Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities.

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.

Design, synthesis, and biological evaluation of 2-amino-6-methyl-phenol derivatives targeting lipid peroxidation with potent anti-ferroptotic activities.

The suppression of ferroptosis is emerging as a promising therapeutic strategy for effectively treating a wide range of diseases, including neurodegenerative disorders, organ ischemia-reperfusion injury, and inflammatory conditions. However, the clinical utility of ferroptosis inhibitors is significantly impeded by the limited availability of rational drug designs. In our previous study, we successfully unraveled the efficacy of ferrostatin-1 (Fer-1) attributed to the synergistic effect of its ortho-diamine (-NH) moiety. In this study, we present the discovery of the ortho-hydroxyl-amino moiety as a novel scaffold for ferroptosis inhibitors, employing quantum chemistry as well as in vitro and in vivo assays. 2-amino-6-methylphenol derivatives demonstrated remarkable inhibition of RSL3-induced ferroptosis, exhibiting EC50 values ranging from 25 nM to 207 nM. These compounds do not appear to modulate iron homeostasis or lipid reactive oxygen species (ROS) generation pathways. Nevertheless, they effectively prevent the accumulation of lipid peroxides in living cells. Furthermore, compound 13 exhibits good in vivo activities as it effectively protect mice from kidney ischemia-reperfusion injury. In summary, compound 13 has been identified as a potent ferroptosis inhibitor, warranting further investigation as a promising lead compound.

Structural Change and Radical Generation of a Cadmium-Based Metal-Organic Framework Induced by an Electric Field.

Herein we report the structural change and radical generation of a cadmium-based metal-organic framework (Cd-MOF) induced by external electric fields. Under a weaker single electric field, different coordination modes of Cd-L lead to 3D → 2D structural change. Under stronger superposed electric fields, Cd-MOF was excited to produce a stable free radical. This study will provide a new avenue for the controlled assembly of MOFs.

Facility-Level Emissions and Synergistic Control of Energy-Related Air Pollutants and Carbon Dioxide in China.

Boilers involve ∼60% of primary energy consumption in China and emit more air pollutants and CO2 than any other infrastructures. Here, we established a nationwide, facility-level emission data set considering over 185,000 active boilers in China by fusing multiple data sources and jointly using various technical means. The emission uncertainties and spatial allocations were significantly improved. We found that coal-fired power plant boilers were not the most emission-intensive boilers with regard to SO2, NOx, PM, and mercury but emitted the highest CO2. However, biomass- and municipal waste-fired combustion, regarded as zero-carbon technologies, emitted a large fraction of SO2, NOx, and PM. Future biomass or municipal waste mixing in coal-fired power plant boilers can make full use of the advantages of zero-carbon fuel and the pollution control devices of coal-fired power plants. We identified small-size boilers, medium-size boilers using circulating fluidized bed boilers, and large-size boilers located in China's coal mine bases as the main high emitters. Future focuses on high-emitter control can substantially mitigate the emissions of SO2 by 66%, NOx by 49%, PM by 90%, mercury by 51%, and CO2 by 46% at the most. Our study sheds light on other countries wishing to reduce their energy-related emissions and thus the related impacts on humans, ecosystems, and climates.

[Fe2S2-Agx]-Hydrogenase Active-Site-Containing Coordination Polymers and Their Photocatalytic H2 Evolution Reaction Properties.

Three [Fe2S2-Agx]-hydrogenase active-site-containing coordination polymers (CPs), {[Fe2S2-Ag1](4-cpmt)2(CO)6(ClO4-)}n (1), {[Fe2S2-Ag2](4-cpmt)2(CO)6(OTf-)2(benzene)}n (2), and {[Fe2S2-Ag2](3-cpmt)2(CO)6(ClO4-)2}n (3), were obtained by a direct synthesis method from ligands [FeFe](4-cpmt)2(CO)6 [L1; 4-cpmt = (4-cyanophenyl)methanethiolate] and [FeFe](3-cpmt)2(CO)6 [L2; 3-cpmt = (3-cyanophenyl)methanethiolate] with silver salts. 1-3 represent the first examples of [FeFe]-hydrogenase-based CPs. It was worth noting that the Ag-S bonding between the Ag centers and S atoms of a [Fe2S2] cluster produced a novel [Fe2S2-Agx] (x = 1 or 2) catalytic site in all three polymers. The results of photochemical H2 generation experiments indicated that 2 and 3 containing [Fe2S2-Ag2] active sites showed obviously improved catalytic performances compared with ligands L1 and L2 and [Fe2S2-Ag1]-containing 1. This work provides a pioneering strategy for the direct synthesis of [Fe2S2]-based CPs or metal-organic frameworks.

Non-negligible contributions to human health from increased household air pollution exposure during the COVID-19 lockdown in China.

BACKGROUND: Ambient and household air pollution are found to lead to premature deaths from all-cause or cause-specific death. The national lockdown measures in China during COVID-19 were found to lead to abrupt changes in ambient surface air quality, but indoor air quality changes were neglected. In this study, we aim to investigate the impacts of lockdown measures on both ambient and household air pollution as well as the short-term health effects of air pollution changes. METHODS: In this study, an up-to-date emission inventory from January to March 2020 in China was developed based on air quality observations in combination with emission-concentration response functions derived from chemical transport modeling. These emission inventories, together with the emissions data from 2017 to 2019, were fed into the state-of-the-art regional chemistry transport model to simulate the air quality in the North China Plain. A hypothetical scenario assuming no lockdown effects in 2020 was also performed to determine the effects of the lockdown on air quality in 2020. A difference-to-difference approach was adopted to isolate the effects on air quality due to meteorological conditions and long-term decreasing emission trends by comparing the PM2.5 changes during lockdown to those before lockdown in 2020 and in previous years (2017-2019). The short-term premature mortality changes from both ambient and household PM2.5 changes were quantified based on two recent epidemiological studies, with uncertainty of urban and rural population migration considerations. FINDINGS: The national lockdown measures during COVID-19 led to a reduction of 5.1 µg m-3 in ambient PM2.5 across the North China Plain (NCP) from January 25th to March 5th compared with the hypothetical simulation with no lockdown measures. However, a difference-to-difference method showed that the daily domain average PM2.5 in the NCP decreased by 9.7 µg m-3 between lockdown periods before lockdown in 2020, while it decreased by 7.9 µg m-3 during the same periods for the previous three-year average from 2017 to 2019, demonstrating that lockdown measures may only have caused a 1.8 µg m-3 decrease in the NCP. We then found that the integrated population-weighted PM2.5, including both ambient and indoor PM2.5 exposure, increased by 5.1 µg m-3 during the lockdown periods compared to the hypothetical scenario, leading to additional premature deaths of 609 (95% CI: 415-775) to 2,860 (95% CI: 1,436-4,273) in the short term, depending on the relative risk chosen from the epidemiological studies. INTERPRETATION: Our study indicates that lockdown measures in China led to abrupt reductions in ambient PM2.5 concentration but also led to significant increases in indoor PM2.5 exposure due to confined indoor activities and increased usages of household fuel for cooking and heating. We estimated that hundreds of premature deaths were added as a combination of decreased ambient PM2.5 and increased household PM2.5. Our findings suggest that the reduction in ambient PM2.5 was negated by increased exposure to household air pollution, resulting in an overall increase in integrated population weighted exposure. Although lockdown measures were instrumental in reducing the exposure to pollution concentration in cities, rural areas bore the brunt, mainly due to the use of dirty solid fuels, increased population density due to the large-scale migration of people from urban to rural areas during the Chinese New Year and long exposure time to HAP due to restrictions in outdoor movement.

Effect of the Coal Preparation Process on Mercury Flows and Emissions in Coal Combustion Systems.

Coal preparation is effective in controlling primary mercury emissions in coal combustion systems; however, the combustion of coal preparation byproducts may cause secondary emissions. The inconsistent coal preparation statistics, unclear mercury distribution characteristics during coal preparation, and limited information regarding the byproduct utilization pathways lead to great uncertainty in the evaluation of the effect of coal preparation in China. This study elucidated the mercury distribution in coal preparation based on the activity levels of 2886 coal preparation plants, coal mercury content database, tested mercury distribution factors of typical plants, and then traced the mercury flows and emissions in the downstream sectors using a cross-industry mercury flow model. We found that coal preparation altered the mercury flows by reducing 68 tonnes of mercury to sectors such as coking and increasing the flows to byproduct utilization sectors. Combusting cleaned coal rather than raw coal reduced the mercury emissions by 47 tonnes; however, this was offset by secondary mercury emissions. Coal gangue spontaneous combustion and the cement kiln coprocessing process were dominant secondary emitters. Our results highlight the necessity of whole-process emission control of atmospheric mercury based on flow maps. Future comprehensive utilization of wastes in China should fully evaluate the potential secondary mercury emissions.