Artificial light at night (ALAN) has emerged as a significant public health concern, yet its effects on cognitive impairment remain poorly understood. This study investigated the impact of 28 consecutive days of 5-lx ALAN exposure on hippocampal function in C57BL/6 J mice. We evaluated locomotor behavior, neuronal morphology, neurogenesis, oxidative stress, and circadian rhythms, revealing that ALAN induces cognitive impairment. ALAN exposure reduced Bmal1 expression, increased reactive oxygen species (ROS) and malondialdehyde accumulation, and disrupted the time-of-day-dependent differences expression of NRF2, SOD1, and GPX1. These alterations suppressed SOD and GPX enzymatic activity, leading to hippocampal oxidative damage. To clarify BMAL1's role, we used adeno-associated virus (AAV) to modulate Bmal1 expression in the hippocampus. ALAN increased hippocampal apoptosis, which was exacerbated by Bmal1 knockdown and mitigated by its overexpression. These findings suggest that ALAN can contribute to memory impairment by disrupting hippocampal damage and impairing neurogenesis through its effect on Bmal1. This study identifies potential molecular targets for preventing and treating cognitive impairment and neurodegenerative disorders.

Fibrotic scars formed after central nervous system injury pose a strong barrier to axonal regeneration. To attenuate the inhibitory effect of fibrotic scars, numerous pre-clinical studies have investigated strategies. Fibroblasts are the main cells involved in the formation of fibrotic scars. In this study, we first used single-cell sequencing data to analyze the changes in fibroblasts after mouse spinal cord injury and screened the specifically highly expressed gene Adamts2 (metallopeptidase with thrombospondin type 1 motif 2). Subsequently, we evaluated the efficacy of Adamts2-targeting RNAi in attenuating the pro-fibrotic phenotype of fibroblasts using an in vitro TGFβ-induced fibroblast model. We found that TGFβ enhanced the expression of Adamts2 in primary spinal cord fibroblasts and regulated the expression of fibrosis-related genes. Moreover, silencing of Adamts2 attenuated the pro-fibrotic activity of TGFβ in spinal cord fibroblasts. Mechanistically, the knockdown of Adamts2 in fibroblasts leads to the upregulation of multiple neurotrophic factors, subsequently activating the AKT and ERK signaling pathways in motor neurons to alleviate inhibitory effects on axonogenesis. Our results demonstrate that Adamts2-specific siRNA significantly suppresses the TGFβ-induced pro-fibrotic phenotype and alleviates its inhibitory effects on motor neuron axonogenesis during co-culture. Collectively, these results indicate that inhibiting Adamts2 effectively suppresses fibroblast-mediated fibrosis, suggesting that targeting Adamts2 is a promising therapeutic strategy for promoting neural repair following spinal cord injury by promoting a neuro-supportive microenvironment.

Abstract Breast cancer is the most common malignancy among women worldwide. Estrogen receptor α (ERα)-positive breast cancer is about 70% in the total breast cancer. It has variable prognosis and high recurrent risk, frequently developing resistance to endocrine therapies. Herein, we have identified that a homeobox transcription factor MSX2 downregulated in ERα-positive breast cancer is correlated with the advanced grade and poor survival outcomes. Our results have demonstrated that MSX2 interacts with ERα to inhibit ERα-mediated transactivation. Mechanistically, MSX2 associates with HDAC1/HDAC2 to form a protein complex. MSX2 is required for recruitment of HDAC1/HDAC2 complex to estrogen response elements (EREs) region on ERα downstream target genes, reducing histone H3K9ac and H3K27ac levels to inactivate gene transcription. Functionally, ectopic expression of MSX2 suppresses cell growth and enhances the sensitivity to anti-estrogen treatment in ERα-positive breast cancer cells. Our results indicate that MSX2 as a novel co-repressor of ERα is involved in suppression of ERα-positive breast cancer progression. Restoring MSX2 protein may provide a promising strategy to overcome endocrine resistance in ERα-positive breast cancer.

Natural aging involves an imbalance in gut bacteria, changes in metabolism, and mild ongoing inflammation. The integrated impact of chitosan oligosaccharide (COS) on microbiota-metabolite-immune interactions in a physiological (non-accelerated) aging context remains unclear. In this study, male C57BL/6J mice (young control; aged vehicle; aged +COS from 10 to 18 months) underwent longitudinal assessment including 16S rRNA profiling, untargeted serum metabolomics, multiplex cytokine measurement, and colonic p53 and p21 immunohistochemistry. The results showed that COS was associated with restructuring of gut community composition, with reduced Firmicutes (67.07% to 32.93%) and increased Bacteroidota (15.29% to 31.22%), alongside marked enrichment of Muribaculaceae (to 52.83%). Discriminant metabolites (VIP > 1 and FDR-adjusted) mapped predominantly to propionate (propanoate) and amino acid-linked pathways. Integrative correlation analysis connected Muribaculaceae with propionate-associated and aromatic amino acid-related metabolites and selected cytokines (including CCL20). COS mitigated age-associated body weight gain and was accompanied by reduced p53 and p21 immunoreactivity in brain and kidney, consistent with attenuation of stress associated senescence signaling. Long-term COS supplementation in naturally aged mice is associated with coordinated shifts in a putative Muribaculaceae-propionate-immune axis and concurrent down-regulation of both p53 and p21. These associative findings warrant mechanistic validation through targeted short-chain fatty acid quantification, receptor signaling assays, microbiota transfer, and functional aging endpoints to clarify causality and translational potential.

The rapid proliferation of synthetic chemicals has significantly outpaced traditional toxicity characterization, leaving a critical data gap in environmental health risk assessment. While the adverse outcome pathway (AOP) framework provides a mechanistic scaffold for organizing toxicity knowledge, it is currently limited by a focus on linear pathways and a bias toward well-studied endpoints. Conversely, the exposome paradigm captures broad environmental stressors but often lacks the mechanistic depth required for causal interpretation. A fundamental challenge remains in developing integrative paradigms that can systematically bridge these multi-scale datasets to decode complex, chemical-induced diseases. Here we show that AOP-ExpoVis, an integrative computational platform, synergizes exposome-disease networks with AOP ontologies to prioritize pathogenic mechanisms through a weighted phenotype-disease scoring algorithm. By integrating chemical, gene, phenotype, and disease associations, the platform identifies key phenotypes and maps them to curated pathways to generate testable mechanistic hypotheses. Validation across three distinct case studies involving 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), arsenic, and perfluoroalkyl substances (PFAS) demonstrated that AOP-ExpoVis accurately identifies both conserved and chemical-specific toxic pathways, such as aryl hydrocarbon receptor activation and lipid metabolism disruption. AOP-ExpoVis provides an open-source tool for rapid mechanistic inference that overcomes the limitations of traditional, single-pathway frameworks. This work advances predictive toxicology by enabling the systematic prioritization of chemical hazards and the refinement of regulatory risk assessment in a data-rich environment.

OBJECTIVE:This study identifies and characterizes the novel compound heterozygous mutations in the KNG1 gene responsible for severe high molecular weight kininogen (HMWK) deficiency in a 3-year-old Chinese boy. METHODS:The proband was identified during preoperative screening due to an isolated, prolonged activated partial thromboplastin time (APTT) without bleeding symptoms. Coagulation profiles, including thromboelastography (TEG), were analyzed. HMWK antigen (HMWK:Ag) levels were quantified by ELISA. Genetic analysis was performed using whole-exome and Sanger sequencing of the KNG1 gene in the proband and his parents. The pathogenicity of the novel variant was assessed according to ACMG/AMP guidelines. RESULTS:Coagulation tests revealed a significantly prolonged APTT and a delayed R time on TEG, which was not corrected with extended incubation. HMWK:Ag levels were severely reduced (1.7 μg/ml) in the proband. Genetic analysis identified compound heterozygous mutations in KNG1: a novel missense variant in exon 5 (c.611C>T, p.Thr204Met) and a known nonsense variant in exon 6 (c.718C>T, p.Arg240*). Bioinformatic tools predicted the p.Thr204Met variant to be deleterious, and it was classified as "Likely Pathogenic." The mutations were inherited in trans, confirming the genetic basis of the HMWK deficiency. CONCLUSION:We report a novel compound heterozygous mutation (c.611C>T and c.718C>T) in the KNG1 gene causing severe HMWK deficiency. This case expands the mutational spectrum of this ultra-rare disorder and highlights that its primary clinical significance is an isolated APTT prolongation without a bleeding diathesis. Genetic diagnosis is crucial to avoid unnecessary treatments, surgical delays, and exposure to blood products in such patients.

Neurological disorders represent a major global public health challenge, causing significant impairments in motor, sensory, and cognitive functions. Among these disorders, Alzheimer's disease, cerebrovascular diseases, and Parkinson's disease are notably prevalent. Despite their widespread impact, effective therapeutic interventions remain limited. Recently, pyroptosis-a highly pro-inflammatory form of programmed cell death characterized by cell swelling, membrane perforation, and the release of cellular contents-has gained considerable attention. While pyroptosis plays a crucial role in host defense against pathogen infections, its excessive activation can trigger sustained inflammatory responses and has been implicated in the pathogenesis and progression of various neurological disorders. This review provides an overview of pyroptosis, including its definition, key molecular components, and associated signaling pathways, while examining its mechanistic roles in neuroinflammation, neurological disorders, cerebrovascular diseases, and neural tumors. Additionally, it explores the influence of other systemic dysregulations on the development of neurological disorders. Research has demonstrated that pyroptosis drives the death of neurons and glial cells through inflammasome activation and the Caspase-Gasdermin pathway, thereby amplifying neuroinflammation and influencing disease progression. Notably, excessive pyroptosis activation exacerbates neural damage in conditions such as Alzheimer's disease, Parkinson's disease, and ischemic brain injury. Consequently, targeting pyroptosis signaling pathways may present promising therapeutic strategies for neurological disorders. This review consolidates recent advancements in the field, offering valuable insights for the development of effective interventions.

Polybrominated diphenyl ethers (PBDEs), a class of brominated flame retardants, are extensively employed in industrial applications. Among these, decabromodiphenyl ether (BDE-209), the predominant congener, is widely incorporated into consumer materials owing to its exceptional flame-suppressive properties and thermal resistance. However, its environmental persistence and bioaccumulative potential classify BDE-209 as a prototypical persistent organic pollutant, with chronic exposure posing non-negligible risks to human health. Despite its prevalence, research addressing BDE-209-induced neurotoxicity remains limited, particularly regarding mechanistic pathways. This study explores BDE-209-triggered microglial necroptosis and its contribution to neuroinflammatory cascades, with a focus on the regulatory role of the JAK2/STAT3 signaling axis. Experimental analyses across cellular and animal models demonstrated that BDE-209 exposure provoked pronounced microglial activation and subsequent neuroinflammatory markers. Concurrently, necroptotic events were identified through hallmark molecular signatures: phosphorylation cascades involving RIPK1, RIPK3, and MLKL, coupled with cytolytic outcomes. Administration of the necroptosis inhibitor NEC-1 markedly attenuated BDE-209-associated neuroinflammation and cellular demise, underscoring the centrality of microglial necroptosis in this pathological process. Mechanistically, BDE-209 potentiates necrosome assembly by activating the JAK2/STAT3 pathway, as evidenced by reduced necroptotic activity upon AG490-mediated JAK2 inhibition. These findings collectively delineate a novel pathway wherein BDE-209 exacerbates neurotoxicity via JAK2/STAT3-driven microglial necroptosis, providing novel mechanistic insights for developing neuroprotective interventions.

Carbon monoxide (CO) is an essential signaling molecule in the human body, and CO imaging is vital for understanding related pathophysiological mechanisms. Herein, we introduce Nile-CO, a novel near-infrared (NIR) fluorescent probe based on the Nile blue fluorophore. Nile-CO exhibits high selectivity, sensitivity, and a rapid response time of less than 5 min, with a turn-on fluorescence signal at 664 nm. Targeting mitochondria, the probe enables imaging of both endogenous and exogenous CO in HeLa cells. Moreover, in a lipopolysaccharide (LPS)-induced mouse inflammation model, Nile-CO effectively tracks CO fluctuations during acute inflammation and allows direct detection of CO levels in eyeball blood samples, highlighting its potential for practical applications in CO-related research.

Oral squamous cell carcinoma (OSCC) progresses from epithelial cell proliferation to malignancy. Given the higher proportion of male patients compared to female patients, the androgen signaling pathway is believed to play a significant role in promoting epithelial cell proliferation. However, the underlying molecular mechanisms remain unclear. Here, we identified RBAP48 as a novel androgen receptor (AR) co-activator in OSCC cells. Our results show that RBAP48 was highly expressed in OSCC tumor tissues from patients with a poor prognosis. Further, RBAP48 knockdown decreased genome-wide oncogene transcription. RBAP48 and AR interacted to activate CCND1 and RAB31 transcription, and upregulated RELA and CCNE1 mRNA expression through an AR-independent pathway. Additionally, RBAP48 promoted OSCC cell proliferation and was involved in the cellular response to drugs and external compounds in vitro, ultimately driving cancer progression. Our results indicate that RBAP48 is a novel oncogene and a promising target for predicting and treating OSCC progression.

Ferroptosis, characterized by iron-dependent phospholipid peroxidation, is recognized as one of the cell death pathways activated following spinal cord injury (SCI). However, the precise regulatory mechanisms governing this process remain poorly understood. Here, this study identified TRIM32, an E3 ubiquitin ligase, as a key enhancer of neuronal ferroptosis. TRIM32 promoted neuronal ferroptosis by accelerating the degradation of GPX4, which is an essential inhibitor of ferroptosis. Conditional deletion of Trim32 in neurons markedly inhibited neuronal ferroptosis and promoted neuronal survival, eventually improving mouse locomotor functional recovery after SCI. However, overexpression of Trim32 showed aggravated neuronal loss and poor behavioral function, which could be attenuated by ferroptosis inhibitor Liproxstatin-1. Mechanistically, TRIM32 interacted with GPX4, promoted K63-linked ubiquitination modification of GPX4 at K107, thus enhanced p62-dependent autophagic degradation of GPX4. Moreover, ROS-ATM-Chk2 signaling pathway phosphorylates TRIM32 at S55, further contributing to GPX4 ubiquitination and degradation and subsequent neuronal ferroptosis after SCI, suggesting a positive feedback loop between ROS and TRIM32. Clinically, lipid peroxidation was significantly promoted in patients with SCI. These findings reveal that TRIM32 functions as a neuronal ferroptosis enhancer which is detrimental to neuronal survival and locomotor functional recovery in mice after SCI by promoting K63-linked ubiquitination and subsequent p62-dependent autophagic degradation of GPX4, suggesting a promising therapeutic target for SCI.

Cardiovascular diseases (CVDs) are the most common non-communicable diseases worldwide. Fine particulate matter (PM2.5) has emerged as a significant modifiable risk factor contributing to the burden of CVDs. This study examines the global burden of CVDs attributable to PM2.5 pollution from 1990 to 2021. Using data from the Global Burden of Disease (GBD) study. We calculated the estimated annual percentage change (EAPC) via log-linear regression and assessed age-standardized rates (ASRs, per 100,000 population) for deaths and disability-adjusted life years (DALYs). While global ASRs for PM2.5-related DALYs declined from 2009.92 to 1161.77 per 100,000, these reductions were unequal: high-income regions, such as North America and Western Europe, achieved substantial progress, whereas low-income regions, particularly Sub-Saharan Africa and South Asia, faced rising burdens from PM2.5 exposure. The study highlights the shift from household to ambient sources of PM2.5 as the main contributor to CVDs, particularly in rapidly industrializing regions, with the total DALYs attributable to PM2.5 increasing from 78.87 million in 1990-99.64 million in 2021. Decomposition analysis identifies population growth, aging, and epidemiological changes as key drivers of the global trends. This study provides evidence-based guidance for the CVDs prevention and PM2.5 air pollution policy.

Decabromodiphenyl ether (BDE-209), a brominated flame retardant widely used in electronics and construction materials, has garnered significant attention due to its environmental persistence and potential health hazards. However, research on the neurotoxic effects of flame retardants is limited, and the molecular mechanisms underlying BDE-209 neurotoxicity are not fully understood. Neuroinflammation, as a key pathway in the pathological progression of neurological disorders, has received extensive attention. This study aimed to elucidate the molecular mechanisms underlying BDE-209-induced neurotoxicity, with a specific focus on pyroptosis, a form of programmed cell death closely linked to neuroinflammation. Using both in vivo mouse models and in vitro HT22 hippocampal neuron cultures, we found that BDE-209 exposure caused significant cognitive deficits in mice and activated the classical pyroptosis pathway in the hippocampus. Further analysis revealed that BDE-209 activated the JAK2/STAT3 pathway and the NLRP3 inflammasome, triggering pyroptotic cell death in HT22 neurons. Remarkably, pharmacological inhibition of NLRP3 with MCC950 and blockade of JAK2/STAT3 signaling with AG490 significantly attenuated pyroptosis, highlighting the therapeutic potential of targeting these pathways. Collectively, our findings provide new insights into the neurotoxic effects of BDE-209, demonstrating that it induces NLRP3-mediated pyroptosis through the JAK2/STAT3 axis. This study enhances our understanding of BDE-209 neurotoxicity and highlights possible intervention strategies to mitigate its harmful effects.

Inorganic mercury (Hg) and methylmercury (MeHg) have emerged as global pollutants owing to their long-term environmental stability and bioaccumulation. These heavy metals enter aquatic systems via industrial emissions, coal combustion, and natural processes, posing a serious threat to ecosystems and human health. This study assesses the impact of Hg2+ and MeHg on the growth and development of brine shrimp (Artemia franciscana) nauplii by analyzing the histopathological effects on their tissues. Brine shrimp nauplii from the Bohai Bay in China were selected as the study subjects and exposed to 1 μmol/L solutions of HgCl₂ and MeHgCl. Tissue sections were continuously taken at different immersion times. After staining with the standard hematoxylin-eosin (HE) method, the tissue morphology of brine shrimp nauplii under different forms of Hg stress was observed under a light microscope. The results showed that MeHg exhibited significantly greater toxicity to brine shrimp nauplii than Hg2+. Under the same exposure time, the MeHg group exhibited more pronounced epithelial cell damage, nuclear material disorder, and nucleoplasm diffusion outside the nucleus than the HgCl₂ group. This finding provides an important theoretical support for further research into the toxicological mechanisms of MeHg and Hg2+, and highlights that the toxic effects of methylmercury on aquatic organisms.

Polybrominated diphenyl ethers (PBDEs) are brominated compounds connected by ester bonds between two benzene rings. There are 209 congeners of PBDEs, classified according to the number and position of the bromine atoms. Due to their low cost and superior flame retardant properties, PBDEs have been extensively used as flame retardants in electronic products, plastics, textiles, and other materials since the 1970s. PBDEs are classified as persistent organic pollutants (POPs) under the Stockholm Convention because of their environmental persistence, bioaccumulation, and toxicity to both humans and wildlife. Due to their extensive use and significant quantities, PBDEs have been detected across a range of environments and biological organisms. These compounds are known to cause damage to the metabolic system, exhibit neurotoxicity, and pose reproductive hazards. This review investigates the environmental distribution and human exposure pathways of PBDEs. Using China-a country with significant PBDE use-as an example, it highlights substantial regional and temporal variations in PBDE concentrations and notes that certain environmental levels may pose risks to human health. The article then examines the toxic effects and mechanisms of PBDEs on several major target organs, summarizing recent research and the specific mechanisms underlying these toxic effects from multiple toxicological perspectives. This review enhances our understanding of PBDEs' environmental distribution, exposure pathways, and toxic mechanisms, offering valuable insights for further research and management strategies.

Excessive exposure to manganese (Mn) through drinking water and food during pregnancy significantly heightens the likelihood of neurodevelopmental damage in offspring. Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn-induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D1, and E2F1) and enhancing negative ones (p27KIP1 and p57KIP2), leading to cell proliferation dysfunction. Mel inhibited the Mn-dependent changes to these proteins and the cell cycle through nuclear receptor-related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus-expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn-induced proliferation dysfunction and cycle arrest in NSCs through Nurr1.

Background While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N 6 -methyladenosine (m 6 A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis. Methods Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling. Results METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a ( eIF3a ) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s). Conclusions Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency.