Cisplatin is a broad-spectrum anticancer agent. Its main side effect - ototoxicity - may impact the quality of patient's life. Eleutheroside E (EE), the main active component of Acanthopanax, exhibits antioxidant and anti-inflammatory properties. This study investigates the protective effects of EE against cisplatin-induced ototoxicity and its underlying mechanisms. We use C57BL/6 J mice, the House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, and cultured cochlear basement membranes in our experiments. We employ network pharmacology and 4D-FastDIA quantitative proteomic analysis. Our results demonstrate that Cisplatin significantly impairs auditory function in mice. However, EE co-treatment preserves auditory function across most measured frequencies, correlating with reduced damage to cochlear hair cells and spiral ganglion neurons(SGNs). Here, we show that EE attenuates cisplatin-induced pro-inflammatory responses and cellular pyroptosis, possibly via downregulation of the MAPK/NF-κB/NLRP3 signaling pathway. In conclusion, EE may offer a promising strategy for reducing Cisplatin's ototoxicity without affecting its antitumor efficacy.

Heat shock poses a major threat to strawberry production, impairing both yield and fruit quality. This study investigated the potential of salicylic acid (SA) spraying (1 mM) to mitigate heat-induced damage (42 °C) in 'Camarosa' and 'Paros' cultivars. Results showed heat shock was the primary factor driving a severe decline in fruit yield by 61%. Although SA failed to mitigate yield loss, it induced divergent, cultivar-specific strategies in biomass partitioning and defense metabolism. 'Camarosa' deployed an inducible, high-cost acclimation strategy, upregulating PAL activity by 56.3% and reconfiguring biomass towards roots, whereas 'Paros' exhibited constitutive tolerance but greater fruit weight sensitivity (34.3% vs. 15.6% reduction). PCA quantified a fundamental physiological trade-off, with PC1 (45.5% of variance) clearly separating a yield and quality cluster from a cluster defined by phenylpropanoid metabolism. This was statistically underpinned by significant negative correlations between PAL activity and both fruit yield (r = -0.63) and vitamin C (r = -0.83), confirming the metabolic cost of phenylpropanoid defense activation. It is concluded that 1 mM SA does not rescue yield but serves as a genotype-specific physiological modulator, indicating that management strategies should prioritize cultivars that balance defense expenditure with reproductive sink strength.

Despite initial positive responses with chemotherapy, many cancer patients experience relapse, continued tumor growth, and metastatic spread due to drug resistance. It is well documented that a rare population of phenotypically heterogeneous cells contributes to intratumour heterogeneity and drug resistance. To date, these rare populations are poorly characterized. To identify the potential role of these rare populations in drug resistance, here we have performed single-cell RNA sequencing of human oral squamous cell carcinomas lines presenting with sensitive, early, and late cisplatin-resistance patterns. The single-cell RNA-sequencing data identified two different transitional clusters within the three, sensitive, early, and late cisplatin-resistant major clusters. The differential gene expression profile and deregulated pathways analysis suggested Brain Abundant Membrane-Attached Signal Protein 1 (BASP1) as a major upregulated gene not only in major drug-resistant clusters but also in transitional clusters. Selective knockdown of BASP1 reverses epithelial to mesenchymal transition (EMT) phenotype in cisplatin-resistant cells and restores cisplatin-induced cell death. Mechanistically, BASP1 positively regulates LIN7A expression through phosphorylation of RAC-alpha serine/threonine-protein kinase as well as by supressing microRNA hsa-mir-501-3p, which in turn induces β-catenin-mediated EMT in chemoresistant cells. Overall, our study demonstrates that BASP1 acts as a key regulator of EMT in cisplatin-resistant oral squamous cell carcinoma and represents a promising therapeutic target to overcome drug resistance in advanced stages of the disease.

Adenosine-to-inosine (A-to-I) RNA editing catalyzed by adenosine deaminase acting on RNA (ADAR) 1 is the most abundant RNA modification in humans. We noticed that there are multiple A-to-I RNA editing sites in the 3'-UTR of cytochrome c (CYCS), a mitochondrial protein involved in the initiation of apoptosis. We aimed to clarify the impact of ADAR1 on the regulation of CYCS expression, its mechanism, and its biological and pharmacological significance. In human hepatocellular carcinoma-derived HepG2 or Huh-7 cells, siRNA-mediated knockdown of ADAR1 (siADAR1) reduced CYCS protein levels without affecting mRNA levels, suggesting that ADAR1 facilitates CYCS translation. Sanger sequence analysis showed that multiple adenosines in the 3'-UTR of CYCS are highly edited by ADAR1. The CYCS protein level in HepG2 CYCS 3'-UTR-deleted cells in which the 3'-UTR of CYCS was deleted by the CRISPR/Cas9 system was not decreased by siADAR1, indicating that the 3'-UTR is required for ADAR1-dependent translational regulation. The pulldown assay revealed that siADAR1 increases the binding of CYCS mRNA to RNA-binding proteins with disordered regions, suggesting that stress granules, a membrane-less organelle formed by such proteins with intrinsically disordered regions, might trap CYCS mRNA and suppress its translation. Treatment with ISRIB, an inhibitor of stress granule formation, attenuated the siADAR1-mediated decrease in CYCS protein levels. Interestingly, sorafenib-induced apoptosis in HepG2 cells was repressed by siADAR1, but this repression was not observed in HepG2 CYCS 3'-UTR-deleted cells. Collectively, this study clarified that ADAR1 upregulates CYCS translation by inhibiting stress granule formation and thereby can facilitate anticancer agent-induced apoptosis.

Since the early 1990s, considerable progress has been made in understanding the teratogenic and embryotoxic effects of metals in mammalian systems. The present updated review synthesizes over three decades of research findings, examining the developmental toxicity of metals across four categories: (a) metals of greatest toxicological significance (arsenic, cadmium, lead, mercury, and uranium), (b) essential trace metals (chromium, cobalt, manganese, selenium, and zinc), (c) other metals with evident biological interest (nickel and vanadium), and (d) metals of pharmacological interest (aluminum and lithium). Recent advances in understanding molecular mechanisms, epigenetic effects, transgenerational impacts, and improved chelation therapies are comprehensively reviewed. The emergence of new analytical techniques has revealed previously unrecognized low-dose effects and complex metal-metal interactions that affect developmental outcomes. Current evidence shows that environmental exposures to multiple metals at concentrations previously considered safe can produce significant developmental toxicity through oxidative stress, epigenetic modifications, and disruption of essential metabolic pathways. Chelating agents, including improved formulations of DMSA and DMPS, continue to show promise in preventing and treating metal-induced developmental toxicity, although their own potential developmental effects require careful consideration.

Neuroblastoma is an aggressive extracranial cancer having causative factors including epigenetic alterations and histone modifications. The epigenetic master regulator, Bmi1 is the essential molecule in the progression of neuroblastoma (NB). The existing small molecule inhibitor-based epigenetic targeted therapy has limitations of aberrant activity and delivery challenges. However, the siRNA degradation limits the therapeutic efficacy and could be countered by the nanodelivery system. Indeed, specific targeting of cancer improves the therapeutic effect. GD2 is the specific molecular hallmark of NB that's how for the first time, anti-GD2 decorated Bmi1 siRNA encapsulated HSA (Human Serum Albumin)-Chitosan nanohybrid is being employed to inhibit targeted epigenetic therapy for NB. The results have shown endowed transfection efficiency, impressive knockdown efficiency, and remarkable tumor growth restriction by improving Bmi1 siRNA stability. The restriction of cell migration and significant downregulation of metastatic hallmark, vimentin reflects the anti-metastatic action of nanohybrids. The first-time exploration of molecular mechanism has revealed Bmi1 mediated Sox2/Slug/Vimentin signaling in NB progression that is inhibited by our nanohybrids. Thus, the present study divulges the immense potential of HSA-Chitosan nanohybrids as the new delivery system for nucleic acid having the promising caliber to be anti-GD2 decorated targeted epigenetic therapeutics in the treatment of NB.

Metabolic reprogramming, exemplified by the Warburg effect, is a hallmark of cancer. Hexokinase 2 (HK2), a key glycolytic enzyme, is frequently overexpressed in cancer, sustaining glucose metabolism and tumor progression. MicroRNAs (miRNAs) post-transcriptionally regulate HK2 by targeting its 3'untranslated region or upstream signaling pathways. While monotherapies often fail due to compensatory pathways and drug resistance, dual-targeting both HK2 and its regulatory miRNAs could achieve substantial metabolic inhibition. This review summarizes recent advances in miRNA-HK2 regulatory networks across cancers and highlights dual-targeting miRNA-HK2 as a promising therapeutic strategy to overcome metabolic plasticity and improve precision, durability, and efficacy in cancer therapy.

Environmental exposures are increasingly recognized as key modulators of the epigenome, contributing to both immediate and long-term disease risk. The field of toxicoepigenomics, which investigates how environmental toxicants alter epigenetic regulation, has demonstrated that exposures to endocrine-disrupting chemicals, heavy metals, polycyclic aromatic hydrocarbons (PAHs), and air pollutants can disrupt gene expression through changes in DNA methylation, histone modifications, non-coding RNA expression, and higher-order chromatin structure. Additionally, lifestyle factors-including diet, physical activity, stress, and sleep-interact with these exposures to shape individual epigenetic profiles and influence health trajectories across the lifespan. This review synthesizes current evidence across major pollutant classes and molecular pathways, emphasizing both well-characterized and emerging mechanisms. Retained introns represent post-transcriptional consequences of chromatin-based epigenetic regulation and serve as sensitive indicators of environmentally induced disruptions in transcriptional elongation and splicing fidelity. We also highlight recent advances in high-throughput technologies, including whole-genome bisulfite sequencing, single-cell epigenomics, and epigenetic clock models, which are rapidly enhancing biomarker discovery and mechanistic understanding. By integrating multilayered epigenetic insights across diverse exposure contexts, this review advances the field of toxicoepigenomics and lays the groundwork for developing robust, exposure-responsive biomarkers of environmental disease. These insights offer significant promise for guiding mechanistic research, improving exposure surveillance, and informing the design of precision strategies in environmental health.

Interest in the effects of pharmaceutical pollution on aquatic habitats has expanded with the growing number and increased distribution of drugs worldwide. In this study, we perform an experiment to examine the effects of two drugs, fluoxetine (known commercially as the anti-depressant Prozac™) and metformin (a widely-used diabetes medication), both of which are common freshwater contaminants. We investigated the effects of the two drugs alone and in combination on Daphnia magna in both in crowded and non-crowded conditions in order to understand how pharmaceutical pollution and naturally-occurring environmental cues might interact to shape phenotypic traits and gene expression. We assayed fecundity, respiration, transgenerational effects, and gene expression levels for three genes. Pharmaceuticals affected offspring, respiration, and gene expression, while crowding affected fecundity. Specifically, fluoxetine induced male production and metformin made offspring sickly. Overall, these drugs and their combination had detectable impacts on many traits, and in some cases the effects depended on crowding conditions. Daphnia, a model system in ecology and ecotoxicology, provides myriad insights into the effects of pollutants, both because of its key role in freshwater food webs and its ability to serve as an experimental system to determine sublethal and lethal effects. Our findings contribute to our current understanding of pharmaceutical pollution and suggest that investigating the risks using more real-world scenarios is important for the maintenance of freshwater drinking supplies and freshwater ecosystems.

Methylmercury (MeHg) is a pervasive neurotoxicant threatening aquatic ecosystems. Selenium (Se) has been reported to protect fish against the adverse MeHg toxicity, yet molecular investigations of their interaction in the brain remain scarce. This study investigated the molecular effects of dietary MeHg and whether organic Se, in the form of selenomethionine (SeMet), could mitigate MeHg-induced change in the brain of rainbow trout (Oncorhynchus mykiss). A 6-month feeding trial was conducted with diets containing low basal Se (0.3 mg/kg) and no mercury (Hg), supplemented with 2 mg Hg/kg diet as MeHg, alone or combined with 1.5 mg Se/kg diet as SeMet. Gene methylation (reduced representation bisulfite sequencing) and expression (RNA sequencing) were assessed, alongside biochemical quantification of DNA methylation-related metabolites (S-adenosylmethionine, SAM, and S-adenosylhomocysteine, SAH) and oxidative stress-related metabolites (reduced glutathione, GSH, and oxidized glutathione, GSSG). SeMet did not prevent MeHg-induced changes in SAM/SAH levels but mitigated MeHg-induced alterations in DNA methylation of genes related to the glutamatergic system, inflammation, and immune response. Transcriptomic analysis revealed antagonistic effects of MeHg and SeMet on energy metabolism pathways, with hypoxia-inducible factor 1 subunit alpha-like 2 identified as a potential key regulator. Although this molecular interaction may reflect SeMet-mediated attenuation of oxidative stress, biochemical data did not confirm changes in GSH/GSSG levels. These findings provide novel insights into the molecular mechanisms underlying MeHg neurotoxicity and its modulation by SeMet in fish brain, highlighting a potential protective role of organic Se against MeHg-induced molecular alterations.

Bromodomain and extra-terminal (BET) proteins function as key epigenetic regulators of oncogenic, inflammation, and immune pathways, however, their therapeutic targeting has been constrained by limitations of monofunctional inhibitors-notably compensatory resistance, narrow therapeutic indexes, and context-specific efficacy. This review delineates a paradigm shift from occupancy-based inhibition toward multidimensional bifunctional engagement, overcoming these barriers through rationally designed dual-target inhibitors (e.g., BET/HDAC, BET/kinases), catalytic degraders (PROTACs, molecular glues), and pathway-directed systems (autophagy-lysosome modulators, apoptotic reactivators, RIPTACs, and TCIPs). Advanced delivery platforms, including antibody-drug conjugates (ADCs) and stimuli-responsive nanocarriers, may enhance spatiotemporal precision and reduce systemic toxicity. By exploiting synergistic epigenetic-kinase cooperativity or leveraging ternary complex-driven degradation, these innovations are redefining the pharmacological landscape for BET proteins. Collectively, such strategies may provide durable efficacy against recalcitrant cancers, inflammatory disorders, and neurodegenerative diseases, suggesting emerging new design principles for epigenetic therapeutics.

Pregnane X receptor (PXR) is a key transcriptional regulator of drug-metabolizing enzymes and transporters, notably CYP3A4, which metabolizes a significant proportion of clinically used drugs. PXR activation can induce CYP3A4 expression, potentially leading to drug-drug interactions (DDIs) by altering the pharmacokinetics of CYP3A4 substrates, particularly for narrow therapeutic index drugs. Conventional induction assays rely on measuring CYP3A4 mRNA and enzyme activity, but mRNA levels often do not correlate with enzyme activity, which can lead to mispredictions of DDIs. To address this gap, we incorporated our newly established Fast and Surfactant-Treated proteomic workflow into the current in vitro induction assay to enable simultaneous quantification of CYP3A4 mRNA, protein, and enzyme activity induction from a single experiment. Using rifampicin as a PXR agonist, we demonstrated that the unified All-in-One assay provided consistent induction parameters with discrete assays, offering a robust method for assessing CYP3A4 induction. We also applied this approach to the tyrosine kinase inhibitors pazopanib and crizotinib, revealing nonuniformities in their induction profiles across mRNA, protein, and enzyme activity endpoints. Specifically, although both tyrosine kinase inhibitors induced CYP3A4 mRNA expression in a dose-dependent manner, they do not lead to protein induction, suggesting that the in vitro induction observed at the mRNA level may not translate to clinical induction. Collectively, these preliminary findings suggest that protein measurements may provide a more holistic representation of CYP3A4 induction and can potentially improve the predictability of clinical DDIs in drug development. SIGNIFICANCE STATEMENT: We described and validated a unified assay that can simultaneously measure CYP3A4 mRNA, protein, and enzyme activity induction from a single human hepatocyte experiment. This unified All-in-One approach has the potential to improve in vitro-in vivo correlation and translation of CYP3A4-mediated induction drug-drug interactions for new chemical entities. However, further work, including the integration of static or dynamic physiologically based pharmacokinetic modeling with protein induction data, will be required to fully confirm these insights.

Cancer is a multifaceted disease driven by genetic mutations and epigenetic dysregulation. Among epigenetic modifiers, histone demethylases like KDM4C (lysine demethylase 4C) play a pivotal role in tumor progression by removing repressive methylation mark at Histone H3K9/H3K36 and altering chromatin structure and gene expression. Overexpression of KDM4C has been implicated in various malignancies, including breast, prostate, colorectal, and hepatocellular carcinomas, hence it is promising drug target. This study employs a structure-based drug discovery strategy to identify natural polyphenolic inhibitors of KDM4C. High-throughput virtual screening, followed by molecular docking, molecular dynamics (MD) simulations, and MM-GBSA free energy calculations, used to assess binding potential. Pectolinarin and compound 202 emerged as top candidates, outperforming the reference ligand (6X9) used from PDBID: 5KR7, in docking scores, and exhibiting robust hydrogen bonding and hydrophobic interactions within the active site. MD simulations over 200 ns confirmed complex stability, indicated by consistently low RMSD and RMSF values. MM-GBSA analysis revealed strong binding affinities with free energy values of -68.4 kcal/mol and -65.7 kcal/mol for Pectolinarin and compound 202, respectively. ADMET predictions supported their drug-likeness, suggesting favorable pharmacokinetic profiles, oral bioavailability, and low toxicity. These findings highlight pectolinarin and compound 202 as promising leads for KDM4C-targeted cancer therapy. Further experimental validation is required to confirm their efficacy and specificity. Overall, this work demonstrates the potential of computational approaches in advancing the discovery of nature-derived epigenetic therapeutics.

CDK9, in complex with cyclin T1 or T2, is essential for mRNA transcription by enabling paused RNA polymerase II to proceed into elongation. Increasing evidence highlights CDK9's involvement in transcriptional addiction in cancer. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which effective targeted therapies remain limited. Here, we aimed to define the therapeutic potential of novel CDK9 inhibitors in TNBC.

TP53 gene mutations are common in breast cancer and are linked to chemoresistance. p63, a p53 family member, can induce apoptosis independently of p53, representing a potential therapeutic target in TP53-mutant tumors. This study evaluated the synergistic effects of SB431542, a TGF-β type I receptor inhibitor, and doxorubicin in TP53-mutant breast cancer cells.

High-risk neuroblastoma (NB) remains a therapeutic challenge with a poor prognosis, necessitating the identification of novel prognostic biomarkers and effective therapeutics.

Multiple myeloma (MM) remains an incurable hematologic malignancy, necessitating novel therapeutic strategies. This study investigates the clinical significance of adiponectin receptors and the anti-myeloma efficacy of their agonist, AdipoRon. Bioinformatic analysis of GEO datasets (GSE124489, GSE187009) revealed significant downregulation of ADIPOR1 and ADIPOR2 in MM patients. Low expression of ADIPOR1 correlated with poor prognosis. Functionally, AdipoRon exerted potent anti-proliferative effects on MM cell lines (U266, RPMI8226) in time- and dose-dependent manners. Mechanistic studies demonstrated that AdipoRon induced mitochondrial apoptosis, evidenced by increased cleavage of PARP and Caspase-9, and triggered G0/G1 cell cycle arrest. At the signaling level, AdipoRon activated the AMPK pathway while concurrently suppressing AKT phosphorylation. The critical role of AMPK was confirmed through pharmacological approaches: the AMPK activator AICAR mimicked AdipoRon's effects, whereas the AMPK inhibitor Compound C partially reversed them. Further investigation identified acetyl-CoA carboxylase (ACC) as a key downstream effector, with ACC inhibition (TOFA) recapitulating AdipoRon's anti-MM effects. Specifically, AdipoRon preferentially suppressed ACC1 expression and subsequently downregulated CPT1A, indicating disruption of fatty acid metabolism. These findings establish that AdipoRon suppresses MM progression through AMPK-driven metabolic reprogramming and apoptosis induction, positioning adiponectin receptor agonism as a promising therapeutic strategy for multiple myeloma.

Ribosomal protein S6 kinase A2 (RPS6KA2) has been identified as a potential prognostic biomarker in several cancers, including breast cancer, glioblastoma, and prostate cancer. However, its functional significance in ovarian cancer is not well characterized. This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer, particularly in relation to cisplatin resistance.

Sustainable crop production demands solutions to reduce the overuse of synthetic nitrogen (N) fertilizers, and plant-growth-promoting bacteria offer a promising strategy by enhancing nutrient acquisition. This study investigated the ability of a nondiazotrophic bacterium, Enterobacter sp. SA187 (SA187), in enhancing Arabidopsis growth under low-nitrate conditions and the underlying mechanisms. Arabidopsis seedlings were grown under different nitrate concentrations with or without SA187 inoculation. Growth traits were quantified alongside shoot and root nitrate and total N contents, and C : N ratios. Transcriptomic profiling (RNA-seq) and qRT-PCR were used to assess modified gene expression. Functional validation was conducted using ethylene-insensitive (ein2-1) and high-affinity nitrate transporter (HATS) mutants (nrt2.5, nrt2.6). SA187 significantly enhanced fresh weight, primary root length, and lateral root density under low nitrate, with benefits increasing as nitrate availability decreased. SA187 improved nitrate accumulation and shoot N allocation, reducing shoot C : N ratios. SA187 regulated expression of HATS and hormone-responsive genes. The growth-promoting effects were abolished in ein2-1, nrt2.5, and nrt2.6 mutants, and SA187-induced regulation of NRT2.5 occurred downstream of ethylene signaling, while NRT2.6 was partly ethylene independent. SA187 promotes growth under low nitrate possibly through ethylene-mediated and HATS-dependent reprogramming of nitrate accumulation and N allocation, supporting its use as a microbial solution for low-input agriculture.

Although the prognosis of hepatocellular carcinoma (HCC) has been improved significantly due to diagnostic innovation and treatment optimization, HCC remains highly lethal, necessitating novel therapeutic targets.