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2-phenylbenzimidazole-5-sulfonic acid (PBSA) is a commonly used organic ultraviolet (UV) filter frequently found in aquatic environments, raising substantial ecological health concerns. While some toxic effects of PBSA on aquatic organisms have been reported, its intergenerational developmental and neurotoxic risks remain poorly understood. In this study, we established a zebrafish life-cycle exposure model to explore the intergenerational toxicity of environmentally relevant concentrations of PBSA (0.2, 2, and 20 μg/L). Offspring were categorized into three exposure groups: parental exposure only (F0+/F1-), parental exposure with continuous F1 exposure (F0+/F1+), and only F1 exposure without parental treatment (F0-/F1+). Our findings demonstrate the transfer of PBSA from parental gonads to F1 embryos. Parental lifetime exposure significantly inhibited somitogenesis and increased mortality and malformation rates in the F1 generation, with the most pronounced developmental damage observed in the F0+/F1+ group. Whole-mount immunohistochemistry revealed that PBSA notably reduced motor neuron axon length in F1 larvae, accompanied by downregulation of developmental-related genes including , , and . Mechanistically, the F0+/F1- group exhibited a marked increase in MDA levels. Excessive ROS accumulation and reduced CAT activity were specifically observed in the F0+/F1+ group, whereas the F0+/F1- and F0-/F1+ groups showed significantly elevated CAT activity, jointly driving developmental and neurotoxic changes. In silico predictions indicated low acute aquatic toxicity of PBSA, contradicting its observed intergenerational risks. Our findings demonstrate that parental lifetime PBSA exposure can induce significant intergenerational neurodevelopmental toxicity in zebrafish offspring by disrupting oxidative balance and neural gene expression, with continuous offspring exposure further aggravating the adverse effects. This research underscores that traditional single-generation toxicity assessments underestimate the ecological dangers of UV filters. It also offers new insights into the environmental risk evaluation of PBSA and similar emerging contaminants.

Silicosis, an irreversible occupational lung disease resulting from prolonged exposure to respirable crystalline silica, faces challenges due to limitations in existing mammalian models. This study evaluated whether laboratory-prepared respirable α-quartz silica could induce immune cell–inflammatory–fibrotic initiation related to silicosis in zebrafish embryos as a tool for early toxicity assessment. Zebrafish embryos at 48 h post-fertilization (hpf) were microinjected into hindbrain ventricle with respirable α-quartz silica (test material 3.056 μm vs. standard material 3.217 μm) derived from natural α-quartz ore. The results indicated a significant decrease in zebrafish survival rates and an increase in malformation rates following exposure respirable α-quartz silica materials. Additionally, alterations in midbrain and hindbrain lengths were observed, while body length remained unaffected. Behavioral assessments revealed reduced touch response rates, decreased average speed, and less time spent in the central zone during open field tests in the treatment groups. In vivo imaging demonstrated sequential recruitment of neutrophils (peak at 18 h post-injection) and macrophages (peak at 24 h post-injection). qPCR analysis revealed upregulation of inflammation-related genes (tnf-α, il-6, il-1β) and fibrosis-related genes (tgf-β, acta-2, collagen). Moreover, the hydroxyproline content, a marker for fibrosis, was significantly elevated, although no mature fibrosis was observed histologically. These findings demonstrate that respirable α-quartz silica elicits pathophysiological changes associated with silicosis early initiation in zebrafish embryos. This supports the utility of the zebrafish embryo as a practical tool for early toxicity assessment and mechanistic studies of silica-induced immune–inflammatory–fibrotic initiation, with potential implications for silica exposure early risk warning.

Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of β-catenin, one with β-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived β-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of β-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of β-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or β-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel β-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF. The liver has an incredible capacity to repair itself or ‘regenerate’ – that is, it has the ability to replace damaged tissue with new tissue. In order to do this, the organ relies on hepatocytes (the cells that form the liver) and bile duct cells (the cells that form the biliary ducts) dividing and transforming into each other to repair and replace damaged tissue, in case the insult is dire. During long-lasting or chronic liver injury, bile duct cells undergo a process called ‘ductular reaction’, which causes the cells to multiply and produce proteins that stimulate inflammation, and can lead to liver scarring (fibrosis). Ductular reaction is a hallmark of severe liver disease, and different diseases exhibit ductular reactions with distinct features. For example, in cystic fibrosis, a unique type of ductular reaction occurs at late stages, accompanied by both inflammation and fibrosis. Despite the role that ductular reaction plays in liver disease, it is not well understood how it works at the molecular level. Hu et al. set out to investigate how a protein called β-catenin – which can cause many types of cells to proliferate – is involved in ductular reaction. They used three types of mice for their experiments: wild-type mice, which were not genetically modified; and two strains of genetically modified mice. One of these mutant mice did not produce β-catenin in biliary duct cells, while the other lacked β-catenin both in biliary duct cells and in hepatocytes. After a short liver injury – which Hu et al. caused by feeding the mice a specific diet – the wild-type mice were able to regenerate and repair the liver without exhibiting any ductular reaction. The mutant mice that lacked β-catenin in hepatocytes showed a temporary ductular reaction, and ultimately repaired their livers by turning bile duct cells into hepatocytes. On the other hand, the mutant mice lacking β-catenin in both hepatocytes and bile duct cells displayed sustained ductular reactions, inflammation and fibrosis, which looked like that seen in patients with liver disease associated to cystic fibrosis. Further probing showed that β-catenin interacts with a protein called CTFR, which is involved in cystic fibrosis. When bile duct cells lack either of these proteins, another protein called NF-B gets activated, which causes the ductular reaction, leading to inflammation and fibrosis. The findings of Hu et al. shed light on the role of β-catenin in ductular reaction. Further, the results show a previously unknown interaction between β-catenin, CTFR and NF-B, which could lead to better treatments for cystic fibrosis in the future.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development 1 , 2 , and increased stiffness is known to promote HCC progression in cirrhotic conditions 3 , 4 . Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1–tensin-1–YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness. Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

BackgroundSIRT6 acts as a tumour suppressor in multiple cancers by regulating glucose and lipid metabolism, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear.ObjectiveWe investigated the role and molecular mechanisms of SIRT6 in ICC development and progression.DesignSpatial transcriptome and single-cell sequencing data from public ICC cohorts and clinical specimens were used to establish the clinical relevance of SIRT6 overexpression. B/R cell-established allografts and AKT/YAP-induced primary ICC mouse models were used to investigate the oncogenic role of SIRT6. The function of SIRT6 in metabolic regulation was assessed using seahorse analysis, metabolomics and isotope tracing. The transcriptional targets of SIRT6 were screened by RNA sequencing and confirmed by dual-luciferase assay and chromatin immunoprecipitation, and the molecular interactions and deacetylation activity of SIRT6 were analysed via co-immunoprecipitation.ResultsSIRT6 was highly expressed in both human and mouse ICC tissues and cell lines. SIRT6 knockdown significantly inhibited ICC cell growth in vitro and ICC development in mouse models. Hydrodynamic co-injection of SIRT6 and AKT resulted in ICC formation in mice. SIRT6 promoted glutamine synthesis by enhancing GLUL transcription and stabilising GLUL protein degradation. SIRT6 silencing decreased glutamine levels, subsequently reducing the levels of nucleotides and amino acids in ICC cells. Thus, SIRT6 or GLUL inhibitors can suppress ICC progression and significantly enhance the sensitivity to chemotherapy.ConclusionsOur findings establish SIRT6 as an oncogenic driver in ICC by orchestrating glutamine metabolic reprogramming and highlight the SIRT6-GLUL axis as a potential therapeutic target for ICC.

The NF1 gene encodes neurofibromin, which is one of the primary negative regulatory factors of the Ras protein. Neurofibromin stimulates the GTPase activity of Ras to convert it from an active GTP-bound form to its inactive GDP-bound form through its GTPase activating protein-related domain (GRD). Therefore, neurofibromin serves as a shutdown signal for all vertebrate RAS GTPases. NF1 mutations cause a resultant decrease in neurofibromin expression, which has been detected in many human malignancies, including NSCLC, breast cancer and so on. NF1 mutations are associated with the underlying mechanisms of treatment resistance discovered in multiple malignancies. This paper reviews the possible mechanisms of NF1 mutation-induced therapeutic resistance to chemotherapy, endocrine therapy and targeted therapy in malignancies. Then, we further discuss advancements in targeted therapy for NF1 -mutated malignant tumors. In addition, therapies targeting the downstream molecules of NF1 might be potential novel strategies for the treatment of advanced malignancies.

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2 , or APC , and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1 -mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1 -mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations. Gain-of-function mutations in CTNNB1 (encoding for b-catenin) leading to deregulated Wnt/β-catenin signaling are frequently observed in patients with hepatocellular carcinoma (HCC). Here the authors show that inhibiting b-catenin with lipid nanoparticles encapsulating siRNA targeting CTNNB1 impairs tumor growth and promotes anti-tumor immunity in preclinical HCC models.

Introduction Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20–30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. Methods Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. Results Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. Conclusion MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.

MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5ʹ- and 3ʹ-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC -expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5ʹ Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors.

In order to examine the relationship between cyber-ostracism and social anxiety among undergraduates, as well as to investigate the mechanisms underlying the effects of cyber-ostracism, rejection sensitivity, and rumination on social anxiety, this study recruited 864 undergraduate students from Jiangsu and Guangdong Provinces in China using a cluster sampling method. The participants completed the Cyber-Ostracism Questionnaire, the Chinese version of the Interaction Anxiousness Scale, the Chinese version of the Rejection Sensitivity Questionnaire, and the Chinese version of the Ruminative Responses Scale. Furthermore, the mediating effects were examined using the structural equation modeling (SEM) method. The results showed that (1) cyber-ostracism was positively related to social anxiety among undergraduates, and (2) rejection sensitivity and rumination played a chain mediating role in the relationship between cyber-ostracism and social anxiety.