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Plant height is a critical agronomic trait that affects crop yield, plant architecture, and environmental adaptability. Gibberellins (GAs) regulate plant height, with DELLA proteins acting as key repressors in the GA signaling pathway by inhibiting GA-induced growth. While DELLA phosphorylation is essential for regulating plant height, the precise mechanisms underlying this process remain incompletely understood. In this study, we identified a cucumber mutant with delayed growth, which exhibited reduced sensitivity to GA treatment. Through bulked segregant analysis (BSA-seq) combined with molecular marker linkage analysis, we successfully identified and cloned the gene responsible for the dwarf phenotype, CsIREH1 (INCOMPLETE ROOT HAIR ELONGATION 1), which encodes an AGC protein kinase. Further research revealed that CsIREH1 interacts with and phosphorylates DELLA proteins, specifically targeting CsGAIP and CsGAI2. We propose that IREH1-dependent phosphorylation of DELLA proteins prevents their excessive accumulation, thereby maintaining normal plant growth. Therefore, investigating the role of IREH1-mediated DELLA phosphorylation provides valuable insights and theoretical foundations for understanding how plants regulate growth mechanisms., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Macrophages are key players in maintaining the balance of tissues and dealing with inflammation, carrying out vital functions specific to different tissues while safeguarding the body against infections. The intricate interplay between oxidative stress and macrophage polarization and how this contributes to pneumonia is not fully understood. Herein, a predominant accumulation of baicalein in lung macrophages of pathogen-infected mice was observed by an alkynyl-modified probe. Baicalein effectively reduces oxidative stress in vivo and in vitro by modulating the KEAP1-NRF2/ARE signaling pathway. Further investigation indicated that baicalein has inhibitory effects on M1 macrophage polarization and phagocytic capacity, reducing inflammatory cytokine expression. As a protein-protein interaction (PPI) inhibitor, baicalein disrupts the KEAP1-NRF2 interaction by competitively binding to the DGR/Kelch domain of KEAP1. This process helps NRF2 move to the nucleus, which activates the antioxidant transcriptional program, suppresses the production of reactive oxygen species (ROS), and mitigates oxidative stress damage. These findings suggest a different approach to developing treatments for oxidative stress that focuses on inhibiting the interaction between KEAP1-NRF2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

DNA methylation is an essential epigenetic modification for gene regulation in plant growth and development. However, the precise mechanisms of DNA methylation remain poorly understood, especially in woody plants. We employed whole-genome bisulfite sequencing (WGBS), assays for transposase-accessible chromatin using sequencing (ATAC-seq), and RNA-Seq to investigate epigenetic regulatory relationships in Populus tomentosa treated with DNA methylation inhibitor 5-azacitidine. Expression-quantitative trait methylation analysis (eQTM), epigenome-wide association study (EWAS), and joint linkage-linkage disequilibrium mapping were used to explore the epigenetic regulatory genes, and using CRISPR/Cas9 to identify the role of candidate genes. Plant developmental abnormalities occurred when DNA methylation levels were substantially reduced. DNA methylation regulated 112 expressed genes via chromatin accessibility, of which 61 genes were significantly influenced by DNA methylation variation at the population level. One DNA methylation-regulated gene, PtoGntK, was located in a major quantitative trait locus (QTL) for poplar growth. Overexpression and CRISPR/Cas9 of PtoGntK revealed it affected poplar height and stem diameter. The PtoRAP2.12 was found to bind to the demethylated accessible region in the PtoGntK promoter, thereby promoting growth in poplar. This study identified key genes with epigenetic regulation for plant growth and provides insights into epigenetic regulation mechanisms in woody plants., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Parathyroid hormone (PTH) receptor agonists promote bone formation but also increase osteoclastogenesis, in part by increasing expression of the receptor activator of nuclear factor kappa-Β ligand (RANKL). In addition to activation of transcription, regulation of mRNA stability is another important molecular mechanism controlling mRNA abundance. PTH treatment for 6 h resulted in a 7.4-fold elevation in RANKL mRNA expression in UAMS-32P cells, despite prior inhibition of cellular transcription by thiophosphoryl (TPL). RANKL mRNA, like other TNF family members, contains AU-Rich Elements (AREs) in the 3' UTR. AU-Rich Element Binding Proteins (ABPs including KSRP, TTP, AUF1 and HuR) bind to AREs and regulate mRNA stability. There was significantly more KSRP bound to RANKL mRNA than any of the other ABPs. PTH did not increase the amount of ABPs bound to the RANKL transcript. However, the level of cellular phosphorylated KSRP was significantly increased in UAMS-32P cells pre-treated with TPL followed by PTH exposure, compared to cells treated with vehicle following TPL. The extent of phosphorylation of cellular AUF1, HuR, and TTP did not increase with PTH treatment. There were no significant changes in the cellular content of total Pin1 and phospho-Pin1 protein with PTH treatment. We conclude that increases in cellular phospho-KSRP following PTH treatment, together with fact that the total amount of the KSRP bound to the RANKL mRNA did not change with PTH-treatment, may indicate that phospho-KSRP plays some role in stabilizing the RANKL transcript., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

HPGD encodes 15-Hydroxyprostaglandin dehydrogenase catalyzing the decomposition of prostaglandin E2 and has not been reported in multiple sclerosis (MS). We previously found that Nr4a1 regulated microglia polarization and inhibited the progression of experimental autoimmune encephalomyelitis (EAE). Bioinformatics analysis suggested that HPGD might be regulated by Nr4a1. Therefore, this study aimed to explore the role of HPGD in microglia polarization and determine whether HPGD mediates the inhibition of EAE by Nr4a1. C57BL/6 mice were treated with MOG 35-55 peptide to induce EAE. BV-2 cells were treated with LPS/IL-4 to induce M1/M2 polarization. We then analyzed the pathological changes of spinal cord tissue, detected the expression levels of M1/M2 genes in tissues and cells, and explored the effect of HPGD on PPARγ activation to clarify the role of HPGD in EAE. The interaction between HPGD and Nr4a1 was verified by ChIP and pull-down assay. HPGD was downregulated in the spinal cord of EAE mice and HPGD overexpression alleviated the progression of EAE. Experiments in vitro and in vivo revealed that HPGD inhibited M1 polarization, promoted M2 polarization and increased PPARγ-DNA complex level. Nr4a1 could bind to the promoter of HPGD and its overexpression increased HPGD level. HPGD overexpression (or knockdown) reversed the effect of Nr4a1 knockdown (or overexpression) on M1/2 polarization. HPGD is regulated by Nr4a1 and inhibits the progression of EAE through shifting the M1/M2 polarization and promoting the activation of PPARγ signaling pathway. This study provides potential targets and basis for the development of MS therapeutic drugs., Competing Interests: Declarations. Ethics Approval: All animal experiments were performed with the approval of the Life Sciences Ethical Review Committee of Zhengzhou University. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The impairment of the p53 pathway was once regarded as inadequately druggable due to the specificity of the p53 structure, its flat surface lacking an ideal drug-binding site, and the difficulty in reinstating p53 function. However, renewed interest in p53-based therapies has emerged, with promising approaches targeting p53 and ongoing clinical trials investigating p53-based treatments across various cancers. Despite significant progress in p53-targeted therapies, challenges persist in identifying effective therapeutic targets within the p53 pathway. In this study, we implemented a molecular screening system to effectively discover p53 activator. As a result, illudin S was identified as a potential inhibitor of the p53-Mdm2 interaction. This compound is particularly intriguing due to its well-documented anti-cancer effects, despite the ambiguity surrounding its precise mechanism of action. Illudin S demonstrated a direct binding affinity to the Mdm2 binding site of p53 through hydrogen bonding, which enhanced the stability and transcriptional activity of p53. The inhibition of the p53-Mdm2 interaction by illudin S led to increased p53 expression. Moreover, this inhibition effectively induced apoptosis and cell cycle arrest in CT26 colorectal cancer cells. Administration of illudin S in a colorectal cancer mouse model resulted in prolonged survival and significant tumor growth inhibition. These findings elucidate the mechanism underlying the anti-cancer effects of illudin S, specifically through its targeting of the p53-Mdm2 interaction in colorectal cancer. Consequently, illudin S emerges as a promising candidate for the development of p53-targeted cancer therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)