Novel meroterpene-like compounds inhibit ferroptosis through Fe2+ chelation.

Colorectal cancer (CRC) is the third most common type of cancer in the world. It is characterized by complex crosstalk between various signaling pathways, as a result of which it is highly challenging to identify optimal therapeutic targets and design treatment strategies. In this study, we tested the effect of 700 compounds on the CRC cell line HT-29 by using the sulforhodamine B assay and screened out 17 compounds that exhibited high toxicity (indicated by an inhibition rate of ≥75% when applied at a concentration of 10µM) against the HT-29 cell line. Next, we investigated the mechanisms underlying the effects of these 17 highly toxic compounds. The results of ferroptosis analysis and electron microscopy showed that compounds 575 and 578 were able to significantly reverse RSL3-induced increase in ferroptosis, while compound 580 had a less pronounced ferroptosis-regulating effect. In subsequent experiments, western blotting showed that compounds 575, 578, and 580, which belong to a class of meroterpene-like compounds that affect ferroptosis, do not induce autophagy or apoptosis in the CRC cell line. Instead, Fe2+ chelation experiments showed that these three compounds can serve as iron chelators by chelating Fe2+ at a 1:1 (chelator: Fe2+) ratio. Specifically, the aldehyde and hydroxyl groups of the benzene ring in these compounds may chelate Fe2+, thus reducing Fe2+ levels in cells and inhibiting ferroptosis. These results indicate that these novel meroterpene-like compounds are potential therapeutic small-molecule candidates for targeting ferroptosis in tumors.

Dimerized sesquiterpenoid [4 + 2] adducts with ferroptosis-promoting activity from Inula britannica Linn.

Inubritanolides C and D (1 and 2), two exo sesquiterpenoid [4 + 2] adducts with unprecedented interconverting conformations of twist-chair and chair, together with two previously undescribed endo [4 + 2] dimers (3 and 4) were discovered from Inula britannica flowers. Dimers 1 and 2 have an undescribed carbon skeleton comprising of eudesmanolide and guaianolide units with the linkage mode of C-11/C-1' and C-13/C-3' via a Diels-Alder cycloaddition reaction. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, ECD, and variable-temperature NMR experiments. Dimer 2 displayed a strong inhibitory effect on breast cancer cells by promoting lipid ROS production, showing its potential as ferroptosis inducer.

Mass Spectrometry Imaging-Based Single-Cell Lipidomics Profiles Metabolic Signatures of Heart Failure.

Heart failure (HF), leading as one of the main causes of mortality, has become a serious public health issue with high prevalence around the world. Single cardiomyocyte (CM) metabolomics promises to revolutionize the understanding of HF pathogenesis since the metabolic remodeling in the human hearts plays a vital role in the disease progression. Unfortunately, current metabolic analysis is often limited by the dynamic features of metabolites and the critical needs for high-quality isolated CMs. Here, high-quality CMs were directly isolated from transgenic HF mice biopsies and further employed in the cellular metabolic analysis. The lipids landscape in individual CMs was profiled with a delayed extraction mode in time-of-flight secondary ion mass spectrometry. Specific metabolic signatures were identified to distinguish HF CMs from the control subjects, presenting as possible single-cell biomarkers. The spatial distributions of these signatures were imaged in single cells, and those were further found to be strongly associated with lipoprotein metabolism, transmembrane transport, and signal transduction. Taken together, we systematically studied the lipid metabolism of single CMs with a mass spectrometry imaging method, which directly benefited the identification of HF-associated signatures and a deeper understanding of HF-related metabolic pathways.

Occurrence of bisphenol diglycidyl ethers and bisphenol analogs, and their associations with DNA oxidative damage in pregnant women.

Bisphenol diglycidyl ethers (BDGEs) and Bisphenol A and its analogs (bisphenols) may have the same exposure routes and coexposure phenomenon in sensitive populations such as pregnant women. Previous biomonitoring studies on BDGEs are limited. Levels of fifteen bisphenols, six BDGEs and the DNA oxidative damage biomarker 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured in the urine of pregnant women recruited in south China (n = 358). We aimed to provide the occurrence of bisphenols and BDGEs in pregnant women, and to investigate the potential relationship between their exposure and oxidative stress. Bisphenol A, bisphenol S, bisphenol F, bisphenol AP and all BDGEs (except for BADGE·2HCl) were frequently detected. The total concentrations of all bisphenols and BDGEs were 0.402-338 and 0.104-32.5 ng/mL, with geometric means of 2.87 and 2.48 ng/mL, respectively. BFDGE was the most abundant chemical of BDGEs, with a median concentration of 0.872 ng/mL, followed by BADGE·H2O·HCl (0.297 ng/mL). Except for pre-pregnancy obesity, maternal age/height, employment, fasting in the morning and parity did not affect the urinary concentrations of BDGEs. Significant and weak correlations were observed between concentrations (unadjusted) of total bisphenols and BDGEs (r = 0.389, p < 0.01), indicating their similar sources and exposure routes. The biomarker 8-OHdG was detected in all samples, with concentrations ranging from 1.98 to 32.6 ng/mL (median: 9.96 ng/mL). Levels of 8-OHdG were positively correlated with urinary several bisphenol concentrations (adjusted ß range: 0.037-0.089, p < 0.05) but were not correlated with those of BDGEs. Further studies should focus on whether BDGEs and bisphenols exert combined effects on oxidative stress. Our study provided the first BDGEs exposure data in pregnant women and indicated that BDGEs exposure was highly prevalent in pregnant women as early as 2015 in south China.

Polycyclic aromatic hydrocarbon exposure and DNA oxidative damage of workers in workshops of a petrochemical group.

The petrochemical industry has promoted the development of economy, while polycyclic aromatic hydrocarbons (PAHs) produced by the industry become the threat for environment and humans. Data on human occupational exposure in petrochemical industry are limited. In the present study, urinary hydroxylated PAH metabolites (OH-PAHs) and a biomarker of DNA oxidative damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)) were measured in 546 workers of a petrochemical group in Northeast China, to investigate PAH exposure and related potential health risk. The concentrations of ∑9OH-PAH in all workers were 0.25-175 µg/g Cre with a median value of 4.41 µg/g Cre. Metabolites of naphthalene were the predominant compounds. The levels of PAH metabolites were significantly different for workers with different jobs, which were the highest for recycling workers (13.7 µg/g Cre) and the lowest for agency managers (5.12 µg/g Cre). Besides, higher levels of OH-PAHs were usually found in males and older workers. There was a dose-response relationship between levels of 8-OHdG and ∑9OH-PAHs (p < 0.01). No difference was observed in concentrations of 8-OHdG for workers of different gender or ages, work history as well as noise. Furthermore, workers simultaneously exposed to other potential pollutants and higher levels of ∑9OH-PAH had significantly higher levels of 8-OHdG compared with those in the corresponding subgroups. Our results suggested that exposure to PAHs or co-exposure to PAHs and potential toxics in the petrochemical plant may cause DNA damage. We call for more researches on the associations among noise, chemical pollution and oxidative stress to workers in the real working environment.

[Study on the angle and depth of needle insertion at Huantiao (GB 30) by three-dimensional reconstruction].

OBJECTIVE: To observe the anatomic structure of Huantiao (GB 30) visually, to imitate the inserting process of the needle to explore the safty of needle insertion and improve the therapeutic effect of acupuncture in clinic. METHODS: Combined with anatomic structure of acupoint, muscles and other tissues related with Huantiao (GB 30) were interactively segmented in VOXEL-MAN with the computer graphics technology. Nerves and blood vessels were reconstructed by establishing mathematic model, and the needle-inserting animation of Huantiso (GB 30) was obtained by running script file. RESULTS: The three-dimensional (3-D) visualization of Huantiao (GB 30) on needle-inserting animation was accomplished, the spatial location and expression of Huantiao (GB 30) in the digitized virtual human body were observed, the virtual inserting process was imitated realistically, and the 3-D animation of needle insertion at Huantiao (GB 30) was created. CONCLUSION: Building mathematic model is favorable for expressing the anatomic structure of Huantiao (GB 30) in 3-D space, imitating the process of needle insertion realistically and observing the spatial structure of the point and the around tissues, which can provide a solid foundation for the safety of needle insertion of acupoints and improve therapeutic effect of acupuncture in clinic.

[Influence of cyclodextrins on the photodegradation of bisphenol A induced by Fe(III)].

Cyclodextrins (CDs) can form a host/guest inclusion complex with bisphenol A(BPA). Under a 250 W metal halide lamp (lambda > or = 365 nm), the effects of different cyclodextrins to oxidation of endocrine disrupter BPA in the Fe(III)-hydroxyl complexes system were investigated. In the presence of alpha- cyclodextrin or beta-cyclodextrin (alpha-CD or beta-CD), the photodegradation efficiency of BPA can be enhanced, but gamma-cyclodextrin (gamma-CD) showed inhibitive effect on the photodegradation efficiency. The initial degradation rate of BPA firstly increased with increasing concentration of beta-CD and alpha-CD from 0 to 60 micromol L(-1), and the maximum rate was reached at the beta-CD concentration of 60 micromol L(-1), and then decreased. But the initial degradation rate of BPA decreased with increasing concentration of gamma-CD. Furthermore, the structures of BPA, CDs and BPA/CDs were optimized used the PM3 method in Gaussian98 software package. The results showed that BPA partly entered the cavity of CDs, which formed different super-molecular host-guest complexes, and resulted in the different photodegradation rates of BPA under UV-vis irradiation.