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PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [exvivo]

ABSTRACT: PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [exvivo]

PROVIDER: PRJNA1179440 | ENA |

REPOSITORIES: ENA

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PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [invitro]

Project description:In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevent the activation of neuroinflammatory reactive astrocytes while promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin regenerative and supportive agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.

2024-10-29 | GSE280579 | GEO

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [exvivo]

2024-10-29 | GSE280578 | GEO

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination

Project description:PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination

| PRJNA1179434 | ENA

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [invitro]

Project description:PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination [invitro]

| PRJNA1179439 | ENA

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-10-29 | GSE280580 | GEO

Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 2]

Project description:Bryostatin 1, like the phorbol ester PMA, activates protein kinase C (PKC) in vitro but paradoxically blocks many phorbol ester responses in vivo. Results with a limited panel of genes suggested that transiency of action was an important mechanism contributing to this differential cellular response. Here, we examined global gene expression in LNCaP and U937 cell lines to probe the extent to which transiency of action captures the difference in response. While different genes showed different patterns of relative response, the overall pattern was reflective of an initial PMA-like response to bryostatin 1 followed by variable transiency of the continued response. This conclusion was further strengthened by detailed time course measurements by qPCR of selected genes. Merle 23, a bryostatin derivative with biological behavior intermediate between that of bryostatin 1 and PMA, was likewise intermediate for transiency of action. Both the LNCaP and U937 cell lines behaved similarly, but the extent of transiency in response to bryostatin 1 was greater in the LNCaP cells.

2017-12-30 | GSE104374 | GEO

Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 1]

2017-12-30 | GSE104373 | GEO

Effect of bryostatin-1 on gene expression profile of Raji cells

Project description:To investigate bryostain's effect on Raji , we performed a whole-transcriptome RNA sequencing experiment for Raji cells treated with Bryostatin and established differntial expression profile comparing to raji treated with DMSO.

2022-08-19 | GSE211351 | GEO

Retinoid X receptor gamma signaling accelerates CNS remyelination

Project description:The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal demyelination in the rat CNS. White matter tracts in the rat caudal cerebellar peduncles were focally demyelinated using 0.1% ethidium bromide, the lesions were isolated using laser capture microdissection at 5, 14 and 28 days postlesion, followed by RNA extraction and Illumina beadarray analysis of differentially expressed transcripts. We found transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination, and that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy. 9 Samples analysed, 3 different time points each with 3 biological replicates.

2010-10-22 | E-GEOD-24821 | biostudies-arrayexpress

TRAP-seq of mouse astrocytes involved in central nervous system remyelination

Project description:Remyelination failure contributes to axonal dysfunction in neurodegenerative disorders. But whether astrocytes, the most abundant glial cell type in demyelinated lesions, support or impede remyelination is controversial. Following focal demyelinated lesions of the mouse corpus callosum induced with the myelin toxin lysolecithin, we used TRAP (translational ribosome affinity purification) sequencing to isolate and sequence ribosome-associated mRNAs which are being actively translated in astrocytes, and studied how the responses and molecular mechanisms in astrocytes are linked to remyelination.

2023-05-17 | E-MTAB-9270 | biostudies-arrayexpress

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