Galangin inhibited ferroptosis through activation of the <scp>PI3K</scp>/<scp>AKT</scp> pathway in vitro and in vivo

Chen, Ke; Xue, Ran; Geng, Yaping; Zhang, Shenshen

doi:10.1096/fj.202200935r

Cited by 27 publications

(19 citation statements)

References 47 publications

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“…Xiong et al demonstrated that PM2.5 exposure induces ferroptosis in neuronal cells by inhibiting CREB [ 40 ]. Chen et al indicated that the bioflavonoid galangin delivered its anti-ferroptosis effects by activating CREB in a hepatic ischemia‒reperfusion model [ 41 ]. Indeed, a link between CREB and GPX4 was previously found during enterocytic cell differentiation [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Chen

Tian

et al. 2023

J Transl Med

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Background Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.

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Section: Discussionmentioning

confidence: 99%

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Chen

Tian

et al. 2023

J Transl Med

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“…Second, ferroptosis agonist had not been used to assess the effects of ferroptosis on ROS. It was reported that inhibition of ferroptosis decreased levels of ROS (15). Moreover, our findings indicate that baicalein inhibited ER stress.…”

Section: Discussionmentioning

confidence: 99%

Baicalein Relieves Brain Injury via Inhibiting Ferroptosis and Endoplasmic Reticulum Stress in a Rat Model of Cardiac Arrest

Zhou¹,

Zhang²,

Wang³

et al. 2022

Shock

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Background: Cardiac arrest (CA) is one of the leading causes of death worldwide. Endoplasmic reticulum (ER) stress and ferroptosis are proven pathological mechanisms implicated in neuronal damage. Baicalein, a ferroptosis Inhibitor, improved outcomes after traumatic brain injury. We aimed to explore the effects of baicalein on brain injury via ferroptosis and ER stress in a rat model of CA. Methods: Cardiac arrest models were established in Sprague-Dawley (SD) rats. The sham group (n = 6) was untreated with inducing ventricular fibrillation to cardiac arrest and cardiopulmonary resuscitation (CPR). Survival rats were randomly divided into five groups (n = 6). Ferroptosis inhibitor and ER stress agonist were administered separately and together in three groups. There was no drug intervention in the remaining group. The neurological deficit scores were recorded. Characteristics of ferroptosis were observed. And the associated protein of ferroptosis and ER stress were determined by Western blot. Cerebral ROS production was measured by using 2′,7′-dichlorofluorescein diacetate as the oxidative fluorescent probe. Results: Baicalein treatment improved neurological outcomes and decreased neurocyte injuries compared with CPR group. The changes of ferroptosis, more specifically, iron content, glutathione peroxidase 4 (GPX4), reactive oxygen species (ROS), arachidonate 15-lipoxygenase (ALOX15) and mitochondrial characteristics, were observed in brain tissue after ROSC. ALOX15 was lower in baicalein group than in CPR group. The morphology and structure of mitochondria in baicalein group were better than in CPR group. The ER stress markers, glucose-regulated protein 78, activating Transcription Factor 4 and C/EBP homologous protein was lower in baicalein group compared with CPR group. ROS in tunicamycin group was higher than in CPR group. And ROS in baicalein +tunicamycin group was lower than in tunicamycin group. Conclusion: Ferroptosis and ER stress are both involved in brain injury after ROSC. Baicalein alleviates brain injury via suppressing the ferroptosis and ER stress, and reduces ROS partly through inhibiting ER stress. Baicalein is a potential drug to relieve brain injury after ROSC.

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“…The levels of phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated cAMP response element-binding protein (p-CREB), and GPX4 were decreased in RSL3-induced HT1080 cells, while galangin treatment restored the levels of these proteins. Meanwhile, PI3K inhibition by LY294002 abolished the galangin-mediated upregulation of GPX4, indicating that the PI3K/AKT/CREB signaling pathway was involved in the antiferroptosis effects of galangin . Quercetin enhanced the expression of lysosomal-associated membrane protein 1 (LAMP-1) by increasing the levels of transcription factor EB (TFEB) in the nucleus .…”

Section: Natural Flavonoids Targeting Ferroptosismentioning

confidence: 99%

“…Analogously, rutin suppressed ferroptosis in small white follicles by regulating the NRF2/HO-1 pathway, thereby improving ovarian aging in laying hens . Galangin, mainly derived from the rhizome of Alpinis officinarum , could protect mouse liver from I/R injury . The levels of phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated cAMP response element-binding protein (p-CREB), and GPX4 were decreased in RSL3-induced HT1080 cells, while galangin treatment restored the levels of these proteins.…”

Section: Natural Flavonoids Targeting Ferroptosismentioning

confidence: 99%

“…109 Galangin, mainly derived from the rhizome of Alpinis of ficinarum, could protect mouse liver from I/R injury. 110 The levels of phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated cAMP response elementbinding protein (p-CREB), and GPX4 were decreased in RSL3-induced HT1080 cells, while galangin treatment restored the levels of these proteins. Meanwhile, PI3K inhibition by LY294002 abolished the galangin-mediated upregulation of GPX4, indicating that the PI3K/AKT/CREB signaling pathway was involved in the antiferroptosis effects of galangin.…”

Section: Flavonesmentioning

confidence: 99%

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Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

Zhou

Zhang

2023

J. Agric. Food Chem.

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Flavonoids are a class of bioactive phytochemicals containing a core 2-phenylchromone skeleton and are widely found in fruits, vegetables, and herbs. Such natural compounds have gained significant attention due to their various health benefits. Ferroptosis is a recently discovered unique iron-dependent mode of cell death. Unlike traditional regulated cell death (RCD), ferroptosis is associated with excessive lipid peroxidation on cellular membranes. Accumulating evidence suggests that this form of RCD is involved in a variety of physiological and pathological processes. Notably, multiple flavonoids have been shown to be effective in preventing and treating diverse human diseases by regulating ferroptosis. In this review, we introduce the key molecular mechanisms of ferroptosis, including iron metabolism, lipid metabolism, and several major antioxidant systems. Additionally, we summarize the promising flavonoids targeting ferroptosis, which provides novel ideas for the management of diseases such as cancer, acute liver injury, neurodegenerative diseases, and ischemia/reperfusion (I/R) injury.

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Galangin inhibited ferroptosis through activation of the PI3K/AKT pathway in vitro and in vivo

Cited by 27 publications

References 47 publications

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Baicalein Relieves Brain Injury via Inhibiting Ferroptosis and Endoplasmic Reticulum Stress in a Rat Model of Cardiac Arrest

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

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