Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective

Hossain, Mohammed Iqbal; Marcus, Joshua M.; Lee, Jun Hee; Garcia, Patrick L.; Singh, Vinodkumar; Shacka, John J.; Zhang, Jianhua; Gropen, Toby; Falany, Charles N.; Andrabi, Shaida A.

doi:10.1080/15548627.2020.1761219

Cited by 84 publications

(43 citation statements)

References 70 publications

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“…These results were consistent with previous studies showing that inhibition of retromer causes a decrease in CI-MPR and lysosome dysfunction (21,22). Under conditions of I/H injury, when cellular autophagy is robustly induced (46,47) and the demand for retrograde transport is significantly upregulated, dysfunction of the retromer is probably destructive to cardiomyocytes.…”

Section: Discussionsupporting

confidence: 93%

Impaired Retrograde Transport Due to Lack of TBC1D5 Contributes to the Trafficking Defect of Lysosomal Cathepsins in Ischemic/Hypoxic Cardiomyocytes

Cui

Zhang

Huang

et al. 2021

Front. Cardiovasc. Med.

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Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.

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Section: Discussionsupporting

confidence: 93%

Impaired Retrograde Transport Due to Lack of TBC1D5 Contributes to the Trafficking Defect of Lysosomal Cathepsins in Ischemic/Hypoxic Cardiomyocytes

Cui

Zhang

Huang

et al. 2021

Front. Cardiovasc. Med.

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“…The OGD model was described as above. 59 , 60 , 61 Hanks’ balanced salt solution (HBSS, Gibco, CA, USA) was replaced with normal medium for 6 h to reoxygenate the cells. Neurons in six-well plates were washed three times in PBS and fixed with 4% paraformaldehyde for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

Chen

Wang

Feng

et al. 2020

Molecular Therapy - Nucleic Acids

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Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various central nervous system diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Herein, we uncovered the function and underlying mechanism of the circRNA UCK2 (circUCK2) in ischemia stroke. The oxygen-glucose deprivation model in HT-22 cells was used to mimic ischemia stroke in vitro . Neuronal viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assays and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining, respectively. Middle cerebral artery occlusion was conducted to evaluate the function of circUCK2 in mice. The levels of circUCK2 were significantly decreased in brain tissues from a mouse model of focal cerebral ischemia and reperfusion. Upregulated circUCK2 levels significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. circUCK2 reduced oxygen glucose deprivation (OGD)-induced cell apoptosis by regulating transforming growth factor β (TGF-β)/mothers against decapentaplegic homolog 3 (Smad3) signaling. Furthermore, circUCK2 functioned as an endogenous miR-125b-5p sponge to inhibit miR-125b-5p activity, resulting in an increase in growth differentiation factor 11 (GDF11) expression and a subsequent amelioration of neuronal injury. Consequently, these findings showed that the circUCK2/miR-125b-5p/GDF11 axis is an essential signaling pathway during ischemia stroke. Thus, the circRNA circUCK2 may serve as a potential target for novel treatment in patients with ischemic stroke.

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“…These two pathways are indispensable in the maintenance of neuronal homeostasis as well as neurodevelopment 43 . In a previous study, substantial evidence was found that autophagy is directly related to some neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) 44 . Boland et al analyzed both postmortem and experimental models of human tissues, and the results suggested that dysfunction of autophagy might be a predominant contributor to pathogenicity across these diseases 45 .…”

Section: Discussionmentioning

confidence: 99%

Piperine Attenuates the Inflammatory Response, Oxidative Stress and Pyroptosis to Facilitate Recovery After Spinal Cord Injury via Autophagy Enhancement

Zhang

Huang

et al. 2021

Preprint

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Background: Spinal cord injury (SCI) is a serious injury that can lead to irreversible motor dysfunction and subsequently result in disability and even death. Due to its complicated pathogenic mechanism, there are no effective drug treatments. Piperine, a natural active alkaloid extracted from black pepper, suppressed inflammation in a previous study. The aim of this study was to investigate the therapeutic effect of piperine in a spinal cord injury model.Methods: Spinal cord injury was induced in C57BL/6 mice by clamping the spinal cord with a vascular clip (15 g force; Oscar) for 1 min. Eighty mice were divided randomly into the following four groups: The Sham group (n = 20), the SCI+Vehicle group (n = 20), the SCI+ Piperine group (n = 20), and the SCI+ Piperine+3MA group (n = 20). Before SCI and every 2 days post-SCI, evaluations of the Basso mouse scale (BMS) were performed. On day 14 after SCI, inclined plane tests and footprint analyses were performed. On postoperative day 3, the spinal cord was harvested to assess pyroptosis, reactive oxygen species (ROS), inflammation, and autophagy. Qualitative or quantitative analysis of the components of these potential mechanisms was performed by Western blotting (WB), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA).Results: Piperine enhanced the functional recovery of spinal cord injury. Additionally, piperine inhibited inflammation, attenuated oxidative stress and pyroptosis, and activated autophagy. However, the effects of piperine on the functional recovery of SCI, ROS-mediated autophagy, inflammation and pyroptosis were reversed by the inhibition of autophagy.Conclusions: Our experiments demonstrated that piperine facilitated the functional recovery of spinal cord injury by inhibiting the inflammatory response, oxidative stress and pyroptosis, which are mediated by the activation of autophagy.

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Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective

Cited by 84 publications

References 70 publications

Impaired Retrograde Transport Due to Lack of TBC1D5 Contributes to the Trafficking Defect of Lysosomal Cathepsins in Ischemic/Hypoxic Cardiomyocytes

Impaired Retrograde Transport Due to Lack of TBC1D5 Contributes to the Trafficking Defect of Lysosomal Cathepsins in Ischemic/Hypoxic Cardiomyocytes

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

Piperine Attenuates the Inflammatory Response, Oxidative Stress and Pyroptosis to Facilitate Recovery After Spinal Cord Injury via Autophagy Enhancement

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