The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture.

BACKGROUND AND AIMS: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. METHODS: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a ß-aminopropionitrile monofumarate-induced AD model. RESULTS: The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%-83.3% for coenzyme Q10 treatment), 150.15% (33.3%-83.3% for 2-week T-5224), and 175.38% (33.3%-91.7% for 3-week T-5224) in the ß-aminopropionitrile monofumarate-induced AD model. CONCLUSIONS: This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor-OXPHOS-AP-1 axis.

Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells.

Cervical cancer is one of the leading causes of cancer death in women. Mitochondrial-mediated ferroptosis (MMF) is a recently discovered form of cancer cell death. However, the role and the underlying mechanism of MMF in cervical cancer remain elusive. Here, using an unbiased screening for mitochondrial transmembrane candidates, we identified mitochondrial carrier 1 (MTCH1) as a central mediator of MMF in cervical cancers. MTCH1-deficiency disrupted mitochondrial oxidative phosphorylation while elevated mitochondrial reactive oxygen species (ROS) by decreasing NAD+ levels. This mitochondrial autonomous event initiated a mitochondria-to-nucleus retrograde signaling involving reduced FoxO1 nuclear translocation and subsequently downregulation of the transcription and activity of a key anti-ferroptosis enzyme glutathione peroxidase 4 (GPX4), thereby elevating ROS and ultimately triggering ferroptosis. Strikingly, targeting MTCH1 in combination with Sorafenib effectively and synergistically inhibited the growth of cervical cancer in a nude mouse xenograft model by actively inducing ferroptosis. In conclusion, these findings enriched our understanding of the mechanisms of MMF in which MTCH1 governed ferroptosis though retrograde signaling to FoxO1-GPX4 axis, and provided a potential therapeutic target for treating cervical cancer.

SENP2-mediated SERCA2a deSUMOylation increases calcium overload in cardiomyocytes to aggravate myocardial ischemia/reperfusion injury.

BACKGROUND: Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is a key protein that maintains myocardial Ca 2+ homeostasis. The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation (small ubiquitin-like modifier) process after ischemia/reperfusion injury (I/RI) in vitro and in vivo . METHODS: Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout (KO) and wild-type mice with I/RI were compared. SUMO-relevant protein expression and localization were detected by quantitative real-time PCR (RT-qPCR), Western blotting, and immunofluorescence in vitro and in vivo . Serca2a-SUMOylation, infarct size, and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes, were detected by immunoprecipitation, triphenyltetrazolium chloride (TTC)-Evans blue staining, and echocardiography respectively. RESULTS: The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO + I/RI groups. Senp1 and Senp2 messenger ribose nucleic acid (mRNA) and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI. However, the highest levels in HL-1 cells were recorded at 12 h. Senp2 expression increased in the cytoplasm, unlike that of Senp1. Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline, reduced the infarction area, and improved cardiac function, while inhibition of Senp1 protein could not restore the above indicators. CONCLUSION: I/RI activated Senp1 and Senp2 protein expression, which promoted Serca2a-deSUMOylation, while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.

Regulatory roles of copper metabolism and cuproptosis in human cancers.

Copper is an essential micronutrient for human body and plays a vital role in various biological processes including cellular respiration and free radical detoxification. Generally, copper metabolism in the body is in a stable state, and there are specific mechanisms to regulate copper metabolism and maintain copper homeostasis. Dysregulation of copper metabolism may have a great connection with various types of diseases, such as Wilson disease causing copper overload and Menkes disease causing copper deficiency. Cancer presents high mortality rates in the world due to the unlimited proliferation potential, apoptosis escape and immune escape properties to induce organ failure. Copper is thought to have a great connection with cancer, such as elevated levels in cancer tissue and serum. Copper also affects tumor progression by affecting angiogenesis, metastasis and other processes. Notably, cuproptosis is a novel form of cell death that may provide novel targeting strategies for developing cancer therapy. Copper chelators and copper ionophores are two copper coordinating compounds for the treatment of cancer. This review will explore the relationship between copper metabolism and cancers, and clarify copper metabolism and cuproptosis for cancer targeted therapy.

Preliminary assessment of cardiotoxicity in chimeric antigen receptor T cell therapy: a systematic review and meta-analysis.

As a novel anticancer therapy, chimeric antigen receptor T (CAR T) cell therapy may lead to cardiotoxic reactions. However, the exact incidence remains unclear. Our study aimed to preliminarily assess the prevalence of cardiotoxicity after CAR T cell treatment using a systematic review and meta-analysis. PubMed, Embase, Web of Science, and Cochrane databases were searched for potentially relevant studies. All types of relevant clinical studies were screened and assessed for risk bias. In most instances, random-effect models were used for data analysis, and heterogeneity between studies was evaluated. Standard quality assessment tools were used to assess quality. The study was registered with PROSPERO (CRD42022304611). Eight eligible studies comprising 3567 patients, including seven observational studies and one controlled study, were identified. The incidence of cardiovascular events was 16.7% [95% confidence interval (CI) 0.138-0.200, P < 0.01)]. Arrhythmia was the most common disorder, with an incidence of 6.5% (95% CI 0.029-0.115, P < 0.01). The occurrence of cardiotoxicity was associated with cytokine release syndrome (CRS), with a prevalence of 18.7% (95% CI 0.107-0.315, P < 0.01). Moreover, such adverse reactions were more common when CRS > 2 (OR = 0.07, 95% CI 0.02-0.29, P < 0.01). The risk of cardiotoxicity was not notably higher in patients receiving CAR T cell therapy than in those receiving traditional anticancer treatment. However, sufficient attention should be paid to this. And further evidence from large-scale clinical trials are needed.

Natural Polysaccharide ß-Glucan Protects against Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress.

Doxorubicin (DOXO) can be used to treat a variety of human tumors, but its clinical application is limited due to severe cardiotoxic side effect. Here, we explore the role of ß-glucan in DOXO-induced cardiotoxicity in mice and study its underlying mechanism. When co-administered with DOXO, ß-glucan was observed to prevent left ventricular dilation and fibrosis. In fact, DOXO reduces the activity of mitochondrial respiratory chain complex and enhances oxidative stress, which in turn impairs heart function. DOXO decreases the ATP production capacity of the heart and increases the ROS content, while ß-glucan can restore the heart capacity and reduce oxidative stress. ß-glucan also increases the activity of antioxidant enzymes GSH-PX and SOD, and reduces the level of MDA in the serum. In addition, the mRNAs of cardiac dysfunction marker genes ANP, BNP and Myh7 were significantly increased after DOXO induction, however, they did not increase when combined with ß-glucan administration. In conclusion, our results indicate that ß-glucan can improve the antioxidant capacity of the heart, thereby serving as a potential therapeutic strategy to prevent DOXO-induced cardiotoxicity.