Development of a coupled model to simulate and assess arsenic contamination and impact factors in the Jinsha River Basin, China.

With the increasing severity of arsenic (As) pollution, quantifying the environmental behavior of pollutant based on numerical model has become an important approach to determine the potential impacts and finalize the precise control strategies. Taking the industrial-intensive Jinsha River Basin as typical area, a two-dimensional hydrodynamic water quality model coupled with Soil and Water Assessment Tool (SWAT) model was developed to accurately simulate the watershed-scale distribution and transport of As in the terrestrial and aquatic environment at high spatial and temporal resolution. The effects of hydro-climate change, hydropower station construction and non-point source emissions on As were quantified based on the coupled model. The result indicated that higher As concentration areas mainly centralized in urban districts and concentration slowly decreased from upstream to downstream. Due to the enhanced rainfall, the As concentration was significantly higher during the rainy season than the dry season. Hydro-climate change and the construction of hydropower station not only affected the dissolved As concentration, but also affected the adsorption and desorption of As in sediment. Furthermore, As concentration increased with the input of non-point source pollution, with the maximum increase about 30%, resulting that non-point sources contributed important pollutant impacts to waterways. The coupled model used in pollutant behavior analysis is general with high potential application to predict and mitigate water pollution.

Electroacupuncture activates the peroxisome proliferators-activated receptor pathway to improve the phenotype of cerebral palsy.

AIM: This study explores the efficacy of electroacupuncture (EA) in treating cerebral palsy (CP) in Sprague-Dawley (SD) pups, specifically CP animal models, and its molecular mechanisms. METHODS: Gait analysis and Y-maze were used to detect the improvement of motor ability and cognitive function of CP rats after EA treatment. Transcription sequencing was used to determine the key pathway for EA to improve the symptoms of CP. PPAR agonists were used to verify the causal relationship between the pathway and the improvement of CP phenotype. RESULTS: The motor ability and cognitive function of CP pups were improved after EA treatment. The results of transcriptome sequencing suggest that the improvement of CP phenotype may be caused by the activation of PPAR pathway. PPAR pathway is widely activated in the epithelium of CP pups treated with EA, which is verified by qPCR. Rosiglitazone (Ros), a PPAR agonist, can improve CP phenotype while activating PPAR pathway, which proves the causal relationship between PPAR pathway activation and CP phenotype improvement. CONCLUSION: Our study demonstrated behavioral improvements and enhanced cognitive functions in CP models after EA treatment by activating PPAR pathway, suggesting new perspectives for CP rehabilitation, and providing theoretical support for acupuncture treatment of CP.

Relative validity of an intelligent ordering system to estimate dietary intake among university students from a medical school in Shanghai, China.

BACKGROUND: Dietary assessment methods have limitations in capturing real-time eating behaviour accurately. Equipped with automated dietary-data-collection capabilities, the "intelligent ordering system" (IOS) has potential applicability in obtaining long-term consecutive, relatively detailed on-campus dietary records among university students with little resource consumption. We investigated (1) the relative validity of IOS-derived nutrient/food intakes compared to those from the 7-day food diary (7DFD); (2) whether including a supplemental food frequency questionnaire (SFFQ) improves IOS accuracy; and (3) sex differences in IOS dietary intake estimation. METHODS: Medical students (n = 221; age = 22.2 ± 2.4 years; 38.5% male and 61.5% female) completed the 7DFD and SFFQ. During the consecutive 7-day survey period, students weighed and photographed each meal before and after consumption. Then, students reviewed their 3-month diet and completed the SFFQ, which includes eight underprovided school-canteen food items (e.g., dairy, fruits, nuts). Meanwhile, 9385 IOS dietary data entries were collected. We used Spearman coefficients and linear regression models to estimate the associations among the different dietary intake assessment methods. Individual- and group-level agreement was assessed using the Wilcoxon signed-rank test, cross-classification, and Bland‒Altman analysis. RESULTS: IOS mean daily energy, protein, fat, and carbohydrate intake estimations were significantly lower (-15-20%) than those of the 7DFD. The correlation coefficients varied from 0.52 (for added sugar) to 0.88 (for soybeans and nuts), with fruits (0.37) and dairy products (0.29) showing weaker correlations. Sixty-two (milk and dairy products) to 97% (soybeans and nuts) of participants were classified into the same or adjacent dietary intake distribution quartile using both methods. The energy and macronutrient intake differences between the IOS + SFFQ and 7DFD groups decreased substantially. The separate fruit intake measurements from each assessment method did not significantly differ from each other (p > 0.05). IOS and IOS + SFFQ regression models generally yielded higher R2 values for males than for females. CONCLUSION: Despite estimation differences, the IOS can be reliable for medical student dietary habit assessment. The SFFQ is useful for measuring consumption of foods that are typically unavailable in school cafeterias, improving the overall dietary evaluation accuracy. The IOS assessment was more accurate for males than for females.

Seizure Detection of EEG Signals Based on Multi-Channel Long- and Short-Term Memory-Like Spiking Neural Model.

Seizure is a common neurological disorder that usually manifests itself in recurring seizure, and these seizures can have a serious impact on a person's life and health. Therefore, early detection and diagnosis of seizure is crucial. In order to improve the efficiency of early detection and diagnosis of seizure, this paper proposes a new seizure detection method, which is based on discrete wavelet transform (DWT) and multi-channel long- and short-term memory-like spiking neural P (LSTM-SNP) model. First, the signal is decomposed into 5 levels by using DWT transform to obtain the features of the components at different frequencies, and a series of time-frequency features in wavelet coefficients are extracted. Then, these different features are used to train a multi-channel LSTM-SNP model and perform seizure detection. The proposed method achieves a high seizure detection accuracy on the CHB-MIT dataset: 98.25% accuracy, 98.22% specificity and 97.59% sensitivity. This indicates that the proposed epilepsy detection method can show competitive detection performance.

The long non-coding RNA CCAT1 promotes erlotinib resistance in cholangiocarcinoma by inducing epithelial-mesenchymal transition via the miR-181a-5p/ROCK2 axis.

Cholangiocarcinoma (CCA) is a common malignancy of the digestive system, and its treatment is greatly challenged by rising chemoresistance. Long non-coding RNAs (lncRNAs) have been shown to play critical roles in the development of drug resistance in tumors. However, the role of the lncRNA CCAT1 in erlotinib resistance in CCA remains unclear. In this investigation, we identified CCAT1 as a pivotal factor contributing to erlotinib resistance in CCA. Furthermore, we uncovered that lncRNA CCAT1 modulated epithelial-mesenchymal transition (EMT) through Rho-associated coiled-coil-forming protein kinase 2 (ROCK2), thereby conferring erlotinib resistance upon CCA cells. Mechanistically, we demonstrated that miR-181a-5p interacted with CCAT1 to modulate the expression of ROCK2. Collectively, these findings shed light on the significant role of CCAT1 in the development of erlotinib resistance in CCA. The functional suppression of CCAT1 holds promise in enhancing the sensitivity to erlotinib by reversing EMT through the miR-181a-5p/ROCK2 signaling pathway. These findings provide valuable insights into the mechanisms underlying erlotinib resistance in CCA and the potential strategies for its treatment.

Humoral and cellular immune responses following Omicron BA.2.2 breakthrough infection and Omicron BA.5 reinfection.

The emergence of novel Omicron subvariants has raised concerns regarding the efficacy of immunity induced by prior Omicron subvariants breakthrough infection (BTI) or reinfection against current circulating Omicron subvariants. Here, we prospectively investigated the durability of antibody and T cell responses in individuals post Omicron BA.2.2 BTI, with or without subsequent Omicron BA.5 reinfection. Our findings reveal that the emerging Omicron subvariants, including CH.1.1, XBB, and JN.1, exhibit extensive immune evasion induced by previous infections. Notably, the level of IgG and neutralizing antibodies were found to correlate with subsequent Omicron BA.5 reinfection. Fortunately, T cell responses recognizing both Omicron BA.2 and CH.1.1 peptides were observed. Furthermore, Omicron BA.5 reinfection may alleviate immune imprinting induced by WT-vaccination, bolster virus-specific ICS+ T cell responses, and promote the phenotypic differentiation of virus-specific memory CD8+ T cells. Antigen-updated or T cell-conserved vaccines are needed to control the transmission of diverse emerging SARS-CoV-2 variants.

Verapamil inhibits respiratory syncytial virus infection by regulating Ca2+ influx.

AIMS: The study evaluated the antiviral effect of Verapamil against respiratory syncytial virus (RSV) and investigated its underlying mechanism. MATERIALS AND METHODS: RSV-infected BALB/c mice were treated with Verapamil. Body weight, survival rates, viral load, lung damage, inflammatory factors, and the expression of RSV fusion (F) protein were analyzed. In cellular studies, intracellular Ca2+ and viral titers were measured in the presence of Verapamil, Calcium Chloride, and EGTA. A time-of-addition assay assessed the antiviral effect of Verapamil. KEY FINDINGS: Mice infected with RSV and treated with Verapamil exhibited a significant decrease in weight loss, an increase in survival rates, and reductions in viral titers, RSV F protein expression, inflammatory responses, and lung tissue injury. Verapamil reduced intracellular calcium levels, which correlated with reduced viral titers. The addition of calcium chloride reversed the anti-viral effects mediated by Verapamil, while EGTA potentiated them. The antiviral activity of Verapamil was observed during the early phase of RSV infection, likely by blocking Ca2+ channels and inhibiting virus replication. SIGNIFICANCE: Verapamil effectively inhibits RSV infection by blocking calcium channels and reducing intracellular calcium levels, thereby impeding viral replication. Thus, Verapamil shows promise as a treatment for RSV.

Role of NLRP3 inflammasome in central nervous system diseases.

The central nervous system (CNS) is the most delicate system in human body, with the most complex structure and function. It is vulnerable to trauma, infection, neurodegeneration and autoimmune diseases, and activates the immune system. An appropriate inflammatory response contributes to defence against invading microbes, whereas an excessive inflammatory response can aggravate tissue damage. The NLRP3 inflammasome was the first one studied in the brain. Once primed and activated, it completes the assembly of inflammasome (sensor NLRP3, adaptor ASC, and effector caspase-1), leading to caspase-1 activation and increased release of downstream inflammatory cytokines, as well as to pyroptosis. Cumulative studies have confirmed that NLRP3 plays an important role in regulating innate immunity and autoimmune diseases, and its inhibitors have shown good efficacy in animal models of various inflammatory diseases. In this review, we will briefly discuss the biological characteristics of NLRP3 inflammasome, summarize the recent advances and clinical impact of the NLRP3 inflammasome in infectious, inflammatory, immune, degenerative, genetic, and vascular diseases of CNS, and discuss the potential and challenges of NLRP3 as a therapeutic target for CNS diseases.

Clinical and Imaging Characteristics of Herlyn-Werner-Wunderlich Syndrome: a Comprehensive Analysis.

PURPOSE: To describe the clinical and imaging characteristics of Herlyn-Werner-Wunderlich syndrome (HWWS). METHODS: This study presented an observational case series involving consecutive patients diagnosed with HWWS, whose medical records were retrospectively reviewed. From June 2012 to December 2022, there were a total of 85 patients with HWWS enrolled in our study. We obtained the medical history, including demographic characteristics, clinical presentation, treatment, complications, and radiologic examinations performed. Patients > 18 years of age (n = 58) were recontacted. RESULT: In our analysis, 27 patients were categorised as having complete obstruction, and 58 were categorised as having incomplete obstruction. The mean age at the onset of symptoms and diagnosis of complete obstruction was significantly younger than incomplete obstruction (P < 0.05). For complete obstruction, the median time between menarche and the onset of symptoms was 2.1 years, while for incomplete obstruction, it was 5.3 years. There was a significantly lower incidence of intermittent mucopurulent discharge, irregular vaginal haemorrhage, and occasional examination findings of complete obstruction than incomplete obstruction (P < 0.05). Complete obstruction was significantly associated with dysmenorrhea and pelvic endometriosis compared with incomplete obstruction (P < 0.05). CONCLUSIONS: There are distinct clinical differences between patients with complete obstruction of the hemivagina and those with incomplete obstruction. HWWS can manifest as various combinations of uterine anomalies, communications anomalies, and renal anomalies. Early recognition and treatment can avoid complications and preserve fertility. KEYSWORDS: Herlyn-Werner-Wunderlich syndrome (HWWS); complete obstruction; incomplete obstruction; obstructed hemivagina; congenital malformation.

Bioprotective Respirator Assembled by Defective Carbon Nitride for Long-Term Light Triggered Health Protection.

Wearing face masks is the best way to stop the spread of respiratory infections. However, if masks are not sterilized, changing them too frequently can actually increase the risk of cross-contamination. Herein, the construction of an antipathogen photocatalytic mask with carbon vacancy-modified carbon nitride nanosheets (g-C3N4-VC Ns) coated on the non-woven fabrics of the out layer of the mask, offering effective and long-term protection against damaging pathogens when exposed to light is reported. The introduced carbon vacancies are found capable of creating energy-disordered sites and inducing energetic electric force to overcome the Coulomb interactions between electron-hole pairs, thus promoting the electron-hole separation to achieve a high generation of reactive oxygen species (ROS). Thanks to its high activity in generating ROS upon exposure to light, the as-prepared photocatalytic mask shows high pathogen sterilization performance. This, in turn, prolongs the mask's protective lifetime, decreases the need for regular replacement, and decreases medical waste production. The work demonstrated here opens new viewpoints in designing pathogens biocidal protective devices for health protection, offering significant promise in specific environment self-protection.

Multi-level feature interaction image super-resolution network based on convolutional nonlinear spiking neural model.

Image super-resolution (ISR) is designed to recover lost detail information from low-resolution images, resulting in high-quality and high-definition high-resolution images. In the existing single ISR (SISR) methods based on convolutional neural networks (CNN), however, most of the models cannot effectively combine global and local information and are also easy to ignore the correlation between different hierarchical feature information. To address these problems, this study proposes a multi-level feature interactive image super-resolution network, which is constructed by the convolutional units inspired by nonlinear spiking mechanism in nonlinear spiking neural P systems, including shallow feature processing, deep feature extraction and fusion, and reconstruction modules. The different omni domain self-attention blocks are introduced to extract global information in the deep feature extraction and fusion stage and formed a feature enhancement module having a Transformer structure using a novel convolutional unit for extracting local information. Furthermore, to adaptively fuse features between different hierarchies, we design a multi-level feature fusion module, which not only can adaptively fuse features between different hierarchies, but also can better interact with contextual information. The proposed model is compared with 16 state-of-the-art or baseline models on five benchmark datasets. The experimental results show that the proposed model not only achieves good reconstruction performance, but also strikes a good balance between model parameters and performance.

In Silico Design of Heterogeneous Microvascular Trees Using Generative Adversarial Networks and Constrained Constructive Optimization.

OBJECTIVE: Designing physiologically adequate microvascular trees is of crucial relevance for bioengineering functional tissues and organs. Yet, currently available methods are poorly suited to replicate the morphological and topological heterogeneity of real microvascular trees because the parameters used to control tree generation are too simplistic to mimic results of the complex angiogenetic and structural adaptation processes in vivo. METHODS: We propose a method to overcome this limitation by integrating a conditional deep convolutional generative adversarial network (cDCGAN) with a local fractal dimension-oriented constrained constructive optimization (LFDO-CCO) strategy. The cDCGAN learns the patterns of real microvascular bifurcations allowing for their artificial replication. The LFDO-CCO strategy connects the generated bifurcations hierarchically to form microvascular trees with a vessel density corresponding to that observed in healthy tissues. RESULTS: The generated artificial microvascular trees are consistent with real microvascular trees regarding characteristics such as fractal dimension, vascular density, and coefficient of variation of diameter, length, and tortuosity. CONCLUSIONS: These results support the adoption of the proposed strategy for the generation of artificial microvascular trees in tissue engineering as well as for computational modeling and simulations of microcirculatory physiology.

Ensemble learning for retinal disease recognition under limited resources.

Retinal optical coherence tomography (OCT) images provide crucial insights into the health of the posterior ocular segment. Therefore, the advancement of automated image analysis methods is imperative to equip clinicians and researchers with quantitative data, thereby facilitating informed decision-making. The application of deep learning (DL)-based approaches has gained extensive traction for executing these analysis tasks, demonstrating remarkable performance compared to labor-intensive manual analyses. However, the acquisition of retinal OCT images often presents challenges stemming from privacy concerns and the resource-intensive labeling procedures, which contradicts the prevailing notion that DL models necessitate substantial data volumes for achieving superior performance. Moreover, limitations in available computational resources constrain the progress of high-performance medical artificial intelligence, particularly in less developed regions and countries. This paper introduces a novel ensemble learning mechanism designed for recognizing retinal diseases under limited resources (e.g., data, computation). The mechanism leverages insights from multiple pre-trained models, facilitating the transfer and adaptation of their knowledge to retinal OCT images. This approach establishes a robust model even when confronted with limited labeled data, eliminating the need for an extensive array of parameters, as required in learning from scratch. Comprehensive experimentation on real-world datasets demonstrates that the ensemble models constructed by the proposed ensemble method show superior performance over the baseline models under sparse labeled data, especially the triple ensemble model, which achieves the accuracy of 92.06%, which is 8.27%, 7.99%, and 11.14% better than the three baseline models, respectively. In addition, compared with the three baseline models learned from scratch, the triple ensemble model has fewer trainable parameters, only 3.677M, which is lower than the three baseline models of 8.013M, 4.302M, and 20.158M, respectively.

Voice Changes of Patients With Nasopharyngeal Carcinoma in Eleven Years After Radiotherapy: A Cross-Sectional Study.

OBJECTIVES: The objective of this study was to assess voice changes in patients with nasopharyngeal carcinoma (NPC) using subjective and objective assessment tools and to make inferences regarding the underlying pathological causes for different phases of radiotherapy (RT). METHODS: A total of 187 (123 males and 64 females) patients with post-RT NPC with no recurrence of malignancy or other voice diseases and 17 (11 males and 6 females) healthy individuals were included in this study. The patients were equally divided into 11 groups according to the number of years after RT. The acoustic analyses, GRBAS (grade, roughness, breathiness, asthenia, and strain) scales, and Voice Handicap Index (VHI)-10 scores were collected and analyzed. RESULTS: The fundamental frequency (F0) parameters in years 1 and 2 and year 11 were significantly lower in patients with NPC than in healthy individuals. The maximum phonation times in years 1 and 11 were significantly shorter than those in healthy individuals. The jitter parameters were significantly different between year 1 and from years 8 to 11 and the healthy individuals. The shimmer parameters were significantly different between years 1, from years 9 to 11, and healthy individuals. Hoarseness was the most prominent problem compared to other items of the GRBAS. The VHI-10 scores were significantly different between years 1 and 2 and year 11 after RT in patients with NPC. CONCLUSIONS: Voice quality was worse in the first 2 years and from years 8 to 11 but remained relatively normal from years 3 to 7 after RT. Patient-reported voice handicaps began during year 3 after RT. The most prominent problem was perceived hoarseness, which was evident in the first 2 years and from years 9 to 11 after RT. The radiation-induced mucous edema, laryngeal intrinsic muscle fibrosis, nerve injuries, upper respiratory tract changes, and decreased lung capacity might be the pathological reasons for voice changes in post-RT patients with NPC.

Upgrading CO2 to sustainable aromatics via perovskite-mediated tandem catalysis.

The directional transformation of carbon dioxide (CO2) with renewable hydrogen into specific carbon-heavy products (C6+) of high value presents a sustainable route for net-zero chemical manufacture. However, it is still challenging to simultaneously achieve high activity and selectivity due to the unbalanced CO2 hydrogenation and C-C coupling rates on complementary active sites in a bifunctional catalyst, thus causing unexpected secondary reaction. Here we report LaFeO3 perovskite-mediated directional tandem conversion of CO2 towards heavy aromatics with high CO2 conversion (> 60%), exceptional aromatics selectivity among hydrocarbons (> 85%), and no obvious deactivation for 1000 hours. This is enabled by disentangling the CO2 hydrogenation domain from the C-C coupling domain in the tandem system for Iron-based catalyst. Unlike other active Fe oxides showing wide hydrocarbon product distribution due to carbide formation, LaFeO3 by design is endowed with superior resistance to carburization, therefore inhibiting uncontrolled C-C coupling on oxide and isolating aromatics formation in the zeolite. In-situ spectroscopic evidence and theoretical calculations reveal an oxygenate-rich surface chemistry of LaFeO3, that easily escape from the oxide surface for further precise C-C coupling inside zeolites, thus steering CO2-HCOOH/H2CO-Aromatics reaction pathway to enable a high yield of aromatics.

The underlying mechanism and targeted therapy strategy of miRNAs cross-regulating EMT process through multiple signaling pathways in hepatocellular carcinoma.

The consistent notion holds that hepatocellular carcinoma (HCC) initiation, progression, and clinical treatment failure treatment failure are affected by the accumulation of various genetic and epigenetic alterations. MicroRNAs (miRNAs) play an irreplaceable role in a variety of physiological and pathological states. meanwhile, epithelial-mesenchymal transition (EMT) is a crucial biological process that controls the development of HCC. miRNAs regulate the intermediation state of EMTor mesenchymal-epithelial transition (MTE)thereby regulating HCC progression. Notably, miRNAs regulate key HCC-related molecular pathways, including the Wnt/ß-catenin pathway, PTEN/PI3K/AKT pathway, TGF-ß pathway, and RAS/MAPK pathway. Therefore, we comprehensively reviewed how miRNAs produce EMT effects by multiple signaling pathways and their potential significance in the pathogenesis and treatment response of HCC. emphasizing their molecular pathways and progression in HCC initiation. Additionally, we also pay attention to regulatory mechanisms that are partially independent of signaling pathways. Finally, we summarize and propose miRNA-targeted therapy and diagnosis and defense strategies forHCC. The identification of the mechanism leading to the activation of EMT programs during HCC disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Consequently, we summarize the latest progress in this direction, with a promising path for further insight into this fast-moving field.

Electrophysiological Changes on Laryngeal Motor Neuropathways Cause Voice Disorders for Postradiotherapy Patients with Nasopharyngeal Carcinoma.

OBJECTIVE: This study explored electrophysiological changes in the laryngeal motor neuropathway and determined whether lesions in the laryngeal motor cortex (LMC) and its descending tract contribute to voice deterioration and peripheral nerve palsy in patients with nasopharyngeal carcinoma (NPC) postradiotherapy (RT). STUDY DESIGNS: Prospective cohort study. METHODS: Twenty-two patients with NPC at 2 to 4years post-RT (8 female and 14 male), 22 patients with NPC at 8 to 10years post-RT (8 female and 14 male), and 22 healthy individuals (9 female and 13 male) were selected to test their magnetic evoked potentials (MEP), motor nerve conduction, and voice quality using transcranial magnetic stimulation, laryngeal electromyography, and the XION DiVAS acoustic analysis software. Three groups were matched according to approximate age. Multiple comparisons were performed among the three groups. RESULTS: The voice quality of post-RT patients with NPC deteriorated compared to that of healthy individuals. Bilateral LMC and their corticonuclear tracts to the bilateral ambiguous nuclei of post-RT patients with NPC were impaired according to multigroup comparisons of MEP amplitudes, latencies, and resting motor thresholds. The vagus and recurrent laryngeal nerves (RLN) of post-RT patients with NPC were impaired according to multigroup comparisons of the amplitude and latencies of the compound muscle action potential and latencies of f-waves. CONCLUSIONS: The voice quality of patients with NPC deteriorated after RT. The pathogenesis of post-RT voice deterioration may involve radiation-induced injuries to the vagus, RLN, and bilateral LMC. Furthermore, radiation-induced injuries to the bilateral LMC may contribute to vagus and RLN palsies. These findings support the use of transcranial approaches to treating voice disorders and peripheral nerve palsies in post-RT patients with NPC. TRIAL REGISTRATION: ChiCTR2100054425; Electrophysiological Study of Vocal-Fold Mobility Disorders After Radiotherapy for NPC Patients via Magnetic Evoked Potential and Their Correlation with Voice Quality Assessment; https://www.chictr.org.cn/bin/project/edit?pid=144429.

Loss of ZNF451 mediates fibroblast activation and promotes lung fibrosis.

BACKGROUND: No effective therapies for pulmonary fibrosis (PF) exist because of the unclear molecular pathogenesis and the lack of effective therapeutic targets. Zinc finger protein 451 (ZNF451), a transcriptional regulator, plays crucial roles in the pathogenesis of several diseases. However, its expression pattern and function in PF remain unknown. This study was designed to investigate the role of ZNF451 in the pathogenesis of lung fibrosis. METHODS: GEO dataset analysis, RT‒PCR, and immunoblot assays were used to examine the expression of ZNF451 in PF; ZNF451 knockout mice and ZNF451-overexpressing lentivirus were used to determine the importance of ZNF451 in PF progression; and migration assays, immunofluorescence staining, and RNA-seq analysis were used for mechanistic studies. RESULTS: ZNF451 is downregulated and negatively associated with disease severity in PF. Compared with wild-type (WT) mice, ZNF451 knockout mice exhibited much more serious PF changes. However, ZNF451 overexpression protects mice from BLM-induced pulmonary fibrosis. Mechanistically, ZNF451 downregulation triggers fibroblast activation by increasing the expression of PDGFB and subsequently activating PI3K/Akt signaling. CONCLUSION: These findings uncover a critical role of ZNF451 in PF progression and introduce a novel regulatory mechanism of ZNF451 in fibroblast activation. Our study suggests that ZNF451 serves as a potential therapeutic target for PF and that strategies aimed at increasing ZNF451 expression may be promising therapeutic approaches for PF.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.