Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Monday, April 14, 2025

USP7 promotes PINK1/Parkin-dependent mitophagy to ameliorate cerebral ischemia–reperfusion injury by deubiquitinating and stabilizing SIRT1

Sounds important for our recovery. Do you really think your incompetent doctor and hospital will ensure human testing gets done? Competent entities would do that!


USP7 promotes PINK1/Parkin-dependent mitophagy to ameliorate cerebral ischemia–reperfusion injury by deubiquitinating and stabilizing SIRT1

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https://doi.org/10.1016/j.brainres.2025.149638
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Highlights

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    USP7 stabilizes SIRT1 via deubiquitination, enhancing mitophagy.
  • •
    USP7-SIRT1 axis activates PINK1/Parkin pathway post-ischemia.
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    USP7 mitigates brain injury by promoting damaged mitochondria clearance.
  • •
    SIRT1 upregulation by USP7 reduces cerebral ischemia–reperfusion damage.
  • •
    USP7-mediated mitophagy offers neuroprotection in stroke models.

neuroprotection(Wrong terminology, neuroprotection gives no sense of urgency! Call it by its' correct name; the neuronal cascade of death! Sounds important to immediately get fixed, neuroprotection is a milquetoast term saying nothing!)

If your doctor tells you they did nothing to stop the neuronal cascade of death in the first week thus letting hundreds of millions to billions of neurons die, you'd sue them for malpractice. Neuroprotection doesn't give any sense of urgency.

Abstract

Background

Cerebral ischemia–reperfusion (CI/R) injury, a major complication of ischemic stroke, is characterized by mitochondrial dysfunction and neuronal apoptosis, and understanding its underlying molecular mechanisms is essential for the development of effective therapeutic strategies. This study aimed to investigate the role of ubiquitin-specific protease 7 (USP7) in CI/R injury and elucidate its regulatory mechanisms.

Methods

A rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and an in vitro neuronal model subjected to oxygen-glucose deprivation/reperfusion (OGD/R) was used to mimic CI/R injury. USP7 was overexpressed or knocked down, with or without co-treatment, using the autophagy inhibitor 3-methyladenine (3-MA). Neurological function was evaluated using standardized scoring systems, and cerebral infarct volume was quantified by TTC staining. Histopathological alterations in the cortex and hippocampus were assessed using hematoxylin-eosin (HE) and Nissl staining. Neuronal viability and apoptosis were measured by CCK-8 assay, TUNEL staining, and flow cytometry. To assess cellular metabolism and oxidative stress, ATP and LDH levels, along with antioxidant markers including SOD, GSH, and GSH-Px, were analyzed using commercial biochemical kits. Mitochondrial morphology and autophagosome formation were visualized using transmission electron microscopy. Gene and protein expression levels were quantified by qRT-PCR and Western blotting, respectively. Immunofluorescence microscopy was performed to evaluate subcellular localization of target proteins and co-localization with mitochondrial membrane markers. Lastly, protein–protein interactions and ubiquitination modification were analyzed by co-immunoprecipitation assays.

Results

USP7 overexpression significantly alleviated neurological deficits, reduced infarct volume, attenuated histological damage, and decreased neuronal apoptosis in the MCAO/R model. In parallel, in the OGD/R model, USP7 overexpression markedly enhanced neuronal viability, suppressed apoptosis, restored ATP production, improved antioxidant capacity (as indicated by increased levels of SOD, GSH, and GSH-Px), and reduced LDH release. Mechanistically, USP7 stabilized SIRT1 protein expression through deubiquitination, which in turn activated the PINK1/Parkin pathway and enhanced mitophagy. This activation was demonstrated by an increased LC3II/LC3I ratio, elevated ATG5 expression, enhanced co-localization of Tomm20 and Parkin, and increased autophagosome formation. Moreover, these protective effects could be abolished when either 3-MA treatment was applied or SIRT1/PINK1 expression was knocked down.

Conclusion

USP7 mitigates CI/R injury by promoting PINK1/Parkin-dependent mitophagy through SIRT1 deubiquitination and stabilization, supporting USP7 as a potential therapeutic target for ischemic stroke.
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