Colorectal cancer (CRC) exhibits altered lipid metabolism associated with therapy resistance. FOXA2, a lipid metabolism activator, mediates fatty acid β-oxidation in CRC, but its role in irinotecan (CPT-11) resistance remains unclear. Through bioinformatics analysis, clinical sample assessment, and cell line validation, we confirmed the expression of FOXA2 in CRC. The impact of FOXA2 on the viability and CPT-11 sensitivity of CRC cells was tested via CCK-8 assay. DNA damage was evaluated using the comet assay and monitoring of γ-H2AX foci. Assay kits determined the concentrations of triglycerides, cholesterol, and phospholipids, as well as the rate of fatty acid β-oxidation. Protein expression related to lipid metabolism (ACLY, SCD1) was identified by WB. Bioinformatic tools were used to analyze the potential transcriptional control of Aldolase B (ALDOB) by FOXA2 and to scrutinize ALDOB expression in CRC. The molecular interaction was substantiated by dual-luciferase and CHIP assays. IHC was performed on an xenograft tumor model in mice to measure FOXA2, ALDOB, and Ki67 expression. Oil Red O staining was applied to detect triglyceride presence, and TUNEL was used to gauge apoptosis. The results showed that FOXA2 overexpression correlated with CPT-11 resistance in CRC. FOXA2 transcriptionally activated ALDOB, enhancing fatty acid β-oxidation and suppressing drug sensitivity. FOXA2 inhibition sensitized CRC cells to CPT-11 in vitro/vivo, while ALDOB overexpression restored resistance. These findings indicate that FOXA2 promotes CPT-11 resistance by upregulating ALDOB-mediated fatty acid β-oxidation. Targeting the FOXA2/ALDOB axis may overcome chemoresistance in CRC.

The United States is currently facing a drug overdose epidemic. The nucleus accumbens core (NAcore), a brain region critical for reward and aversion behaviors, undergoes structural and functional synaptic adaptations in response to chronic drug exposure. However, the molecular mechanisms underlying these adaptations remain poorly understood. In this study, we investigate the role of dual-specificity phosphatase 5 (DUSP5), a phosphatase known to deactivate extracellular signal-regulated kinase (ERK), in cocaine-induced neuroplasticity. While prior research has linked other DUSP family members to various drugs of abuse, the specific role of DUSP5 in cocaine addiction remains unexplored. We hypothesized that lack of DUSP5 contributes to cocaine-induced maladaptive synaptic plasticity in NAcore. To test this, we employed a rat cocaine self-administration model and molecular analyses and mined publicly available single-cell RNA sequencing data from cocaine-treated NAcore. Our findings reveal a role for DUSP5 in cocaine-related synaptic and behavioral adaptations, highlighting DUSP5 and DUSP5-associated signaling pathways as potential mechanisms underlying substance use disorders and as candidates for therapeutic intervention.

Cisplatin is one of the most effective chemotherapeutic agents used in the treatment of ovarian cancer. However, the frequent development of cisplatin resistance remains a significant limitation, leading to therapeutic failure and poor patient outcomes. Cisplatin cytotoxicity is attributed to the generation of toxic DNA lesions, which can be recognized and processed by a variety of proteins, including the high mobility group box 1 (HMGB1) protein. HMGB1 is a multifunctional protein, which is involved in chromatin remodeling and multiple DNA damage repair pathways. In this study, we investigated the role of HMGB1 in modulating cisplatin sensitivity in human ovarian cancer cells. Using cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines, we employed siRNA-mediated HMGB1 knockdown to assess its impact on the cellular responses to cisplatin treatment. In clonogenic survival assays, HMGB1 depletion resulted in a significant reduction in colony formation in cisplatin-resistant cells upon cisplatin exposure, compared with nontargeting siRNA treated cells. Additionally, HMGB1 inhibition significantly enhanced cisplatin-induced apoptosis in the cisplatin-resistant cells. Mechanistically, HMGB1-depleted cells exhibited altered DNA damage responses via modulation of ATM/CHK2 and ATR/CHK1 activity following cisplatin treatment. Notably, DNA immunoblot and modified alkaline comet assay results demonstrated that HMGB1 depletion stimulated cisplatin-DNA adduct formation and impaired the removal of cisplatin-DNA adducts, particularly in the cisplatin-resistant cells. Collectively, these findings uncover novel functions of HMGB1 in mediating cisplatin sensitivity, emphasizing its potential as a therapeutic target to overcome cisplatin resistance in ovarian cancer.

Jasmonic acid (JA) is a critical signal controlling ripening and trait development in non-climacteric (NC) fruit. However, the mechanisms governing the JA biosynthesis remain unclear. Here, the signaling mechanisms for the JA biosynthesis are explored in strawberry (Fragaria vesca), a model NC fruit. The JA biosynthesis is demonstrated to be tightly coupled with the signaling of ABA, a pivotal signal controlling NC fruit ripening. When overexpressed or knocked out by CRISPR/Cas9 editing, FvSnRK2.6, a gene encoding a component of ABA signaling, promotes or inhibits JA production and aroma production, respectively. Moreover, FvSnRK2.6 phosphorylates FvJAZ12, a jasmonate ZIM-domain repressor, at the S142 residue, thereby promoting its degradation. Transforming the FvJAZ12 knockout mutant with FvJAZ12S142A inhibits the production of ABA-induced aroma and JA. Furthermore, our current study reveals that FvMYC2, a transcription factor directly repressed by FvJAZ12, binds to cis-acting elements in the promoters of FvAOC3, FvAOS, FvLOX3, and FvOPR3, thus directly regulating JA biosynthesis. Thus, this study reveals an ABA signaling cascade that leads to JA biosynthesis, thereby elucidating the signaling mechanism governing the JA production during strawberry fruit ripening.

Hypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals.

Phosphorus (P) is an essential nutrient for plant growth and development. Phosphate transporter 1 (PHT1) is a transmembrane protein that mediates the uptake and translocation of inorganic phosphate (Pi) in plants. Despite extensive research on the PHT1 family across various species, the PHT1 genes in Eucalyptus grandis are poorly documented and not identified comprehensively.

Cervical cancer poses a significant threat to women's health, and its metastasis is one of the leading causes of cancer-related deaths. Tubeimoside I (TBMS1) is a traditional Chinese medicinal herb with anticancer properties. We previously demonstrated the anticancer effect of TBMS1 in cervical cancer by inducing autophagy-related cell death. Nevertheless, whether and how TBMS1 prevents cervical cancer metastasis remain unclear.

Nanotechnology and transcriptomics are revolutionizing agriculture by improving sustainability and efficiency. Nanoparticles facilitate the slow release of nutrients for better crop absorption, while transcriptomic analysis uncovers gene expression changes. In a comparative study of zinc-responsive groundnut using bulk ZnSO4 and zinc oxide nanoparticles (nano ZnO), zinc nanoparticles were synthesized from ZnSO4 via a precipitation method. Characterization included particle size analysis (67.5 nm), zeta potential, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and fourier-transform infrared spectroscopy. RNA was isolated from leaf samples treated with either bulk ZnSO4 or nano ZnO after seed treatment and two foliar sprays over 73 days. Transcriptome sequencing with the Oxford Nanopore Sequencer enabled de novo annotation and differential gene expression analysis. In the bulk ZnSO4 versus control comparison, 971 contigs were identified, revealing 792 significant differentially expressed genes (DEGs). For nano ZnO, 971 contigs were also found, with 851 significant DEGs. Pathway network analysis highlighted isoprene biosynthesis as crucial for promoting plant growth and enhancing yield by altering photosynthesis and secondary metabolites. Key genes, DXR and DBR, involved in the isoprene biosynthetic pathway, were identified as vital for isoprene production and zinc metabolism. DBR facilitates redox reactions crucial for producing isoprene precursors and maintaining zinc homeostasis by supporting the function of zinc-containing proteins. Meanwhile, DXR, as a key enzyme in the MEP pathway, links isoprene production to zinc-dependent metabolic processes. Overall, this study suggests that nano-form zinc application enhances the isoprene biosynthetic pathway, leading to improved plant growth and resilience.

The study examined the effects of a plant product artemisinin (ARS) on epithelial-mesenchymal transition and drug resistance in cervical cancer cells mediated via the Wnt/β-catenin signaling pathway. ARS inhibited invasion and migration of CaSki and HeLa cancer cells, up-regulated expression of ICAM-1, MMP-9, and E-cadherin proteins, as well as down-regulated expression of vimentin. In both cell lines, ARS down-regulated mRNA and protein expression of P-glycoprotein, ATP-binding cassette transporters B and G2; it also reduced expression of β-catenin protein. In comparison with the cells treated with Wnt/β-catenin pathway inhibitor iCRT3, the combined treatment of the cells with ARS and iCRT3 reduced their invasion and migration, down-regulated expression of MMP-9, ICAM-1, vimentin, and β-catenin proteins, as well as up-regulated expression of E-cadherin.

Male Wistar rats were subjected to mild, moderate, and heavy physical exercises (10 swimming sessions), after which they were euthanized (immediately or 30 days after the last session). Animals of the experimental groups received meldonium (100-120 mg/kg of body weight) with food for 10 days of swimming. Heavy exercise led to the development of degeneration, necrotic patches, and cellular infiltration in the liver and a decrease of the TGF-β1 level. In 30 days after the last swimming session, an increase in both the level of TGF-β1 in the cytoplasmic fraction and the expression of the tgfb1 gene were observed. The level of TGF-β1 increased by 1.8 times against the background of meldonium treatment and decreased by 1.6 times in 30 days; tgfbl expression also decreased by 1.3 times in comparison with that in rats exposed to a similar exercise without meldonium (p < 0.05). The use of meldonium against the background of heavy physical exercise contributed to the achievement of gene expression and cytokine levels approaching the target values observed in intact animals and prevent severe alterative changes in the liver.

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.