Inhibition of the RLR signaling pathway by SARS-CoV-2 ORF7b is mediated by MAVS and abrogated by ORF7b-homologous interfering peptide.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and characterized by dysregulated immune response. Studies have shown that the SARS-CoV-2 accessory protein ORF7b induces host cell apoptosis through the tumor necrosis factor alpha (TNF-α) pathway and blocks the production of interferon beta (IFN-ß). The underlying mechanism remains to be investigated. In this study, we found that ORF7b facilitated viral infection and production, and inhibited the RIG-I-like receptor (RLR) signaling pathway through selectively interacting with mitochondrial antiviral-signaling protein (MAVS). MAVS439-466 region and MAVS Lys461 were essential for the physical association between MAVS and ORF7b, and the inhibition of the RLR signaling pathway by ORF7b. MAVSK461/K63 ubiquitination was essential for the RLR signaling regulated by the MAVS-ORF7b complex. ORF7b interfered with the recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) and the activation of the RLR signaling pathway by MAVS. Furthermore, interfering peptides targeting the ORF7b complex reversed the ORF7b-suppressed MAVS-RLR signaling pathway. The most potent interfering peptide V disrupts the formation of ORF7b tetramers, reverses the levels of the ORF7b-inhibited physical association between MAVS and TRAF6, leading to the suppression of viral growth and infection. Overall, this study provides a mechanism for the suppression of innate immunity by SARS-CoV-2 infection and the mechanism-based approach via interfering peptides to potentially prevent SARS-CoV-2 infection.IMPORTANCEThe pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and continues to be a threat to public health. It is imperative to understand the biology of SARS-CoV-2 infection and find approaches to prevent SARS-CoV-2 infection and ameliorate COVID-19. Multiple SARS-CoV-2 proteins are known to function on the innate immune response, but the underlying mechanism remains unknown. This study shows that ORF7b inhibits the RIG-I-like receptor (RLR) signaling pathway through the physical association between ORF7b and mitochondrial antiviral-signaling protein (MAVS), impairing the K63-linked MAVS polyubiquitination and its recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) to MAVS. The most potent interfering peptide V targeting the ORF7b-MAVS complex may reverse the suppression of the MAVS-mediated RLR signaling pathway by ORF7b and prevent viral infection and production. This study may provide new insights into the pathogenic mechanism of SARS-CoV-2 and a strategy to develop new drugs to prevent SARS-CoV-2 infection.

Sulfated Polysaccharide-Based Nanocarrier Drives Microenvironment-Mediated Cerebral Neurovascular Remodeling for Ischemic Stroke Treatment.

Stroke is a leading cause of global mortality and severe disability. However, current strategies used for treating ischemic stroke lack specific targeting capabilities, exhibit poor immune escape ability, and have limited drug release control. Herein, we developed an ROS-responsive nanocarrier for targeted delivery of the neuroprotective agent rapamycin (RAPA) to mitigate ischemic brain damage. The nanocarrier consisted of a sulfated chitosan (SCS) polymer core modified with a ROS-responsive boronic ester enveloped by a red blood cell membrane shell incorporating a stroke homing peptide. When encountering high levels of intracellular ROS in ischemic brain tissues, the release of SCS combined with RAPA from nanoparticle disintegration facilitates effective microglia polarization and, in turn, maintains blood-brain barrier integrity, reduces cerebral infarction, and promotes cerebral neurovascular remodeling in a mouse stroke model involving transient middle cerebral artery occlusion (tMCAO). This work offers a promising strategy to treat ischemic stroke therapy.

ISMI-VAE: A deep learning model for classifying disease cells using gene expression and SNV data.

Various studies have linked several diseases, including cancer and COVID-19, to single nucleotide variations (SNV). Although single-cell RNA sequencing (scRNA-seq) technology can provide SNV and gene expression data, few studies have integrated and analyzed these multimodal data. To address this issue, we introduce Interpretable Single-cell Multimodal Data Integration Based on Variational Autoencoder (ISMI-VAE). ISMI-VAE leverages latent variable models that utilize the characteristics of SNV and gene expression data to overcome high noise levels and uses deep learning techniques to integrate multimodal information, map them to a low-dimensional space, and classify disease cells. Moreover, ISMI-VAE introduces an attention mechanism to reflect feature importance and analyze genetic features that could potentially cause disease. Experimental results on three cancer data sets and one COVID-19 data set demonstrate that ISMI-VAE surpasses the baseline method in terms of both effectiveness and interpretability and can effectively identify disease-causing gene features.

Feasibility of sulfated BPA and BPS as wastewater-based epidemiology biomarkers: Insights from wastewater and reported human urine analysis.

In wastewater-based epidemiology (WBE), the selection of appropriate biomarkers presents a significant challenge. Recently, sulfated bisphenols have garnered attention as potential WBE biomarkers due to their increased stability in wastewater compared to glucuronide conjugates. This study aims to comprehensively assess the feasibility of employing sulfated BPA and BPS as WBE biomarkers by analyzing both WBE and human biomonitoring data. To conduct this research, wastewater samples were collected from six domestic wastewater treatment plants in Guangzhou, China, and urinary concentration of BPA and BPS were obtained from peer-reviewed literature. The results revealed that mean urinary concentrations of BPA and BPS, calculated using Monte Carlo simulations, significantly exceeded those reported in human biomonitoring studies. Furthermore, the per capita mass load ratio of sulfated BPA and BPS in human urine to the mass load in wastewater was found to be below 10 %. This outcome suggests that the excretion of BPA-S and BPS-S in urine does not make a substantial contribution to wastewater, hinting at the existence of other notable sources. Consequently, our study concludes that sulfated BPA-S and BPS-S are not suitable candidates as WBE biomarkers. This work provides a referenceable analytical framework for evaluating the feasibility of WBE biomarkers and emphasizes the necessity for caution when utilizing WBE to assess human exposure to chemicals.

Warm Acupuncture Reduces Pain and Inflammation in Rats with Lumbar Disc Herniation Induced by Autologous Nucleus Pulposus Transplantation via Regulating p38MAPK/NF-κB Pathway.

Background: : Warm acupuncture (WA) has analgesic and anti-inflammatory effects. However, the underlying mechanism of these effects remain unclear. Objectives: : To explore the analgesic and anti-inflammatory effects of WA and the potential underlying mechanism in male Sprague-Dawley rats with non-compressive lumbar disk herniation (LDH) caused by autologous nucleus pulposus (NP) transplantation. Methods: : We used low-frequency (2 Hz) electrical stimulation and WA (40℃) to treat GB30 and BL54 acupoints in rats for 30 mins per day. We monitored the paw withdrawal threshold of rats during the experiment and measured serum cytokine levels using commercial kits. Dorsal root ganglion (DRG) tissue pathology was analyzed via H&E staining. We used qRT-PCR to measure the mRNA expression levels of IL-1ß, IL-6, and TNF-α genes in DRG. Western blot was used to analyze the expression levels of IL-1ß, IL-6, TNFα, P-p38MAPK, p38MAPK, P-IκBα, IκB α, and NF-κB p65 proteins. Results: : WA treatment significantly increased the pain threshold of rats, reduced serum IL-6, PEG2, NO, SP, NP-Y, and MMP-3 levels, and effected histopathological improvements in the DRG in rats. Moreover, WA treatment significantly downregulated the expression levels of inflammation-associated genes (Il-1ß, Il-6, and Tnf-α) and proteins (IL-1ß, IL-6, TNF-α, P-p38MAPK, P-IκBα, and NF-κB p65) in the DRG of non-compressive LDH rats. Conclusion: : WA can alleviate pain and inhibit inflammatory response in rats with non-compressive LDH caused by autologous NP transplantation, and these effects are likely associated with the inhibition of the p38MAPK/NF-κB pathway.

Isolation and identification of active components from Grifola frondosa and its anti-EV71 virus effect.

BACKGROUND: It is reported that anti-enterovirus 71 (EV71) drugs have some side effects on human health. Notably, fungi plays a crucial role in promoting human health and anti-virus. Grifola frondosa is a type of large medicinal and edible fungi, rich in active substances. The present study aimed to investigate the anti-EV71 effect of G. frondosa and the potential active substances. RESULTS: In the present study, the water extract of G. frondosa was subjected to ethanol precipitation to obtain the water-extracted supernatant of G. frondosa (GFWS) and water-extracted precipitation of G. frondosa. Their inhibitory effects on EV71 virus were studied based on a cell model. The results showed that GFWS had stronger security and anti-EV71 effects. In addition, the chemical constituents of GFWS were identified by ultra-high performance liquid chromatography-tandem mass spectrometry, which were selected for further separation and purification. Three compounds, N-butylaniline, succinic acid and l-tryptophan, were isolated from GFWS by NMR spectroscopy. It is noteworthy that N-butylaniline and l-tryptophan were isolated and identified from the G. frondosa fruiting bodies for the first time. Our study found that l-tryptophan has anti-EV71 virus activity, which reduced EV71-induced apoptosis and significantly inhibited the replication process after virus adsorption. Furthermore, it could also bind to capsid protein VP1 to prevent the virus from attaching to the cells. CONCLUSION: l-tryptophan was an inhibitor of the EV71 virus, which could be used in infant nutrition and possibly provide a new drug to treat hand, foot and mouth disease. © 2024 Society of Chemical Industry.

Optimization strategy of community planning for environmental health and public health in smart city under multi-objectives.

As population density increases, environmental hygiene and public health become increasingly severe. As the space where residents stay for the longest time and have the most profound impact on their physical and mental health, the quality of the environment in urban communities largely determines the degree to which residents engage in physical activity, bear the risk of pollution exposure, and obtain healthy food. Therefore, in order to ensure the physical and mental health of residents, this study proposes community planning guided by environmental hygiene and public health, and establishes an environmental health assessment system for this purpose. This system evaluates the community environment from four aspects: land use, service facilities, site convenience, and environmental quality. Established the diversity, density, road network connectivity and facilities accessibility nine criteria, as well as the land function of mix, plot ratio, food environment, network ring α and connected ß index, pavement risk level, green configuration and neighborhood material environment disorder degree of 27 indicators of community built environmental evaluation index system. The data is collected through field survey, questionnaire distribution, resident interview and data mapping, and the established evaluation index system is used to evaluate the construction environment of the community. The experimental research data included population data, CAD plan, land use data, street data, POI point data, building data and bus station data, etc. 273 questionnaires were distributed, 264 were recovered, 8 invalid questionnaires were removed, and 256 valid questionnaires were obtained. These experiments confirm that land use, service facilities, site convenience, and environmental quality have a significant impact on the built environment of communities, with impact weights of 0.513, 0.227, 0.135, and 0.125, respectively. The above weights are calculated based on the index judgment matrix and the eigenvectors. The scores of land use, service facilities, site convenience, and environmental quality for the study subjects were 3.44, 1.46, 0.94, and 0.51, respectively, among them, the land use score is less than 3.85, the 1 service facility score is less than 1.71, the site convenience score is less than 1.01, and the environmental quality score is less than 0.94; indicating that the community has serious problems such as single land use types, pollution exposure, and difficulty in obtaining healthy food. Therefore, community planning and transformation based on land use, service facilities, venue convenience, and environmental quality can effectively improve the physical and mental health of residents. In the specific community transformation plan, artificial intelligence and data-driven methods can be used to optimize the land use plan, service facility configuration, site convenience transformation and environmental quality improvement, so as to formulate the optimal community transformation plan and improve the comfort and happiness of community residents. In the future, on the basis of the existing research, the selection of community types will be further enriched and the research cases will be expanded. And through the in-depth practical study of the case, the constructed evaluation index system is optimized and improved to make it more scientific. At the same time, as urban renewal and design have entered the era of stock planning, based on the more perfect evaluation index system, more specific and detailed system discussion of the built communities with public health problems, in order to provide more detailed services for the construction of a better and healthy living environment in the future.

Construction and screening of spin-crossover-sponge materials based on iron(II)-triazole coordination polymers.

Iron(II)-triazole coordination polymers have attracted considerable interest for their synthetic versatility, which allows tuning their spin-crossover (SCO) properties. Embedding SCO solid particles in sponge matrices is a simple, powerful, and generic approach to construct processable SCO materials. Here, we have studied a series of magnetic frameworks based on partial ligand substitution by using different chemical mixtures of two organic ligands, yielding four isostructural coordination polymers. The integration of the hygroscopic SCO material has endowed the composite sponge with the ability to capture moisture under ambient conditions. In particular, not only does a spin-crossover transition during absorption occur, but also a color variation has been achieved by varying humidity. The consequences of cooperativity and the exposed surface of the composite sponge on the spin transition were evaluated and the most promising materials among them were screened. This work provides guiding significance for the fabrication and practical application of spin-crossover-sponge materials.

Immune regulation and inflammation inhibition of Arctium lappa L. polysaccharides by TLR4/NF-κB signaling pathway in cells.

Arctium lappa L. polysaccharides (ALP) are important active ingredients of burdocks with various bioactivities. In the present study, a crude polysaccharide was extracted from A. lappa L. roots and purified using DEAE-52 and Sephacryl™ S-400 columns to reach 99 % purity. This neutral polysaccharide contained fructose, glucose, galactose and arabinose in a ratio of 0.675:0.265:0.023:0.016 and had a Mw of 4256 Da. The immunomodulatory activity and intestinal inflammation inhibitory effects of ALP were investigated in in vitro models, including lipopolysaccharide-induced macrophage RAW264.7 and interleukin (IL)-1ß-induced colon Caco-2 cells. The results revealed that ALP possessed both antioxidant and anti-inflammatory effects by decreasing nuclear factor-E2-related factor 2 mRNA expression and reactive oxygen species. Furthermore, ALP was found to have inhibitory effects on pro-inflammatory cytokines, including IL-8, IL-6, IL-1ß, and tumor necrosis factor-α, as well as inflammatory cytokines, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 by down-regulating the Toll-like receptor 4 (TLR4)/NF-κB (nuclear factor-kappa B signaling) pathway. It indicated that A. lappa L. was an ideal source of bioactive polysaccharides having potential to be developed as functional foods or nutraceuticals to improve immune system and prevent/treat intestinal inflammation.

Arctium lappa L. roots inhibit the intestinal inflammation of dietary obese rats through TLR4/NF-κB pathway.

Long-term consumption of Arctium lappa L. roots can lead to weight loss. To explore the relationship between anti-obesity and anti-inflammation, the effects and mechanism of A. lappa L. root powder (ARP) on intestinal inflammation in obese rats were investigated. Dietary obese rats were successfully established by feeding a high-fat and high-sugar diet. The control group (n = 6) consumed a normal diet. The intestines were compared among the groups (each n = 6) with and without the administration of ARP (intragastric 7.5 g/kg·bw/d). Real-time quantitative reverse transcription-polymerase chain reaction and western blotting analysis revealed that ARP effectively inhibited the expression of pro-inflammatory and inflammatory cytokines in the colons of obese rats. These cytokines included interleukin (IL)-1ß, IL-8, IL-6, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. The inhibition rates for all these cytokines exceeded 88 %. Moreover, ARP demonstrated the ability to down-regulate key genes involved in Toll-like receptor 4 (TLR4) complexes, namely Tlr4, myeloid differentiation protein-2 (Md2), and myeloid differentiation factor 88 (Myd88), along with downstream signaling molecules such as tumor necrosis factor receptor associated factor 6 (TRAF6) and nuclear factor-κB (NF-κB), with inhibition rates over 81 %. Additionally, ARP was observed to inhibit protein levels of TLR4, NF-κB, IL-1ß, and TNF-α in the colons of obese rats, with inhibition rates of 65.6 ± 10.9 %, 84.4 ± 19.9 %, 80.8 ± 14.4 %, and 68.4 ± 17.5 %, respectively. This study confirmed the effectiveness of ARP in inhibiting intestinal inflammation through the blockade of the TLR4/NF-κB signaling pathway. It also suggested that ARP holds potential in improving intestinal health in the context of obesity, implying its possible application in the prevention and treatment of obesity and related metabolic diseases.

Effects of epigallocatechin-3-gallate on oxidative stress, inflammation, and bone loss in a rat periodontitis model.

Background/purpose: Epigallocatechin-3-gallate (EGCG) is playing an increasingly important role in the treatment of oral diseases. However, its mechanisms remain to be clarified. This study aimed to investigate the effect of EGCG on oxidative and inflammatory stress and bone loss in experimental periodontitis. Materials and methods: Periodontitis was induced in rats, followed by gavage using different concentrations of EGCG for 5 weeks. The levels of interleukin-1ß (IL-1ß), interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD) and malondialdehyde (MDA) in rats were measured. The degree of alveolar bone loss and the number of inflammatory cells were detected. The integrated optical density of nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase-1 (HO-1), NLR pyrin domain-containing 3 (NLRP3) and nuclear factor-kappaB p65 (NF-κB p65) was measured. Results: EGCG (200 mg/kg) significantly reduced alveolar bone loss in the ligated maxillary molars and the number of inflammatory cells in the EGCG-200 group compared with the periodontitis, EGCG-100 and EGCG-400 groups. 200 mg/kg was the optimal dose of EGCG and was used in subsequent experiments. The expression levels of IL-1ß, IL-18, TNF-α and MDA were significantly lower and the expression level of SOD was significantly higher in the EGCG-200 group compared with the periodontitis group. The expression of NLRP3 and NF-κB p65 was significantly decreased, while the expression of Nrf2 and HO-1 was significantly increased in the EGCG-200 group compared with the periodontitis group. Conclusion: These results suggest that EGCG inhibits oxidative stress and inflammatory responses in the periodontitis model by modulating the Nrf2/HO-1/NLRP3/NF-κB p65 signaling pathway, thereby decreasing alveolar bone loss.

USP14 Positively Modulates Head and Neck Squamous Carcinoma Tumorigenesis and Potentiates Heat Shock Pathway through HSF1 Stabilization.

The ubiquitin-proteasome system is a pivotal intracellular proteolysis process in posttranslational modification. It regulates multiple cellular processes. Deubiquitinating enzymes (DUBs) are a stabilizer in proteins associated with tumor growth and metastasis. However, the link between DUBs and HNSCC remains incompletely understood. In this study, therefore, we identified USP14 as a tumor proliferation enhancer and a substantially hyperactive deubiquitinase in HNSCC samples, implying a poor prognosis prediction. Silencing USP14 in vitro conspicuously inhibited HNSCC cell proliferation and migration. Consistently, defective USP14 in vivo significantly diminished HNSCC tumor growth and lung metastasis compared to the control group. Luciferase assays indicated that HSF1 was downstream from USP14, and an evaluation of the cellular effects of HSF1 overexpression in USP14-dificient mice tumors showed that elevated HSF1 reversed HNSCC growth and metastasis predominantly through the HSF1-HSP pathway. Mechanistically, USP14 encouraged HSF1 expression by deubiquitinating and stabilizing HSF1, which subsequently orchestrated transcriptional activation in HSP60, HSP70, and HSP90, ultimately leading to HNSCC progression and metastasis. Collectively, we uncovered that hyperactive USP14 contributed to HNSCC tumor growth and lung metastasis by reinforcing HSF1-depedent HSP activation, and our findings provided the insight that targeting USP14 could be a promising prognostic and therapeutic strategy for HSNCC.

Phototransformation of extracellular polymeric substances in activated sludge and their interaction with microplastics.

Substantial amounts of extracellular polymeric substances (EPS) are present in sludge from wastewater treatment plants (WWTP), and EPS can significantly affect the fate, bioavailability, and toxicity of microplastics (MPs) that coexist in the effluent, however, the mechanism of action between EPS and microplastics remains unclear. In addition, ultraviolet (UV) disinfection is indispensable in the wastewater treatment process in WWTP, which can significantly affect the characteristics of EPS. Therefore, it is of great significance to study the photochemical characteristics of EPS and the effect on binding MPs. In this study, using multispectral technology and two-dimensional correlation spectroscopy analysis, indicates that the molecular weight and aromaticity of EPS after phototransformation were reduced. The results showed that the adsorption of EPS on PSMPs was in the order of TB-EPS > LB-EPS > S-EPS, which was positively correlated with the SUVA254, but negatively correlated with O/C of EPS. This indicates that the main adsorption mechanisms of PSMPs on EPS were π-π and hydrophobicity. The adsorption capacity of S-EPS, LB-EPS and TB-EPS to PSMPs decreased with the increasing of illumination time. After phototransformation, the adsorption sensitivity and reaction sequence of EPS and PSMPs did not change much. This research provides a theoretical basis for understanding the photochemical transformation of extracellular polymers and the morphology and migration of microplastics in sewage treatment, and evaluating the impact of microplastics on ecosystems.

Effect of microplastics on the binding properties of Pb(ii) onto dissolved organic matter: insights from fluorescence spectra and FTIR combined with two-dimensional correlation spectroscopy.

Heavy metal cations are a typical type of inorganic pollutant that has persistent distribution characteristics in aquatic environments and are easily adsorbed on carriers, posing serious threats to ecological safety and human health. Some studies have shown that the coexistence of dissolved organic matter (DOM) and microplastics (MPs) promotes the adsorption of heavy metal cations, but the mechanism of promoting the adsorption process has not been thoroughly studied. In this study, the effect of polystyrene microplastics (PSMPs) on the binding properties of Pb2+ onto humic acid (HA) in aquatic environments was investigated by spectral analysis and two-dimensional correlation (2D-COS) analysis. When PSMPs co-existed with HA, the adsorption capacity of Pb2+ increased. On the one hand, Pb2+ is directly adsorbed on HA through the mechanism of complexation reaction, ion exchange and electrostatic interaction. On the other hand, Pb2+ is first adsorbed on PSMPs by electrostatic action and indirectly adsorbed on HA in the form of PSMPs-Pb2+ owing to the interaction between HA and PSMPs, which increases the adsorption amount of Pb2+ on HA. This study is significant for studying the migration and regression of heavy metal cation contaminants when PSMPs co-exist with DOM in an aqueous environment.

Preparation of low molecular weight polysaccharides from Tremella fuciformis by ultrasonic-assisted H2O2-Vc method: Structural characteristics, in vivo antioxidant activity and stress resistance.

Different methods were used to degrade Tremella fuciformis polysaccharides (TFP) and prepare low molecular weight polysaccharides of Tremella fuciformis (TFLP) to improve their bioavailability. It was found that the TFLP prepared by ultrasonic-assisted H2O2-Vc method showed the highest level of antioxidant activity and stress resistance in C. elegans. The structural characteristics, in vivo antioxidant and stress resistance of TFLP-1 were evaluated after isolation and purification of TFLP, it was found that TFLP-1 was an acid polysaccharide with a molecular weight of 75770 Da, which mainly composed of mannose. Meanwhile, it could regulate the antioxidant activity and stress resistance in C. elegans by upregulating the transcription of fat-5, fat-7, acs-2, glp-1, hsf-1, hsp-1, mtl-1, nhr-49, skn-1 and sod-3 mRNA. The improvement effects were closely related to the significant regulation of galactose metabolism, alpha linolenic acid metabolism, and pantothenate and CoA biosynthesis metabolic pathways. These results provided insights into the high value application of Tremella fuciformis in the food industry and the development of antioxidant related functional foods.

Rapid imaging and product screening with low-cost line-field Fourier domain optical coherence tomography.

Fourier domain optical coherence tomography (FD-OCT) is a well-established imaging technique that provides high-resolution internal structure images of an object at a fast speed. Modern FD-OCT systems typically operate at speeds of 40,000-100,000 A-scans/s, but are priced at least tens of thousands of pounds. In this study, we demonstrate a line-field FD-OCT (LF-FD-OCT) system that achieves an OCT imaging speed of 100,000 A-scan/s at a hardware cost of thousands of pounds. We demonstrate the potential of LF-FD-OCT for biomedical and industrial imaging applications such as corneas, 3D printed electronics, and printed circuit boards.

Large-scale biomonitoring of bisphenol analogues and their metabolites in human urine from Guangzhou, China: Implications for health risk assessment.

Bisphenol analogues (BPs) are ubiquitous in the environment and have gained significant attention regarding their associated health risks. However, there is a lack of comprehensive biomonitoring data on BPs and their metabolites in human urine. To address this, we conducted a study evaluate the exposure to BPs in the general population of Guangzhou, China. A total of 1440 urine samples were collected from volunteers and analyzed for the presence of BPs and their metabolites after being pooled into 36 groups based on age and gender. The findings revealed the common detection of ten free-form BPs, as well as the urinary metabolites of BPA and BPS, in the pooled urine samples. BPA was the predominant free-form compound, constituting 50% of the total BPs. The primary urinary metabolites of BPA and BPS are BPA-G and BPS-G, respectively, indicating glucuronidation as their primary metabolic pathway. The composition of urinary metabolites of BPA and BPS varied by age and sex, while the concentration of total BPs in urine was not significantly associated with age and sex. Enzymatic hydrolysis yielded a mean amplification of individual BPs concentrations in urine samples ranging from 1.8 times (BPA) to 4.6 times (BPS). Based on the outcomes, it was estimated that conjugated forms accounted for 96.9%, 96.2%, 94.7%, 94.1%, 92.6%, 89.1%, 87.3%, 87.2%, 87.1% and 85.8% of BPP, BPAF, BPZ, BPE, BPAP, BPF, BPA, BPC, BPS and BPF, respectively, in the pooled urine samples. Preliminary risk assessments indicated that the estimated daily intake of BPA was much higher than the latest proposed tolerable daily intake. Due to the unavailability of health-based guideline values for alternative BPs, some of them exhibit daily intakes comparable to BPA, implying that greater attention should be paid to health risks associated with exposure to BPs.

YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells.

Fos-related antigen 1 (Fra-1) is a nuclear transcription factor that regulates cell growth, differentiation, and apoptosis. It is involved in the proliferation, invasion, apoptosis and epithelial mesenchymal transformation of malignant tumor cells. Fra-1 is highly expressed in gastric cancer (GC), affects the cycle distribution and apoptosis of GC cells, and participates in GC occurrence and development. However, the detailed mechanism of Fra-1 in GC is unclear, such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis. In this study, we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry. Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression, and affected GC cell proliferation. Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1 (HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells. Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation. These results will help to discover new molecular targets for the early diagnosis, treatment, and prognosis prediction of GC.

Effects of altered glycolysis levels on CD8+ T cell activation and function.

CD8+ T cells are an important component of the body's adaptive immune response. During viral or intracellular bacterial infections, CD8+ T cells are rapidly activated and differentiated to exert their immune function by producing cytokines. Alterations in the glycolysis of CD8+ T cells have an important effect on their activation and function, while glycolysis is important for CD8+ T cell functional failure and recovery. This paper summarizes the importance of CD8+ T cell glycolysis in the immune system. We discuss the link between glycolysis and CD8+ T cell activation, differentiation, and proliferation, and the effect of altered glycolysis on CD8+ T cell function. In addition, potential molecular targets to enhance and restore the immune function of CD8+ T cells by affecting glycolysis and the link between glycolysis and CD8+ T cell senescence are summarized. This review provides new insights into the relationship between glycolysis and CD8+ T cell function, and proposes novel strategies for immunotherapy by targeting glycolysis.