Amifostine ameliorates cerebral ischaemia-reperfusion injury
via p38-mediated oxidative stress and mitochondrial dysfunction

Cheng, Hui-Feng; Lv, MiaoJun; Mi, Rulin; Xue, Gui

doi:10.5114/fn.2020.102436

Cited by 8 publications

(3 citation statements)

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“…The present study attempted to identify the neuroprotective effect of dBd on cerebral i/r injury and the underlying metabolic pathway by analyzing high-throughput metabolomic data and using multivariate statistical methods to elucidate its therapeutic mechanism. initially, it was demonstrated that improving mitochondrial dysfunction attenuated brain i/r injury, which is consistent with previous studies (34,35). DBD could significantly reduce the neurological deficit and cerebral infarction volume in Mcao/r rats.…”

Section: Discussionsupporting

confidence: 90%

Metabolomic analysis and pharmacological validation of the cerebral protective effect of 3,4‑dihydroxybenzaldehyde on cerebral ischemia‑reperfusion injury

et al. 2022

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3,, one of the active components of Gastrodia elata, has a cerebral protective effect and can effectively combat cerebral ischemia/reperfusion (I/R) injury in rats. However, the metabolite profiles and underlying mechanisms associated with dBd remain unclear. To explore the level of energy metabolism and pharmacological targets in brain tissue following dBd treatment of stroke. The right middle cerebral artery of the rats was occluded for 2 h and reperfused for 24 h to simulate brain i/r injury. Pharmacological results showed that dBd reduced cerebral infarct volume, improved neurological function and increased adenosine triphosphate (aTP) content. Mitochondria are the primary sites for aTP generation and cellular energy supply and decreasing mitochondrial dysfunction can alleviate the energy expenditure of ischemic stroke. Through further experiments, it was found that mitochondrial damage was recovered following dBd treatment, which was manifested by the improvement of mitochondrial morphology under an electron microscope and the reduction of oxidative stress damage. The metabolomics of middle cerebral artery occlusion/reperfusion (Mcao/r) rat brain tissue was studied by the liquid chromatography-tandem mass spectrometry metabolomics method. Significantly different metabolites were screened and the pathways involved included amino sugar and nucleotide sugar metabolism and pentose phosphate pathway. Finally, the present study performed targeted metabolic profiling and validated potential therapeutic targets. uridine diphosphate n-acetylglucosamine (udP-Glcnac) levels were decreased in the Mcao/r group but significantly increased in the DBD group. TdT-mediated duTP nick end labeling (Tunel) staining, hematoxylin and eosin staining and western blotting showed that brain cell apoptosis was inhibited and neuronal morphology improved. among them, the regulatory enzyme o-Glcnac transferase (OGT) of UDP-GlcNAc appeared to be significantly increased and neuronal apoptosis was inhibited following dBd treatment, which was verified by western blotting. Therefore, by analyzing mitochondrial dysfunction following i/r and the characterization of potential markers in mitochondrial energy metabolism, it was shown that oGT could inhibit neuronal apoptosis as a potential therapeutic target for brain i/r injury.

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Section: Discussionsupporting

confidence: 90%

Metabolomic analysis and pharmacological validation of the cerebral protective effect of 3,4‑dihydroxybenzaldehyde on cerebral ischemia‑reperfusion injury

et al. 2022

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“…The mitochondrial injury pathway is one of the main pathways of renal tubular epithelial cells. The decrease in mtDNA copy number and the release of Cyt C from mitochondria to cytosol are markers of the internal pathways of apoptosis ( Bhargava and Schnellmann, 2017 ; Cheng et al, 2020 ). We further evaluated the viability of tubular cell in the renal cortex using a TUNEL assay.…”

Section: Resultsmentioning

confidence: 99%

Hyperhomocysteinemia exacerbates acute kidney injury via increased mitochondrial damage

Zhang

Dong

et al. 2022

Front. Physiol.

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Acute kidney injury (AKI) is a complex and common set of multifactorial clinical syndromes, and associated with increased in-hospital mortality. There is increasing evidence that Hyperhomocysteinemia (HHcy) is highly associated with the development of a variety of kidney diseases, including AKI. However, the pathogenesis of HHcy in AKI remains unclear. In this study, we investigated the effect and mechanism of HHcy on cisplatin-induced AKI in mice and NRK-52E cells cultured with HHcy. We confirmed that mice with HHcy had higher serum levels of creatinine and more severe renal tubule injury after cisplatin injection. We found that HHcy aggravated renal mitochondrial damage, mainly manifested as decreased ATP β, significantly increased cytoplasmic Cyt C expression and the ADP/ATP ratio, and a significantly decreased mitochondrial DNA (mtDNA) copy number. In addition, we found that HHcy accelerated cisplatin-induced renal DNA damage; culturing NRK-52E cells with homocysteine (Hcy) could significantly increase apoptosis and mitochondrial damage. Interestingly, we found that Mdivi-1 reduced Hcy-induced mitochondrial damage, thereby reducing the level of apoptosis. In conclusion, these results suggest that HHcy might aggravate the development of AKI by increasing mitochondrial damage and that reducing Hcy levels or inhibiting mitochondrial damage may be a potential therapeutic strategy to delay the development of AKI.

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“…It has been reported that the expression of p-STAT3 was co-localized with NLRP3-positive cells and upregulated NLRP3 via STAT3-dependent histone acetylation [49]. p38 mitogen-activated protein kinase (MAPK) activity is involved in the in ammatory response during stroke, as supported by the observation that p-p38 expression is upregulated in the ischemia area [23,50]. p38 MAPK signaling pathway induced the activation of the NLRP3 in ammasome and macrophage pyroptosis [51].…”

Section: Discussionmentioning

confidence: 92%

Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke

Guo

Lee

et al. 2021

Mol Neurobiol

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A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroin ammatory response and in ammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. In ammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38.The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P signi cantly reduced cell death and attenuated the neuroin ammatory response as determined by reduced CD68 and MPO. C + P decreased ischemiainduced in ammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the colocalization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroin ammation and NLRP3 in ammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for e cacious therapy following ischemic stroke.

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Amifostine ameliorates cerebral ischaemia-reperfusion injury via p38-mediated oxidative stress and mitochondrial dysfunction

Cited by 8 publications

References 0 publications

Metabolomic analysis and pharmacological validation of the cerebral protective effect of 3,4‑dihydroxybenzaldehyde on cerebral ischemia‑reperfusion injury

Metabolomic analysis and pharmacological validation of the cerebral protective effect of 3,4‑dihydroxybenzaldehyde on cerebral ischemia‑reperfusion injury

Hyperhomocysteinemia exacerbates acute kidney injury via increased mitochondrial damage

Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke

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