β-ionone, a cyclic isoprenoid and structural analogue of β-carotene's end ring, is ubiquitous in aquatic systems. However, the developmental impacts of β-ionone on aquatic organisms remain largely unexplored. This study investigated the effects of β-ionone exposure (0, 189, 945, and 1890 μg/L) on zebrafish (Danio rerio) embryonic development from 2 to 120 hours post-fertilization (hpf). Our results demonstrate that β-ionone induces dose-dependent developmental toxicity characterized by reactive oxygen species (ROS) overproduction and increased apoptosis. Comprehensive transcriptomic analysis identified activation of the aryl hydrocarbon receptor (AhR) signaling pathway as the primary mechanistic basis for this toxicity. Molecular docking confirmed strong binding interactions between β-ionone and AhR (ΔG = -10 kcal/mol), suggesting direct receptor activation. Further validation demonstrated that β-ionone activates transcription of AhR target genes while significantly enhancing Phase I and Phase II metabolic enzyme activities. Our findings suggest that the AhR signaling pathway may play a critical role in mediating β-ionone-induced developmental toxicity in zebrafish. Given these effects, β-ionone warrants classification as a potential environmental contaminant requiring further ecological risk assessment.

Roles and changes of m6A modification and unfolded protein response (UPR) signaling molecules have not been clarified in the renal cell injury induced by cadmium. Our present results indicated that cell apoptosis rate and oxidative stress were both increased in the renal tissue cells of CdSO4-treated mice when compared with the control group. Detailed analysis further revealed an upward trend in the comprehensive RNA m6A modification levels, accompanied by an increase in the expressions of its regulatory proteins, including Mettl3, Mettl16, Alkbh5, Fto, Ythdc2, Ythdf2, etc. as the concentration of cadmium treatment intensified. In addition, the protein expressions of UPR signaling molecules such as Atf4, Atf6, Perk, Xbp1, Grp78, Bax, and Caspase-12 in the cadmium treated group were higher than those in the control group, whereas the expression of the anti-apoptotic protein Bcl-2 was notably reduced. A significant correlation was noted between the levels of m6A modification and the protein expressions of UPR signaling molecules. Of particular note, SRAMP predictions suggested that the mRNAs encoding UPR signaling molecules are modified with multiple m6A modification sites. Interestingly, immunofluorescence studies illuminated an upsurge in Ythdf2 expression within both the renal medulla and cortex, with a notable translocation from the cytoplasm to the nuclear compartment following cadmium treatment. Concurrently, Xbp1 levels ascended across the entire kidney, predominantly localizing to the cytoplasm. However, the distribution patterns of Ythdf2 and XBP1 throughout the kidney were distinct, with no clear evidence of co-localization between the two. In conclusion, our findings revealed that m6A modification and its regulatory proteins as well as UPR signaling molecules are all involved in the cadmium-induced renal tissue cell damage. It appears that the m6A modification, orchestrated by a suite of regulatory proteins, may serve as a modulator of UPR signaling molecules. This study furnishes a scientific framework for pinpointing pivotal targets in the etiology of cadmium-induced renal toxicity, offering insights into the realms of RNA epigenetics and UPR signaling responses.

Proteolysis-targeting chimeras (PROTACs) have the potential to revolutionize cancer treatment by specifically targeting and degrading oncogenic proteins. Using the ubiquitin-proteasome system, PROTACs allow the selective degradation of disease-causing proteins, including those traditionally deemed "undruggable" by conventional small-molecule inhibitors. By catalytically eliminating rather than inhibiting proteins, PROTACs provide sustained target suppression with lower doses and reduced toxicity. Their bifunctional design linking a protein of interest to an E3 ligase drives targeted ubiquitination and subsequent proteasomal degradation. Recent progress demonstrates promise in treating solid and hematologic malignancies, with several candidates advancing to clinical trials. This review provides a comprehensive overview of developing PROTACs, from understanding their mechanism to clinical applications, and highlights their emerging role in overcoming drug resistance and advancing the limits of cancer treatment. In addition, the authors discuss the challenges of optimizing PROTACs, including issues related to pharmacokinetics, E3 ligase compatibility, and the delivery of PROTACs to tumors. With their modularity, adaptability, and precision, PROTACs represent a next-generation platform for personalized cancer therapy across various patient groups.

The MADS-box transcription factor (TF) superfamily, one of the largest gene groups in plants, is essential for regulating stress responses. However, its function in rice under pesticide stress remains unknown. To address this gap, we investigated the traits and roles of the rice MADS-box gene family under pesticide exposure. Transcriptome analysis of rice (Oryza sativa) treated with fluroxypyr-meptyl (FLUME) and oxyfluorfen (OFF) revealed 30 OsMADS-box genes and 3 MADS-box differentially expressed genes (DEGs). Phylogenetic analysis classified these genes into 12 subfamilies: Mα, Mβ, Mγ, SOC1, E, A, AGL12, SVP, ANR1, Bs, B, and MIKC*. Chromosomal mapping revealed uneven distribution of OsMADS-box genes across all 12 chromosomes, with segmental duplication contributing to gene family expansion. Collinearity analysis identified 14 orthologous gene pairs within rice and additional orthologous gene pairs shared with other plant species: 4 with Arabidopsis (Arabidopsis thaliana), 17 with soybean (Glycine max), 45 with maize (Zea mays), and 36 with wild sugarcane (Saccharum spontaneum). Structural analysis showed that OsMADS-box genes possess diverse gene architectures, cis-acting elements, motif compositions, and conserved domains, enabling responses to biotic and abiotic stress. Docking studies of OFF, FLUME, and the three MADS-box DEGs identified key amino acid residues implicated in pesticide binding. qRT-PCR confirmed preferential expression of several MADS-box DEGs under OFF- and FLUME-induced stress. Protein-protein interaction network analysis further supported the involvement of OsMADS-box proteins in FLUME and OFF metabolism. These findings provide insights into the OsMADS-box superfamily and offer valuable resources for functional studies on their roles in pesticide metabolism.

The mechanisms by which methyl jasmonate (MeJA) enhances cadmium (Cd) tolerance in Malus remain unclear. The physicochemical and molecular responses of Malus hupehensis exposed to 0 or 50 μM Cd with or without exogenous 5 μM MeJA or 50 μM ibuprofen (IBU) for 3 d were explored via a hydroponic experiment. MeJA alleviated Cd-induced growth inhibition, photosynthetic suppression, and oxidative damage. Cd increased the activities of some antioxidant enzymes and levels of endogenous MeJA, which were further enhanced by MeJA application. MeJA decreased the proportion of water-soluble Cd, thereby decreasing Cd mobility and accumulation in all tissues. MeJA increased cell wall (CW) component contents and -COO/-OH groups, thereby improving Cd binding capacity and restricting cellular Cd mobility. MeJA-responsive differentially expressed genes (DEGs) regulated phenylpropanoid biosynthesis and pentose and glucuronate interconversions. MeJA downregulated Cd uptake and transport genes but upregulated Cd detoxification genes and CW metabolic genes. Weighted gene coexpression network analysis (WGCNA) revealed that two key modules strongly correlated with Cd tolerance, including hub transcription factors (TFs) that regulate hormone signaling, phenylpropanoid biosynthesis, and carbohydrate metabolism. Overall, MeJA effectively enhanced Malus plant tolerance by reducing Cd accumulation, enhancing cell wall immobilization and modulating transcriptional regulation.

The network affected by fumonisin in banana fruit during Fusarium proliferatum infection remains largely elusive. Here, integrative transcriptomic and metabolomic analyses in banana peel after inoculation with fumonisin biosynthesis mutation (ΔFpfum21) and wild-type F. proliferatum strains were employed to investigate fumonisin-mediated regulation. Results showed that defense-related genes and metabolites involved in hormone, transcription factor, reactive oxygen species, and lipid metabolism were disturbed during F. proliferatum infection but recovered in ΔFpfum21-inoculated banana peel, suggesting potential targets by fumonisin. In contrast, ΔFpfum21 strain inoculation resulted in downregulation of the triacylglycerol content and CYP450s, patatin-like protein 2, suggesting their potential roles as biomarkers or susceptibility factors in response to fumonisin. Additionally, energy metabolism and ubiquitin-dependent protein degradation pathways were related to the fumonisin-mediated F. proliferatum virulence to banana fruit. This study offered new insights into the molecular dynamics in fumonisin-mediated regulation of banana peel during F. proliferatum infection, causing crown rot.

Escherichia coli, Staphylococcus aureus, and Salmonella pullorum are significant pathogens that threaten livestock and poultry health. Although antibiotics and synthetic antimicrobial agents can combat these pathogens, antibiotic resistance remains a major concern. Recent decades have seen growing interest in antibiotic alternatives. Juglone, a natural naphthoquinone compound from Juglandaceae plant, exhibits strong antimicrobial activity against S. aureus. However, its antimicrobial mechanism is not yet fully understood. This study investigated the antimicrobial mechanism of juglone from the perspectives of cell biology, cell morphology, and transcriptomics.

Secondary soil salinization adversely affects plant growth in greenhouse in China. Previous studies have suggested that the putative molybdate transporter SlMOT2 may be involved in nitrate stress tolerance in tomatoes. However, the precise regulatory mechanisms remain unclear.

The metastasis and chemotherapy resistance of gastric cancer significantly contribute to treatment failure and mortality. Based on previous studies, we hypothesized that Heat Shock Protein 90 (HSP90) interacts with and upregulates Pseudouridine Synthase 7 (PUS7), which in turn promotes THUMP Domain Containing 1 (THUMPD1) expression, driving gastric cancer progression and drug resistance. Differential gene expression analysis revealed that HSP90, PUS7, and THUMPD1 are overexpressed in multiple tumor types and positively correlate with tumor mutational burden (TMB) and microsatellite instability (MSI). Mechanistically, HSP90 interacts with PUS7 to regulate THUMPD1 expression, enhancing tumor cell proliferation, migration, epithelial-mesenchymal transition (EMT), angiogenesis, and cisplatin resistance. Functional inhibition of HSP90 and THUMPD1 suppressed these oncogenic processes, while PUS7 overexpression exacerbated them. These findings highlight the HSP90/PUS7/THUMPD1 axis as a critical regulator of gastric cancer progression and a potential therapeutic target.

Through targeted next-generation sequencing of 83 non-small cell lung cancer (NSCLC) patients with first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance, we detected 11% TET2 mutations in the T790M-negative subgroup. To explore the molecular mechanism of TET2 in EGFR TKI resistance, reduced representation bisulfite sequencing (RRBS) was adopted to analyze the global genomic methylation profiles and detect the differentially methylated genes in the TET2-knockdown (KD) PC9 and control PC9 cell lines, following bioinformatics analysis of gene ontology (GO) functions and kyoto encyclopedia of genes and genomes (KEGG) signaling to screen for genes associated with drug resistance. TET2 KD attenuated gefitinib-induced apoptosis and decreased the sensitivity of EGFR-mutant lung cancer cells to gefitinib. Forty-three drug resistance genes with hypermethylated promoter regions were identified via RRBS and bioinformatic analysis in PC9TET2 KD cells. Then, 10 candidate genes were screened for further validation. RT‒PCR demonstrated that the expression of AXIN2 and CSK was significantly lower in PC9TET2 KD cells than in control cells. Furthermore, AXIN2 KD attenuated gefitinib-induced apoptosis and decreased the sensitivity of PC9 cells to gefitinib. Importantly, we found that the demethylation drug decitabine (DCA) could reverse gefitinib resistance in PC9TET2 KD cells and mouse models. These results indicate that the methylation of AXIN2 induced by TET2 repression is a novel resistance mechanism of EGFR TKIs in EGFR-mutant NSCLC. Demethylation drugs have the potential to overcome EGFR TKI resistance induced by loss-of-function TET2 mutations.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the rapid proliferation of immature myeloid cells and poor clinical outcomes. Despite conventional treatments such as chemotherapy and hematopoietic stem cell transplantation, relapse and resistance remain major challenges. Epigenetic alterations-particularly dysregulated DNA methylation and microRNA (miRNA) expression- are crucial in AML pathogenesis.

The mitochondrial unfolded protein response (UPRmt), a crucial mechanism for maintaining mitochondrial homeostasis, has recently been shown to regulate innate immune responses. Resveratrol, a natural polyphenolic compound abundant in grapes and peanuts, exhibits diverse biological activities including anti-inflammatory, antioxidant, anti-aging, and anticancer effects. However, whether resveratrol modulates innate immunity and its underlying mechanisms remain unclear. In this study, we demonstrated that resveratrol significantly enhanced resistance to Pseudomonas aeruginosa PA14 infection in a dose-dependent manner. This protective effect was mediated not through direct antimicrobial activity, but rather via upregulation of the antimicrobial peptide irg-1 and reduction of intestinal bacterial load. Mechanistically, resveratrol activated the ATFS-1-dependent UPRmt pathway, leading to increased expression of ATFS-1 and its downstream immune- and mitochondrial-protective genes. In human A549 cells, resveratrol attenuated P. aeruginosa PA14 cytotoxicity by activating the UPRmt through ATF5. The conservation of this mechanism was further validated in mice, where resveratrol treatment improved survival, reduced bacterial burden in lung tissue, and upregulated mitochondrial-protective genes. Our study identifies the ATFS-1/ATF5-UPRmt axis as a novel mechanism through which resveratrol enhances innate immunity, providing a foundation for developing natural compound-based anti-infective therapies. These findings advance our understanding of plant polyphenols in immune regulation and offer potential strategies to address antibiotic resistance.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, for the cell invasion assay experiments shown in Fig. 4B, the 'Con' and 'LPA+HF' data panels contained an overlapping section, such that data which were intended to show the results of differently performed experiments appeared to have been derived from the same original source. The authors were contacted by the Editorial Office to offer an explanation for this possible anomaly in the presentation of the data in this paper, although up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further.  [International Journal of Oncology 44: 309‑318, 2014; DOI: 10.3892/ijo.2013.2157].

The aim of this study was to evaluate the antioxidant effects of Cymbopogon citratus, citral, and green-synthesized silver nanoparticles derived from the extract in mitigating oxidative stress-induced liver damage in diabetes mellitus. Seventy rats were randomly split into seven groups: a control group of healthy rats received normal saline, a cosolvent group of Type 2 diabetics received olive oil, a negative control group of Type 2 diabetics, and groups of diabetic rats receiving various treatments: metformin (100 mg/kg), Cymbopogon citratus extract (30 mg/kg), citral (30 mg/kg), and green-synthesized silver nanoparticles (30 mg/kg). Type 2 diabetes was induced in rats using 90 mg/kg of nicotinamide and 65 mg/kg of streptozotocin. After 6 weeks, the rats were anesthetized to extract blood samples. The serum levels of the liver function test (serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, and alkaline phosphatase) were measured. They were then euthanized by CO2 inhalation. Liver tissue was used to investigate histopathology, antioxidant activity, and Nrf2 gene expression. In the diabetes group, liver function tests increased, while TAC decreased and MDA increased (p < 0.05). The expression of the Nrf2 gene decreased compared to the control group (p < 0.05). In the treatment groups, the liver function tests and MDA decreased, while TAC and the expression of the Nrf2 gene increased compared to the Type 2 diabetes group (p < 0.05). The histopathological examination showed a return to normal condition. The study found that Cymbopogon citratus, specifically citral and green-synthesized silver nanoparticles, effectively mitigated oxidative stress-induced liver damage in diabetes.

Approximately 50% of colorectal cancer (CRC) patients exhibit high levels of Fusobacterium nucleatum (Fn), which is associated with chemotherapy resistance. As Fn itself cannot be directly targeted for therapy in vivo, elucidating the mechanism underlying Fn-induced chemotherapy resistance is crucial, though it remains unclear.

Ewing sarcoma (ES) is a highly aggressive pediatric bone cancer with limited treatment options for metastatic or recurrent cases. This study investigated the antitumor effects of kaempferol, a natural flavonoid, on ES and its underlying molecular mechanisms. In vitro experiments demonstrated that kaempferol significantly inhibited the proliferation, migration, and invasion of SK-ES-1 cells in a dose- and time-dependent manner. Mechanistically, kaempferol upregulated miR-26b-5p, which directly targeted and suppressed FAM98A, a pro-oncogenic protein. This regulation led to the inhibition of the EGFR/PI3K/AKT/NF-κB signaling pathway, reducing tumor growth and metastasis. In vivo studies further confirmed that kaempferol suppressed ES tumor growth in a xenograft mouse model, while miR-26b-5p knockdown partially reversed this effect. Our findings suggest that kaempferol exerts its antitumor activity in ES by modulating the miR-26b-5p/FAM98A axis and downstream signaling pathways, highlighting its potential as a novel therapeutic agent for ES treatment.

Hodgkin lymphoma (HL) develops in the part of the immune system that is centrally aggravated by the NF-κB signaling. Selectively targeting IKKβ to downregulate the NF-κB-mediated disease progression helps control this dreadful malignancy. This study evaluated novel and selective IKKβ inhibitors to downregulate aberrant NF-κB signaling in HL. GROMACS, GMX_MMPBSA, and PLIP were used after high-throughput virtual screening against the ChemBridge library to identify leads. The in vitro effectiveness was evaluated using flow cytometry, luminometry, and spectrometry on RPMI 666 and Hs 445 cells. HTVS identified SIKB-7543 with favorable binding affinities of -14.2 kcal/mol toward IKKβ. MD simulations established stable bonding for SIKB-7543 and IKKβ with RSMD values around 0.07 nm. The ΔG binding calculation was -50.46 kcal/mol, favoring sturdy binding. ADME analysis favored small-molecule characteristics. SIKB-7543 inhibited IKKβ activity with an IC50 value of 118 nM. The compound effectively controlled the proliferation of RPMI 666 and Hs 445 cells with GI50 values of 345.6 nM and 320.5 nM, respectively. SIKB-7543 prompted dose-responsive apoptosis in the HL cells. Cell-cycle analysis demonstrated a concentration-dependent increase in the sub-G₀ population in both cell lines following SIKB-7543 treatment, while decreasing the NF-κB-p65 (Rel A) positive populations in TNFα-stimulated RPMI 666 and Hs 445 cells dose-dependently. Results suggest SIKB-7543 is a selective IKKβ inhibitor that downregulates aberrant NF-κB signaling, controls proliferation, and induces apoptosis, warranting further preclinical developments to counter HL malignancy.

Subinhibitory concentrations of various antibiotics can exacerbate microbial virulence. Acinetobacter baumannii is often resistant to oxacillin; however, the effect of low oxacillin concentrations on oxacillinase-producing bacteria remains unclear. Herein, oxacillinase producer A. baumannii ATCC-strains 2093 (motile) and 19606 (non-motile) were pre-exposed to sub-bactericidal concentrations (subMBC) of oxacillin (0.25, 0.5, and 1.0 mg/mL) and incubated at 37 °C. Growth kinetics, twitching and swarming-like motility, biofilm formation, exopolysaccharide production, transformation capability, and gene expression were determined. All oxacillin subMBC conditions exerted bacteriostatic effects in both strains. Pre-exposing the motile strain with 0.25 and 0.5 mg/mL of oxacillin for 1 h increased the twitching motility (4.2 ± 0.3 cm; control = 3.5 cm), whereas pre-exposure for 2 h it increased swarming-like motility (2.95 ± 0.15 cm; control = 2.7 cm). This strain also increased the biofilm production by effect of all 6 h-oxacillin subMBC treated bacteria (≤ 1.42 Biofilm Formation Index (BFI); control = 0.6 BFI), whereas the strain 19606 reduced biofilm up to 1 BFI (control = 2 BFI). The antibiotic also reduced the exopolysaccharide production in almost all treated cells from both strains. The transformation efficiency (TE) of strain 19606 increased X̄ = 19 ± 11% more than the control by effect of all DNA and oxacillin conditions studied; however, the TE for strain 2093 was lower than the control. The expression of genes for resistance (bla-OXA), twitching (pilA/tonB) and swarming-like motilities (dat/ddc), and biofilm production (csuE) were altered by the oxacillin subMBC. Overall, exposure of oxacillinase-producing A. baumannii to oxacillin subMBC increases several virulence factors, representing a potential public health risk.

How developing organisms respond to a changing environment is a fundamental question. Pollutants and temperature are major environmental factors. Using the bristle patterning of Drosophila as a model system, we observed that cold temperature and methotrexate, a medical drug that contaminates wastewaters, increase dorsocentral (DC) bristle number, a trait normally robust. The patterning of bristles is well understood and involves the achaete-scute (ac-sc) proneural genes. Modular enhancers activate ac-sc expression in groups of cells, called proneural clusters, from which bristle precursors are selected by lateral inhibition, a process involving Notch signalling and ac-sc auto-activation. In addition, ac-sc basal expression is controlled by a cocktail of repressive factors. We observed that the deletion of the DC enhancer prevents the induction of ectopic DC bristles by methotrexate but does not stop low temperature to induce DC bristles. Indeed, we show that methotrexate has a strong synergy with mutants of factors that regulate the DC enhancer and extends the zone of activity of this enhancer. In contrast, temperature interacts with repressors of ac-sc basal expression. Thus, methotrexate and temperature both affect DC bristle patterning but by distinct mechanisms, methotrexate on the DC enhancer and cold independently of this enhancer.

Tea (Camellia sinensis), a widely cultivated crop across more than 50 countries, is highly vulnerable to drought stress, which impairs growth and reduces yield. This study examines the potential of exogenously applied salicylic acid (SA), abscisic acid (ABA), and shikimic acid (ShA) in enhancing drought tolerance in tea plants. Plants were pre-treated with SA, ABA, and ShA for 4 days, followed by 10 days of drought stress during which no water was provided by either foliar spray or soil irrigation. Leaf samples collected on day 15 were analyzed for various physiological and biochemical markers, including antioxidant enzyme activities (POD and GST), reactive oxygen species (H2O2) levels, and contents of total chlorophyll, carotenoids, and proline. Results showed that all treatments mitigated drought-induced physiological damage, reduced oxidative stress, and elevated antioxidant enzyme activity compared to untreated control plants under drought conditions. Treated plants also exhibited higher proline and chlorophyll levels, suggesting improved osmotic regulation and photosynthetic efficiency. Among the treatments, SA demonstrated the most pronounced enhancement of drought tolerance. To clarify the functional roles and relationships of 76 genes found through a literature review associated with the SA and ShA pathways under drought stress were examined using Gene Ontology (GO) enrichment, subcellular localization, and KEGG pathway analysis. These findings indicate that exogenous application of SA, ABA, and ShA enhances drought resilience in tea by strengthening antioxidant defenses and maintaining cellular integrity, presenting a promising approach to sustaining tea production in drought-prone areas. Future studies should explore the potential of combining these inducers with genetic or microbial strategies to further enhance drought resilience in tea plants.