fb12dd26e3d10a397dcaf1c87c0b7d6a pmc_34199099.pdf 5a553188c52414dddf78b5979c087b501d36fb22 pmc_34199099.pdf 49e962c5405207b792807a16ac90aebde4306c7cebc6b8fd7ed8a138648e5ee6 pmc_34199099.pdf Title: Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach Subject: Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP. Keywords: eltrombopag; primary immune thrombocytopenia; immunomodulation; in silico; systems biology; mathematical modelling; artificial intelligence Author: Maria L. Lozano, Cristina Segú-Vergés, Mireia Coma, María T. Álvarez-Roman, José R. González-Porras, Laura Gutiérrez, David Valcárcel and Nora Butta Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Jun 27 13:06:15 2021 CEST ModDate: Sun Jun 27 13:15:30 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2038550 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MOCBVF+VnURWPalladioL Type 1 Custom yes yes no 10 0 FNHDCN+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 FMRJJF+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 JZMOGQ+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 VORBJF+CMSY10 Type 1 Builtin yes yes no 28 0 QGYAWM+SFRM0800 Type 1 Custom yes yes no 32 0 FJDQIS+VnURWPalladioL-Bold Type 1 Custom yes yes no 37 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 45 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 48 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 70 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 74 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 78 0 OEWVVO+PazoMath-Italic Type 1 Builtin yes yes no 93 0 GOCQIR+EURM10 Type 1 Builtin yes yes no 97 0 FDNFCP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 107 0 FDNFDA+PalatinoLinotype CID TrueType Identity-H yes yes yes 110 0 FDNFDB+PalatinoLinotype TrueType WinAnsi yes yes no 116 0 FDNFDC+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 119 0 FDNFDD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 125 0 FDNFCP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 132 0 FDNFDA+PalatinoLinotype CID TrueType Identity-H yes yes yes 135 0 FDNFDB+PalatinoLinotype TrueType WinAnsi yes yes no 141 0 FDNFDC+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 144 0 FDNFDD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 150 0 FDNFCP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 160 0 FDNFDA+PalatinoLinotype CID TrueType Identity-H yes yes yes 163 0 FDNFDB+PalatinoLinotype TrueType WinAnsi yes yes no 169 0 FDNFDD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 172 0 FDNFCP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 185 0 FDNFDA+PalatinoLinotype CID TrueType Identity-H yes yes yes 188 0 FDNFDB+PalatinoLinotype TrueType WinAnsi yes yes no 194 0 FDNFDD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 197 0 FDNFCP+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 210 0 FDNFDA+PalatinoLinotype CID TrueType Identity-H yes yes yes 213 0 FDNFDB+PalatinoLinotype TrueType WinAnsi yes yes no 219 0 FDNFDD+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 222 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:13:00 CEST RepresentationInformation: pmc_34199099.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:14:17 CEST Size: 2038550 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 577 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Primary Immune Thrombocytopenia Interactome Destination: subsection.2.1 Item: Title: Eltrombopag Could Increase TGF- Expression through MPL Signaling Destination: subsection.2.2 Item: Title: Signaling of Eltrombopag through MPL on Immune Cells Could Affect IFN-, PPAR, and FOXP3 Function Destination: subsection.2.3 Item: Title: Eltrombopag Could Interact with the BCL2 Protein Family Destination: subsection.2.4 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: TPMS Technology: Systems Biology-Based Model Creation Destination: subsection.4.1 Item: Title: Human Biological Network and Molecular Definition of Clinical Concepts Destination: subsection.4.2 Item: Title: Human Physiological Rules and Mechanism Of Action Models Destination: subsection.4.3 Item: Title: Chemical Similarity Destination: subsection.4.4 Item: Title: Docking Analysis Destination: subsection.4.5 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Elucidating the Mechanism of Action of the Attributed Immunomodulatory Role of Eltrombopag in Primary Immune Thrombocytopenia: An In Silico Approach Author: Maria L. Lozano, Cristina Segú-Vergés, Mireia Coma, María T. Álvarez-Roman, José R. González-Porras, Laura Gutiérrez, David Valcárcel and Nora Butta Subject: Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP. 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Annotation: Subtype: Link Rect: 136, 400, 173, 410 Annotation: Subtype: Link Rect: 422, 376, 460, 387 Annotation: Subtype: Link Rect: 378, 341, 415, 352 Annotation: Subtype: Link Rect: 519, 318, 557, 329 Annotation: Subtype: Link Rect: 59, 308, 95, 318 Annotation: Subtype: Link Rect: 396, 284, 433, 295 Annotation: Subtype: Link Rect: 440, 284, 476, 295 Annotation: Subtype: Link Rect: 59, 250, 97, 260 Annotation: Subtype: Link Rect: 337, 226, 375, 237 Annotation: Subtype: Link Rect: 381, 226, 417, 237 Annotation: Subtype: Link Rect: 202, 204, 240, 214 Annotation: Subtype: Link Rect: 246, 204, 282, 214 Checksum: fd825d67 Type: CRC32 Checksum: fb12dd26e3d10a397dcaf1c87c0b7d6a Type: MD5 Checksum: 5a553188c52414dddf78b5979c087b501d36fb22 Type: SHA-1 Checksum: 49e962c5405207b792807a16ac90aebde4306c7cebc6b8fd7ed8a138648e5ee6 Type: SHA-256