Ferroptosis inhibitor alleviates sorafenib-induced cardiotoxicity by attenuating KLF11-mediated FSP1-dependent ferroptosis.

Sorafenib is a standard first-line drug for advanced hepatocellular carcinoma, but the serious cardiotoxic effects restrict its therapeutic applicability. Here, we show that iron-dependent ferroptosis plays a vital role in sorafenib-induced cardiotoxicity. Remarkably, our in vivo and in vitro experiments demonstrated that ferroptosis inhibitor application neutralized sorafenib-induced heart injury. By analyzing transcriptome profiles of adult human sorafenib-treated cardiomyocytes, we found that Krüppel-like transcription factor 11 (KLF11) expression significantly increased after sorafenib stimulation. Mechanistically, KLF11 promoted ferroptosis by suppressing transcription of ferroptosis suppressor protein 1 (FSP1), a seminal breakthrough due to its ferroptosis-repressing properties. Moreover, FSP1 knockdown showed equivalent results to glutathione peroxidase 4 (GPX4) knockdown, and FSP1 overexpression counteracted GPX4 inhibition-induced ferroptosis to a substantial extent. Cardiac-specific overexpression of FSP1 and silencing KLF11 by an adeno-associated virus serotype 9 markedly improved cardiac dysfunction in sorafenib-treated mice. In summary, FSP1-mediated ferroptosis is a crucial mechanism for sorafenib-provoked cardiotoxicity, and targeting ferroptosis may be a promising therapeutic strategy for alleviating sorafenib-induced cardiac damage.

Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis.

BACKGROUND: Currently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity. METHODS: Original data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity. Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h. RESULTS: Overall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C-C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes. GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity. CONCLUSION: In the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.

NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a prevalent complication in patients with diabetes, resulting in high morbidity and mortality. However, the molecular mechanisms of diabetic cardiomyopathy have yet to be fully elucidated. In this study, we investigated a novel target, NOX1, an isoform of superoxide-producing NADPH oxidase with key functional involvement in the pathophysiology of DCM. The DCM rat model was established by a high-fat diet combined with streptozotocin injections. DCM rats elicited myocardial fibrosis exacerbation, which was accompanied by a marked elevation of NOX1 expression in cardiac tissue. In particular, a specific NOX1 inhibitor, ML171, effectively decreased myocardial fibrosis and protected against cardiac dysfunction in DCM rats. Rat neonatal cardiac fibroblasts were incubated with high glucose (HG, 33 mM) as an in vitro model of DCM. We also observed that the expression of NOX1 was upregulated in HG-cultured cardiac fibroblasts. Silencing of NOX1 was found to attenuate myocardial fibrosis and oxidative stress in HG-induced cardiac fibroblasts. Furthermore, the upregulation of NOX1 by hyperglycemia induced activation of the TLR2/NF-κB pathway both in vitro and in vivo, whereas these effects were significantly attenuated with NOX1 gene silencing and further enhanced with NOX1 gene overexpression. In summary, we demonstrated that NOX1 induced activation of the TLR2/NF-κB pathway and increased reactive oxygen species production accumulation, which ultimately increased myocardial fibrosis and deteriorated cardiac function in diabetic cardiomyopathy. Our study revealed that NOX1 was a potential therapeutic target for DCM.

ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression.

Sorafenib is the unique recommended molecular-targeted drug for advanced hepatocellular carcinoma, but its clinical use is limited due to cardiotoxicity. As sorafenib is an efficient ferroptosis inducer, the pathogenesis of this compound to ferroptosis-mediated cardiotoxicity is worth further study. Mice were administered 30 mg/kg sorafenib intraperitoneally for 2 weeks to induce cardiac dysfunction and Ferrostatin-1 (Fer-1) was used to reduce ferroptosis of mice with sorafenib-induced cardiotoxicity. Sorafenib reduced levels of anti-ferroptotic markers involving Slc7a11 and glutathione peroxidase 4 (GPX4), increased malonaldehyde malondialdehyde, apart from causing obvious mitochondria damage, which was alleviated by Fer-1. In vitro experiments showed that Fer-1 inhibited lipid peroxidation and injury of H9c2 cardiomyoblasts induced by sorafenib. Both in vitro and in vivo experiments confirmed that the expression of Slc7a11 was down regulated in sorafenib-induced cardiotoxicity, which can be partially prevented by treatment with Fer-1. Overexpression of Slc7a11 protected cells from ferroptosis, while knock-down of Slc7a11 made cardiomyoblasts sensitive to ferroptosis caused by sorafenib. Finally, by comparing data from the GEO database, we found that the expression of ATF3 was significantly increased in sorafenib treated human cardiomyocytes. In addition, we demonstrated that ATF3 suppressed Slc7a11 expression and promoted ferroptosis. Based on these findings, we concluded that ATF3/Slc7a11 mediated ferroptosis is one of the key mechanisms leading to sorafenib-induced cardiotoxicity. Targeting ferroptosis may be a novel therapeutic approach for preventing sorafenib-induced cardiotoxicity in the future.

Performance and Reading Time of Automated Breast US with or without Computer-aided Detection.

BackgroundComputer-aided detection (CAD) systems may be used to help radiologists interpret automated breast (AB) US images. However, the optimal use of CAD with AB US has, to the knowledge of the authors, not been determined.PurposeTo compare the performance and reading time of different readers by using AB US CAD system to detect breast cancer in different reading modes.Materials and MethodsIn this retrospective study, 1485 AB US images (282 with malignant lesions, 695 with benign lesions, and 508 healthy) in 1452 women (mean age, 43.7 years; age range, 19-82 years) including 529 (36.4%) women who were asymptomatic were collected between 2016 and 2017. A CAD system was used to interpret the images. Three novice readers with 1-3 years of US experience and three experienced readers with 5-10 years of US experience were assigned to read AB US images without CAD, at a second reading (after the reader completed a full unaided interpretation), and at concurrent reading (use of CAD at the start of the assessment). Diagnostic performances and reading times were compared by using analysis of variance.ResultsFor all readers, the mean area under the receiver operating characteristic curve improved from 0.88 (95% confidence interval [CI]: 0.85, 0.91) at without-CAD mode to 0.91 (95% CI: 0.89, 0.92; P < .001) at the second-reading mode and 0.90 (95% CI: 0.89, 0.92; P = .002) at the concurrent-reading mode. The mean sensitivity of novice readers in women who were asymptomatic improved from 67% (95% CI: 63%, 74%) at without-CAD mode to 88% (95% CI: 84%, 89%) at both the second-reading mode and the concurrent-reading mode (P = .003). Compared with the without-CAD and second-reading modes, the mean reading time per volume of concurrent reading was 16 seconds (95% CI: 11, 22; P < .001) and 27 seconds (95% CI: 21, 32; P < .001) shorter, respectively.ConclusionComputer-aided detection (CAD) was helpful for novice readers to improve cancer detection at automated breast US in women who were asymptomatic. CAD was more efficient when used concurrently for all readers.© RSNA, 2019Online supplemental material is available for this article.See also the editorial by Slanetz in this issue.