This research investigates the molecular mechanisms of benzyl butyl phthalate (BBP) in atopic dermatitis (AD) using network toxicology and molecular dynamics simulation. The environmental toxicity of BBP was systematically predicted and assessed using ADMETlab and ProTox-II. Structural information on BBP was obtained from PubChem, and potential targets were identified using STITCH and CHEMBL. AD-related target genes were retrieved from OMIM and GeneCards. A PPI network was constructed using STRING and Cytoscape to identify key targets. GO and KEGG pathway analyses were conducted to characterize the biological functions and signaling pathways associated with the targets. Molecular docking of BBP with core targets was performed using CB-Dock2. Finally, 100 ns molecular dynamics simulations of BBP-core target complexes were conducted using Gromacs. A total of 119 potential AD-related targets were identified, with six core targets (AKT1, CASP3, KRAS, SRC, EGFR, TNF) highlighted through PPI network analysis. GO and KEGG analyses demonstrated the involvement of these targets in BP, CC, MF, and signaling pathways, with a notable focus on the PI3K-Akt signaling pathway. Molecular docking analysis revealed strong binding affinities between BBP and the core targets, while molecular dynamics simulations confirmed stable interactions between BBP and AKT1, CASP3, and KRAS. This study systematically identifies key targets and molecular mechanisms underlying BBP-induced AD by integrating network toxicology, molecular docking, and molecular dynamics simulations. The findings establish a hierarchical framework linking chemical exposure, molecular interactions, and pathological phenotypes, providing insights into the toxic mechanisms of environmental pollutants from a molecular dynamics perspective.

Background: Doxycycline, a tetracycline antibiotic known for inhibiting matrix metalloproteinases, has shown potential antihypertensive effects. However, its role in modulating the renin–angiotensin system remains poorly understood. This study aims to specifically evaluate Doxycycline’s effects on key RAS components and blood pressure responses to clarify its underlying mechanism and support its development as a targeted antihypertensive therapeutic candidate.Materials and Methods: This study integrated an in-silico and experimental approach to assess the antihypertensive effects of doxycycline. Bioinformatics analyses were first conducted, including target prediction, gene ontology enrichment, hub-gene identification, PPI network construction, and KEGG pathway analysis, followed by molecular docking and molecular dynamics simulations to predict doxycycline’s interactions with key RAS targets. To validate these computational findings, qRT-PCR was performed to measure the expression of selected genes in kidney tissues from hypertensive rats.Results: Bioinformatics analysis identified six key target genes, including AGT, AGTR1, AGTR2, REN, ACE, and ACE2. Molecular docking showed that doxycycline exhibited stronger binding affinity to AGTR1 (-8.346 kcal/mol) than its native ligand. Molecular dynamics confirmed the stability of the doxycycline–AGTR1 complex at 20 ns. Gene expression analysis of kidney tissues from hypertensive rats revealed a significant reduction in AGTR1 expression in the group treated with doxycycline 15 mg/kg (p<0.05), while no significant change was observed at 30 mg/kg.Conclusion: Low-dose doxycycline may modulate the renin–angiotensin pathway through AGTR1 inhibition, indicating its potential as a candidate for further antihypertensive research and warranting more comprehensive in vivo evaluation.Keywords: Hypertension, doxycycline, molecular docking, gene expression, Renin-Angiotensin System

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative motor neuron disease with a pathophysiology that features dysregulated natural killer (NK) cells that are capable of damaging neurons. Although NK cells are associated with ALS progression and survival, their specific characteristics and how these characteristics change over the course of disease is unknown. The current study examines NK cell gene expression during ALS with the goal of identifying dysregulated genes and pathways in NK cells over the course of disease in order to identify potential new therapeutic targets. ALS participants with an El Escorial ALS diagnosis were recruited from the University of Michigan Pranger ALS Clinic, and control participants were recruited via internet-based notifications. Blood was collected from participants and NK cells were isolated from participants with ALS at two timepoints (baseline and longitudinal) and age- and sex-matched healthy controls at one timepoint. RNA was extracted from the NK cells and quantified using a transcript-counting technology for 578 immune-related genes. Differential gene expression analysis was used to identify individual genes that were dysregulated in ALS at baseline and longitudinally, While GO and KEGG pathway analyses were performed to identify dysregulated pathways at both timepoints. NK cells from participants with ALS (n=36, median age 62.6 years (54.5-69.4), 50% female) showed a 2-fold or greater reduced expression of four pro-inflammatory genes at baseline relative to control participants (N=35, median age 64.3 years (55.2-71.8), 51% female) including IFNG, FCGR1A/B, and FAS; in ALS participants over 130 genes showed a 2-fold change in expression. Dysregulated genes and pathways at the later timepoint were related to cell polarization, activation, signaling, and cell-cell adhesion. In particular, genes associated with classical Type 1 inflammation decreased while Type 2 genes increased. NK cells grow more dysregulated with ALS progression, shifting from a classical Type 1 phenotype to a Type 2 phenotype, though a larger study will be needed to confirm these initial findings. The findings also suggest NK cells contribute to early, but not late, ALS progression. Targeting specific NK cell pathways during early ALS may be a viable therapeutic strategy.

TCN1 knockdown inhibits the progression and glycolysis of non-small cell lung cancer via regulating B3GNT3.

Mechanism study of selenium nanoparticles alleviating heat stress in rainbow trout hepatocytes by regulating lncRNA expression.

Nitrogen removal enhancement mechanism of Biochar/GO-modified denitrifying biocathode treating low C/N ratio wastewater.

Both target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Silene conoidea L.

Response of microbe-DOM interactions to bioavailability in heterogeneous water diversion systems.

Mining of key genes involved in the sulforaphane biosynthetic pathway of moringa and cloning, expression, and functional verification of MoMYR1.

Gut microbiota underlies the growth differences between cultured and wild juveniles of Holothuria leucospilota.

Integrated metabolomics to systematically monitor quality indicators and metabolic dynamics in stored Ophiocordyceps sinensis.

Far-infrared irradiation suppresses pyroptosis in ischemic flaps through TRPV3-mediated activation of the A2AR/EPAC1/Rap1 signaling pathway.

Burkholderia seminalis suppresses Fusarium wilt infection in banana by modulating cell wall integrity.

Acute low-dose benzo[a]pyrene exposure induces neurodegenerative syndrome in cyp1a low-expression zebrafish: A novel living Bioindicator for dioxin-like environmental pollutants.

The purpose of this study was to explore the composition and function of immune cell subsets at the single cell level in thymus and peripheral blood of patients with myasthenia gravis (MG). A total of 9701 and 23846 cells respectively originated from the peripheral blood and thymus samples of 2 MG patients, and 6930 cells from the peripheral blood of 2 gender- and aged-matched healthy controls were selected for single-cell RNA sequencing. UMAP, GO, KEGG pathway analysis, Monocle3 and Velcyto were performed to analyze the composition, molecular and functional properties, and developmental trajectory of immune cell subsets. Four major cell populations of T cells, B cells, myeloid cells, and NK cells were identified, as well as their 15 cell subpopulations. An absolute predominance of T cells was found in the thymus and peripheral blood of MG patients, and the proportions of memory B cells in both plasma and thymus showed an increasing trend while the number of naïve B cells demonstrated a decreasing trend in MG patients compared with healthy controls. Besides, the monocytes in the peripheral blood of MG patients had the strongest interactions with other cells. Furthermore, CXCL, GAS, and CD30 signaling pathways were more enriched within MG peripheral blood. Our research clarifies the cellular heterogeneity in the pathogenesis of MG and characterizes the immune microenvironment of thymic tissues in MG patients.

Background Spinal cord injury (SCI) leads to irreversible neurological deficits, with emerging evidence highlighting the pivotal regulatory role of gut microbiota in neural repair through the bidirectional gut-brain axis. This study investigates age-related differences in SCI progression by longitudinally profiling multi-omics signatures in young versus aged mice, integrating spinal cord transcriptomics with gut microbiome analysis. Methods A traumatic SCI model was established at the thoracic level 10 in mice. The gut microbiota was analyzed through 16S rRNA sequencing. Spinal cord gene expression was profiled using transcriptome sequencing. Correlation analysis was performed to evaluate associated between gut microbiota shifts and differential cytokines expression. Results Aging significantly altered spinal cord gene expression profiles after SCI, KEGG pathway analysis revealed that differentially expressed genes (DEGs) in young and aged SCI mice were highly similar, predominantly involving immune and inflammatory response pathways. The age-dependent upregulation of inflammatory cytokines were observed under both sham and post-SCI conditions. Additionally, aging was associated with distinct shifts in gut microbiota composition across different phases of SCI. The abundance of certain bacterial genera, such as Lactobacillus and Dubosiella , which was significantly reduced in the acute phase, continued to decline in an age-dependent manner during the chronic phase. Correlation analysis indicated that alterations in the abundance of the gut microbiota were closely associated with variations in spinal cord inflammatory cytokine levels. Conclusion This study delineates host-microbiome interactions in SCI and sheds light on potential mechanisms underlying age-related impairment of neural repair capacity.

Micropropagation is an increasingly sought-after propagation method in the cannabis industry as growers seek to maximize production efficiency, improve multiplication rates and cultivate plants that are free from biotic stress. However, knowledge about the impact of micropropagation on cannabis is still limited in the scientific literature, as most studies have primarily focused on optimizing environmental parameters and growth conditions. In vitro cultures of three cannabis cultivars (Critical Purple Kush, Green Crack, and Gelato) were initiated and maintained for 60weeks with subcultures every three weeks. Leaf samples were collected at the start and after every five subcultures for DNA extraction, and the genomes were sequenced using 3D-GBS and EM-seq to identify genetic (SNPs) and epigenetic (DMPs) variations, followed by GO and KEGG pathway analyses. The results revealed thatgenomic variants from our CPK (16,169), GC (15,472) and GEL (16,605) samples were mostly located within the intergenic regions. Mutations seem to mostly occur during culture initiation and the first five subcultures, plateauing afterwards up to the 20th subculture. Methylation sequencing revealed that DMPs were less frequent than SNPs, with differential methylation levels showing cultivar-specific patterns varying between CPK, GC and GEL with respectively 22%, 9% and 13% for promoter regions, 13%, 5% and 6% for exon regions, 4%, 4% and 3% for intron regions and 61%, 82% and 78% for intergenic regions. These results indicate a strong cultivar dependency of epimutation and suggest their potential phenotypic impact. GO and KEGG pathway enrichment analyses of genes harboring SNPs and DMPs revealed functional associations relevant to cannabis micropropagation. Our results highlight the importance of monitoring both genetic and epigenetic stability for long-term cannabis cultivation.

The addition of Bifidobacterium animalis subsp. lactis and prebiotics to fermented milk can enhance its flavor and sensory properties; however, research on the effects of their combined supplementation on flavor profiles remains limited. This study investigated the impact of simultaneously adding B. lactis IU100 and resistant starch type III (RS3) to fermented milk on flavor and texture. The results showed that co-supplementation shortened the fermentation time by 1 h. It also increased hardness by 28.8%, springiness by 1.14 mm, and water holding capacity by 12.45%, accompanied by the formation of a more continuous and dense gel network. Headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME-GC-MS) combined with odor activity value analysis indicated the enrichment of 115 key aromatic compounds, among which ethyl caprylate, ethyl n-butyrate, 1-octanol, and 2,3-heptanedione were identified as representative flavor compounds associated with fruity and creamy notes. KEGG pathway analysis revealed that 24 differential metabolites were predominantly enriched in purine metabolism and amino acid-related pathways. Within these pathways, coordinated enzymatic reactions convert α-keto acids and fatty acid metabolites into key flavor esters and catalyze the formation of volatile alcohols from amino acids and aromatic fatty acid precursors. Overall, this combined strategy effectively optimized fermentation efficiency, texture, and flavor through the targeted reprogramming of microbial metabolic flux.

This study aimed to investigate the relationship between genes and metabolites involved in glycogen metabolism across different tissues of Yili mares using joint transcriptomic and metabolomic analyses. Glycogen content was measured in various tissues (pincer, trapezius, latissimus dorsi, gluteus medius, semitendinosus, external abdominal obliques, liver, and heart) from seven Yili mares. The liver, as the visceral tissue with the highest glycogen content, and the gluteus medius, as the muscle with the highest glycogen content, were selected for transcriptomic sequencing and metabolomic analysis. KEGG pathway analysis of differentially expressed genes and metabolites in the liver and the gluteus medius revealed several key pathways associated with glycogen metabolism, including pentose and glucuronic acid interconversion, glycolysis/gluconeogenesis, the TCA cycle, fructose and mannose metabolism, and the pentose phosphate pathway. The gluteus medius tissue exhibited differential expression of 1485 metabolites and 7366 genes compared to the liver, with correlation coefficients between some genes and metabolites in the aforementioned pathways exceeding 0.8. This study highlights the regulatory differences in glycogen synthesis between liver and muscle tissues in Yili horses from multiple perspectives. Notably, genes such as ACO1, ACLY, PCK2, and FBP1, along with metabolites like leucine, tyrosine, and valine, play significant roles in regulating glycogen synthesis in the liver. It is hypothesized that these genes and metabolites contribute to the observed differences in energy metabolism between liver and muscle tissues in Yili horses; however, further in vivo and in vitro experiments are needed to validate this hypothesis.

Abstract Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype with limited therapeutic options and poor prognosis. Monocarboxylate transporter 4 (MCT4) is a key lactate efflux transporter involved in cancer metabolism. However, the mechanistic role of MCT4 in TNBC progression and its potential as a therapeutic target remain unclear. Methods: MCT4 expression was analyzed in TNBC patient tissues and correlated with clinical outcomes. MDA-MB-231 cells were subjected to hypoxia treatment and paclitaxel (PTX) exposure. MCT4 was knocked down using siRNA. Cell proliferation, invasion, migration, and PTX sensitivity were assessed. In vivo xenograft experiments were performed to evaluate tumor growth and drug response. RNA-sequencing and KEGG pathway analysis were conducted. Lactate secretion and glucose uptake were measured. Western blot analysis examined MAPK pathway proteins and histone modifications. CUT&Tag sequencing analyzed histone H3K9 lactylation changes and associated gene transcription. Results: MCT4 was significantly overexpressed in TNBC tissues and high expression correlated with poor patient prognosis. Both hypoxia and PTX treatment upregulated MCT4 expression in MDA-MB-231 cells. MCT4 knockdown markedly inhibited cell proliferation, invasion, and migration while enhancing PTX sensitivity. In vivo xenograft studies confirmed that MCT4 knockdown significantly retarded tumor growth and increased PTX sensitivity. RNA-sequencing revealed that MCT4 knockdown dramatically downregulated MAPK signaling pathway. Metabolically, MCT4 knockdown reduced both lactate secretion and glucose uptake. Western blot analysis confirmed that MCT4 knockdown decreased MAPK pathway-related proteins. Under hypoxic conditions, RNA-sequencing showed MAPK pathway activation, which was accompanied by increased histone lactylation levels and H3K9 lactylation. MCT4 knockdown reversed these histone modifications. CUT&Tag analysis revealed that hypoxia-induced H3K9 lactylation promoted transcription of MAPK pathway genes. Notably, MCT4 was not identified among the genes with increased H3K9 lactylation-mediated transcription, suggesting that MCT4 functions as an upstream regulator of histone lactylation rather than a downstream target, establishing a direct mechanistic link between lactate metabolism and gene regulation. Conclusions: This study demonstrates that MCT4 promotes TNBC progression through a novel lactate-histone lactylation-MAPK axis. MCT4 facilitates lactate production and efflux, which drives histone H3K9 lactylation and subsequent activation of MAPK signaling genes, ultimately enhancing cancer cell aggressiveness and chemoresistance. Our findings are validated both in vitro and in vivo, providing strong mechanistic evidence for MCT4 as a therapeutic target in TNBC. Clinical Relevance: MCT4 represents a promising biomarker for TNBC prognosis and a novel therapeutic target. Targeting MCT4-mediated lactate metabolism could enhance chemotherapy efficacy and improve clinical outcomes in TNBC patients. This metabolic-epigenetic crosstalk mechanism opens new avenues for combination therapy strategies. Citation Format: Y. Peng, Q. Luo, S. Liu. Mct4 drives triple-negative breast cancer progression via lactate-induced histone lactylation and mapk pathway activation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-10.