scholarly journals Aberrant mitochondrial function in patient-derived neural cells from CDKL5 deficiency disorder and Rett syndrome

2019 ◽  
Vol 28 (21) ◽  
pp. 3625-3636
Author(s):  
Smita Jagtap ◽  
Jessica M Thanos ◽  
Ting Fu ◽  
Jennifer Wang ◽  
Jasmin Lalonde ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Rett Syndrome ◽  
Mitochondrial Function ◽  
Progenitor Cell ◽  
Neural Progenitor Cell ◽  
Neural Cells ◽  
Wild Type ◽  
Expression Of Genes ◽  
Mutant Lines ◽  
Differential Expression Of Genes

Abstract The X-linked neurodevelopmental diseases CDKL5 deficiency disorder (CDD) and Rett syndrome (RTT) are associated with intellectual disability, infantile spasms and seizures. Although mitochondrial dysfunction has been suggested in RTT, less is understood about mitochondrial function in CDD. A comparison of bioenergetics and mitochondrial function between isogenic wild-type and mutant neural progenitor cell (NPC) lines revealed increased oxygen consumption in CDD mutant lines, which is associated with altered mitochondrial function and structure. Transcriptomic analysis revealed differential expression of genes related to mitochondrial and REDOX function in NPCs expressing the mutant CDKL5. Furthermore, a similar increase in oxygen consumption specific to RTT patient–derived isogenic mutant NPCs was observed, though the pattern of mitochondrial functional alterations was distinct from CDKL5 mutant–expressing NPCs. We propose that aberrant neural bioenergetics is a common feature between CDD and RTT disorders. The observed changes in oxidative stress and mitochondrial function may facilitate the development of therapeutic agents for CDD and related disorders.

scholarly journals Progesterone Increases Rat Neural Progenitor Cell Cycle Gene Expression and Proliferation Via Extracellularly Regulated Kinase and Progesterone Receptor Membrane Components 1 and 2

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3186-3196 ◽  
Author(s):  
Lifei Liu ◽  
Junming Wang ◽  
Liqin Zhao ◽  
Jon Nilsen ◽  
Kelsey McClure ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Progesterone Receptor ◽  
Progenitor Cell ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Mammalian Brain ◽  
Cell Cycle Gene ◽  
Cell Cycle Genes ◽  
Expression Of Genes ◽  
Membrane Components

Progesterone receptor (PR) expression and regulation of neural progenitor cell (NPC) proliferation was investigated using NPC derived from adult rat brain. RT-PCR revealed that PRA mRNA was not detected in rat NPCs, whereas membrane-associated PRs, PR membrane components (PGRMCs) 1 and 2, mRNA were expressed. Progesterone-induced increase in 5-bromo-2-deoxyuridine incorporation was confirmed by fluorescent-activated cell sorting analysis, which indicated that progesterone promoted rat NPC exit of G0/G1 phase at 5 h, followed by an increase in S-phase at 6 h and M-phase at 8 h, respectively. Microarray analysis of cell-cycle genes, real-time PCR, and Western blot validation revealed that progesterone increased expression of genes that promote mitosis and decreased expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent on conversion to metabolites and was antagonized by the ERK1/2 inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. PGRMC1 small interfering RNA treatment, together with computational structural analysis of progesterone and its isomers, indicated that the proliferative effect of progesterone is mediated by PGRMC1/2. Progesterone mediated NPC proliferation and concomitant regulation of mitotic cell cycle genes via a PGRMC/ERK pathway mechanism is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain.

Response of macrophages and neural cells in contact with reduced graphene oxide microfibers

2018 ◽  
Vol 6 (11) ◽  
pp. 2987-2997 ◽  
Author(s):  
M. C. Serrano ◽  
M. J. Feito ◽  
A. González-Mayorga ◽  
R. Diez-Orejas ◽  
M. C. Matesanz ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Cell Growth ◽  
Reduced Graphene Oxide ◽  
Progenitor Cell ◽  
Neural Progenitor Cell ◽  
Raw 264.7 ◽  
Neural Cells ◽  
Raw 264.7 Macrophages ◽  
Reduced Graphene ◽  
M2 Phenotype

rGO microfibers mediate polarization of RAW-264.7 macrophages towards an M2 phenotype and support neural progenitor cell growth.

scholarly journals Regulation of neural progenitor cell state by ephrin-B

2008 ◽  
Vol 181 (6) ◽  
pp. 973-983 ◽  
Author(s):  
Runxiang Qiu ◽  
Xiuyun Wang ◽  
Alice Davy ◽  
Chen Wu ◽  
Kiyohito Murai ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Signaling Pathway ◽  
Progenitor Cell ◽  
Neural Progenitor Cells ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Dominant Negative ◽  
Neural Cells ◽  
Protein Signaling ◽  
Cell State

Maintaining a balance between self-renewal and differentiation in neural progenitor cells during development is important to ensure that correct numbers of neural cells are generated. We report that the ephrin-B–PDZ-RGS3 signaling pathway functions to regulate this balance in the developing mammalian cerebral cortex. During cortical neurogenesis, expression of ephrin-B1 and PDZ-RGS3 is specifically seen in progenitor cells and is turned off at the onset of neuronal differentiation. Persistent expression of ephrin-B1 and PDZ-RGS3 prevents differentiation of neural progenitor cells. Blocking RGS-mediated ephrin-B1 signaling in progenitor cells through RNA interference or expression of dominant-negative mutants results in differentiation. Genetic knockout of ephrin-B1 causes early cell cycle exit and leads to a concomitant loss of neural progenitor cells. Our results indicate that ephrin-B function is critical for the maintenance of the neural progenitor cell state and that this role of ephrin-B is mediated by PDZ-RGS3, likely via interacting with the noncanonical G protein signaling pathway, which is essential in neural progenitor asymmetrical cell division.

scholarly journals Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

2019 ◽  
Author(s):  
David Lenin Ebenezer ◽  
Panfeng Fu ◽  
Yashaswin Krishnan ◽  
Mark Maienschein-Cline ◽  
Hong Hu ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Pseudomonas Aeruginosa ◽  
Differential Expression ◽  
Lung Inflammation ◽  
Mouse Lung ◽  
Rna Seq ◽  
Wild Type ◽  
Expression Of Genes ◽  
Whole Transcriptome ◽  
Differential Expression Of Genes

Abstract BACKGROUND Pseudomonas aeruginosa (PA) is an opportunistic Gram-negative bacterium that causes serious life threatening and nosocomial infections including pneumonia. PA has the ability to alter host genome to facilitate its invasion, thus increasing the virulence of the organism. Sphingosine-1- phosphate (S1P), a bioactive lipid, is known to play a key role in facilitating infection. Sphingosine kinases (SPHK) 1&2 phosphorylate sphingosine to generate S1P in mammalian cells. We reported earlier that Sphk2-/- mice offered significant protection against lung inflammation, compared to wild type (WT) animals. Therefore, we profiled the differential expression of genes between the protected group of Sphk2-/- and the wild type controls to better understand the underlying protective mechanisms related to the Sphk2 deletion in lung inflammatory injury. Whole transcriptome shotgun sequencing (RNA-Seq) was performed on mouse lung tissue using NextSeq 500 sequencing system. RESULTS: Two-way analysis of variance (ANOVA) analysis was performed and differentially expressed genes following PA infection were identified using whole transcriptome of Sphk2-/- mice and their WT counterparts. Pathway (PW) enrichment analyses of the RNA seq data identified several signaling pathways that are likely to play a crucial role in pneumonia caused by PA such as those involved in: 1. Immune response to PA infection and NF-κB signal transduction; 2. PKC signal transduction; 3. Impact on epigenetic regulation; 4. Epithelial sodium channel pathway; 5. Mucin expression; and 6. Bacterial infection related pathways. Our genomic data suggests a potential role for SPHK2 in PA-induced pneumonia through elevated expression of inflammatory genes in lung tissue. Further, validation by RT-PCR on 10 differentially expressed genes showed 100% concordance in terms of vectoral changes as well as significant fold change. CONCLUSION: Using Sphk2-/- mice and differential gene expression analysis, we have shown here that S1P/SPHK2 signaling could play a key role in promoting PA pneumonia. The identified genes promote inflammation and suppress others that naturally inhibit inflammation and host defense. Thus, targeting SPHK2/S1P signaling in PA-induced lung inflammation could serve as a potential therapy to combat PA-induced pneumonia. Key Words: Pseudomonas aeruginosa; Lung infection; Sphingosine kinase 2; Sphingolipids; Gene Profiling; Resistance to Infection

scholarly journals Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
David L. Ebenezer ◽  
Panfeng Fu ◽  
Yashaswin Krishnan ◽  
Mark Maienschein-Cline ◽  
Hong Hu ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Pseudomonas Aeruginosa ◽  
Differential Expression ◽  
Lung Inflammation ◽  
Mouse Lung ◽  
Rna Seq ◽  
Wild Type ◽  
Expression Of Genes ◽  
Whole Transcriptome ◽  
Differential Expression Of Genes

Abstract Background Pseudomonas aeruginosa (PA) is an opportunistic Gram-negative bacterium that causes serious life threatening and nosocomial infections including pneumonia. PA has the ability to alter host genome to facilitate its invasion, thus increasing the virulence of the organism. Sphingosine-1- phosphate (S1P), a bioactive lipid, is known to play a key role in facilitating infection. Sphingosine kinases (SPHK) 1&2 phosphorylate sphingosine to generate S1P in mammalian cells. We reported earlier that Sphk2−/− mice offered significant protection against lung inflammation, compared to wild type (WT) animals. Therefore, we profiled the differential expression of genes between the protected group of Sphk2−/− and the wild type controls to better understand the underlying protective mechanisms related to the Sphk2 deletion in lung inflammatory injury. Whole transcriptome shotgun sequencing (RNA-Seq) was performed on mouse lung tissue using NextSeq 500 sequencing system. Results Two-way analysis of variance (ANOVA) analysis was performed and differentially expressed genes following PA infection were identified using whole transcriptome of Sphk2−/− mice and their WT counterparts. Pathway (PW) enrichment analyses of the RNA seq data identified several signaling pathways that are likely to play a crucial role in pneumonia caused by PA such as those involved in: 1. Immune response to PA infection and NF-κB signal transduction; 2. PKC signal transduction; 3. Impact on epigenetic regulation; 4. Epithelial sodium channel pathway; 5. Mucin expression; and 6. Bacterial infection related pathways. Our genomic data suggests a potential role for SPHK2 in PA-induced pneumonia through elevated expression of inflammatory genes in lung tissue. Further, validation by RT-PCR on 10 differentially expressed genes showed 100% concordance in terms of vectoral changes as well as significant fold change. Conclusion Using Sphk2−/− mice and differential gene expression analysis, we have shown here that S1P/SPHK2 signaling could play a key role in promoting PA pneumonia. The identified genes promote inflammation and suppress others that naturally inhibit inflammation and host defense. Thus, targeting SPHK2/S1P signaling in PA-induced lung inflammation could serve as a potential therapy to combat PA-induced pneumonia.

scholarly journals Genetic deletion of Sphk2 confers protection against Pseudomonas aeruginosa mediated differential expression of genes related to virulent infection and inflammation in mouse lung

2019 ◽  
Author(s):  
David Lenin Ebenezer ◽  
Panfeng Fu ◽  
Yashaswin Krishnan ◽  
Mark Maienschein-Cline ◽  
Hong Hu ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Pseudomonas Aeruginosa ◽  
Differential Expression ◽  
Lung Inflammation ◽  
Mouse Lung ◽  
Rna Seq ◽  
Wild Type ◽  
Expression Of Genes ◽  
Whole Transcriptome ◽  
Differential Expression Of Genes

Abstract BACKGROUND Pseudomonas aeruginosa (PA) is an opportunistic Gram-negative bacteria that causes serious life threatening and nosocomial infections including pneumonia. PA has the ability to alter host genome to facilitate its invasion thus increasing the virulence of the organism. Sphingosine-1 phosphate (S1P), a bioactive lipid is known to play a key role in facilitating infection. Sphingosine kinases (SPHK)1&2 phosphorylate sphingosine to generate S1P in mammalian cells. We reported earlier that Sphk2-/- mice offered significant protection against lung inflammation, compared to wild type (WT) animals. Therefore, we profiled the differential expression of genes between the protected group of Sphk2-/- and the wild type controls to better understand the underlying protective mechanisms Sphk2 deletion in lung inflammatory injury. Whole transcriptome shotgun sequencing (RNA seq) was performed on mouse lung tissue using NextSeq 500 sequencing system. RESULTS: Two-way ANOVA analysis was performed and differentially expressed genes following PA infection were identified using whole transcriptome of Sphk2-/- mice and their wild WT counterparts. Pathway (PW) enrichment analyses of the RNA seq data identified several signaling pathways that are likely to play a crucial role in pneumonia caused by PA such as those involved in: 1. Immune response to PA infection and NF-κB signal transduction; 2. PKC signal transduction; 3. Impact on epigenetic regulation; 4. Epithelial sodium channel pathway; 5. Mucin expression; and 6. Bacterial infection related pathways. Our data clearly suggests a role for SPHK2 in PA-induced pneumonia through elevated expression of inflammatory genes in lung tissue. Further, validation by RT-PCR on 10 differentially expressed genes showed 100% concordance in terms of vectoral changes, and 70% of genes showed concordance for significant fold change. CONCLUSION: Using Sphk2-/- mice and differential gene expression analysis, we have shown here that S1P/SPHK2 signaling plays a key role in promoting PA pneumonia. The identified genes promote inflammation, and suppress others that naturally inhibit inflammation and host defense. We therefore propose a key role for SPHK2/S1P signaling in PA-induced lung inflammation, and could serve as a potential therapeutic target to combat PA-induced pneumonia.

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