&lt;p&gt;Salvianolic Acid Alleviated Blood–Brain Barrier Permeability in Spontaneously Hypertensive Rats by Inhibiting Apoptosis in Pericytes via P53 and the Ras/Raf/MEK/ERK Pathway&lt;/p&gt;

Wu, Qiliang; Yuan, Xiaochen; Li, Bingwei; Han, Ruiqin; Zhang, Honggang; Xiu, Ruijuan

doi:10.2147/dddt.s245959

Cited by 11 publications

(3 citation statements)

References 53 publications

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“…Being a well known double-edged sword, on the one hand protecting cells while on the other activating cell death mechanisms [ 2 , 40 ], we conclude that severe stroke conditions per se induce negative HIF-1 effects in the pericyte compartment. Pericyte death may be mediated by HIF-1-induced p53 as elevated expression has been observed in pericytes of different origin under various injury conditions [ 56 , 57 ]. However, evidence also suggests activated pericytes acquire an ability to become multipotent stem cells, differentiating into neuronal and microglial lineage cells post stroke [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome

et al. 2021

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Pericytes play essential roles in blood-brain barrier integrity and their dysfunction is implicated in neurological disorders such as stroke although the underlying mechanisms remain unknown. Hypoxia-inducible factor-1 (HIF-1), a master regulator of injury responses, has divergent roles in different cells especially during stress scenarios. On one hand HIF-1 is neuroprotective but on the other it induces vascular permeability. Since pericytes are critical for barrier stability, we asked if pericyte HIF-1 signaling impacts barrier integrity and injury severity in a mouse model of ischemic stroke. We show that pericyte HIF-1 loss of function (LoF) diminishes ischemic damage and barrier permeability at 3 days reperfusion. HIF-1 deficiency preserved barrier integrity by reducing pericyte death thereby maintaining vessel coverage and junctional protein organization, and suppressing vascular remodeling. Importantly, considerable improvements in sensorimotor function were observed in HIF-1 LoF mice indicating that better vascular functionality post stroke improves outcome. Thus, boosting vascular integrity by inhibiting pericytic HIF-1 activation and/or increasing pericyte survival may be a lucrative option to accelerate recovery after severe brain injury.

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Section: Discussionmentioning

confidence: 99%

Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome

et al. 2021

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“…Our mouse model of VCID-HF has an increased BBB permeability that was restored by treatment with PNA5. The BBB regulates the movement of molecules and cells from the blood to the brain via an endothelial-cell barrier [ 7 , 83 , 84 ]. Previous studies have demonstrated that increased BBB permeability is observed in many types of dementia, including VCID and AD [ 85 , 86 ].…”

Section: Discussionmentioning

confidence: 99%

PNA5, A Novel Mas Receptor Agonist, Improves Neurovascular and Blood-Brain-Barrier Function in a Mouse Model of Vascular Cognitive Impairment and Dementia

2023

Aging dis

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It is well established that decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms accelerate neurodegenerative disease progressions, including vascular cognitive impairment and dementia (VCID). Previous studies in our laboratory have shown that our novel glycosylated Angiotensin-(1-7) Mas receptor agonist PNA5 reverses cognitive deficits, decreases ROS production, and inhibits inflammatory cytokine production in our preclinical mouse model of VCID that is induced by chronic heart failure (VCID-HF). In the present study, the effects of VCID-HF and treatment with PNA5 on microglia activation, blood-brain-barrier (BBB) integrity, and neurovascular coupling were assessed in our mouse model of VCID-HF. Three-month-old male C57BL/6J mice were subjected to myocardial infarction (MI) to induce heart failure for four weeks and then treated with subcutaneous injections of extended-release PNA5. Microglia activation, BBB permeability, cerebral perfusion, and neurovascular coupling were assessed. Results show that in our VCID-HF model, there was an increase in microglial activation and recruitment within the CA1 and CA3 regions of the hippocampus, a disruption in BBB integrity, and a decrease in neurovascular coupling. Treatment with PNA5 reversed these neuropathological effects of VCID-HF, suggesting that PNA5 may be an effective disease-modifying therapy to treat and prevent VCID. This study identifies potential mechanisms by which heart failure may induce VCID and highlights the possible mechanisms by which treatment with our novel glycosylated Angiotensin-(1-7) Mas receptor agonist, PNA5, may protect cognitive function in our model of VCID.

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“…p53 is considered the most critical transcription factor that induces apoptosis in cancer cells [ 21 ], which is reflected by the fact that most anticancer therapeutics, including chemotherapy and radiotherapy, induce apoptosis by activating p53 [ 22 , 23 ]. p53 is engaged in broad crosstalk with inflammatory elements, such as MAPK pathways [ 24 , 25 ], and it is a multifunctional protein that plays many roles in determining a cell’s fate in response to cellular stress [ 26 , 27 ]. The level and function of p53 proteins are known to be regulated by posttranslational modifications, such as phosphorylation, acetylation, methylation, and ubiquitinoylation [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel ERK2 Degrader Z734 Induces Apoptosis of MCF–7 Cells via the HERC3/p53 Signaling Pathway

Xiong

Yao³

et al. 2022

Molecules

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Breast cancer is one of the leading causes of death worldwide, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as ERK inhibitors and degraders, have been intensively investigated. The targets of ERK participate in the regulation of critical cellular mechanisms and underpin the progression of anticancer therapy. In this study, we identified a novel small molecule, which we named Z734, as a new mitogen–activated protein kinase 1 (ERK2) degrader and demonstrated that Z734 inhibits cell growth by inducing p53–mediated apoptotic pathways in human breast cancer cells. Treatment with Z734 resulted in the inhibition of cancer cell proliferation, colony formation and migration invasion, as well as cancer cell death via apoptosis. In addition, the Co–IP and GST pulldown assays indicated that the HECT and RLD domains containing E3 ubiquitin protein ligase 3 (HERC3) could directly interact with ERK2 through the HECT domain, promoting ERK2 ubiquitination. We also observed a strong link between HERC3 and p53 for the modulation of apoptosis. HERC3 can increase the protein and phosphorylation levels of p53, which further promotes apoptotic activity. In a xenograft mouse model, the effect was obtained in a treatment group that combined Z734 with lapatinib compared with that of the single–treatment groups. In summary, our results indicated that Z734 actively controls the development of breast cancer through apoptosis, and HERC3 may mediate ERK2 and p53 signaling, which offers new potential targets for clinical therapy.

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<p>Salvianolic Acid Alleviated Blood–Brain Barrier Permeability in Spontaneously Hypertensive Rats by Inhibiting Apoptosis in Pericytes via P53 and the Ras/Raf/MEK/ERK Pathway</p>

Cited by 11 publications

References 53 publications

Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome

Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome

PNA5, A Novel Mas Receptor Agonist, Improves Neurovascular and Blood-Brain-Barrier Function in a Mouse Model of Vascular Cognitive Impairment and Dementia

A Novel ERK2 Degrader Z734 Induces Apoptosis of MCF–7 Cells via the HERC3/p53 Signaling Pathway

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