Background Iron oxide nanoparticles have been approved by food and drug administration for clinical application as magnetic resonance imaging (MRI) and are considered to be a biocompatible material. Large iron oxide nanoparticles are usually used as transversal (T2) contrast agents to exhibit dark contrast in MRI. In contrast, ultrasmall iron oxide nanoparticles (USPIONs) (several nanometers) showed remarkable advantage in longitudinal (T1)-weighted MRI due to the brighten effect. The study of the toxicity mainly focuses on particles with size of tens to hundreds of nanometers, while little is known about the toxicity of USPIONs. Results We fabricated Fe3O4 nanoparticles with diameters of 2.3, 4.2, and 9.3 nm and evaluated their toxicity in mice by intravenous injection. The results indicate that ultrasmall iron oxide nanoparticles with small size (2.3 and 4.2 nm) were highly toxic and were lethal at a dosage of 100 mg/kg. In contrast, no obvious toxicity was observed for iron oxide nanoparticles with size of 9.3 nm. The toxicity of small nanoparticles (2.3 and 4.2 nm) could be reduced when the total dose was split into 4 doses with each interval for 5 min. To study the toxicology, we synthesized different-sized SiO2 and gold nanoparticles. No significant toxicity was observed for ultrasmall SiO2 and gold nanoparticles in the mice. Hence, the toxicity of the ultrasmall Fe3O4 nanoparticles should be attributed to both the iron element and size. In the in vitro experiments, all the ultrasmall nanoparticles (< 5 nm) of Fe3O4, SiO2, and gold induced the generation of the reactive oxygen species (ROS) efficiently, while no obvious ROS was observed in larger nanoparticles groups. However, the ·OH was only detected in Fe3O4 group instead of SiO2 and gold groups. After intravenous injection, significantly elevated ·OH level was observed in heart, serum, and multiple organs. Among these organs, heart showed highest ·OH level due to the high distribution of ultrasmall Fe3O4 nanoparticles, leading to the acute cardiac failure and death. Conclusion Ultrasmall Fe3O4 nanoparticles (2.3 and 4.2 nm) showed high toxicity in vivo due to the distinctive capability in inducing the generation of ·OH in multiple organs, especially in heart. The toxicity was related to both the iron element and size. These findings provide novel insight into the toxicology of ultrasmall Fe3O4 nanoparticles, and also highlight the need of comprehensive evaluation for their clinic application. Graphical Abstract

Heart failure (HF), the leading cause of death among men and women world-wide, causes great health and economic burdens. HF can be triggered by many factors, such as coronary artery disease, heart attack, cardiomyopathy, hypertension, obesity, etc., all of which have close relations with calcium signal and the level of reactive oxygen species (ROS). Calcium is an essential second messenger in signaling pathways, playing a pivotal role in regulating the life and death of cardiomyocytes via the calcium-apoptosis link mediated by the cellular level of calcium. Meanwhile, calcium can also control the rate of energy production in mitochondria that are the major resources of ROS whose overproduction can lead to cell death. More importantly, there are bidirectional interactions between calcium and ROS, and such interactions may have therapeutic implications in treating HF through finely tuning the balance between these two by certain drugs. Many naturally derived products, e.g., flavones and isoflavones, have been shown to possess activities in regulating calcium and ROS simultaneously, thereby leading to a balanced microenvironment in heart tissues to exert therapeutic efficacies in HF. In this mini review, we aimed to provide an updated knowledge of the interplay between calcium and ROS in the development of HF. In addition, we summarized the recent studies (in vitro, in vivo and in clinical trials) using natural isolated flavones and isoflavones in treating HF. Critical challenges are also discussed. The information collected may help to evoke multidisciplinary efforts in developing novel agents for the potential prevention and treatment of HF.

The new coronavirus disease (COVID-19), as a new infectious disease, has relatively strong ability to spread from person to person. This paper studies several meteorological factors and air quality indicators between Shenzhen and Wenzhou, China, and conducts modelling analysis on whether the transmission of COVID-19 is affected by atmosphere. A comparative assessment is made on the characteristics of meteorological factors and air quality in these two typical cities in China and their impacts on the spread of COVID-19. The article uses meteorological data and air quality data, including 7 variables: daily average temperature, daily average relative humidity, daily average wind speed, nitrogen dioxide (NO 2), atmospheric fine particulate matter (PM 2.5), carbon monoxide (CO) and ozone (O 3), a distributed lag non-linear model (DLNM) is constructed to explore the correlation between atmospheric conditions and non-imported confirmed cases of COVID-19, and the relative risk is introduced to measure the lagging effects of meteorological factors and air pollution on the number of non-imported confirmed cases. Our finding indicates that there is significant differences in the relationship between 7 predictors and the transmission of COVID-19 in Shenzhen and Wenzhou. However, all predictors between the two cities have a non-linear relationship with the number of non-imported confirmed cases. The lower daily average temperature has increased the risk of epidemic transmission in the two cities. As the temperature rises, the risk of epidemic transmission in both cities will significantly decrease. The average daily relative humidity has no significant effects on the epidemic situation in Shenzhen, but the lower relative humidity reduces the risk of epidemic spread in Wenzhou. In contrast, meteorological data have significant impacts on the spread of COVID-19 in Wenzhou. The four predictors (NO 2 , PM 2.5 , CO, and O 3) have significant effects on the number of nonimported confirmed cases. Among them, PM 2.5 has a significant positive correlation with the number of non-imported confirmed cases. Daily average wind speed, NO 2 and O 3 have different effects on the number of non-imported confirmed cases in different cities.