Drug library screen identifies inhibitors of toxic astrogliosis

Masvekar, Ruturaj; Kósa, Péter; Barbour, Christopher; Milstein, Joshua L.; Bielekova, Bibiana

doi:10.1016/j.msard.2022.103499

Cited by 3 publications

(4 citation statements)

References 53 publications

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“…This suggests that Hp expression may be positively correlated with the ER stress levels in cardiac tissues ( Fu et al, 2012 ). Serpina3 has been detected as a marker of ER stress in astrocytes in immune system diseases ( Masvekar et al, 2022 ), and the role played by its Serpina3n (a protein from the same family) in ER stress has never been described. The role of NOX4, a member of the NADPH oxidase family, in ER stress in CVDs has garnered greater attention, as NOX4 participates in two UPR signaling pathways ( Wu et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

Qin

Wang²,

Zhang³

et al. 2023

Front. Genet.

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Background: Growing evidence has supported that chronic psychological stress would cause heart damage, However the mechanisms involved are not clear and effective interventions are insufficient. Cannabinoid type 2 receptor (CB2R) can be a potential treatment for cardiac injury. This study is aimed to investigate the protective mechanism of CB2R agonist against chronic psychological stress-induced cardiac injury.Methods: A mouse chronic psychological stress model was constructed based on a chronic unpredictable stress pattern. Mice were performed a three-week psychological stress procedure, and cardiac tissues of them were collected for whole-transcriptome sequencing. Overlap analysis was performed on differentially expressed mRNAs (DE-mRNAs) and ER stress-related genes (ERSRGs), and bioinformatic methods were used to predict the ceRNA networks and conduct pathway analysis. The expressions of the DE-ERSRGs were validated by RT-qPCR.Results: In the comparison of DE mRNA in Case group, Control group and Treatment group, three groups of ceRNA networks and ceRNA (circ) networks were constructed. The DE-mRNAs were mainly enriched in chromatid-relevant terms and Hematopoietic cell lineage pathway. Additionally, 13 DE-ERSRGs were obtained by the overlap analysis, which were utilized to establish a ceRNA network with 15 nodes and 14 edges and a ceRNA (circ) network with 23 nodes and 28 edges. Furthermore, four DE-ERSRGs (Cdkn1a, Atf3, Fkbp5, Gabarapl1) in the networks were key, which were mainly enriched in response to extracellular stimulus, response to nutrient levels, cellular response to external stimulus, and FoxO signaling pathway. Finally, the RT-qPCR results showed almost consistent expression patterns of 13 DE-ERSRGs between the transcriptome and tissue samples.Conclusion: The findings of this study provide novel insights into the molecular mechanisms of chronic psychological stress-induced cardiac diseases and reveal novel targets for the cardioprotective effects of CB2R agonists.

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Section: Discussionmentioning

confidence: 99%

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

Qin

Wang²,

Zhang³

et al. 2023

Front. Genet.

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“…BAFF/APRIL signaling pathway correlating with IgG index. Nevertheless, we acknowledge that some recently discovered biological processes linked to MS severity, such as toxic astrogliosis (40)(41)(42), are not yet annotated in IPA and were missed. 2.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms associated with multiple sclerosis progression, severity and phenotype

Kósa

Lumbard

Wang

et al. 2022

Preprint

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While current treatments of multiple sclerosis (MS) effectively inhibit formation of focal lesions and relapses, most patients experience progression independent of relapse activity (PIRA). To understand PIRA, we analyzed nine prospectively acquired clinical and imaging outcomes in 176 relapsing-remitting and 215 progressive MS patients and 45 healthy volunteers, along with matched cellular and >5000 protein data in 1,042 cerebrospinal fluid (CSF) samples. Regressing out physiological aging and sex effects identified MS-related processes. Among these, compartmentalized inflammation and its effector mechanisms such as pyroptosis showed the strongest association with MS severity, irrespective of clinical categorization of patients. However, molecular processes affected localization of CNS injury: patients with predominant brain damage had proportionally higher neuroinflammation, while fibrosis and tissue hypoxia were linked to principal involvement of spinal cord. We did not identify inflammation-unrelated neurodegeneration; instead, CNS-related processes were beneficial, such as synaptogenesis. Machine learning-based CSF biomarker models predicted nine clinical and volumetric imaging outcomes in the independent cohort with accuracy exceeding published MS models. These data show intra-individual diversity of putative disease mechanisms in MS and implicate processes related to compartmentalized neuroinflammation as leading candidate mechanisms of PIRA. Future drug development should include CNS-penetrant anti-inflammatory agents.

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“…Dantrolene is a drug used for treating spasms and has been identified as a potential therapeutic agent for MS through drug library screening. This phenomenon could be due to its ability to block Ca 2+ release from depleted endoplasmic reticulum into the cytosol and/or mitochondria, reducing astrocyte activation (Masvekar et al, 2022). Proteasome inhibitors, heat shock protein 90 inhibitors and dantrolene are antispasmodic drugs that inhibit calcium release from the endoplasmic reticulum in CNS cells (Masvekar et al, 2022), thereby reducing astrocyte activation and alleviating MS progression.…”

Section: Connections Among Neurological Disorders Astrocytes and Drugsmentioning

confidence: 99%

“…This phenomenon could be due to its ability to block Ca 2+ release from depleted endoplasmic reticulum into the cytosol and/or mitochondria, reducing astrocyte activation (Masvekar et al, 2022). Proteasome inhibitors, heat shock protein 90 inhibitors and dantrolene are antispasmodic drugs that inhibit calcium release from the endoplasmic reticulum in CNS cells (Masvekar et al, 2022), thereby reducing astrocyte activation and alleviating MS progression. Abnormal bile acid metabolism represents a potential target in MS. Metabolomic studies revealed low levels of circulating bile acid metabolites in MS patients; tauroursodeoxycholic acid prevents astrocytes from transitioning into a neurotoxic phenotype and improves neuropathology in animal models of MS (Bhargava et al, 2020).…”

Section: Connections Among Neurological Disorders Astrocytes and Drugsmentioning

confidence: 99%

The function of astrocytes and their role in neurological diseases

Yuan,

Huang,

Jiang

et al. 2023

Eur J of Neuroscience

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Astrocytes have countless links with neurons. Previously, astrocytes were only considered a scaffold of neurons; in fact, astrocytes perform a variety of functions, including providing support for neuronal structures and energy metabolism, offering isolation and protection and influencing the formation, function and elimination of synapses. Because of these functions, astrocytes play an critical role in central nervous system (CNS) diseases. The regulation of the secretiory factors, receptors, channels and pathways of astrocytes can effectively inhibit the occurrence and development of CNS diseases, such as neuromyelitis optica (NMO), multiple sclerosis, Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The expression of aquaporin 4 in AS is directly related to NMO and indirectly involved in the clearance of Aβ and tau proteins in AD. Connexin 43 has a bidirectional effect on glutamate diffusion at different stages of stroke. Interestingly, astrocytes reduce the occurrence of PD through multiple effects such as secretion of related factors, mitochondrial autophagy and aquaporin 4. Therefore, this review is focused on the structure and function of astrocytes and the correlation between astrocytes and CNS diseases and drug treatment to explore the new functions of astrocytes with the astrocytes as the target. This, in turn, would provide a reference for the development of new drugs to protect neurons and promote the recovery of nerve function.

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Drug library screen identifies inhibitors of toxic astrogliosis

Cited by 3 publications

References 53 publications

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

Molecular mechanisms associated with multiple sclerosis progression, severity and phenotype

The function of astrocytes and their role in neurological diseases

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