution

180

160

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“…With the network influence strategy, breaking down the system's robustness to push the system from one that favors the diseased state to one that favors a healthy state is a difficult task. The preferred targets of the network influence strategy are considered as the connected nodes located in vulnerable points of disease-related networks such as in intermodular, bridging positions [60][61][62][63][64][65] . In signaling networks, the strategy of influencing preferred nodes in the network inhibits certain outputs of the signaling network, while leaving others intact to redirect the signal flow in the network [66][67][68] .…”

Section: Hitting Parallel Pathwaysmentioning

confidence: 99%

Diverse array-designed modes of combination therapies in Fangjiomics

Wang

2015

Acta Pharmacol Sin

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In line with the complexity of disease networks, diverse combination therapies have been demonstrated potential in the treatment of different patients with complex diseases in a personal combination profile. However, the identification of rational, compatible and effective drug combinations remains an ongoing challenge. Based on a holistic theory integrated with reductionism, Fangjiomics systematically develops multiple modes of array-designed combination therapies. We define diverse "magic shotgun" vertical, horizontal, focusing, siege and dynamic arrays according to different spatiotemporal distributions of hits on targets, pathways and networks. Through these multiple adaptive modes for treating complex diseases, Fangjiomics may help to identify rational drug combinations with synergistic or additive efficacy but reduced adverse side effects that reverse complex diseases by reconstructing or rewiring multiple targets, pathways and networks. Such a novel paradigm for combination therapies may allow us to achieve more precise treatments by developing phenotype-driven quantitative multi-scale modeling for rational drug combinations.

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“…Systems-level molecular networks have a 100-fold larger size. Estimates of the number of possible states of the yeast interactome range from 10 7,200 to 10 79,000,000,000 [159], which are all unimaginably high numbers. The number of possible states of the human interactome, which is an order of magnitude larger, must be even higher.…”

Section: Propagation Of Signals In Cellular Networkmentioning

confidence: 99%

“…Earlier works already pointed towards an allo-network type drug action, like the suggestion of inter-protein propagation of allosteric effects [10,168] and the possible use of such an effect in drug design [7]. In fact, drugs that can be considered allo-network drugs already exist.…”

Section: Allo-network Drugs: Extension Of the Concept Of Allosteric Dmentioning

confidence: 99%

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

Szilágyi¹,

Nussinov²,

Csermely

2013

CTMC

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Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same protein. Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein interaction and signaling networks of the cell. Allo-network drugs influence the pharmacological target protein indirectly using specific inter-protein network pathways. We show that allo-network drugs may have a higher efficiency to change the networks of human cells than those of other organisms, and can be designed to have specific effects on cells in a diseased state. Finally, we summarize possible methods to identify allo-network drug targets and sites, which may develop to a promising new area of systems-based drug design.

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Cause-effect relationships in medicine: a protein network perspective

Cited by 33 publications

References 89 publications

Physiological regulatory networks: ecological roles and evolutionary constraints

Physiological regulatory networks: ecological roles and evolutionary constraints

Diverse array-designed modes of combination therapies in Fangjiomics

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

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