Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

Josefsson, Emma C.; Vainchenker, William; James, Chloé

doi:10.3390/ijms21207591

Cited by 34 publications

(26 citation statements)

References 76 publications

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“…Bcl-2 family members includes anti-apoptotic,e.g. Bcl-2, Bcl-xL and Mcl-1and pro-apoptotic, e.g.Bax and Bak [ 21 ]. Pro-apoptotic proteins interact with mitochondrial outer membrane.…”

Section: Discussionmentioning

confidence: 99%

Role of MicroRNA-326 and its Target Genes Bcl-xL and Bak as Potential Markers in Platelet Storage Lesion in Blood Banks

Elgendy

Swelem

Aboudiba

et al. 2022

Indian J Hematol Blood Transfus

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Platelet transfusion is crucial in the management of various conditions such as quantitative and qualitative platelet disorders. A serious problem that impacts public health is the shortage of Platelet concentrates (PCs) that frequently affect few blood donors’ countries, such as Egypt. This has necessitated the need to establish novel standards for determining the quality of PC during storage. It was found that microRNAs (miRNA) differential expression profile is a helpful tool for recognition of physiological platelet changes during storage. The aim of the current study was to highlight the role of platelet miRNA-326 and its putative target apoptotic genes, Bcl-xL and Bak, and their role in platelet storage lesion (PSL). Differential expression of miRNA-326 and its target genes in the apoptotic pathway, Bcl-xL and Bak was done using quantitative real time PCR (QR-PCR) on different storage points at day 0, day 3 and day 5 in blood bank. The results of the current study revealed over expression of miRNA-326 throughout days of storage resulted in down regulation of Bcl-xL gene and subsequently up regulation of Bak gene. MiRNA-326 contributes to platelet apoptosis and PSL through inhibition of anti-apoptotic Bcl-xL expression and enhancing pro-apoptotic Bak expression. Differential miRNA-326 and its target gene, Bcl-xL and Bak, expression levels at different points of platelets storage are promising tools as biomarkers for platelets undergoing PSL in blood banks.

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“…Bcl-2 family members includes anti-apoptotic,e.g. Bcl-2, Bcl-xL and Mcl-1and pro-apoptotic, e.g.Bax and Bak [ 21 ]. Pro-apoptotic proteins interact with mitochondrial outer membrane.…”

Section: Discussionmentioning

confidence: 99%

Role of MicroRNA-326 and its Target Genes Bcl-xL and Bak as Potential Markers in Platelet Storage Lesion in Blood Banks

Elgendy

Swelem

Aboudiba

et al. 2022

Indian J Hematol Blood Transfus

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“…Additionally, TLR2 induction activates wnt b-catenin signalling pathway components, indicating a cross talk between wnt and TLR pathway leading to megakaryocyte maturation (Undi et al 2016 ). BCl-X L is the key pro-survival protein that is essential for survival of megakaryocyte and platelet (Josefsson et al 2020 ). Megakaryocyte-specific deletion of BCl-X L in mice triggers megakaryocyte apoptosis and a failure of platelet shedding, which leading to severe thrombocytopenia (Josefsson et al 2011 ).…”

Section: Discussionmentioning

confidence: 99%

DMAG, a novel countermeasure for the treatment of thrombocytopenia

Jia

Zeng

et al. 2021

Mol Med

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Background Thrombocytopenia is one of the most common hematological disease that can be life-threatening caused by bleeding complications. However, the treatment options for thrombocytopenia remain limited. Methods In this study, giemsa staining, phalloidin staining, immunofluorescence and flow cytometry were used to identify the effects of 3,3ʹ-di-O-methylellagic acid 4ʹ-glucoside (DMAG), a natural ellagic acid derived from Sanguisorba officinalis L. (SOL) on megakaryocyte differentiation in HEL cells. Then, thrombocytopenia mice model was constructed by X-ray irradiation to evaluate the therapeutic action of DMAG on thrombocytopenia. Furthermore, the effects of DMAG on platelet function were evaluated by tail bleeding time, platelet aggregation and platelet adhesion assays. Next, network pharmacology approaches were carried out to identify the targets of DMAG. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate the underling mechanism of DMAG against thrombocytopenia. Finally, molecular docking simulation, molecular dynamics simulation and western blot analysis were used to explore the relationship between DAMG with its targets. Results DMAG significantly promoted megakaryocyte differentiation of HEL cells. DMAG administration accelerated platelet recovery and megakaryopoiesis, shortened tail bleeding time, strengthened platelet aggregation and adhesion in thrombocytopenia mice. Network pharmacology revealed that ITGA2B, ITGB3, VWF, PLEK, TLR2, BCL2, BCL2L1 and TNF were the core targets of DMAG. GO and KEGG pathway enrichment analyses suggested that the core targets of DMAG were enriched in PI3K–Akt signaling pathway, hematopoietic cell lineage, ECM-receptor interaction and platelet activation. Molecular docking simulation and molecular dynamics simulation further indicated that ITGA2B, ITGB3, PLEK and TLR2 displayed strong binding ability with DMAG. Finally, western blot analysis evidenced that DMAG up-regulated the expression of ITGA2B, ITGB3, VWF, p-Akt and PLEK. Conclusion DMAG plays a critical role in promoting megakaryocytes differentiation and platelets production and might be a promising medicine for the treatment of thrombocytopenia. Graphical Abstract

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“…Additionally, TLR2 induction activates wnt b-catenin signalling pathway components, indicating a cross talk between wnt and TLR pathway leading to megakaryocyte maturation (Undi et al 2016). BCl-X L is the key pro-survival protein that is essential for survival of megakaryocyte and platelet (Josefsson et al 2020). Megakaryocyte-speci c deletion of BCl-X L in mice triggers megakaryocyte apoptosis and a failure of platelet shedding, which leading to severe thrombocytopenia (Josefsson et al 2011).…”

Section: Discussionmentioning

confidence: 99%

DMAG, a Novel Countermeasure for the Treatment of Thrombocytopenia

Lin

Zeng

et al. 2021

Preprint

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Background: Thrombocytopenia is one of the most common hematological disease that can be life-threatening caused by bleeding complications. However, the treatment options for thrombocytopenia remain limited. Methods: In this study, giemsa staining, phalloidin staining and flow cytometry were firstly used to identify the effects of 3,3'-Di-O-methylellagic acid 4'-glucoside (DMAG), a natural ellagic acid derived from Sanguisorba officinalis L. (SOL) on megakaryocyte differentiation in HEL cells. Then, thrombocytopenia mice model was constructed by X-ray irradiation to evaluate the therapeutic action of DMAG on thrombocytopenia. Next, network pharmacology approachs were carried out to identify the targets of DMAG. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrich-ment analyses were performed to elucidate the underling mechanism of DMAG against thrombocytopenia. Finally, Molecular docking simulation, molecular dynamics simulation and western blot analysis were used to explore the relationship between DAMG with its targets.Results: DMAG significantly promoted megakaryocyte differentiation and maturation of HEL cells. DMAG administration accelerated platelet recovery and megakaryopoiesis in thrombocytopenia mice. Network pharmacology revealed that ITGA2B, ITGB3, VWF, PLEK, TLR2, BCL2, BCL2L1 and TNF were the core targets of DMAG. GO and KEGG pathway enrichment analyses suggested that the core targets of DMAG were enriched in PI3K-Akt signaling pathway, hematopoietic cell lineage, ECM-receptor interaction and platelet activation. Molecular docking simulation and molecular dynamics simulation further indicated that ITGA2B, ITGB3, PLEK and TLR2 displayed strong binding ability with DMAG. Finally, western blot analysis evidenced that DMAG up-regulated the expression of ITGA2B, ITGB3, VWF and PLEK. Conclusion: DMAG plays a critical role in promoting megakaryocytes differentiation and platelets production and might be a promising medicine for the treatment of thrombocytopenia.

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Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

Cited by 34 publications

References 76 publications

Role of MicroRNA-326 and its Target Genes Bcl-xL and Bak as Potential Markers in Platelet Storage Lesion in Blood Banks

Role of MicroRNA-326 and its Target Genes Bcl-xL and Bak as Potential Markers in Platelet Storage Lesion in Blood Banks

DMAG, a novel countermeasure for the treatment of thrombocytopenia

DMAG, a Novel Countermeasure for the Treatment of Thrombocytopenia

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