Transient overexpression assays and RNA sequencing (RNA-seq) showed that the transcription factor HmPIF1 enhances lead (Pb) tolerance in Hydrangea by improving antioxidant capacity and altering transporter protein expression. Lead (Pb) soil contamination has caused serious ecological and environmental issues. Hydrangea represents a promising candidate species for phytoremediation, whereas research on its Pb-tolerant genes remains relatively limited. This study aimed to explore the Pb tolerance function of HmPIF1 at the physiological and transcriptional levels. Results showed that Pb stress significantly upregulated the expression of HmPIF1. Subcellular localization and transcriptional autoactivation assays demonstrated that HmPIF1 is a nuclear-localized transcription factor without transcriptional autoactivation activity. Transient overexpression experiments confirmed that eight substances, including glutathione reductase, superoxide dismutase, and total protein, were key physiological factors for HmPIF1-enhanced Pb tolerance in Hydrangea leaves, while transcriptomic analysis identified "photosynthesis" and "glutathione metabolism" as likely the core regulatory pathways. Furthermore, HmPIF1 overexpression promoted Pb accumulation in leaves, accompanied by differential expression of ion transporter proteins. Taken together, HmPIF1 positively regulates plant Pb tolerance and enhances Pb uptake in leaves, which may be achieved through multiple regulatory pathways including photosynthesis, antioxidation and ion transporter-mediated processes. These findings provide a theoretical basis for subsequent related research.

Spinocerebellar ataxia type 8 (SCA8) is a member of a group of dominantly inherited, debilitating neurological diseases caused by CAG•CTG expansions for which there are no effective treatments. RAN translation, which was discovered in SCA8, has previously been shown to occur across CAG and CUG expansion transcripts, making treatments for SCA8 potentially relevant to a broad group of diseases, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, Huntington's disease, and myotonic dystrophy type 1. In addition, CUG and CAG expansion transcripts have been reported to cause RNA gain-of-function effects. Using SCA8 BAC transgenic mice as a model for CAG•CTG expansion diseases, we now show that metformin improves ambulatory performance using rotarod, DigiGait, and open-field testing. At the molecular level, metformin-treated mice show reduced RAN protein levels and improved splicing, without altering sense or antisense RNA levels. Metformin-treated mice also show decreased neuroinflammation, with reduced astrogliosis and fewer activated microglia. These data provide strong preclinical support for testing metformin in clinical trials for SCA8 and potentially the broader group of CAG•CTG repeat expansion disorders.

Bisphenols are widely used industrial chemicals with endocrine-disrupting properties, and their potential association with carcinogenesis has drawn considerable attention. Cervical cancer, as a prevalent gynecological malignancy, has a pathogenesis that is not yet fully understood, particularly regarding the influence of environmental factors. In this study, we systematically investigated the molecular effects of bisphenols on cervical cancer using multi-dimensional bioinformatics approaches. WGCNA analysis identified key modules closely associated with the disease, which were integrated with predicted bisphenols targets to screen for core genes, including AR, CDC25C, CDK2, and KIF11. Functional enrichment analysis suggested that bisphenols may disrupt cell cycle regulation, the G2/M checkpoint, and p53-mediated tumor suppressor pathways. Molecular docking and 100-ns molecular dynamics simulations indicated that various bisphenols can stably bind to core target proteins, with binding patterns influenced by halogenation or aromatic substitutions. Gene expression and immunohistochemical analyses showed that CDC25C, CDK2, and KIF11 were significantly upregulated in cervical cancer tissues, whereas AR was predominantly expressed in normal epithelium. Immune infiltration analysis further suggested that CDC25C, CDK2, and KIF11 may modulate the infiltration of B cells, CD8⁺ T cells, and macrophages, implying that bisphenols-induced molecular perturbations could impact the tumor microenvironment. This study provides a reference for further exploration of the links between environmental exposures and cervical cancer development and lays a foundation for mechanistic investigations.

Salt stress is a major abiotic factor limiting plant growth and productivity. One of the primary consequences of salinity is the enhanced production of reactive oxygen species (ROS). This study investigates the role of glycolate oxidase (GOX), a key enzyme in photorespiration and a source of ROS, in the salinity response of Arabidopsis thaliana. We used two GOX T-DNA insertion mutants, gox1 and gox2, alongside wild-type (WT) plants, grown hydroponically under control conditions or exposed to 100 mM NaCl for 24 h. Results showed that shoot and root fresh weight did not differ significantly between genotypes and after 24 h of NaCl treatment. In addition, both mutants, particularly gox2, accumulated less Na+ and Cl- in shoots and roots than WT. This result was supported by ion flux analysis in roots. This fact was associated with the upregulation of key ion transporters: NHX1 (Na+compartmentalization), SOS1 (Na+ exclusion), and KUP11 and HAK5 (K+ uptake). Additionally, gox2 showed differential regulation of nitrate/Cl- transporters, with downregulation of NPF2.4, SLAH1, and SLAH3 and upregulation of NPF2.5 and NPF7.2. Furthermore, gox2 exhibited reduced oxidative damage and increased peroxidase activity under salt stress. These findings suggest that GOX2 expression may regulate plant resilience to salinity by improving ion homeostasis and antioxidative responses.

Nanobiotechnology offers sustainable strategies to enhance plant resistance by activating innate immune responses. This study evaluates the effect of chitosan nanoparticles (CNPs) on transcriptional activation of defense-associated genes in Arabidopsis thaliana.

Celastrus paniculatus (CP) is a traditional medicinal plant widely used in Ayurveda and Southeast Asian medicine for enhancing memory and treating cognitive dysfunction. Although CP has been reported to exhibit antioxidant, anti-inflammatory, and neuroprotective effects, its direct impact on activity-dependent synaptic plasticity remains insufficiently characterized. This study is aimed at investigating the effects of CP seed extract on memory performance and synaptic plasticity in a rat model, with a particular focus on AMPA receptor modulation and associated synaptic proteins. Five-week-old male Sprague-Dawley rats were randomly assigned to five groups: control, CP (80 mg/kg), donepezil (1.5 mg/kg), scopolamine (1 mg/kg), and scopolamine followed by CP. Treatments were administered daily for 14 days. Spatial memory performance was assessed using the Morris water maze. Following behavioral testing, hippocampal tissue was collected for immunohistochemical analysis of Arc protein and Western blotting of pSer831-GluA1, Arc, and PSD-95. CP-treated rats exhibited significantly reduced escape latency and increased time in the target quadrant, with outcomes comparable to those of donepezil-treated rats. In scopolamine-pretreated rats, CP administration reversed memory deficits by enhancing platform crossings and reducing escape latency. Molecular analysis revealed that CP significantly upregulated hippocampal expression of pSer831-GluA1, Arc, and PSD-95, indicating enhanced AMPA receptor trafficking and synaptic integrity. CP seed extract enhances spatial memory and synaptic plasticity by modulating critical molecular components of the glutamatergic synapse. These findings suggest that CP may support memory performance in both baseline conditions and in animals with scopolamine-induced deficits.

The link between glutaminolysis and osteoarthritis (OA) has only recently begun to be elucidated. Here, we report the association of obesity- and injury-induced cartilage damage with impaired glutaminolysis in chondrocytes. Defective glutaminolysis triggered the onset and progression of OA, with enhanced catabolism and decreased anabolism. Supplementation of α-ketoglutarate (αKG), a key component in glutaminolysis and an epigenetic factor, effectively protected cartilage against degradation in vivo via a TCA cycle- and HIF-1α-independent manner. Mechanistically, OA pathogenic factors increased H3K27me3 deposition on promoters of key glutaminolysis genes, including Slc1a5 and Gls1, leading to impaired glutaminolysis. Conversely, αKG facilitated Kdm6b-dependent H3K27me3 demethylation of not only glutaminolysis genes to rescue Gln metabolism but also Ube2o to reverse OA. Elevated Ube2o expression led to TRAF6 ubiquitination and subsequent inhibition of NF-κB signaling, thereby reversing the pathological reprogramming of glycolysis and oxidative phosphorylation and protecting against cartilage destruction. Collectively, these results demonstrated that OA pathogenic factors impair glutaminolysis through epigenetic regulation, which further exacerbate OA. Moreover, αKG restores metabolic homeostasis and alleviates OA through H3K27me3 demethylation.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuroinflammation, which collectively drive progressive memory loss, cognitive decline, and behavioral changes. Increasing evidence implicates epigenetic dysregulation as a key contributor to these pathological processes by altering gene expression programs. Serotonergic psychedelics, which primarily act as agonists of the serotonin 2 A receptor (5-HT₂AR), have recently attracted attention for their ability to robustly promote neuroplasticity and induce sustained transcriptional changes in the brain. Preclinical studies indicate that these compounds can modulate epigenetic mechanisms, including histone modifications and DNA methylation (DNAm). This review examines the emerging intersection between psychedelic-induced epigenetic modulation and AD pathology, and proposes that targeted engagement of 5-HT₂Ars may help counteract epigenetic abnormalities that contribute to AD pathogenesis.

Small cell lung cancer (SCLC) is known for its rapid growth and early metastasis, and SCLC patients are highly susceptible to chemoresistance. Studies have shown that the combination of ferroptosis induction and TRX pathway inhibition can significantly inhibit SCLC tumor growth, but the molecular mechanisms underlying ferroptosis in SCLC are poorly understood. In this study, we explored the regulatory role of the ALDH1L2-related metabolic pathway in SCLC chemoresistance by machine learning. We found that ALDH1L2 expression is a poor prognostic factor for SCLC patients and that high ALDH1L2 expression can negatively regulate the level of cellular lipid peroxidation and inhibit ferroptosis, thereby promoting SCLC chemoresistance. Mechanistically, ALDH1L2 interacts with the TRX2-PRDX3 antioxidant network to reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress and decrease cellular susceptibility to ferroptosis, thus promoting SCLC chemoresistance. In addition, we found that thiostrepton, a PRDX3 inhibitor, can synergize with chemotherapy to suppress tumor growth in SCLC, suggesting that thiostrepton might be a promising new tool for overcoming SCLC chemoresistance.

The clinical utility of histone deacetylase inhibitors (HDACi) like vorinostat (SAHA) in lymphoma is constrained by poor pharmacokinetics and off-target toxicity. To address this, we developed a reactive oxygen species (ROS)-responsive homodimeric SAHA prodrug (SAHA-tk-SAHA) linked via a thioketal bridge, which self-assembled into PEGylated nanoparticles (tk-diSAHA NP). These monodisperse nanoparticles (119.3 ± 4.0 nm) demonstrated excellent stability and ROS-triggered drug release (68.18 ± 2.25% with 10 mM H2O2 vs 6.24% in PBS over 48 h). In vitro, tk-diSAHA NP induced G0/G1 cell cycle arrest and apoptosis in lymphoma cells. In A20 lymphoma-bearing mice, intravenous tk-diSAHA NP achieved superior tumor growth inhibition (615.18 ± 147.88 mm3) compared to oral SAHA (1134.78 ± 311.31 mm3, p < 0.05), with enhanced histone H3 acetylation in tumors and no appreciable systemic toxicity. This ROS-activatable nanoprodrug platform presents a promising strategy to enhance the efficacy and safety of HDACi-based epigenetic therapy for lymphoma.

High expression of Lysine-Specific Demethylase 5B (KDM5B) in lung cancer drives tumorigenesis and immunosuppression. KDM5B is negatively correlated with endoplasmic reticulum (ER)-phagy receptors such as TEX264, indicating that selective induction of ER-phagy may degrade KDM5B. Our work revealed that chemotherapeutic drug Teniposide (Ten) was a potent anti-lung cancer agent, which could increase the stability of TEX264. The present study aims to elucidate the critical target and mechanism by which Ten inhibits KDM5B through TEX264-associated ER-phagy against lung cancer. Ten exhibited potent lung cancer suppression ability, as evidenced by the weakened proliferation of organoids and tumor grafts in mice along with activation of the immune microenvironment. Highly-expressed KDM5B demonstrated down-regulation upon Ten treatment, which may be attributed to its degradation via ER-phagy. Blockage of ER-phagy weakened Ten-mediated KDM5B degradation. Insightful investigations discovered that Ten activated OTUD3, a deubiquitylase, which stabilized TEX264, a crucial receptor for ER-phagy. Notably, genetic knockdown of TOP2A impacted little on the Ten-mediated ER-phagy. OTUD3 silencing dampened Ten-driven ER-phagy and KDM5B inhibition. To summarize, these findings demonstrate that Ten effectively inhibits lung cancer and activates immunocytes by KDM5B inhibition, which is regulated by TEX264-associated ER-phagy. Most importantly, OTUD3 serves as an essential target for enhancement of TEX264 stabilization.

Psammomys obesus, widely known as sand rat, develops obesity during captivity. To assess the role of confinement stress on metabolic alterations and sweet taste perception, the gustatory cue involved in obesity, we administered corticosterone (CORT) intraperitoneally in male Psammomys obesus to yield a stressful condition. CORT administration was found to increase preference for sweet solutions in a two bottle-choice paradigm in these animals. Moreover, CORT administration increased the messenger ribonucleic acid (mRNA) expression of sweet test receptor in fungiform taste bud cells. As regards liver, CORT increased mRNA expression encoding glucose-6-phosphatase (G-6-P), phosphoenolpyruvate carboxykinase 1 (PEPCK1) and stearoyl-CoA desaturase-1 (SCD-1). Interestingly, CORT decreased gut peptide YY (PYY), insulin, and triglyceride levels in the blood. Our study demonstrates that corticosterone, known to be released during the captivity period, might play a key role in the development of obesity by influencing sweet taste perception, release of a gut peptide and modifications in lipid/glucidic metabolic enzymatic pathways in Psammomys obesus.

Bisphenol A (BPA) is an endocrine-disrupting chemical widely used in polycarbonate plastics and epoxy resins, resulting in human exposure primarily through food-contact materials and thermal paper, as well as environmental sources. Studies suggest that BPA has adverse effects on trophoblast cells, which are critical for placental formation, and that the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may contribute to BPA-induced cellular dysfunction. However, the mechanisms by which BPA affects placental trophoblast function remain incompletely understood. This study aimed to explore the connection between ER stress/UPR signaling and BPA-induced trophoblast disfunction. BeWo cells were stimulated with forskolin to induce a syncytium formation, a hallmark of trophoblast differentiation, and then exposed to different concentrations of BPA. The effect of BPA on differentiation and secretion capacity, viability, and apoptosis of the trophoblast cells was examined comparing the results with data related to ER stress. Our findings provide evidence that ER stress/UPR activation is involved in BPA-induced trophoblast dysfunction and that BPA-induced apoptosis may be linked to ER stress. In conclusion, this study offers mechanistic insights into how BPA impacts trophoblast cells and may help in understanding the pregnancy-related adverse outcomes associated with BPA exposure.

This study aimed to investigate the effects of soluble epoxide hydrolase (sEH) inhibition on osteoclast differentiation and activity in vitro and in vivo, as well as to elucidate the signaling pathways associated with osteoclastogenesis. Primary murine bone marrow monocytes were stimulated with macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B ligand to induce osteoclastogenesis and treated with the sEH inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) (0.1-10 μM). Tartrate-resistant acid phosphatase staining, gene expression analyses, and immunofluorescence were used to evaluate osteoclast formation, transcriptional regulation, and cell fusion. A murine model of ligature-induced periodontitis was used to assess in vivo effects of sEH inhibition (TPPU 10 mg/kg). Alveolar bone loss was quantified by histomorphometry, and gingival gene expression was analyzed. In vitro, sEH inhibition significantly reduced tartrate-resistant acid phosphatase-positive multinucleated osteoclast formation, downregulated the expression of key transcription factors and osteoclast activity-related genes. Immunofluorescence analysis revealed attenuation of mitogen-activated protein kinase signaling and reduced dendritic cell-specific transmembrane protein expression, indicating impaired cell fusion. In vivo, TPPU treatment preserved alveolar bone structure, reduced osteoclast-like cell numbers, and decreased the expression of osteoclastic markers in gingival tissues during experimental periodontitis. sEH acts as a crucial regulator of osteoclast differentiation and function. Pharmacological inhibition of sEH suppresses osteoclastogenesis and protects against inflammatory bone loss. Therefore, targeting sEH may represent a novel therapeutic approach to modulate osteoclast activity and prevent bone destruction in periodontitis and other bone-resorptive diseases. SIGNIFICANCE STATEMENT: This study provides direct evidence that soluble epoxide hydrolase inhibition modulates osteoclast differentiation and fusion, contributing to reduced inflammatory bone loss. By demonstrating effects on osteoclast-intrinsic pathways while also influencing the inflammatory microenvironment, our findings support soluble epoxide hydrolase as a pharmacological target for chronic inflammatory bone-resorptive diseases.

Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C14H6N2O8) is a naturally bioactive compound that has been reported to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective gene expression. However, its effects on age-related OA and the underlying mechanisms remain unclear.

The expression patterns and potential regulatory correlates of CLDN3 in cancers remain insufficiently characterised, necessitating further investigation. We employed R software alongside bioinformatics platforms to analyse the aberrant expression of CLDN3. Experiments in vitro, including proliferation, wound healing, cell cycle progression and apoptosis assays, were conducted to evaluate the role of CLDN3 in CRC. Co-immunoprecipitation (CO-IP) and immunofluorescence analyses were conducted to investigate the interaction between CLDN3 and TRIM28. Western blotting was employed to evaluate the effect of TRIM28 on CLDN3 SUMOylation and protein stability. CLDN3 was found to be overexpressed in several cancers. Genomic alterations and promoter hypomethylation were identified as key contributors to CLDN3 dysregulation. Bioinformatic analysis suggests that CLDN3 is associated with tumour progression and poor prognosis by influencing pathways, it also contributes to immune dysregulation and chemo-resistance mechanisms. Knockdown of CLDN3 in CRC cells decreased proliferation and migration. CLDN3 overexpression was shown to reduce the sensitivity to 5-FU in CRC cells. CO-IP and immunofluorescence confirmed a direct interaction between CLDN3 and TRIM28. Western blot analysis demonstrated that TRIM28 mediates CLDN3 SUMOylation and degradation. CLDN3 influences the growth and chemotherapy resistance of CRC cells, its interaction with TRIM28 makes the TRIM28/CLDN3 axis as a promising therapeutic target for CRC.

MT mitigates Cd toxicity by enhancing photosystem and antioxidant system activities, and related gene expression in GCC. NAC, HSF, and MYB-related families may play key roles in MT-induced Cd tolerance. Cadmium (Cd), a toxic heavy metal non-essential to plants, has detrimental impacts on both the environment and human health. Melatonin (MT) plays an important protective role in plants against stresses such as heavy metal toxicity. However, the detailed mechanism underlying MT alleviating Cd toxicity remains unclear in ground-cover chrysanthemum (Chrysanthemum morifolium Ramat., GCC). GCC seedlings were pre-treated with MT solution (150 μM) via foliar spraying and subsequently grown under Cd stress, after which the growth, physiological, and transcriptomic responses of the plant were investigated. The results demonstrated that MT pre-treatment inhibited the Cd-induced chlorophyll degradation in GCC seedlings, while it enhanced chlorophyll synthesis and related gene expression by promoting electron transfer efficiency and maintaining the integrity of the oxygen-evolving complex in photosynthesis. Furthermore, MT + Cd treatment upregulated 11 photosystem I (PSI), 13 PSII, eight light-harvesting complex I (LHCI), and 20 LHCII-related genes as compared with Cd treatment alone. MT also alleviated oxidative stress and boosted antioxidant capacity by conserving the activities and gene expression levels of superoxide dismutase, peroxidase, and key enzymes in the ascorbate-glutathione cycle and thioredoxin-peroxiredoxin pathway. In addition, MT reduced the generation rate of O2·- by 27.64%, malondialdehyde by 68.36%, and H2O2 by 44.97%, alleviating the Cd-induced damage. Weighted gene co-expression network analysis provided additional evidence that MT improved GCC tolerance to Cd by modulating the expression of transcription factors (e.g., NAC, HSF, and MYB-related families) related to abiotic stress.

Polyploid rice exhibits superior cadmium tolerance via enhanced antioxidant activity, reduced Cd accumulation, and transporter regulation, with zinc nanoparticles further mitigating toxicity and modulating stress-responsive genes. Cadmium (Cd) contamination poses a serious threat to rice production by impairing plant growth and yield. To investigate the mechanisms of Cd tolerance, we compared diploid rice (E22) and its polyploid counterpart (T42) under Cd stress (50 mg kg-1 soil) with or without zinc supplementation (25 mg kg-1 soil). Upon Cd exposure, E22 exhibited a 7.8% decline in plant weight and seed set, while T42 experienced only a 4.71% reduction in plant weight, demonstrating its enhanced tolerance to Cd toxicity. Consistently, Cd accumulation was markedly lower in T42 across multiple tissues. Under Cd stress, T42 maintained lower levels of H₂O₂ and malondialdehyde while exhibiting enhanced antioxidant activity, including elevated peroxidase, superoxide dismutase, catalase, and glutathione, compared to E22. The more complete organelles in T42 likely contributed to its improved Cd tolerance. Notably, supplementation with ZnO-NPs reduced Cd accumulation in both diploid and polyploid rice. Transcriptomic analysis revealed that starch metabolism-related genes (OsISA1 and OsISA2) were strongly expressed in T42, whereas tubulin genes (OsTB16 and OsTB50) were strongly expressed in T42 under Zn treatment. In contrast, photosynthesis-related genes show remarkable differential expressions between E22 and T42, suggesting different adaptive strategies in E22 and T44, as evidenced by impaired photosynthesis in E22 under stress. Overall, these findings demonstrate that polyploid rice possesses enhanced resilience to Cd stress through coordinated regulation of tubulin, metal transporters, and antioxidant systems, with ZnO-NPs further mitigating Cd toxicity.

Aberrant DNA methylation patterns are increasingly recognized as contributors to a wide range of conditions, including metabolic, oncogenic, and neurodevelopmental disorders. Nutritional factors, such as choline, can shape methylation potential via methyl group donation. The purpose of this narrative review is to synthesize current evidence on the DNA methylation landscapes underlying health and disease paradigms, with a focus on the role of choline as a compelling target for modulating epigenetic states. A comprehensive literature review search was conducted in PubMed to identify relevant studies, with additional articles retrieved from review papers.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer, increasingly associated with loss of androgen receptor (AR) signaling, and in many cases induction of stemness phenotypes and neuroendocrine features. However, targeted therapies for this stage of the disease are currently lacking. In this study, we demonstrated the critical role of the epigenetic regulator UHRF1 in the enzalutamide resistance development of prostate cancer. We have shown that UHRF1 is highly expressed in enzalutamide-resistant prostate cancer cells and its expression correlates with the loss of AR-dependent glandular features. Knocking down UHRF1 led to increased AR expression and enhanced the activity of canonical AR signaling pathway in prostate cancer cells. The combination of UHRF1 knockdown with enzalutamide treatment demonstrated synergistic tumor inhibitory effects both in vitro and in vivo. Mechanistically, UHRF1 was found to bind to AR and promote its ubiquitination and degradation. Furthermore, inhibition of UHRF1 restored AR pathway activity and re-sensitized resistant prostate cancer cells to enzalutamide. Therefore, our findings elucidate an intracellular molecular mechanism that promotes prostate cancer lineage plasticity and suggest that UHRF1 may serve as a potential therapeutic target for overcoming resistance to AR-targeted therapies.