An adverse outcome pathway-based approach to assess aurantio-obtusin-induced hepatotoxicity

Hu, Manjiang; Zhong, Yizhou; Li, Jun; Zheng, Shaozhen; Lin, Li; Lin, Xi; Liang, Beibei; Huang, Yuji; Xian, Hongyi; Li, Zhiming; Zhang, Bingli; Wang, Bo; Meng, Hao; Du, Junbao; Ye, Rongyi; Lü, Zhi; Yang, Xifei; Yang, Xingfen; Huang, Zhenlie

doi:10.1016/j.tox.2022.153293

Cited by 10 publications

(4 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, a link between CREB and GPX4 was previously found during enterocytic cell differentiation [ 42 ]. However, another recent study found the opposite effect of CREB on ferroptosis, revealing that CREB regulates acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in hepatoma to promote ferroptosis and induce hepatotoxicity [ 43 ]. Therefore, the effect of CREB on ferroptosis might depend on the binding gene or the disease condition.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…NAC are generally less toxic, but this does not guarantee they are all safe. Recent studies have confirmed that triptolide [ 242 ], toosendanin [ 243 ], aurantio-obtusin [ 244 ], and Epimedium koreanum Nakai [ 245 ] all induced hepatotoxicity by triggering ferroptosis. NAC that triggers ferroptosis in HSCs and HCC cells may also cause damage to healthy hepatocytes.…”

Section: Discussion and Prospectsmentioning

confidence: 99%

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

Wu,

Zhu,

Liu

et al. 2024

Antioxidants

View full text Add to dashboard Cite

Ferroptosis is an emerging type of regulated cell death usually accompanied by the accumulation of ferrous ions (Fe2+) and lipid peroxides. As the metabolic hub of the body, the liver is crucial for iron storage and lipid metabolism. The liver seems to be closely related to ferroptosis through iron and lipid metabolism. Liver disease greatly threatens host health, and exploring effective interventions is essential. Mounting studies have demonstrated that ferroptosis is one of the possible pathogenic mechanisms involved in liver disease. Targeting ferroptosis may provide a promising opportunity for treating liver disease. However, drugs targeting ferroptosis are extremely limited. Therefore, it is an urgent need to develop new and safe ferroptosis regulators. Natural active compounds (NAC), especially those derived from traditional Chinese medicine, have recently shown great therapeutic potential in liver disease via modulating ferroptosis-related genes or pathways. Here, we outline the molecular mechanism of ferroptosis and systematically summarize the regulatory function of NAC on ferroptosis in liver disease. Finally, we discuss the application prospects and potential problems concerning NAC as ferroptosis regulators for managing liver disease.

show abstract

“…42 Chen et al confirmed that CREB was involved in modulating ferroptosis of lung fibroblasts (HT1080 cells). 43 Furthermore, Xiong et al 44 and Hu et al 45 revealed that CREB participated in regulating ferroptosis of neuronal cells and liver cells. We found that knockdown of CREB could obviously promote ferroptosis of eosinophils.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of CREB promotes glucocorticoids action on airway inflammation in pediatric asthma by promoting ferroptosis of eosinophils

2023

Allergol Immunopathol

View full text Add to dashboard Cite

Background: Pediatric asthma is a common chronic disease of childhood with airway inflammation. Cyclic adenosine monophosphate response element binding protein (CREB) plays a significant role in the transcription of proinflammatory genes, but its role in pediatric asthma has remained unclear. Herein, we investigated the functions of CREB in pediatric asthma. Methods: Eosinophils were purified from the peripheral blood of interleukin 5 (IL5) transgenic (IL5T) neonatal mice. The contents of CREB, long-chain fatty-acid–CoA ligase 4, transferrin receptor protein 1, ferritin heavy chain 1, and glutathione peroxidase 4 in eosinophils were examined by Western blot analysis. The viability of eosinophils, and the mean fluorescence intensity of Siglec F, C-C motif chemokine receptor 3 (CCR3), and reactive oxygen species were examined by flow cytometry. The concentration of iron in eosinophils was assessed by a commercial kit. The contents of malondialdehyde, glutathione, glutathione peroxidase, IL-5, and IL-4 were discovered by enzyme-linked-immunosorbent serologic assay. The C57BL/6 mice were randomly divided into four groups: sham, ovalbumin (OVA), OVA+Ad-shNC, and OVA+Ad-shCREB. The bronchial and alveolar structures were evaluated by hematoxylin and eosin staining. Leukocytes and eosinophils in the blood were measured using a HEMAVET 950. Results: The abundance of CREB in eosinophils was enhanced by CREB overexpression vector transfection, but reduced by short hairpin (sh)CREB transfection. Downregulation of CREB triggered the cell death of eosinophils. Knockdown of CREB could obviously contribute to ferroptosis of eosinophils. In addition, downregulation of CREB facilitated dexamethasone (DXMS, a type of glucocorticoid)-induced eosinophils death. Moreover, we established an asthma mouse model by OVA treatment. The CREB was upregulated in OVA group mice, but Ad-shCREB treatment obviously downregulated CREB level. Downregulation of CREB diminished OVA-induced asthmatic airway inflammation by reducing the number of inflammatory cells and the levels of proinflammatory factors. Downregulated CREB enhanced the antiinflammatory effect of DXMS in OVA-induced mice. Conclusion: Inhibition of CREB promoted the effect of glucocorticoids on airway inflammation in pediatric asthma through promoting ferroptosis of eosinophils.

show abstract

An adverse outcome pathway-based approach to assess aurantio-obtusin-induced hepatotoxicity

Cited by 10 publications

References 65 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

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

Inhibition of CREB promotes glucocorticoids action on airway inflammation in pediatric asthma by promoting ferroptosis of eosinophils

Contact Info

Product

Resources

About