To summarize the role of endoplasmic reticulum stress (ERS) in the pathogenesis of diabetic retinopathy (DR) and evaluate potential ERS-targeted interventions.

Soil salinity is a major constraint to crop establishment and yield, particularly during germination and early seedling development of Brassica napus. Here, we report that zinc oxide nanoparticles (ZnONPs) biosynthesized using Pseudomonas aeruginosa alleviate salinity stress through coordinated physiological, biochemical, and molecular mechanisms. Comprehensive physicochemical analyses confirmed the formation of hexagonal wurtzite ZnONPs with a plate-like morphology (thickness ~ 54.5 nm) and an optical band gap of 3.01 eV. Canola seeds were primed with ZnONPs (25-100 mg L⁻¹) under control or 150 mM NaCl stress and subsequently grown in hydroponics. Salt stress reduced germination (41%), biomass, and vigor, while elevating lipid peroxidation and reactive oxygen species. ZnONPs, particularly at 50 mg L⁻¹, restored germination to control levels, enhanced shoot (52 cm) and root (35 cm) elongation, and nearly doubled salt-stressed biomass. ZnONP treatment suppressed malondialdehyde and H₂O₂ accumulation below control values, while up-regulating superoxide dismutase and catalase activity. Furthermore, ZnONPs reduced osmolyte (proline and glycine betaine) accumulation, increased chlorophyll content, lowered Na⁺, and elevated K⁺ and Zn uptake, thereby improving ion homeostasis. Transcript analysis revealed that salinity strongly induced the stress-responsive kinase BnSRK2D (~ 86-fold) and repressed auxin-responsive genes, whereas 50 mg L⁻¹ ZnONPs normalized these responses, down-modulating stress signaling and restoring auxin pathways. Collectively, these findings demonstrate that biogenic ZnONPs mitigate salinity stress in B. napus through integrated regulation of antioxidant defense, ion balance, and hormone-mediated gene expression, highlighting their potential as sustainable nanopriming agents for crop improvement under saline conditions.

Capecitabine has been commonly used for the treatment of early-stage triple-negative breast cancer (TNBC) patients; however, the resistance limits its curative potential. Here, we perform multi-omics data analysis and immunohistochemical (IHC) staining of biological samples from patients in the CBCSG010 clinical trial who were randomized to receive adjuvant docetaxel-anthracycline-based chemotherapy with or without capecitabine. We find that patients with a better prognosis in the capecitabine group exhibited an immune-inflamed microenvironment and upregulation of interferon pathways. Moreover, we identify interferon-related TANK-binding kinase 1-binding protein 1 (TBKBP1) as the key gene involved in capecitabine resistance. We uncover that TBKBP1 promotes capecitabine resistance through impairment of activated immune cells infiltration in vivo. Mechanistically, TBKBP1 negatively regulates type I interferon pathway activated by capecitabine treatment, by promoting autophagy-mediated protein degradation of TANK binding kinase 1 (TBK1). In summary, our study implicates TBKBP1 in mediating capecitabine resistance and may serve as a potential therapeutic target for the treatment of TNBC.

Medulloblastoma and glioblastoma are the most common malignant primary brain tumors in children and adults, respectively. Tumor-associated macrophages and microglia are key non-cancerous cell types in these tumors. These cells interact with CD24, a so called "don't eat me signal" expressed on tumor cells, through Siglec-10, a receptor that contributes to immune evasion by promoting an immunosuppressive environment. The CD24/Siglec-10 interaction in context of malignant brain tumors has been scarcely studied.In silico analyses reveal that CD24 gene expression correlates with specific gene signatures associated with prognosis in both medulloblastoma and glioblastoma. In both human- and mouse brain tumors, Siglec-10+ cells co-express the microglia-associated molecule TREM2. Treatment with mitoxantrone as an immunogenic cell-death-inducing cytostatic agent led to a dose-dependent reduction in cell viability and cell surface CD24 levels in both murine and human brain tumor cell cultures. Intratumoral mitoxantrone administration in a murine CD24-high glioma model extended survival, decreased tumor size, reduced Siglec-10+/TREM2+ cell populations, and increased anti-tumor CD8+ cells. These findings suggest that targeting the CD24/Siglec-10 axis with mitoxantrone may modulate the tumor microenvironment and enhance anti-tumor immunity. Keywords: CD24, Siglec-10, Mitoxantrone, Malignant brain tumor, Immunotherapy.

Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogeneous and dependent on factors such as the genetic background and metabolic state of cells, as well as on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line. To more comprehensively profile the effects of small-molecule perturbations and their influence on heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models. We have also built a web interface for the extensive amount of data to allow users to explore the data as a resource for understanding chemical perturbation of diverse cell types.

The AT-Rich Interaction Domain (ARID) family plays critical roles in malignancies. Although numerous members have been shown to influence cancer processes, there is a lack of a general understanding of the ARID family in colon cancer. To address this gap, we used bioinformatic technologies to investigate the role of the ARID family as a whole and to identify the crucial member. Subsequently, cell growth assays, transwell assays, and animal models were employed to validate the key member's effect on colon cancer growth and metastasis. Furthermore, bioinformatics and immunohistochemistry were utilised to explore the potential mechanisms and evaluate the efficacy of a targeted intervention strategy. Our results showed that the ARID family was upregulated in colon cancer, with ARID3A being the main component that promoted colon cancer development. Specifically, ARID3A enhanced colon cancer cell proliferation, migration, and invasion both in vivo and in vitro. Mechanistically, this promotional effect could be associated with ARID3A promoting PGE2 synthesis and triggering macrophage infiltration. Notably, aspirin treatment reduced the PGE2 level, which significantly inhibited the malignant behaviour of ARID3A-overexpressing cells. In conclusion, ARID3A was a key member of the ARID family in the development of colon cancer. ARID3A was an underlying biomarker for aspirin administration.

Astragalus polysaccharide (APS) has recently emerged as a potent antitumor agent, however its impact on breast cancer (BC) remains inadequately understood. The current research aimed to examine the regulatory mechanism of APS in the pathogenesis of BC examining its influence on N6-methyladenosine (m6A) modification of MAL2. The effect of APS on the malignant phenotypes of BC was assessed by CCK8, EdU, transwell and tumor xenograft model assays. The differentially expressed genes (DEGs) in BC were identified by GEPIA-BC database, and their expression levels were determined by qRT-PCR in the BC cells. The role of MAL2 in BC malignancy was examined by EdU and transwell assays. Furthermore, bioinformatics analysis was first employed to explore the m6A modification site of MAL2 mediated by METTL3, which was then validated through MeRIP, western blotting, and qRT-PCR assays. APS was found to significantly reduce the cell proliferation, migration, as well as invasion of MCF-7 (IC50: 1014 μg/ml) and MDA-MB-231 (IC50: 685 μg/ml) cell lines. Additionally, it effectively suppressed tumor growth in vivo. The bioinformatics analysis revealed that among the five DEGs, MAL2 was significantly downregulated upon APS treatment both BC cell lines. Furthermore, the overexpression of MAL2 partially reversed the anti-tumor effects of APS. Notably, METTL3 modulates the m6A modification of MAL2 to regulate tumorigenesis in BC. APS prevents BC progression in association with reduced METTL3 expression and altered m6A modification of MAL2, suggesting that MAL2 may represent a potential therapeutic target to enhance the efficacy of APS.

Lung squamous cell carcinoma (LUSC) has a scarcity of actionable therapeutic targets. Through integrative multi-omics analysis combining Mendelian randomization and colocalization of LUSC genome-wide association studies with functional quantitative trait loci, we identified the enzyme GGPPS as a causal driver with robust genetic support (PP·H4 = 74.1%) and showed that its elevated expression predicted reduced survival and accelerated tumor progression. Functional interrogation demonstrated that GGPS1 knockdown potently suppressed proliferation in vitro (CCK-8, EdU and colony formation) and in vivo (xenografts studies). Mechanistically, GGPPS drives oncogenesis through its catalytic activity in mediating protein geranylgeranylation: geranylgeranylated RHOA activated ROCK1-dependent phosphorylation of the p65 subunit of NF-κB to induce transcription of IL1B, whereas geranylgeranylated RAC1 promoted STAT1 nuclear translocation for direct IL1RAP transactivation. Critically, pharmacological inhibition abolished GGPPS-driven geranylgeranylation-dependent signaling: JSH-23 reversed both the proliferation mediated by RHOA and NF-κB p65 and the upregulation of IL1B potentiated by GGPS1 overexpression; and NSC23766 blocked the RAC1/STAT1-dependent IL1RAP activation amplified by GGPPS elevation, confirming that both axes are indispensable for GGPPS-dependent proliferation. Collectively, this GGPPS-mediated geranylgeranylation axis, converging on IL-1 pathway amplification, represents a central therapeutic vulnerability in LUSC, highlighting GGPPS as a promising macromolecular target for this recalcitrant malignancy.

Long non-coding RNAs (lncRNAs) are regulatory macromolecules essential for organismal growth, development, and metabolic homeostasis. This study systematically examined the dynamic expression profiles and biological functions of insulin-responsive lncRNAs in chicken skeletal muscle using RNA sequencing and molecular biology approaches. By leveraging glucose dynamics from insulin tolerance tests, strand-specific RNA-seq analysis of pectoralis muscle was performed at early-phase (15 min) and late-phase (120 min) post-insulin stimulation, identifying 134 and 225 insulin-responsive lncRNAs, respectively. Functional enrichment analysis revealed distinct temporal patterns: early-phase insulin-responsive lncRNAs are primarily involved in basic regulation, early metabolism, and immune-inflammatory signaling (e.g., NOD-like receptor and Toll-like receptor pathways), while late-phase lncRNAs dominate immune responses, homeostatic regulation, cell death, and lipid metabolism-related pathways (e.g., necroptosis, cytokine-cytokine receptor interaction). A time-dependent insulin-responsive lncRNA, LncFKBP5, was identified as a key regulator linked to muscle development and metabolism. It exhibits distinct spatiotemporal expression patterns, peaks in embryonic muscle, and responds dynamically to insulin, glucose, and pyruvate. Functional assays in primary myoblasts demonstrated that LncFKBP5 knockdown enhances proliferation and glycolysis but suppresses myogenic differentiation and glycogen synthesis. These findings not only map the temporal architecture of insulin-responsive lncRNAs in avian muscle but also establish LncFKBP5 as a key molecular integrator of myogenesis and glucose metabolism, offering novel targets for improving metabolic health in poultry.

Trimethyltin chloride (TMT) is a highly toxic organotin pollutant commonly found in the environment, posing serious risks to humans and animals. To explore the potential toxicity mechanism of TMT on vascular systems, we developed models exposing vascular smooth muscle cells (VSMCs) and male Balb/c mice to TMT. Levels of reactive oxygen species (ROS) and glutathione (GSH) were measured using fluorescence methods and assay kits, while the expression of genes related to glutathione peroxidase 4 (GPX4), Nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 (NRF2/HO-1) pathway, autophagy-lysosome, and ubiquitination proteasome pathway were analyzed through Western blot and immunofluorescence. The findings indicated that exposure to TMT activated the GPX4-dependent lipid peroxidation pathway, leading to cell death in VSMCs, rather than necrosis or apoptosis. This conclusion was supported by several key indicators: a dose-dependent increase in ROS levels, alongside a dose-dependent decrease in GSH and GPX4 levels. Further in-depth analysis elucidated that TMT-induced GPX4 degradation and subsequent cell death are primarily mediated by the ubiquitination-proteasome pathway. Notably, this process occurs independently of the NRF2/HO-1 signaling pathways or the autophagy-lysosome system. In conclusion, TMT exposure causes dose-dependent GPX4 degradation via the ubiquitination proteasome pathway, leading to cell death in VSMCs and vascular injury.

Polystyrene nanoplastics (PS-NPs), a group of increasingly common environmental pollutants, pose emerging risks to microbial ecology and food safety. This study examines the concentration- and time-dependent effects of PS-NPs (low exposure: 2.5-5 mg/L; moderate exposure: 10-20 mg/L; high exposure: 50-100 mg/L) on Salmonella enterica, a major foodborne pathogen. Under realistic environmental conditions, PS-NPs influenced bacterial viability, membrane integrity, and oxidative stress levels, with higher concentrations causing lipid peroxidation and membrane disruption. Gene expression analyses showed early upregulation of stress-related, biofilm-associated, virulence, and adhesion genes, indicating an adaptive response to PS-NP-induced stress. Biofilm formation increased with moderate to high PS-NP exposure, confirmed by exopolysaccharide measurement and confocal microscopy. However, prolonged or high-dose exposure resulted in downregulation of efflux systems (acrB, tolC), quorum-sensing regulators (lsrA, invF), and antimicrobial resistance genes (marR, tetC), suggesting stress-related trade-offs. Notably, transient activation of marA and acrA indicates potential NP-induced cross-resistance mechanisms. These results imply that PS-NPs act as environmental stressors capable of altering bacterial virulence and survival strategies, with significant implications for microbial behavior in plastic-contaminated ecosystems and food processing environments. Collectively, our results emphasize the urgent need to reevaluate NP exposure in the context of public health and antimicrobial resistance.

Parasitic weeds in the Orobanchaceae family pose a major threat to crop production worldwide. Parasitic plants develop specialized invasive structures called haustoria, which penetrate host tissues to establish connections and absorb nutrients. The formation of prehaustoria, early-stage haustorial structures, is triggered by host-derived haustorium-inducing factors (HIFs), such as 2,6-dimethoxy-1,4-benzoquinone (DMBQ) and syringic acid. Since prehaustorium formation is a critical initial step in parasitism, its inhibition represents a promising strategy for controlling parasitic weeds. In this study, we performed a chemical screening to identify inhibitors of prehaustorium formation and discovered a compound, designated Haustorium INhibiting Compound 55 (HINC55), that effectively inhibits prehaustorium formation in the parasitic plants Striga (Striga hermonthica) and Phtheirospermum japonicum. Notably, HINC55 suppressed prehaustorium induction by quinones and phenolics, but not by cytokinins in Striga. Furthermore, HINC55 inhibited DMBQ-induced stomata closure in both Arabidopsis (Arabidopsis thaliana) and P. japonicum, suggesting that HINC55 functions as an inhibitor of plant quinone signaling. We used HINC55 to evaluate the composition of HIFs in host root exudates. HINC55 partially suppressed prehaustorium formation in Striga and almost completely in P. japonicum when induced by host root exudates, reflecting the broader HIF responsiveness of Striga. Transcriptome analysis further confirmed the stronger suppression in P. japonicum in response to rice (Oryza sativa) root exudate than in Striga. Overall, HINC55 serves as a tool for investigating plant quinone signaling and dissecting host-parasite chemical communications, as well as a compound for developing novel strategies to control parasitic weeds.

Emerging and reemerging viruses pose a significant threat to global health. Although direct-acting antivirals have shown success, their efficacy is limited by the rapid emergence of drug-resistant viral variants. Hence, there is an urgent need for additional broad spectrum antiviral therapeutic strategies. Here, we identify by phenotypic screening a set of stereochemically defined photoreactive small molecules (photo-stereoprobes) that stereoselectively suppress SARS-CoV-2 replication in human lung epithelial cells. Structure-activity relationship-guided chemical proteomics identified the eukaryotic translation termination factor 1 (ETF1) as a target of the photo-stereoprobes, and this interaction was recapitulated with recombinant purified ETF1. We found that the photo-stereoprobes modulate programmed ribosomal frameshifting mechanisms essential for SARS-CoV-2 infection without causing ETF1 degradation, thus distinguishing the photo-stereoprobes from other known ETF1-directed small molecules. We finally show that the photo-stereoprobes also inhibit the replication of additional viruses with noncanonical ribosomal frameshifting mechanisms. Our findings identify a mechanistically distinct class of ETF1 ligands that implicate host translation termination processes as a potential drug target for antiviral development.

Claudin-18 isoform-2 (CLDN18.2) is a novel biomarker and therapeutic target for gastric cancer (GC). It may exhibit the intratumoral heterogeneity and varying expressions between biopsy and surgically resected specimens as well as pre- and post-chemotherapy, which could impact patient selection for the targeted agents.

Soil contamination with Cadmium (Cd) is one of the major environmental issues facing the world, which poses a tremendous threat to plant growth. Heavy-metal ATPase (HMA), essential to regulate plants' metal homeostasis, has been extensively identified in abundant plant species. However, the HMA gene family members in Chrysanthemum indicum have not been identified.

Selenium (Se) is an essential micronutrient for humans, yet its dietary availability largely depends on plant-based foods. In rice, Se uptake occurs mainly via sulfate transporters due to the chemical similarity between sulfate and selenate. While the role of transporters such as OsSULTR1;2 has been described in japonica rice, little is known about their regulation in indica aromatic cultivars like Super Basmati, which are naturally enriched in Se and widely consumed across Asia. This study aimed to characterize the transcriptional regulation of OsSULTR genes in Basmati rice under selenate exposure to identify candidate transporters contributing to Se biofortification.

CaWRKY6 functions together with CaERF3 to regulate ROS production, thus positively modulating pepper salt stress response. Salt stress significantly inhibits the growth and productivity of plants. Pepper (Capsicum annuum L.), a widely cultivated economic horticultural crop, exhibits high sensitivity to salinity. This study investigates the role of the transcription factor CaWRKY6 in modulating pepper's responses to salt stress. Our findings indicate that CaWRKY6 predominantly localizes at the cell nucleus, and its expression is significantly induced upon salt treatment. The CaWRKY6-silenced pepper plants exhibit heightened sensitivity to salt stress, as evidenced by increased malondialdehyde (MDA) levels and decreased proline content. Additionally, CaWRKY6-silenced pepper plants show elevated levels of reactive oxygen species (ROS). Through a yeast two-hybrid screen, CaERF3 is identified as an interactor of CaWRKY6. Silencing CaERF3 expression induces a similar sensitive salt response and elevated ROS levels as observed in CaWRKY6-silenced plants. Collectively, our results demonstrate that the CaWRKY6-CaERF3 module positively regulates salt stress responses in pepper by modulating ROS homeostasis.

Histamine receptor H1 (HRH1) is upregulated within the tumor microenvironment, where it supports tumorigenesis by several mechanisms. Cationic amphiphilic drugs targeting HRH1 are currently under investigation for repurposing into cancer therapy. Herein, we showed that Clemizole, a first-generation HRH1 antagonist that selectively accumulates within the liver, could be used as a template to design small-molecule epigenetic modifiers targeting histone deacetylases (HDACs) and histone lysine demethylases (KDMs). The resulting HDACi and KDMi have midnanomolar to single-digit micromolar IC50s and potency enhancement of 15-105 folds relative to Clemizole. Several of these compounds elicited cancer cell line-dependent cytotoxicity. Representative lead KDMi, Cle-C6K, and Cle-C8K caused transcriptome-level perturbations favoring cell cycle inhibition and apoptosis. Moreover, Cle-C8K is nontoxic and selectively accumulated in the liver of C57BL/6 mice. Collectively, our data reveal that Clemizole could be repositioned to design liver tissue-accumulating epigenetic-modifying small molecules as potential targeted antiliver cancer agents.

Brassinosteroids impact the development of G-fibers - specialized cells that generate tension in plants. To explore the functional and genetic relationships between G-fibers and twining stems of Phaseolus vulgaris, we applied an active brassinosteroid and a brassinosteroid inhibitor to perturb G-fiber development and probed these phenotypes through gene expression and anatomical analyses. Brassinosteroid treatment generated phenotypes that affected three key features of twining: elongation, circumnutation, and G-fiber development. We examined anatomical and biochemical changes in the G-fibers through cross-sections, macerations, and immunohistochemistry. RNA sequencing and differential gene expression analysis allowed us to identify unique gene expression patterns for each treatment. Brassinosteroid treatment led to significantly elongated internodes with disrupted circumnutation and long, thin-walled G-fibers. By contrast, inhibitor treatment produced short internodes with thick G-fibers. These phenotypes corresponded with significant differential expression of xyloglucan endotransglucosylase/hydrolase (XTH) genes, both at the onset of elongation and later, during G-layer deposition. Detection of xyloglucan in the G-layer, along with in situ hybridization, confirmed active xyloglucan remodeling after twining. Our results confirm the presence of xyloglucan in the G-layer of common bean, underscoring its importance in G-fiber function, and suggest a regulatory role for XTH genes in shaping the twining growth habit through modulation of cell wall properties.

Depression is a chronic psychiatric disorder and belongs to one of the leading causes of suicide worldwide. Peroxiredoxins (Prdxs) play a critical role in scavenging excess reactive oxygen species (ROS) and mitigating oxidative stress. However, the role and underlying mechanisms of Prdxs in depression have not been fully illustrated.