DNA methylation plays an important role in systemic lupus erythematosus (SLE) pathogenesis by regulating immune cell function and disease progression. Dietary factors, particularly methyl-donor micronutrients such as folic acid and vitamin B12, may influence DNA methylation patterns and autoimmune responses. However, their specific effects in SLE, especially in adipose tissue that is a key modulator of systemic inflammation, remain unclear. Given the high prevalence of obesity in SLE and its impact on disease severity, understanding the interaction between nutritional status, epigenetics, and immune dysregulation is crucial. This study examines whether folic acid and vitamin B12 supplementation modulate adipose tissue DNA methylation in female SLE patients, considering their nutritional status, to uncover potential mechanisms influencing disease progression and therapeutic response. This is a randomized, double-blind, placebo-controlled trial with premenopausal women with inactive SLE, classified as normal weight (NW, n = 23) or excess body weight (EBW, n = 27). Participants received daily supplementation of folic acid (400 mcg) and vitamin B12 (2000 mcg) or placebo for 12 weeks. Phenotypic characteristics and adipose tissue DNA methylation profiles were assessed before and after intervention using the Illumina EPIC BeadChip platform.

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, is associated with extremely poor patient prognosis. Temozolomide (TMZ) resistance remains a major cause of treatment failure. Protein arginine methyltransferase 6 (PRMT6) plays critical roles in tumorigenesis, but its function and regulatory mechanisms in GBM TMZ resistance have not been elucidated. While the hypoxic microenvironment is a hallmark feature of GBM, its epigenetic regulatory mechanisms in drug resistance remain unclear.

Brominated flame retardants (BFRs) such as tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCDD), and decabromodiphenyl ethane (DBDPE) are extensively used in a variety of consumer products, including electronics, textiles, and furniture. However, their environmental persistence and potential for neurodevelopmental toxicity have raised increasing concern. Legacy compounds such as TBBPA and HBCDD are undergoing regulation or being phased out, while alternatives like DBDPE remain poorly characterized, leaving uncertainties regarding their suitability as replacements. In order to rapidly fill knowledge gaps on these data poor substances and avoid regrettable substitutions, we established a high-throughput, mechanism-based in vivo toxicity screening platform. A RNAi approach on Caenorhabditis elegans Transcription Factors (TF) was used to assess biological pathways that were triggered by BFR exposure, leading to neurotoxicity (assessed via locomotion behavior). Using a 384-TF RNAi library, we identified 44 TFs modulating TBBPA-induced neurotoxicity. Pathway analyses (Reactome and CTD) highlighted retinoic acid receptor signaling as a key event, which mapped to four neurodevelopmental AOPs (AOP 520, 523, 532, and 533). Gene expression analysis of sex-1 and unc-55 confirmed retinoic acid signaling pathway activation. Application of the same framework to HBCDD and DBDPE revealed partially conserved behavioral and molecular responses, supporting the cross-chemical applicability of the TBBPA-derived AOP network. These findings demonstrate the utility of C. elegans-based TF RNAi screening as a fit-for-purpose New Approach Methodology (NAM) for mechanistic toxicology. By linking molecular initiating events to adverse outcomes, this strategy enables early hazard identification and read across strategy via AOP-informed, animal-free chemical risk assessment within next-generation risk assessment (NGRA) frameworks.

Brassinosteroid (BR)-mediated salt tolerance is a crucial mechanism for maize (Zeamays L.) adaptation to saline-alkaline environments. This study aimed to elucidate the molecular mechanism underlying BR-induced salt tolerance in maize, focusing on the regulatory roles of ZmWRKY104 and ZmCCaMK. Key results showed that ZmWRKY104 directly interacts with ZmCCaMK in the nucleus in a non-phosphorylation-dependent manner, forming a novel regulatory module. BR treatment upregulates ZmWRKY104 expression, and overexpression of ZmWRKY104 significantly enhances the activities of antioxidant enzymes (APX and SOD). Co-expression of ZmWRKY104 and ZmCCaMK synergistically promotes the antioxidant defense system in maize. Transgenic maize overexpressing ZmWRKY104 exhibits obvious salt tolerance advantages under 100 mM NaCl stress compared to wild-type plants, including reduced leaf yellowing, increased plant height and root length, as well as decreased electrolyte leakage (EL) and malondialdehyde (MDA) content. Collectively, this study identifies a novel non-phosphorylation-dependent WRKY-CCaMK regulatory module in the BR signaling pathway, which enhances BR-induced maize salt tolerance by synergistically activating antioxidant defense. The findings highlight ZmWRKY104 as a candidate gene and provide a potential molecular mechanism for salt-tolerant maize breeding in saline-alkaline regions of northern China.

Calcineurin inhibitors, including tacrolimus (FK506), are used as immunosuppressive agents and can cause unexplained calcineurin inhibitor-induced pain syndrome (CIPS). We investigated how FK506 affects the expression of NaV1.7, a voltage-gated Na+ channel implicated in pain perception that is upregulated in dorsal root ganglion (DRG) neurons in several pain disorders. We generated a model of FK506-induced pain by administering FK506 to NaV1.7-ChR2 mice, which exhibit light-responsive pain. To evaluate nociceptive responses, paw withdrawal threshold (PWT) was measured using the von Frey test. The optogenetic place aversion (OPA) and light irradiation paw withdrawal tests were also performed. On the 11th day of initial injection, DRGs were dissected from mice under anesthesia and analyzed for NaV1.7 expression using quantitative reverse transcription PCR (RT-qPCR). PWT was also measured for mice that received the selective NaV1.7 inhibitor or vehicle. PWT was lower in FK506-treated mice than in those administered the vehicle on the 8th and 12th days after initial FK506 injection (p < 0.05). Mechanical hypersensitivity was reversible and peaked at around 10 days after FK506 administration. OPA and light irradiation paw withdrawal test results corroborated the hypersensitivity to light-responsivity. NaV1.7 mRNA levels in DRG were higher in FK506-treated mice than in those administered the vehicle on the 11th day (p < 0.05). A selective NaV1.7 inhibitor reversed FK506-induced pain. Increased NaV1.7 expression in DRG neurons may be responsible for FK506-induced peripheral neuropathy. Our findings suggest that endogenous calcineurin regulates NaV1.7 expression. Thus, selective NaV1.7 inhibition could be a potential therapeutic strategy for CIPS.

Monocropping poses a significant challenge in the sustainable cultivation of many medicinal plants, including Glehnia littoralis F. Schmidt ex Miq. G. littoralis, known for its culinary and medicinal properties, faces cultivation challenges due to continuous cropping, largely because of autoallelopathy. Phenolic compounds, specifically dibutyl phthalate (DBP) and 2,4-di-tert-butylphenol (2,4-DTBP), from G. littoralis cropped soil, significantly inhibit its seed germination and growth. This study examines the effects of these compounds on seed germination, focusing on phenotypic changes, gene expression, and spatial metabolic profiles. This research investigates the impact of DBP and 2,4-DTBP on G. littoralis seed germination through phenotypic analysis, transcriptomic profiling of gene expression, and spatial metabolic profiling using metabolomics techniques.

Silicon (Si) has shown potential in mitigating salt stress in cotton, but the underlying mechanisms remain not fully understood. In this study, hydroponic experiments assessed effects of exogenous Si (0.4 mmol L-1) on growth, water status, and related physiology indexes of cotton seedlings under 150 mmol L-1 NaCl stress. We investigated whether Si enhances salt tolerance via water balance maintenance and transcriptional regulation using RNA-Seq.

Lignin is a promising biostimulant for enhancing plant growth and stress tolerance. In this study, bamboo kraft lignin (BKL) and its oxygen-alkali-modified derivative (OBKL) were applied to maize seedlings to elucidate the structure-function relationship. The increased hydrophilic groups of OBKL improved its capacity to enhance water and nutrient uptake, resulting in a 50% increase in root elongation, 65% enhancement in photosynthesis, and a 106% rise in transpiration. Low-molecular-weight OBKL promoted chlorophyll synthesis and stress resilience, whereas high-molecular-weight lignin suppressed growth. Transcriptomics analysis revealed that OBKL upregulated 1333 genes, including key transcription factors such as AP2/ERF, WRKY, MYB, and NAC, which are involved in regulating cell proliferation, tropisms, carbon metabolism, and stress responses. Genomes and Gene Ontology analysis further identified plant hormone signal transduction regulated by lignin as a major pathway. These findings reveal that OBKL is an effective biostimulant for improving crop productivity and environmental adaptability.

Atmospheric nanoplastics are emergingly found to deposit on leaves of terrestrial plants and adversely affect plant growth. Lipid remodeling has been verified as one of the important strategies for plants to respond to abiotic stress; however, its molecular response to atmospheric nanoplastics in crop leaves remains unclear. In this study, maize leaves were exposed to 50 nm polystyrene nanoplastics (PSNPs) with pristine (nPS), carboxy (nPS-COOH), and amino groups (nPS-NH2) at environmentally relevant doses (1 and 10 μg/d). Ten-day exposure of nPS-NH2 induced the strongest phenotypic and physiological inhibition regardless of the exposure dose. All PSNPs were internalized into maize leaves via the stomatal pathway, accumulating dose-dependently. Meanwhile, the highest PSNP absorption efficiency was found in nPS-NH2 treatment (0.208%), which was 3.92- and 2.37-fold of those in the treatments of nPS and nPS-COOH, respectively. The significant inhibitory effect of three PSNPs on the biosynthesis of 31 membrane "structural" and "signaling" lipids and their gene expression in maize leaves was found through lipidomics and transcriptomics analysis. Five key genes (LACS4, GPAT2, LPP2, DGK1, and PLD1) involved in membrane lipid metabolisms were identified by weighted gene coexpression network analysis. These findings provide valuable insights into the interactions between atmospheric NPs and crop growth from the molecular perspective of lipid remodeling.

Mesenchymal stem cells (MSCs) are used to treat various degenerative diseases. However, their therapeutic potential is limited by cellular aging during in vitro cultivation. This study aimed to explore whether cannabidiol (CBD) can delay MSC aging by enhancing the expression of Sirtuin 1 (SIRT1) and autophagy, two key anti-aging regulators.

Bisphenol A (BPA) and its structural analogues are widely used in plastics production, raising concern due to endocrine-disrupting properties. While many analogues share structural similarities with BPA, their endocrine-disrupting effects remain insufficiently characterized. Cyclo-di-bisphenol A diglycidyl ether (cyclo-di-BADGE), tetrabromobisphenol S (TBBPS), bisphenol SIP (BPSIP), and bisphenol TMC (BPTMC) are particularly understudied. We assessed the estrogenic activity of these four BPA analogues compared to BPA. Transactivation assays in HEK-293 cells expressing estrogen receptor alpha (ERα) revealed that BPTMC was a more potent ERα agonist than BPA, with an EC50 of 87 ± 20 nM versus 400 ± 100 nM for BPA, while the other tested analogues showed no significant agonistic activity. In silico analysis attributed this higher affinity to greater hydrophobicity and a bulkier bridging group between its phenolic rings. None of the compounds inhibited 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activity. However, BPTMC selectively inhibited 17β-HSD2 (IC50 = 4.8 ± 0.6 µM) but not BPA. Importantly, 24 h exposure of ERα-positive MCF-7 breast cancer cells to 1 µM BPTMC upregulated the expression of the ERα target genes GREB1, TFF1, and PGR, comparable to 10 nM E2, which was abolished by 100 nM of the ERα antagonist fulvestrant. Moreover, BPTMC stimulated MCF-7 cell proliferation at nanomolar concentrations over 72 h, and cell count analyses confirmed this effect. BPA also increased cell numbers, and both effects were reversed by fulvestrant. Collectively, we identified BPTMC as a potent ERα agonist capable of eliciting transcriptional and mitogenic responses at low concentrations, raising concerns about its endocrine-disrupting and breast cancer-promoting effects.

Antiestrogen therapies, such as Tamoxifen (TAM), are widely used in managing estrogen receptor-positive (ER+) breast cancer (BC); however, resistance to these agents remains a significant clinical challenge. Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, lacking approved targeted therapies and exhibiting poor patient outcomes. Transforming growth factor-β (TGF-β), a dual-functional cytokine involved in tumor suppression and progression, has gained attention for its crucial role in breast cancer development and metastasis. Therefore, evaluating the impact of antiestrogens on TGF-β pathway components may help identify novel therapeutic targets for TNBC. This study investigated the expressions of TGF-β1, TGF-β2, and SMAD-3 in four human BC cell lines (MCF-7, MDA-MB-231, MDA-MB-468, and SK-BR-3) following treatment with optimal cell-line-specific doses of TAM and its active metabolite, 4-Hydroxytamoxifen (4-OH-TAM). In TNBC cells, antiestrogen treatment resulted in elevated TGF-β1 expression, accompanied by increased TGF-β2 and SMAD-3, particularly in metastatic MDA-MB-231 cells. Gene expression analysis also revealed that TGF-β1 was upregulated in short-term TAM treatment in MDA-MB-231 cells, whereas 4-OH-TAM had minimal impact. Long-term exposure led to opposite patterns with TGF-β1 decreasing in TAM of MDA-MB-231 cells but increasing in MCF-7 cells, while TGF-β1 elevates in 4-OH-TAM in MDA-MB-231 cells, suggesting cell line and duration-specific responses. Functional assays further showed differential anti-migratory effects, with TAM more effective in MDA-MB-231 and 4-OH-TAM in MCF-7 cells. These findings highlight TGF-β1 as a potential biomarker for TNBC and for predicting responses to antiestrogen therapies, warranting further mechanistic and functional validation.

Auxin response factors (ARFs) are crucial transcriptional regulators involved in the auxin pathway that control auxin-induced gene transcription during plant growth and development. This study identified 18 FvARF genes distributed disproportionately across seven chromosomes and classified into five distinct phylogenetic clades. All the FvARF proteins contained the conserved B3 and Auxin_resp domains, and 11 of them possessed the Aux/IAA domain. Further bioinformatics analysis revealed their consistency and differentiation in their sequence characteristics. Cis-element analysis predicted that FvARF1a, FvARF2, FvARF9, FvARF16b, FvARF16c, and FvARF19a promoters contained auxin-responsive elements. Transcriptome data revealed that expression levels of several FvARF genes-FvARF2, FvARF4, FvARF6a, and FvARF8-were higher in the pith and cortex of early-stage strawberry fruit. qRT-PCR indicated the elevated expression of FvARF2 at stage 3 (6-7 days post-anthesis [DPA]). Additionally, the FvARF2 gene responded to exogenous auxin. The function of FvARF2 in early strawberry fruit development was confirmed through transient transformation assays. Collectively, these results provide a comprehensive characterisation of ARF gene family members in strawberry, with functional evidence implicating FvARF2 in regulating early-stage fruit development.

This study investigates the impact of different arsenic (As) species (arsenite (As3+), arsenate (As5+), and their mixture) on Litchi chinensis Sonn. fruit quality and underlying mechanisms through foliar spray treatments on 3-year-old litchi trees. The results revealed that As accumulation and distribution vary significantly across tissues, with leaves and peels exhibiting 40 times higher As levels than those in the flesh. As3+ treatment resulted in the highest total As accumulation in fruits by the end of ripening, whereas mixed treatments prolonged the persistence of bioavailable As (particularly As3+), leading to sustained stress. As exposure reduced yields by an average of 36 % (As3+) and moderately inhibited fruit development (As5+ and mixed treatment). Mechanistically, As speciation reshaped the sugar-acid metabolic network primarily by modulating the PPC-MDH axis. The analysis revealed that As exposure upregulated PPC and MDH pathways, redirecting carbon flux toward ascorbate-derived organic acid accumulation (e.g., tartaric acid), while increased TCA cycle activity negatively regulated sugar accumulation. Mixed treatments induced complex shifts in gene expression, reflecting the combined effects of oxidative stress and metabolic perturbations. Notably, As3+ exhibited 10-fold higher toxicity than As5+ due to stronger thiol group binding and enzymatic inhibition. These findings underscore the risks of As contamination in litchi production, underscoring the need for monitoring As species in fertilizers and mitigating their accumulation to ensure food safety and sustainability.

Antibiotic persistence, typically attributed to dormant bacteria, is known to be a major cause of treatment failure. However, despite many years of intense research, no clear consensus on its mechanism has emerged. Here, we demonstrate that high survival under antibiotics may originate from two fundamentally different growth-arrest archetypes: either from a regulated growth arrest, leading to a protected dormant cellular state, or from a dysregulated disrupted growth arrest. Using modeling and experimental approaches including transcriptomics, microcalorimetry, and microfluidics, we unveil the characteristics and vulnerabilities of each growth-arrest archetype. In particular, disrupted bacteria show a general impairment of membrane homeostasis. This understanding resolves previous conflicting results regarding characteristics of persisters and allows tailoring treatments that target the different growth-arrested bacteria. The fundamental distinction between regulated and disrupted growth arrests should be broadly relevant for the description of cells under stress.

Lysine lactylation is a crucial posttranslational modification (PTM) that regulates protein function. Here, this study revealed that L-lactic acid promotes host immune response and inhibits viral infection by inducing Interferon Regulatory Factor 9 (IRF9) L-lactylation. We first found L-lactylation modification (L-Kla) of IRF9 mediated by AARS1. Further studies demonstrated that IRF9 L-lactylation potentiates type I interferon (IFN-I) signaling by promoting IRF9-STAT2 interaction, thereby boosting antiviral immune response. Intriguingly, L-lactic acid exhibits dual effects on viral infection: L-lactic acid exhibits antiviral effects at physiological and moderately elevated levels but proviral effects at high levels. Furthermore, we found that the viruses can achieve immune evasion by promoting SIRT1-mediated delactylation of IRF9. Interestingly, we uncovered that metformin promotes IRF9 L-lactylation by both accumulating lactic acid and disrupting virus-induced IRF9-SIRT1 interaction. These findings renew the understanding of the roles of lactic acid in antiviral immune response and determine metformin's immunomodulatory effects on antiviral immunity through regulating IRF9 L-lactylation.

Recurrence and metastasis are the leading causes of poor prognosis and death in lung cancer, and the mechanism of cancer metastasis has not yet been fully elucidated. As a gut-specific homeobox (HOX) transcription factor, intestine-specific HOX (ISX) is a proto-oncogene induced by the inflammatory factor IL-6. Notably, ISX overexpression can induce the epithelial-mesenchymal transition (EMT) response, and promotes tumor cell migration and invasion. In the present study, a lung cancer cell model with overexpression of ISX was established by infecting lung cancer cells with lentivirus. Reverse transcription-quantitative polymerase chain reaction was first used to verify the expression of the EMT-related gene induced by ISX overexpression. Furthermore, transcriptome sequencing and analysis showed that the overexpression of ISX induced significant changes in the gene expression profile of human lung cancer cells. In addition, type I collagen α1 chain (COL1A1), a highly expressed gene in various tumor tissues and cells, was shown to promote tumor cell migration and invasion, possibly by promoting EMT, and was significantly upregulated in human lung cancer cells overexpressing ISX. These results suggested that ISX may promote lung cancer migration and invasion by increasing the expression of COL1A1. In addition, four drugs that are currently used to treat lung cancer were screened. Of these, Iressa® (gefitinib) was revealed to significantly inhibit the viability, migration and invasion of lung cancer cells that stably overexpress ISX by downregulating the expression of COL1A1. In conclusion, these findings may help to prevent tumor metastasis and spread, and the potential molecular mechanism by which ISX promotes the development and migration of lung cancer was suggested. The current findings provide novel targets, and a scientific basis for the prevention and treatment of lung cancer, which may reduce costs for patients, their families and society.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by a lack of key hormone receptors in tumor cells. As there are limited treatment options for these patients, it is crucial to understand the underlying mechanisms by which TNBC constantly evolves and evades treatments. In this regard, the pervasive nature of transcription provides a potential reservoir of transcripts, including both coding and noncoding, that TNBC leverages to sustain a proliferative advantage and support tumor growth. TNBC is affected by energy sources such as glucose, which can have a profound impact on gene expression regulation mediated by various molecules, including noncoding RNAs, at the cellular level. In this study, we demonstrate that glucose modulates the gene expression profile mediated by the microRNA-503 host gene (MIR503HG), which has been previously implicated in TNBC. To comprehensively characterize the impact of glucose on MIR503HG-regulated genes and cellular pathways, we sequenced total RNA, performed gene set enrichment analyses, and determined the relation between gene expression and patient outcomes. Analysis of gene subsets specific to various glucose environments identified clinical outcomes for breast cancer patients across different molecular subtypes. Our findings indicate that MIR503HG has potential as a diagnostic marker and may be useful in the clinical management of TNBC.

To investigate the effect of urotensin II(UII)/UII receptor(UT) on hepatic carboxylesterase1f(Ces1f) expression in acute liver failure(ALF) mice.

Salmonella infection severely affects the healthy development of livestock and poultry, as well as food safety and public health. The critical role of type I fimbriae (TIFs) in promoting Salmonella pathogenicity makes them important targets for exploring inhibitors of Salmonella infection. In this study, we found that naringenin (Nar) inhibited the invasion of Salmonella into HeLa cells but did not affect bacterial motility. Nar reduced the transcription levels of the TIF structural proteins FimA and FimH and the chaperone proteins FimC and FimD, as determined via RT-qPCR. Molecular docking and surface plasmon resonance (SPR) assays confirmed that Nar was bound to FimZ, which directly regulates the expression of TIF, resulting in a reduction in TIF formation accompanied by a decrease in biofilm formation and bacterial adhesion to cells and alleviation of the inflammatory response. In vivo, Nar prolonged the survival of mice infected with Salmonella, improved the survival rate, reduced the inflammation level and bacterial load, and significantly alleviated histopathological damage. These results provide alternative strategies and promising lead compounds for controlling Salmonella infection.