In Silico Dynamic Molecular Interaction Networks for the Discovery of New Therapeutic Targets

Vujasinovic, Todor; Žampera, André Siniša; Jackers, Pascale; Sanoudou, Despina; Depaulis, Antoine

doi:10.2174/138161210791792822

Cited by 3 publications

(6 citation statements)

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“…We then analyzed the modulation of the full genome microarray data generated on RHE stimulated or not stimulated by VFB by the in silico PROPAGAPATH7 dynamic system, with special focus on the possible links between TLR2 stimulation and IL8 and CCL20 modulation.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, to investigate the possible signaling endogenous pathways linking TLR2 – an identified keratinocyte target of VFB/LRP-VFB involved in the signal transduction of bacterial elements – to the strongly upregulated chemokines chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8) that play a major role in the regulation of skin homeostasis, we tested the potential of the PROPAGAPATH7 in silico model. PROPAGAPATH7 is a dynamic and oriented signaling propagation pathway database, developed by Helios Biosciences (Romainville, France), originally developed, validated, and enriched with immunological and neural cell propagation data.…”

Section: Introductionmentioning

confidence: 99%

“…PROPAGAPATH7 is a dynamic and oriented signaling propagation pathway database, developed by Helios Biosciences (Romainville, France), originally developed, validated, and enriched with immunological and neural cell propagation data. We wanted to evaluate the potency of this model to detect minimal propagation pathways – potentially not already identified by conventional studies – when confronted with data from human skin epidermal keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

“…We used a combination of full genome expression studies and PROPAGAPATH analysis7 to understand which endogenous pathways the keratinocytes trigger in response to VF stimulation.…”

Section: Introductionmentioning

confidence: 99%

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A new Vitreoscilla filiformis extract grown on spa water-enriched medium activates endogenous cutaneous antioxidant and antimicrobial defenses through a potential Toll-like receptor 2/protein kinase C, zeta transduction pathway

Mahé

Perez²,

Tacheau³

et al. 2013

CCID

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Vitreoscilla filiformis (VF) biomass (VFB) has been widely used in cosmetic preparations and shown to modulate the major inducible free-radical scavenger mitochondrial superoxide dismutase in skin cells. By adding La Roche-Posay (LRP) thermal spring water to the VF culture medium, we obtained a biomass (LRP-VFB) with a similar mitochondrial superoxide dismutase activation capacity to VF. Also, the new biomass more powerfully stimulated mRNA expression and antimicrobial peptides in reconstructed epidermis. Interestingly, a predictive computer model that analyzed transducing events within skin epidermal cells suggested that this protective activity may involve the Toll-like receptor 2/protein kinase C, zeta transduction pathway. Protein kinase C, zeta inhibition was effectively shown to abolish VFB-induced gene stimulation and confirmed this hypothesis. This thus opens new avenues for investigation into the improvement of skin homeostatic defense in relation to the control of its physiological microbiota and innate immunity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We used a combination of full genome expression studies and PROPAGAPATH analysis7 to understand which endogenous pathways the keratinocytes trigger in response to VF stimulation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A new Vitreoscilla filiformis extract grown on spa water-enriched medium activates endogenous cutaneous antioxidant and antimicrobial defenses through a potential Toll-like receptor 2/protein kinase C, zeta transduction pathway

Mahé

Perez²,

Tacheau³

et al. 2013

CCID

View full text Add to dashboard Cite

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“…Approaches using systems biology may be useful for integrating all aspects of a given phenomenon and may constitute promising strategies. However, models of any scale have advantages and limitations (Vujasinovic et al, 2010 ). We have created a small-scale, simple model that focuses on the dynamics of TDP-43 and does not contain other related molecules.…”

Section: Discussionmentioning

confidence: 99%

Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data

et al. 2018

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Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay. The level of nuclear TDP-43 is tightly regulated by these mechanisms, which control the amount of mRNA that may be translated. Based on the results of previous experiments, we developed an in silico model that mimics the intracellular dynamics of TDP-43 and examined TDP-43 metabolism under various conditions. We discovered an inherent trade-off in this mechanism between transcriptional redundancy, which maintains the robustness of TDP-43 metabolism, and vulnerability to specific interfering factors. These factors include an increased tendency of TDP-43 to aggregate, impaired nuclear-cytoplasmic TDP-43 transport, and a decreased efficiency of degrading abnormal proteins, all of which are functional abnormalities related to the gene that causes familial ALS/FTD. When these conditions continue at a certain intensity, the vulnerability of the autoregulatory machinery becomes apparent over time, and transcriptional redundancy enters a vicious cycle that ultimately results in TDP-43 pathology. The results obtained using this in silico model reveal the difference in TDP-43 metabolism between normal and disease states. Furthermore, using this model, we simulated the effect of a decrease in TDP-43 transcription and found that this decrease improved TDP-43 pathology and suppressed the abnormal propagation of TDP-43. Therefore, we propose a potential therapeutic strategy to suppress transcriptional redundancy, which is the driving force of the pathological condition caused by the specific factors described above, in patients with ALS presenting with TDP-43 pathology. An ALS animal model exhibiting TDP-43 pathology without overexpression of exogenous TDP-43 should be developed to investigate the effect of alleviating the transcriptional redundancy of TARDBP.

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An in silico target identification using Boolean network attractors: Avoiding pathological phenotypes

Poret

Boissel²

2014

Comptes Rendus. Biologies

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Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose function should be therapeutically altered in order to cure the considered pathology. This work proposes an algorithm for in silico target identification using Boolean network attractors. It assumes that attractors of dynamical systems, such as Boolean networks, correspond to phenotypes produced by the modeled biological system. Under this assumption, and given a Boolean network modeling a pathophysiology, the algorithm identifies target combinations able to remove attractors associated with pathological phenotypes. It is tested on a Boolean model of the mammalian cell cycle bearing a constitutive inactivation of the retinoblastoma protein, as seen in cancers, and its applications are illustrated on a Boolean model of Fanconi anemia. The results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice, thus requiring it to be used in combination with wet lab experiments. Nevertheless, it is expected that the algorithm is of interest for target identification, notably by exploiting the inexpensiveness and predictive power of computational approaches to optimize the efficiency of costly wet lab experiments.

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In Silico Dynamic Molecular Interaction Networks for the Discovery of New Therapeutic Targets

Cited by 3 publications

References 50 publications

A new Vitreoscilla filiformis extract grown on spa water-enriched medium activates endogenous cutaneous antioxidant and antimicrobial defenses through a potential Toll-like receptor 2/protein kinase C, zeta transduction pathway

A new Vitreoscilla filiformis extract grown on spa water-enriched medium activates endogenous cutaneous antioxidant and antimicrobial defenses through a potential Toll-like receptor 2/protein kinase C, zeta transduction pathway

Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data

An in silico target identification using Boolean network attractors: Avoiding pathological phenotypes

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