Proteomic insights from extracellular vesicles into the molecular mechanisms of health effects induced by Per- and polyfluoroalkyl substances.

Per- and polyfluoroalkyl substances (PFASs) can induce a range of adverse health effects, with the precise molecular mechanisms remaining elusive. Extracellular vesicles (EVs) have demonstrated their potential to elucidate unknown molecular mechanisms. Building upon the close alignment of their biological functions with the observed health effects of PFASs, this study innovatively focuses on proteomic insights from EVs into the molecular mechanisms underlying the systemic health effects of PFASs. Through rat exposure experiments and proteomics technology, it not only demonstrated the occurrence of PFASs in EVs but also revealed the alterations in the serum EVs and the expression of their protein cargos following mixed exposure to PFASs, leading to changes in related pathways. These changes encompass various biological processes, including proteasome activity, immune response, cytoskeletal organization, oxidative stress, cell signaling, and nervous system function. Particularly noteworthy is the uncovering of the activation of the proteasome pathway, highlighting significant key contributing proteins. These novel findings provide a new perspective for exploring the molecular mechanism underlying the systemic health effects of PFASs and offer reliable screening for potential biomarkers. Additionally, comparisons with serum confirmed the potential of serum EVs as biological responders and measurable endpoints for evaluating PFASs-induced toxicity.

HDAC7 promotes ovarian cancer malignancy via AKT/mTOR signalling pathway.

Ovarian cancer is of the most lethal malignancy and causes serious threat to women health worldwide. A deep understanding of molecular mechanisms underlying ovarian cancer progression is critical for the development of promising therapeutic strategies. In this study, we aimed to employ immunohistochemistry to determine the protein level of HDAC7 in patient tissues, our data showed HDAC7 levels are upregulated in tumour tissues. In addition, we also performed Kaplan-Meier survival analysis to investigate the association between HDAC7 expression and clinical prognosis, and found that HDAC7 expression was associated with poor prognosis in ovarian cancer patients. Inhibition of HDAC7 cells resulted in lower cell proliferation, invasion and colony formation. Furthermore, we also found that HDAC7 inhibition suppressed PI3K/AKT/mTOR pathway. In contrast, exogenous HDAC7 expression activated the PI3K/AKT/mTOR pathway in HDAC7 knockout cells and rescued the cell proliferation, invasion and colony formation. However, inhibition of p-AKT induced lower cell proliferation, metastasis and colony formation abilities. In murine model, HDAC7 KO significantly decreased the tumour burden. These data indicate that HDAC7 is involved in regulation of PI3K/AKT/mTOR pathway and targeting of HDAC7 could be potential therapeutic strategy in the treatment of ovarian cancer.

Effect of Multimorbidity on Old-Age Disability Among Adults Over 50 Years Old: Evidence From a Meta-Analysis.

This is a meta-analysis study to assess the relationship between multimorbidity and disability among older adults over 50 years old. Population-based studies, aged ≥ 50 years, assessing associations between multimorbidity (numbers and patterns) and disability in older adults, and reporting risk estimation with odds ratios (OR), were included. Homogeneity (I2), risk of bias, and publication bias were assessed. PROSPERO registration: 411007, and this meta-analysis was reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) recommendations. Twelve studies were included. For the older adults with 2 chronic conditions and ≥ 3 chronic conditions, the ORs of disability are 2.52 (95% CI 2.30-2.76) and 3.38 (95% CI 3.05-3.75), respectively. Among three multimorbidity patterns, the combination of cardiovascular and metabolic diseases pattern (OR 8.01, 95% CI 7.60-8.44) had the highest disability incidence rate. Chronic conditions in the multimorbidity patterns of combination of cardiovascular and metabolic diseases and mental health problems have an enhancement effect (1 + 1 > 2) on old-age disability impairment, whereas those in the multimorbidity pattern of musculoskeletal disorders have a dampening effect (1 + 1 < 2). The differentiated and specific early interventions should be developed based on the different multimorbidity patterns to prevent the old-age functional decline and disability in older adults.

Structural characteristics of a purified Evodiae fructus polysaccharide and its gastroprotection and relevant mechanism against alcohol-induced gastric lesions in rats.

Evodiae fructus polysaccharide (EFP) has been previously shown to protect against alcohol-induced gastric lesions. However, which and how active fractions in EFP exert gastroprotection remains unclear. This study aimed to characterize the structure of the purified fraction (EFP-2-1) of EFP, and investigate its gastroprotection and underlying mechanisms. EFP-2-1 was obtained through column chromatography, and was characterized using instrumental analytical techniques. Gastroprotective effect of EFP-2-1 was evaluated using alcohol-induced gastric lesions in rats, and its mechanism was explored through proteomics, metabolomics and diversity sequencing. Results showed that EFP-2-1 had a molecular weight of 7.3 kDa, and consisted mainly of rhamnose, galacturonic acid, galactose and arabinose. Its backbone contained HG and RG-I domains, and branched with →5)-α-l-Araf-(1→, α-l-Araf-(1→ and →4)-ß-d-Galp-(1→ residues. EFP-2-1 reduced gastric lesions and the levels of MDA, TNF-α and IL-6, activated PPARγ, primarily altered protein digestion and absorption and bile secretion metabolic pathways, regulated gut microbiota like Faecalibaculum and Lachnoclostridium, and increased short-chain fatty acids production. Correlations were observed among the gut microbiota, metabolites and biochemical indexes influenced by EFP-2-1. These findings suggest that EFP-2-1 is an active fraction of EFP for protecting against alcohol-induced gastric lesions, which may be linked to PPARγ activation, gut microbiota and serum metabolism.

[Retracted] Electroacupuncture attenuates cervical spinal cord injury following cerebral ischemia/reperfusion in stroke­prone renovascular hypertensive rats.

[This retracts the article DOI: 10.3892/etm.2014.1619.].

GDH1-catalytic glutaminolysis feedback activate EGFR/PI3K/AKT pathway and reprogram glioblastoma metabolism.

BACKGROUND: Glutamine is an important nutriment for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known. METHODS: Knockdown and overexpression cells were obtained to explore the functional roles of GDH1 in cell proliferation, tumor formation and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay and western blot were performed to verify the regulation of EGFR-AKT pathway by the glutamate dehydrogenase 1 (GDH1, also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis. RESULTS: Here, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3, and then promotes the activation of PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays important roles in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose condition dependent on KDM6A-mediated demethylation of H3K27. CONCLUSION: These findings suggest a novel function of glutaminolysis in regulation of signal transduction and metabolism reprograming, provide further evidence for unique role of glutaminolysis in GBM progression.

An in situ-activated and chemi-excited photooxygenation system based on G-poly(thioacetal) for Aß1-42 aggregates.

The abnormal aggregation of Aß proteins, inflammatory responses, and mitochondrial dysfunction have been reported as major targets in Alzheimer's disease (AD). Photooxygenation of the amyloid-ß peptide (Aß) is viewed as a promising therapeutic intervention for AD treatment. However, the limitations of the depth of the external light source passing through the brain and the toxic side effects on healthy tissues are two significant challenges in the photooxidation of Aß aggregates. We proposed a method to initiate the chemical stimulation of Aß1-42 aggregate oxidation through H2O2 and correct the abnormal microenvironment of the lesions by eliminating the cascading reactions of oxidative stress. The degradable G-poly(thioacetal) undergoes cascade release of cinnamaldehyde (CA) and thioacetal triggered by endogenous H2O2, with CA in turn amplifying degradation by generating more H2O2 through mitochondrial dysfunction. A series of novel photosensitizers have been prepared and synthesized for use in the photodynamic oxidation of Aß1-42 aggregates under white light activation. The nanoparticles (BD-6-QM/NPs) self-assembled from BD-6-QM, bis[2,4,5-trichloro-6-(pentoxycarbonyl) phenyl] ester (CPPO), and G-poly(thioacetal) not only exhibit H2O2-stimulated controlled release but also can be chemically triggered by H2O2 to generate singlet oxygen to inhibit Aß1-42 aggregates, reducing the Aß1-42-induced neurotoxicity.

NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.

Mitochondria are essential for cell metabolism and survival as they produce the majority of cellular ATP through oxidative phosphorylation as well as regulate critical processes such as cell proliferation and apoptosis. NIPSNAP family of proteins are predominantly mitochondrial matrix proteins. However, the molecular and cellular functions of the NIPSNAPs, particularly NIPSNAP3A, have remained elusive. Here, we demonstrated that NIPSNAP3A knockdown in HeLa cells inhibited their proliferation and migration and attenuated apoptosis induced by Actinomycin D (Act-D). These findings suggested a complex relationship between cellular processes and mitochondrial functions, mediated by NIPSNAP3A. Further investigations revealed that NIPSNAP3A knockdown not only inhibited mitochondrial fission through reduction of DRP1-S616, but also suppressed cytochrome c release in apoptosis. Collectively, our findings highlight the critical role of NIPSNAP3A in coordinating cellular processes, likely through its influence on mitochondrial dynamics.

A novel method for quality evaluation of Radix Angelica sinensis based on molecularly imprinted electrochemical sensor.

Rapid and sensitive detection of n-butylidenephthalide (NBP) is crucial for quality control of Radix Angelica Sinensis (RAS) and its related pharmaceuticals due to their shared pharmacological effects, such as immune enhancement and anti-tumor properties. Current detection methods struggle to quantify NBP quickly and accurately. A molecularly imprinted polymer (MIP)-based electrochemical sensor has been developed, forming a film on PCN-222(Fe) via electropolymerization for the rapid and selective detection of NBP. o-Phenylenediamine (o-PD) was polymerized onto PCN-222(Fe), utilizing its high surface area and porous structure to create a high-performance MIP (MIP/PCN-222(Fe)) sensor. This sensor detects NBP binding at the molecularly imprinted sites through a redox probe, with current changes reflecting the NBP content in the sample. This sensor exhibits a strong affinity for NBP, with a linear detection range from 200 nM to 1 mM, a detection limit of 76 nM, and high specificity towards similar phthalide compounds. Experimental results show that the MIP/PCN-222(Fe) sensor can accurately quantify NBP in real samples, offering a simplified method with promising applications for RAS quality evaluation.

USP36 SUMOylates Las1L and Promotes Its Function in Pre-Ribosomal RNA ITS2 Processing.

Ribosome biogenesis is a highly regulated cellular process requiring a large cohort of accessory factors to ensure the accurate production of ribosomes. Dysregulation of ribosome biogenesis is associated with the development of various human diseases, including cancer. The Las1L-Nol9 endonuclease-kinase complex is essential for the cleavage of the rRNA internal transcribed spacer 2 (ITS2), the phosphorylation of the 5'-hydroxyl end of the resulting precursor, and, thus, the maturation of the 60S ribosome. However, how the Las1L-Nol9 complex is regulated in cells is unclear. In this study, we report that the nucleolar ubiquitin-specific protease USP36 is a novel regulator of the Las1L-Nol9 complex. USP36 interacts with both Las1L and Nol9 and regulates their stability via deubiquitination. Intriguingly, USP36 also mediates the SUMOylation of Las1L, mainly at lysine (K) 565. Mutating K565 to arginine (R) does not affect the levels of Las1L and the formation of the Las1L-Nol9 complex, but abolishes its function in ITS2 processing, as unlike wild-type Las1L, the K565R mutant failed to rescue the defects in the ITS2 processing induced by the knockdown of endogenous Las1L. These results suggest that USP36-mediated Las1L SUMOylation is critical for ITS2 processing and that USP36 plays a critical role in ribosome biogenesis by regulating the Las1L-Nol9 complex. SIGNIFICANCE: This study identifies USP36 as a deubiquitinating and small ubiquitin-like modifier ligase dual-function enzyme to mediate Las1L deubiquitination and SUMOylation. Las1L SUMOylation at K565 plays a critical role in pre-rRNA ITS2 processing. Thus, our study reveals a novel downstream pathway for USP36-regulated ribosome biogenesis.

Uncertainty quantification in epigenetic clocks via conformalized quantile regression.

DNA methylation (DNAm) is a chemical modification of DNA that can be influenced by various factors, including age, environment, and lifestyle. An epigenetic clock is a predictive tool that measures biological age based on DNAm levels. It can provide insights into an individual's biological age, which may differ from their chronological age. This difference, known as the epigenetic age acceleration, may indicate the state of one's health and risk for age-related diseases. Moreover, epigenetic clocks are used in studies of aging to assess the effectiveness of anti-aging interventions and to understand the underlying mechanisms of aging and disease. Various epigenetic clocks have been developed using samples from different populations, tissues, and cell types, typically by training high-dimensional linear regression models with an elastic net penalty. While these models can predict mean biological age with high precision, there is a lack of uncertainty quantification which is important for interpreting the precision of age estimations and for clinical decision-making. To understand the distribution of a biological age clock beyond its mean, we propose a general pipeline for training epigenetic clocks, based on an integration of high-dimensional quantile regression and conformal prediction, to effectively reveal population heterogeneity and construct prediction intervals. Our approach produces adaptive prediction intervals not only achieving nominal coverage but also accounting for the inherent variability across individuals. By using the data collected from 728 blood samples in 11 DNAm datasets from children, we find that our quantile regression-based prediction intervals are narrower than those derived from conventional mean regression-based epigenetic clocks. This observation demonstrates an improved statistical efficiency over the existing pipeline for training epigenetic clocks. In addition, the resulting intervals have a synchronized varying pattern to age acceleration, effectively revealing cellular evolutionary heterogeneity in age patterns in different developmental stages during individual childhoods and adolescent cohort. Our findings suggest that conformalized high-dimensional quantile regression can produce valid prediction intervals and uncover underlying population heterogeneity. Although our methodology focuses on the distribution of aging in children, it is applicable to a broader range of populations to improve understanding of epigenetic age beyond the mean. This inference-based toolbox could provide valuable insights for future applications of epigenetic interventions for age-related diseases.

A method for the quantitative analysis of Lycium barbarum polysaccharides (LBPs) using Fourier-transform infrared spectroscopy (FTIR): From theoretical computation to experimental application.

Lycium barbarum polysaccharides (LBPs) is one of the most important active substances in Lycium barbarum (LB). It is a challenge to quantitatively determine the content due to their complex structures and lack of suitable reference standard in practice. In this study, a quantitative analysis method of LBPs in LB was established based on Fourier-transform infrared spectroscopy (FTIR). The stretching vibration of CO on the pyranose ring of saccharide at 921 cm-1 was selected as the characteristic absorption band by theoretical calculation, which can't be impacted by the preparation methods and interfered by the component monosaccharides. The molecular weight CRM of dextran (Mw 63.3 kDa) served as the reference standard. The introducing internal standard (KSCN) can obtain a good precision (RSD = 1.10 %) and effectively compensate for the analysis errors caused by the environment, quality loss and uneven distribution during the tablet pressing processes. The methodological verification suggested that the method had good accuracy according to the recovery rate (96.61 %-105.45 %) and the blank recovery (92.39 %-99.37 %), respectively. The LOD and LOQ of CRMD were 0.10 mg and 0.32 mg, respectively. The polysaccharide content of LB from 24 different regions (0.50-2.54 %) and 10 batches of LB extracts (7.09-10.56 %) determined by the developed method less than the ones using phenol-sulfuric acid assay (1.95 %-4.83 % for LB and 9.83-15.53 % for extracts, respectively). The established method based on FTIR could be served as a supplement to phenol-sulfuric acid assay and a rapid quantitative assay for polysaccharides products. In additional, this study provided a new idea for the quantitative analysis of plant polysaccharides.

Screening of promising molecules against potential drug targets in Yersinia pestis by integrative pan and subtractive genomics, docking and simulation approach.

This study focuses on Yersinia pestis, the bacterium responsible for plague, which posed a severe threat to public health in history. Despite the availability of antibiotics treatment, the emergence of antibiotic resistance in this pathogen has increased challenges of controlling the infections and plague outbreaks. The development of new drug targets and therapies is urgently needed. This research aims to identify novel protein targets from 28 Y. pestis strains by the integrative pan-genomic and subtractive genomics approach. Additionally, it seeks to screen out potential safe and effective alternative therapies against these targets via high-throughput virtual screening. Targets should lack homology to human, gut microbiota, and known human 'anti-targets', while should exhibit essentiality for pathogen's survival and virulence, druggability, antibiotic resistance, and broad spectrum across multiple pathogenic bacteria. We identified two promising targets: the aminotransferase class I/class II domain-containing protein and 3-oxoacyl-[acyl-carrier-protein] synthase 2. These proteins were modeled using AlphaFold2, validated through several structural analyses, and were subjected to molecular docking and ADMET analysis. Molecular dynamics simulations determined the stability of the ligand-target complexes, providing potential therapeutic options against Y. pestis.

A highly specific red-emitting fluorescent probe for monitoring of Cu2+ in living cells and zebrafish.

A novel seminaphthorhodafluor-based fluorescent probe was designed and prepared. It exhibited an outstanding off-on fluorescence response (about 45-fold enhancement) to Cu2+ because the structure changed from a spirocyclic form to a ring-open state. It showed satisfactory detection performances for Cu2+ with fast response speed, high selectivity and anti-interference, and a low detection limit (22.9 nM) due to its long emission wavelength and off-on fluorescence response mode. This probe was also satisfactorily applied for the monitoring of Cu2+ in living cells and zebrafish.

Impact of geochemistry and microbes on the methylmercury production in mangrove sediments.

Unraveling the geochemical and microbial controls on methylmercury (MeHg) dynamics in mangrove sediments is important, as MeHg can potentially pose risks to marine biota and people that rely on these ecosystems. While the important role of sulfate-reducing bacteria in MeHg formation has been examined in this ecologically important habitat, the contribution of non-Hg methylating communities on MeHg production remains particularly unclear. Here, we collected sediment samples from 13 mangrove forests in south China and examined the geochemical parameters and microbial communities related to the Hg methylation. MeHg concentrations were significantly correlated to the OM-related parameters such as organic carbon content, total nitrogen, and dissolved organic carbon concentrations, suggesting the importance of OM in the MeHg production. Sulfate-reducing bacteria were the major Hg-methylators in mangrove sediments. Desulfobacteraceae and Desulfobulbaceae dominated the Hg-methylating microbes. Classification random forest analysis detected strong co-occurrence between Hg methylators and putative non-Hg methylators, thus suggesting that both types of microorganisms contribute to the MeHg dynamics in the sediments. Our study provides an overview of MeHg contamination in south China and advances our understanding of Hg methylation in mangrove ecosystems.

Causal association between mental disorders and cerebrovascular diseases: Evidence from Mendelian randomization study.

BACKGROUND AND OBJECTIVE: Observational studies have suggested that mental disorders and cerebrovascular diseases (CVDs) may be risk factors for each other, but genetic evidence of a causal relationship is still lacking. We used Mendelian randomization (MR) studies to explore the causal relationship between mental disorders and CVDs from the genetic perspective. METHODS: To investigate the causal association between major depressive disorder (MDD), anxiety, attention deficit/hyperactivity disorder (ADHD), bipolar disorder and schizophrenia five kinds of mental disorders and CVDs using two-sample two-way MR analysis based on publicly available genome-wide association study (GWAS) data. We used as instrumental variables (IVs) single-nucleotide polymorphisms (SNPs) that were strongly associated with mental disorders and CVDs. IVW method was used as the main analysis method, and MR-IVW, MR-Egger methods, MR-PRESSO test, leave-one-out analysis and funnel plot were used for sensitivity analysis. We further conducted a meta-analysis to summarize the currently available MR analyses. RESULTS: The results of forward MR study showed that there was a significant causal relationship between ADHD and AS (any stroke) (p(AS) = 0.001, OR (95%CI) =1.118 (1.047-1.195)), any ischemic stroke (AIS) (p(AIS) = 0.004, OR (95%CI) =1.118(1.035-1.206)) and large artery stroke (LAS) (p(LAS) = 0.026, OR (95%CI): 1.206(1.023-1.422)). No heterogeneity, pleiotropy and outliers were found in sensitivity analysis. The reverse MR study showed that IA (intracranial aneurysm) (p(IA) = 0.033, OR (95%CI) = 1.123(1.009-1.249)) and UIA (unruptured intracranial aneurysm) (p(UIA) = 0.015, OR (95%CI) =1.040(1.008-1.074)) were risk factors for schizophrenia. Sensitivity analysis showed no pleiotropy, but there was heterogeneity. After excluding outliers, MR analysis showed that IA and UIA were still risk factors for schizophrenia. Our meta-analyses found statistical significance in causal relationships between ADHD and LAS (OR (95%CI) =1.18 (1.06-1.32), p = 0.003), IA and schizophrenia (OR (95%CI) =1.05 (1.02-1.08), p = 0.002) and UIA and schizophrenia (OR (95%CI) =1.03 (1.01-1.06), p = 0.010). CONCLUSION: The MR study and meta-analysis suggest that genetically predicted ADHD is a risk factor for LAS, and IA and UIA increase the risk of schizophrenia. The result has implications for the development of feasible prevention strategies in the future.

Elastin-like polypeptide-functionalized nanobody for column-free immunoaffinity purification of aflatoxin B1.

A column-free immunoaffinity purification (CFIP) technique for sample preparation of aflatoxin B1 (AFB1) was developed using an AFB1-specific nanobody (named G8) and an elastin-like polypeptide (ELP). The reversible phase transition between liquid and solid in response to temperature changes was exhibited by the ELP which was derived from human elastin. The G8 was tagged with ELPs of various lengths (20, 40, 60, and 80 repeat units) at the C-terminus using recursive directional ligation (RDL). Coding sequences were then subcloned into pET30a at the multiple cloning sites. Bioactive recombinant proteins were produced by expressing them as inclusion bodies in Escherichia coli BL21 (DE3), then dissolved and refolded. Analysis by indirect competitive enzyme-linked immunosorbent assay (icELISA) and transition temperature (Tt) measurement confirmed that the refolded G8-ELPs preserved the ability to recognize AFB1 as well as phase transition when the temperature rose above Tt. To establish the optimal conditions for cleaning AFB1, the effects of various parameters on recovery were investigated. The recovery in ELISA tests was 95 ± 3.67% under the optimized CFIP workflow. Furthermore, the CFIP-prepared samples were applied for high-performance liquid chromatography (HPLC) detection. The recovery in the CFIP-HPLC test ranged from 54 ± 1.86% to 98 ± 3.58% for maize, rice, soy sauce, and vegetable oil samples. To the best of our knowledge, this is the first report combining the function of both nanobody and ELP to develop a cleanup technique for small molecules in a complex matrix. The CFIP for the sample pretreatment was easy to use and inexpensive. In contrast to conventional immunosensitivity materials, the reagent utilized in the CFIP was entirely biosynthesized without any chemical coupling reactions. This suggests that the nanobody-ELP may serve as a useful dual-functional reagent for the development of sample cleaning or purification methods.

Effort-reward imbalance and well-being among psychiatric nurses: the mediating role of burnout and decent work.

BACKGROUND: Psychiatric nurses face additional challenges due to negative perceptions, workplace violence, and a lack of respect, impacting their well-being and job satisfaction, which are crucial for improving psychiatric care and patient outcomes. OBJECTIVES: This study aims to examine the relationship between effort-reward imbalance, well-being, burnout, and decent work among psychiatric nurses. METHODS: This study used a cross-sectional design. Data were collected using a convenience sampling method in February 2024 from 397 psychiatric nurses at two psychiatric hospitals in Hangzhou and Huzhou, Zhejiang Province. The Effort-Reward Imbalance Scale, Decent Work Perception Scale, Maslach Burnout Inventory-General Survey, and General Well-Being Schedule Scale were used for data collection. Data analysis was conducted using SPSS 26.0 and the PROCESS macro. RESULTS: The study found that effort-reward imbalance among psychiatric nurses was negatively correlated with decent work (r = -0.564, p < 0.001) and well-being (r = -0.541, p < 0.001), and positively correlated with burnout (r = 0.603, p < 0.001). Burnout mediated the relationship between effort-reward imbalance and well-being (95% CI [-0.386, -0.257]), while decent work also served as a mediator (95% CI [-0.100, -0.012]). Additionally, burnout and decent work were found to mediate the relationship between effort-reward imbalance and well-being (95% CI [-0.050, -0.006]). CONCLUSION: This study highlights the impact of effort-reward imbalance on well-being, confirming that burnout and decent work serve as mediators. Enhancing support, fair compensation, reasonable work schedules, and professional development can promote psychiatric nurses' perception of decent work and improve their well-being.

Design of Auto-Adaptive Drug Delivery System for Effective Delivery of Peptide Drugs to Overcoming Mucus and Epithelial Barriers.

Oral administration of peptide represents a promising delivery route, however, it is hindered by the harsh gastrointestinal environment, leading to low in vivo absorption. In this study, auto-adaptive protein corona-AT 1002-cationic liposomes (Pc-AT-CLs) are constructed with the characteristic of hydrophilic and electrically neutral surface properties for the encapsulation of liraglutide. BSA protein corona is used to coat AT-CLs reducing the adherence of mucus, and may fall off after penetrating the mucus layer. Transmucus transport experiment demonstrated that the mucus penetration amount of Pc-AT-CLs are 1.45 times that of AT-CLs. After penetrating the mucus layer, AT-CLs complete transmembrane transport by the dual action of AT and cationic surface properties. Transmembrane transport experiment demonstrated that the apparent permeability coefficient (Papp) of AT-CLs is 2.03 times that of CLs. In vivo tests demonstrated that Pc-AT-CLs exhibited a significant hypoglycemic effect and enhanced the relative bioavailability comparing to free liraglutide. Pc-AT-CLs protect liraglutide from degradation, facilitate its absorption, and ultimately improve its oral bioavailability.

Macrophages regulate plaque progression in diabetic Apoe-/- mice dependent on Pi4p/Nlrp3 signaling pathway.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. METHODS: The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe-/-) and Apoe-/- DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe-/- mice to explore the effects on atherosclerosis. RESULTS: DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe-/- mice. CONCLUSIONS: Our data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.