Calycosin alleviates cerebral ischemia/reperfusion injury by repressing autophagy via STAT3/FOXO3a signaling pathway

Xu, Shouchao; Huang, Ping; Yang, Jiehong; Du, Hai; Wan, Haitong

doi:10.1016/j.phymed.2023.154845

Cited by 25 publications

(9 citation statements)

References 29 publications

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“…In addition, the imbalance between the oxidative and antioxidant systems promotes the activation of autophagy, and excessive autophagy causes brain tissue damage after CIRI. 39 , 40 Compared to that in the sham group, the expression of Beclin‐1 was upregulated, the level of P62 was downregulated, and the rate of LC3II/LC3I was increased after CIRI. Notably, compared with that in the vehicle group, VAPB or PTPIP51 knockdown further upregulated Beclin‐1 and LC3II/LC3I and lowered P62 (Figure 5A,B ).…”

Section: Resultsmentioning

confidence: 92%

“…MAMs are believed to regulate autophagy, 22,23 therefore, we hypothesized that the destruction of MAMs may cause autophagy disorders. In addition, the imbalance between the oxidative and antioxidant systems promotes the activation of autophagy, and excessive autophagy causes brain tissue damage after CIRI 39,40 . Compared to that in the sham group, the expression of Beclin‐1 was upregulated, the level of P62 was downregulated, and the rate of LC3II/LC3I was increased after CIRI.…”

Section: Resultsmentioning

confidence: 98%

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Mitochondria‐associated endoplasmic reticulum membranes tethering protein VAPB‐PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy

Li,

Zhang,

et al. 2024

CNS Neurosci Ther

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AimsMitochondria‐associated endoplasmic reticulum membranes (MAMs) serve as a crucial bridge connecting the endoplasmic reticulum (ER) and mitochondria within cells. Vesicle‐associated membrane protein‐associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) are responsible for the formation and stability of MAMs, which have been implicated in the pathogenesis of various diseases. However, the role of MAMs in ischemic stroke (IS) remains unclear. We aimed to investigate the role of MAMs tethering protein VAPB‐PTPIP51 in experimental cerebral ischemia.MethodsWe simulated cerebral ischemia–reperfusion injury (CIRI) by using a mouse middle cerebral artery occlusion (MCAO) model.ResultsWe observed a decrease in VAPB‐PTPIP51 expression in the brain tissue. Our findings suggested compromised MAMs after MCAO, as a decreased mitochondria–ER contact (MERC) coverage and an increased distance were observed through the transmission electron microscope (TEM). Upon VAPB or PTPIP51 knockdown, the damage to MAMs was exacerbated, accompanied by excessive autophagy activation and increased reactive oxygen species (ROS) production, resulting in an enlarged infarct area and exacerbated neurological deficits. Notably, we observed that this damage was concomitant with the inhibition of the PI3K/AKT/mTOR pathway and was successfully mitigated by the treatment with the PI3K activator.ConclusionsOur findings suggest that the downregulation of VAPB‐PTPIP51 expression after IS mediates structural damage to MAMs. This may exacerbate CIRI by inhibiting the PI3K pathway and activating autophagy, thus providing new therapeutic targets for IS.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 98%

Mitochondria‐associated endoplasmic reticulum membranes tethering protein VAPB‐PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy

Li,

Zhang,

et al. 2024

CNS Neurosci Ther

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“…Regulation of autophagy levels after CIRI may be a potential neuroprotective target. S. Xu et al confirmed that calycosin can mitigate CIRI by suppressing the STAT3/FOXO3a signaling pathway and inhibiting overactivated autophagy, as demonstrated in both in vivo and in vitro (PC12 cells) studies [ 37 ]. Similarly, W.Y.…”

Section: Discussionmentioning

confidence: 98%

Moderate Hyperkalemia Regulates Autophagy to Reduce Cerebral Ischemia-Reperfusion Injury in a CA/CPR Rat Model

Wang,

Tian,

Shen

et al. 2023

Brain Sciences

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Background: Cerebral ischemia-reperfusion injury (CIRI) can cause irreversible brain damage and autophagy has been implicated in the pathophysiology. Increasing serum potassium (K+) levels reduces CIRI, but the relationship between its protective mechanism and autophagy is unclear. In this study, we aimed to find the optimal degree of raising serum (K+) and to investigate the relationship between high (K+) and autophagy and the underlying mechanisms in a cardiac arrest/cardiopulmonary resuscitation (CA/CPR) rat model. Methods: Sprague Dawley (SD) rats were divided into four groups: S group, N group, P group, and Q group. The rats S group and N group were administered saline. The rats P group and Q group were administered 640 mg/kg of potassium chloride (KCl) continuously pumped at 4 mL/h (21.3 mg/(kg·min) and divided according to the electrocardiogram (ECG) changes during the administration of KCl. After 24-h of resuscitation, neural damage was assessed by measuring neurological deficit score (NDS), oxidative stress markers, and pathological staining of the cerebral cortex. The level of autophagy and the expression of mTOR-ULK1-Beclin1 pathway-related proteins were evaluated using transmission electron microscopy (TEM), immunostaining, and western blotting. Results: Our results revealed that high (K+) improved NDS and decreased the oxidative stress markers. The autophagosomes, autolysosomes, and lysosomes were decreased following treatment KCl. Furthermore, the levels of micro-tubule-associated protein 1 light chain 3 (LC3) Ⅱ/Ⅰ, Unc-51-like kinase 1 (ULK1), and Beclin1 were decreased, whereas mTOR expression was increased in the cortex. Conclusion: The results demonstrated that moderate hyperkalemia could alleviate autophagy after CIRI via regulating the mTOR-ULK1-Beclin1 pathway.

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“…Recent studies demonstrate the ability of calycosin to mitigate cardiovascular disorders by activating autophagy via several pathways. Details of the mechanisms whereby calycosin enhances autophagy in SMCs, inhibits VC, and mitigates cardiovascular diseases remain unclear [ 19 , 26 , 27 ]. The results of the present study demonstrate that calycosin reduces β-GP-induced calcification and autophagic flux damage in rat thoracic aortic SMC (A7r5).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Calycosin Inhibited Vascular Calcification

Zhou,

Li,

Jiang

et al. 2023

Nutrients

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Vascular calcification (VC) is a pathological condition frequently observed in cardiovascular diseases. Primary factors contributing to VC are osteogenic differentiation of vascular smooth muscle and hydroxyapatite deposition. Targeted autophagy (a lysosome-mediated mechanism for degradation/recycling of unnecessary cellular components) is a useful approach for inhibiting VC and promoting vascular cell health. Calycosin has been shown to alleviate atherosclerosis by enhancing macrophage autophagy, but its therapeutic effect on VC has not been demonstrated. Using an in vitro model (rat thoracic aortic smooth muscle cell line A7r5), we demonstrated effective inhibition of VC using calycosin (the primary flavonoid component of astragalus), based on the enhancement of autophagic flux. Calycosin treatment activated AMPK/mTOR signaling to induce initiation of autophagy and restored mTORC1-dependent autophagosome–lysosome fusion in late-stage autophagy by promoting soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation, thereby preventing stoppage of autophagy in calcified cells. Calycosin substantially reduced degrees of both osteogenic differentiation and calcium deposition in our VC cell model by enhancing autophagy. The present findings clarify the mechanism whereby calycosin mitigates autophagy stoppage in calcified smooth muscle cells and provide a basis for effective VC treatment via autophagy enhancement.

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Calycosin alleviates cerebral ischemia/reperfusion injury by repressing autophagy via STAT3/FOXO3a signaling pathway

Cited by 25 publications

References 29 publications

Mitochondria‐associated endoplasmic reticulum membranes tethering protein VAPB‐PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy

Mitochondria‐associated endoplasmic reticulum membranes tethering protein VAPB‐PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy

Moderate Hyperkalemia Regulates Autophagy to Reduce Cerebral Ischemia-Reperfusion Injury in a CA/CPR Rat Model

Molecular Mechanism of Calycosin Inhibited Vascular Calcification

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