Sirt1 Overexpression Inhibits Fibrous Scar Formation and Improves Functional Recovery After Cerebral Ischemic Injury Through the Deacetylation of 14–3-3ζ

Chen, Yue; Huang, Jiagui; Liu, Jie; Zhu, Huimin; Li, Xuemei; Wen, Jun; Tian, Mingfen; Ren, Jiangxia; Zhou, Li; Yang, Qin

doi:10.1007/s12035-023-03378-9

Cited by 3 publications

(1 citation statement)

References 51 publications

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“…The profibrotic factor TGF-β1 (10 ng/ml) [ 24 , 48 – 50 ], the TGF-β1 receptor kinase inhibitor SB431542 (20 µM) [ 51 , 52 ], and the CK2 inhibitor TBB (5 µmol/l) [ 24 , 53 ] are commonly used for in vitro studies of fibrosis in a variety of tissues. In our previous research, BRD4 protein expression in primary meningeal fibroblasts was significantly upregulated by 10 ng/ml TGF-β1 and downregulated by 20 µM SB431542 in vitro [ 44 , 52 ]. TBB (2.5 mg/kg/d and 10 mg/kg/d) administered by intraperitoneal injection inhibited fibrosis in a dose-dependent manner in vivo [ 14 , 24 ].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of CK2 Diminishes Fibrotic Scar Formation and Improves Outcomes After Ischemic Stroke via Reducing BRD4 Phosphorylation

Li,

Yang,

Jiang

et al. 2024

Neurochem Res

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Fibrotic scars play important roles in tissue reconstruction and functional recovery in the late stage of nervous system injury. However, the mechanisms underlying fibrotic scar formation and regulation remain unclear. Casein kinase II (CK2) is a protein kinase that regulates a variety of cellular functions through the phosphorylation of proteins, including bromodomain-containing protein 4 (BRD4). CK2 and BRD4 participate in fibrosis formation in a variety of tissues. However, whether CK2 affects fibrotic scar formation remains unclear, as do the mechanisms of signal regulation after cerebral ischemic injury. In this study, we assessed whether CK2 could modulate fibrotic scar formation after cerebral ischemic injury through BRD4. Primary meningeal fibroblasts were isolated from neonatal rats and treated with transforming growth factor-β1 (TGF-β1), SB431542 (a TGF-β1 receptor kinase inhibitor) or TBB (a highly potent CK2 inhibitor). Adult SD rats were intraperitoneally injected with TBB to inhibit CK2 after MCAO/R. We found that CK2 expression was increased in vitro in the TGF-β1-induced fibrosis model and in vivo in the MCAO/R injury model. The TGF-β1 receptor kinase inhibitor SB431542 decreased CK2 expression in fibroblasts. The CK2 inhibitor TBB reduced the increases in proliferation, migration and activation of fibroblasts caused by TGF-β1 in vitro, and it inhibited fibrotic scar formation, ameliorated histopathological damage, protected Nissl bodies, decreased infarct volume and alleviated neurological deficits after MCAO/R injury in vivo. Furthermore, CK2 inhibition decreased BRD4 phosphorylation both in vitro and in vivo. The findings of the present study suggested that CK2 may control BRD4 phosphorylation to regulate fibrotic scar formation, to affecting outcomes after ischemic stroke.

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Section: Methodsmentioning

confidence: 99%

Inhibition of CK2 Diminishes Fibrotic Scar Formation and Improves Outcomes After Ischemic Stroke via Reducing BRD4 Phosphorylation

Li,

Yang,

Jiang

et al. 2024

Neurochem Res

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Cerebral [18F]AIF-FAPI-42-Based PET Imaging of Fibroblast Activation Protein for Non-invasive Quantification of Fibrosis After Ischemic Stroke

Tang,

Liu,

Peng

et al. 2024

Transl. Stroke Res.

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The double-edged sword of transforming growth factor β 1: a systematic review of pre-clinical stroke models

Hewitt,

Ali,

Hubbard

et al. 2024

Preprint

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Stroke is a leading cause of death, with those that survive often suffering significant disability. Strokes are classified as ischemic, occlusion of a blood vessel leading to reduction in cerebral blood flow, or hemorrhagic, the rupture of a vessel causing bleeding into the brain. Transforming growth factor beta 1 (TGF-β1), a pleiotropic cytokine, has been investigated in stroke due to its wide-ranging effects on proliferation, extracellular matrix deposition and inflammation. This systematic review examined the role of TGF-β1 in pre-clinical studies of both ischemic and hemorrhagic stroke. A search was performed across PubMed, Web of Science and Scopus, including English-language animal studies which examined TGF-β1 signaling as an outcome or intervention. 89 studies were ultimately included: 68 ischemic and 21 hemorrhagic stroke. Studies were assessed for bias following the SYRCLE guidelines for pre-clinical studies, followed by extraction of the methodology and the role of TGF-β1. Compliance with SYRCLE guidelines was found to be low and the methodological approaches for creating stroke models were variable. A range of interventions were shown to modify TGF-β1 expression or signaling, with exogenous TGF-β1 improving outcomes in all included ischemic stroke studies. TGF-β1 was found to play a protective role in 76% of ischemic stroke studies whereas it was only protective in 33% of hemorrhagic stroke studies, with likely involvement in fibrosis development in the latter. Our findings suggest a marked difference in the function of TGF-β1 between these types of stroke, and it is hypothesized that blood cytotoxicity following hemorrhagic stroke may generate a more sustained expression of TGF-β1 than seen in ischemic stroke. This may lead to TGF-β1 mediated fibrosis and post-hemorrhagic hydrocephalus, as opposed to the neuroprotective role played by the same molecule following ischemic stroke. These findings highlight the possible clinical utility of exogenous TGF-β1 therapies after ischemic stroke, and TGF-β1 inhibitors after hemorrhagic stroke, to reduce morbidity and disability caused by these events.

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Sirt1 Overexpression Inhibits Fibrous Scar Formation and Improves Functional Recovery After Cerebral Ischemic Injury Through the Deacetylation of 14–3-3ζ

Cited by 3 publications

References 51 publications

Inhibition of CK2 Diminishes Fibrotic Scar Formation and Improves Outcomes After Ischemic Stroke via Reducing BRD4 Phosphorylation

Inhibition of CK2 Diminishes Fibrotic Scar Formation and Improves Outcomes After Ischemic Stroke via Reducing BRD4 Phosphorylation

Cerebral [18F]AIF-FAPI-42-Based PET Imaging of Fibroblast Activation Protein for Non-invasive Quantification of Fibrosis After Ischemic Stroke

The double-edged sword of transforming growth factor β 1: a systematic review of pre-clinical stroke models

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