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Four metabolites of mogrol were separated, identified and characterized. Their antitumor activity was evaluated, and the results showed side chain modification would probably enhance the cytotoxicity. Therefore, three types of amines, alcohols and rigid planar derivatives were synthesized. Compounds 20 and 21 containing a tetrahydro-β-carboline structure at the end of the side chain exhibited IC50 values around 2–9 μM against A549 and CNE1 cell comparing with 80–90 μM of mogrol. Structure analysis suggested that the perhydrocyclopentanophenanthrene moiety and the tetrahydro-β-carboline moiety could probably enhance the activity through an intramolecular synergistic effect. [ABSTRACT FROM AUTHOR]

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other renal cancers. This TFE3 fusion-driven OXPHOS program, together with heightened glutathione levels found in renal cancers, renders tRCCs sensitive to reductive stress - a metabolic stress state induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1 , which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1a and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability to OXPHOS-dependent tRCC cells. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring., Competing Interests: Declaration of Interests S.R.V. has consulted for Jnana Therapeutics within the past 3 years and receives research support from Bayer. L.B-P. is a co-founder, holds equity in and is a consultant for Scorpion Therapeutics.

Drought stress significantly impacts global rice production, highlighting the critical need to understand the genetic basis of drought resistance in rice. Here, through a genome-wide association study, we reveal that natural variations in DROUGHT RESISTANCE GENE 9 (DRG9), encoding a double-stranded RNA (dsRNA) binding protein, contribute to drought resistance. Under drought stress, DRG9 condenses into stress granules (SGs) through liquid-liquid phase separation via a crucial α-helix. DRG9 recruits the mRNAs of OsNCED4, a key gene for the biosynthesis of abscisic acid, into SGs and protects them from degradation. In drought-resistant DRG9 allele, natural variations in the coding region, causing an amino acid substitution (G267F) within the zinc finger domain, increase DRG9's binding ability to OsNCED4 mRNA and enhance drought resistance. Introgression of the drought-resistant DRG9 allele into the elite rice Huanghuazhan significantly improves its drought resistance. Thus, our study underscores the role of a dsRNA-binding protein in drought resistance and its promising value in breeding drought-resistant rice., (© 2024. The Author(s).)

Corn steep liquor-assisted microbial remediation has been proposed as a promising strategy to remediate cadmium (Cd)-contaminated soil. In this study, we determined Bacillus subtilis (K2) with a high cadmium (Cd) accumulation ability and Cd resistance. However, studies on this strategy used in the Cd uptake of Chinese cabbage are lacking, and the effect of the combined incorporation of corn steep liquor and K2 on the functions and microbial interactions of soil microbiomes is unclear. Here, we study the Cd uptake and transportation in Chinese cabbage by the combination of K2 and corn steep liquor (K2 + C7) in a Cd-contaminated soil and corresponding microbial regulation mechanisms. Results showed that compared to inoculant K2 treatment alone, a reduction of Cd concentration in the shoots by 14.4% and the dry weight biomass of the shoots and the roots in Chinese cabbage increased by 21.6% and 30.8%, respectively, under K2 + C7 treatment. Meanwhile, hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) levels were decreased by enhancing POD and SOD activity, thereby reversing Cd-induced oxidative damage. Importantly, inoculation of K2 would decrease the diversity of the microbial community while enhancing the abundance of dominant species. These findings provide a promising strategy for reducing the Cd accumulation in Chinese cabbage and recovering soil ecological functions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Key Message: Here, we report that ZmAGO18b encoding an argonaute protein is a negative regulator of maize resistance against southern leaf blight. Southern leaf blight caused by fungal pathogen Cochliobolus heterostrophus is a destructive disease on maize throughout the world. Argonaute (AGO) proteins, key regulators in small RNA pathway, play important roles in plant defense. But whether they have function in maize resistance against C. heterostrophus is unknown. Association analysis between the nucleic variation of 18 ZmAGO loci with disease phenotype against C. heterostrophus was performed, and the ZmAGO18b locus was identified to be associated with resistance against C. heterostrophus. Overexpression of ZmAGO18b gene suppresses maize resistance against C. heterostrophus, and mutation of ZmAGO18b enhances maize resistance against C. heterostrophus. Further, we identified the resistant haplotype of ZmAGO18b by association analysis of natural variation in ZmAGO18b genomic DNA sequences with seedling resistance phenotypes against C. heterostrophus and confirmed the resistant haplotype is co-segregated with resistance phenotypes against C. heterostrophus in two F 2 populations. In sum, this study reports that ZmAGO18b negatively regulates maize resistance against C. heterostrophus., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Studying the interaction of pore-forming toxins, including perfringolysin O (PFO), with lipid is crucial to understanding how they insert into membranes, assemble, and associate with membrane domains. In almost all past studies, symmetric lipid bilayers, i.e., bilayers having the same lipid composition in each monolayer (leaflet), have been used to study this process. However, practical methods to make asymmetric lipid vesicles have now been developed. These involve a cyclodextrin-catalyzed lipid exchange process in which the outer leaflet lipids are switched between two lipid vesicle populations with different lipid compositions. By use of alpha class cyclodextrins, it is practical to include a wide range of sterol concentrations in asymmetric vesicles. In this article, protocols for preparing asymmetric lipid vesicles are described, and to illustrate how they may be applied to studies of pore-forming toxin behavior, we summarize what has been learned about PFO conformation and its lipid interaction in symmetric and in asymmetric artificial lipid vesicles., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the restoration of function after spinal cord injury (SCI) in patients of different ages who have underwent intraspinal transplantation of olfactory ensheathing cells (OECs)., Methods: One hundred and seventy-one SCI patients were included in this study. Of them, 139 were male and 32 were female, with age ranging from 2 to 64 years (mean, 34.9 years). In all SCI patients the lesions were injected at the time of operation with OECs. According to their ages, the patients were divided into 5 groups: 51 years group (n = 14). The spinal cord function was assessed based on the American Spinal Injury Association (ASIA) Classification System before and 2 - 8 weeks after OECs transplantation. One-way ANOVA and q test were used for statistical analysis, and the data were expressed as mean +/- SD., Results: After surgery, the motor scores increased by 5.2 +/- 4.8, 8.6 +/- 8.0, 8.3 +/- 8.8, 5.7 +/- 7.3 and 8.2 +/- 7.6 in 5 age groups respectively (F = 1.009, P = 0.404); light touch scores increased by 13.9 +/- 8.1, 15.5 +/- 14.3, 12.0 +/- 14.4, 14.1 +/- 18.5 and 24.8 +/- 25.3 respectively (F = 1.837, P = 0.124); and pin prick scores increased by 11.1 +/- 7.9, 17.2 +/- 14.3, 13.2 +/- 11.8, 13.6 +/- 13.9 and 25.4 +/- 24.3 respectively (F = 2.651, P = 0.035). Restoration of pin prick in > 51 years group was better than other age groups except 21 - 30 years group., Conclusion: OECs transplantation can improve the neurological function of spinal cord of SCI patients regardless of their ages. Further research into the long-term outcomes of the treatment will be required.