The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury.

Ferroptosis is a nonapoptotic form of regulated cell death that has been reported to play a central role in cardiac ischemia‒reperfusion (I/R) injury. N-acetyltransferase 10 (NAT10) contributes to cardiomyocyte apoptosis by functioning as an RNA ac4c acetyltransferase, but its role in cardiomyocyte ferroptosis during I/R injury has not been determined. This study aimed to elucidate the role of NAT10 in cardiac ferroptosis as well as the underlying mechanism. The mRNA and protein levels of NAT10 were increased in mouse hearts after I/R and in cardiomyocytes that were exposed to hypoxia/reoxygenation. P53 acted as an endogenous activator of NAT10 during I/R in a transcription-dependent manner. Cardiac overexpression of NAT10 caused cardiomyocyte ferroptosis to exacerbate I/R injury, while cardiomyocyte-specific knockout of NAT10 or pharmacological inhibition of NAT10 with Remodelin had the opposite effects. The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan. Mechanistically, NAT10 induced the ac4C modification of Mybbp1a, increasing its stability, which in turn activated p53 and subsequently repressed the transcription of the anti-ferroptotic gene SLC7A11. Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R.

Photoacoustic imaging-guided triple-responsive nanoparticles with tumor hypoxia relief for improving chemotherapy/ photothermal/photodynamic synergistic therapy against breast cancer.

Chemo-photothermal/photodynamic synergistic therapy is a new effective cancer treatment method to overcome the limitations of single chemotherapy. However, the limited low photothermal conversion efficiency, the hypoxic tumor microenvironment, and premature leakage of the drug constrain their clinical applications. To address these challenges, an all-in-one biodegradable polydopamine-coated UiO-66 framework nanomedicine (DUPM) was developed to co-deliver the drug doxorubicin hydrochloride (DOX) and the excellent photothermal material MoOx nanoparticles (NPs). The results showed that DUPM exhibited good physicochemical stability and efficiently accumulated tumor tissues under pH-, glutathione-, and NIR-triggered drug release behaviour. Of note, the synthesized MoOx NPs endowed DUPM with self-supporting oxygen production and generated more reactive oxygen species (1O2 and·OH), besides, it induces Mo-mediated redox reaction to deplete excessive glutathione thus relieving tumor hypoxia to enhance PDT, further improving synergistic therapy. Meanwhile, DUPM showed strong absorption in the near-infrared range and high photothermal conversion efficiency at 808 nm (51.50%) to realize photoacoustic imaging-guided diagnosis and treatment of cancer. Compared with monotherapy, the in vivo anti-tumor efficacy results showed that DUMP exerted satisfactory tumor growth inhibition effects (94.43%) with good biocompatibility. This study provides a facile strategy to develop intelligent multifunctional nanoparticles with tumor hypoxia relief for improving synergistic therapy and diagnosis against breast cancer.

Exosomes secreted from cardiomyocytes suppress the sensitivity of tumor ferroptosis in ischemic heart failure.

Heart failure (HF) patients in general have a higher risk of developing cancer. Several animal studies have indicated that cardiac remodeling and HF remarkably accelerate tumor progression, highlighting a cause-and-effect relationship between these two disease entities. Targeting ferroptosis, a prevailing form of non-apoptotic cell death, has been considered a promising therapeutic strategy for human cancers. Exosomes critically contribute to proximal and distant organ-organ communications and play crucial roles in regulating diseases in a paracrine manner. However, whether exosomes control the sensitivity of cancer to ferroptosis via regulating the cardiomyocyte-tumor cell crosstalk in ischemic HF has not yet been explored. Here, we demonstrate that myocardial infarction (MI) decreased the sensitivity of cancer cells to the canonical ferroptosis activator erastin or imidazole ketone erastin in a mouse model of xenograft tumor. Post-MI plasma exosomes potently blunted the sensitivity of tumor cells to ferroptosis inducers both in vitro in mouse Lewis lung carcinoma cell line LLC and osteosarcoma cell line K7M2 and in vivo with xenograft tumorigenesis model. The expression of miR-22-3p in cardiomyocytes and plasma-exosomes was significantly upregulated in the failing hearts of mice with chronic MI and of HF patients as well. Incubation of tumor cells with the exosomes isolated from post-MI mouse plasma or overexpression of miR-22-3p alone abrogated erastin-induced ferroptotic cell death in vitro. Cardiomyocyte-enriched miR-22-3p was packaged in exosomes and transferred into tumor cells. Inhibition of cardiomyocyte-specific miR-22-3p by AAV9 sponge increased the sensitivity of cancer cells to ferroptosis. ACSL4, a pro-ferroptotic gene, was experimentally established as a target of miR-22-3p in tumor cells. Taken together, our findings uncovered for the first time that MI suppresses erastin-induced ferroptosis through releasing miR-22-3p-enriched exosomes derived from cardiomyocytes. Therefore, targeting exosome-mediated cardiomyocyte/tumor pathological communication may offer a novel approach for the ferroptosis-based antitumor therapy.

[Pollution Characteristics and Health Risk of Heavy Metals in Fugitive Dust Around Zhaotong City].

In order to explore the pollution characteristics and health risks of heavy metals in fugitive dust around the urban areas of Zhaotong City, road dust and soil dust samples were collected in the Zhaoyang District of Zhaotong City in May 2019. The dust samples were suspended using a particle resuspension system to obtain PM2.5 (particulate matter with an aerodynamic diameter less than or equal to 2.5 µm). The concentrations of Ca, Al, Fe, Mg, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, As, Cd, and Pb in PM2.5 were quantified by ICP-MS and ICP-OES. By analyzing 10 types of heavy metals in PM2.5, the results showed that the average concentration of Mn was the highest in the soil fugitive dust, followed by Cr, Ni, Zn, Cu, Co, Pb, V, As, and Cd. The average concentration of Zn in the road fugitive dust was the highest, followed by Mn, Cu, Cr, Pb, Ni, As, Co, V, and Cd. The enrichment factor (EF) indicated that Cd was strongly enriched in the two types of fugitive dust. The EFs of Cu, Zn, and Pb in road fugitive dust showed a moderate enrichment, and they were higher than those in soil fugitive dust. Correlation and principal component analysis showed that heavy metals in the two types of fugitive dust were affected by coal burning sources. At the same time, heavy metals in soil fugitive dust were affected by agricultural activity sources, and heavy metals in road fugitive dust were affected by traffic sources. The results of the health risk assessment indicated that the carcinogenic risks of Cr, Co, Ni, As, and Cd in soil fugitive dust were higher than those in road fugitive dust. The non-carcinogenic risks of heavy metals in the two types of fugitive dust for children were higher than those for adults, and the non-carcinogenic risks of Cu, Zn, and Pb in road fugitive dust were higher than those in soil fugitive dust.

Concentrations, Source Characteristics, and Health Risk Assessment of Toxic Heavy Metals in PM2.5 in a Plateau City (Kunming) in Southwest China.

To explore the mass concentration levels and health risks of heavy metals in the air in dense traffic environments, PM2.5 samples were collected at three sites in the city of Kunming in April and October 2013, and January and May 2014. Ten heavy metals--V, Cr, Mn, Co, Ni, Cu, Zn, As, Cd and Pb--were analyzed by ICP-MS, and the results showed PM2.5 concentrations significantly higher in spring and winter than in summer and autumn, especially for Zn and Pb. The concentration of heavy metals on working days is significantly higher, indicating that vehicle emissions are significant contributors. An enrichment factor analysis showed that Cr, Mn, Ni, Cu, Zn, As, Cd and Pb come mainly from anthropogenic sources, while V and Co may be both anthropogenic and natural. The correlation and principal component analysis (PCA) showed that Ni, Cu, Zn, Cd and Pb mainly come from vehicles emissions and metallurgical industries; Cr and Mn, from vehicles emissions and road dust; and As, mainly from coal combustion. The health risk assessment shows that the non-carcinogenic risk thresholds of the heavy metals in PM2.5 to children and adult men and women are all less than 1. The carcinogenic risk of Cr for men and women in traffic-intensive areas exceeds 10-4, reaching 1.64 × 10-4 and 1.4 × 10-4, respectively.

Mettl14 Attenuates Cardiac Ischemia/Reperfusion Injury by Regulating Wnt1/ß-Catenin Signaling Pathway.

N6-methyladenosine (m6A) methylation in RNA is a dynamic and reversible modification regulated by methyltransferases and demethylases, which has been reported to participate in many pathological processes of various diseases, including cardiac disorders. This study was designed to investigate an m6A writer Mettl14 on cardiac ischemia-reperfusion (I/R) injury and uncover the underlying mechanism. The m6A and Mettl14 protein levels were increased in I/R hearts and neonatal mouse cardiomyocytes upon oxidative stress. Mettl14 knockout (Mettl14+/-) mice showed pronounced increases in cardiac infarct size and LDH release and aggravation in cardiac dysfunction post-I/R. Conversely, adenovirus-mediated overexpression of Mettl14 markedly reduced infarct size and apoptosis and improved cardiac function during I/R injury. Silencing of Mettl14 alone significantly caused a decrease in cell viability and an increase in LDH release and further exacerbated these effects in the presence of H2O2, while overexpression of Mettl14 ameliorated cardiomyocyte injury in vitro. Mettl14 resulted in enhanced levels of Wnt1 m6A modification and Wnt1 protein but not its transcript level. Furthermore, Mettl14 overexpression blocked I/R-induced downregulation of Wnt1 and ß-catenin proteins, whereas Mettl14+/- hearts exhibited the opposite results. Knockdown of Wnt1 abrogated Mettl14-mediated upregulation of ß-catenin and protection against injury upon H2O2. Our study demonstrates that Mettl14 attenuates cardiac I/R injury by activating Wnt/ß-catenin in an m6A-dependent manner, providing a novel therapeutic target for ischemic heart disease.