Accumulation characteristics and fate modeling of phthalic acid esters in surface water from the Three Gorges Reservoir area, China.

Phthalic acid esters (PAEs) are a group of compounds widespread in the environment. To investigate the occurrence and accumulation characteristics of PAEs, surface water samples were collected from the Three Gorges Reservoir area, China. The total concentrations of 11 analyzed PAEs (∑11PAEs) in the collected water samples ranging from 197.7 to 1,409.3 ng/L (mean ± IQR: 583.1 ± 308.4 ng/L). While DEHP was the most frequently detected PAE, DnBP and DnNP were the most predominant PAEs in the analyzed water samples with a mean contribution of 63.3% of the ∑11PAEs. The concentrations of the ∑11PAEs in the water samples from the upper reaches of the Yangtze River were significantly higher than those from the middle reaches. To better understand the transport and fate of the PAEs, seven detected PAEs were modeled by Quantitative Water Air Sediment Interaction (QWASI). The simulated and measured values were close for most PAEs, and differences are within one order of magnitude even for the worst one. For all simulated PAEs, water and particle inflow were main sources in the reservoir, whereas water outflow and degradation in water were important removal pathways. The contribution ratios of different sources/losses varied from PAEs, depending on their properties. The calculated risk quotients of DnNP in the Three Gorges Reservoir area whether based on monitoring or simulating results were all far exceeded the safety threshold value, implying the occurrence of this PAE compound may cause potential adverse effects for the aquatic ecology of the Three Gorges Reservoir area.

Combined intestinal microbiota and transcriptomic analysis to investigate the effect of different stocking densities on the ability of Pacific white shrimp (Litopenaeus vannamei) to utilize Chlorella sorokiniana.

Aiming to investigate the impact of different stocking densities on the ability of Pacific white shrimp (Litopenaeus vannamei) to utilize Chlorella sorokiniana (CHL), a 3 × 2 factorial design stocking experiment was used in this study. Specifically, shrimp was fed with two dietary protein sources (fishmeal [FM] and CHL) at low (LSD; 100 per m3), medium (MSD; 200 per m3) and high (HSD; 300 per m3) stocking densities for 8 weeks. The growth performance and resistance to Vibrio parahaemolyticus (1.0 × 107 CFU/mL) of shrimp decreased with the increase of stocking density, but dietary CHL improved this result. Differences between the CHL and FM groups for V. parahaemolyticus resistance were significant only under high-density conditions (P < 0.05). Significant interactions between stocking density and protein source were found on the activities of catalase (CAT), superoxide dismutase (SOD) and phenol oxidase (PO), and the contents of malondialdehyde (MDA) in the hepatopancreas and the activities of intestinal amylase, most of which were significantly different between CHL and FM groups only at high stocking density (P < 0.05). Analysis of 16S rDNA sequencing showed that dietary CHL increased the alpha diversity of intestinal microbiota, inhibited the colonization of pathogenic bacteria and enhanced the abundance of beneficial bacteria. Transcriptomic results showed that at high stocking densities, differentially expressed genes (DEGs) in the FM vs CHL group were mostly upregulated and primarily enriched in immune and metabolic related pathways including Toll, immune deficiency (Imd) and glycolysis-gluconeogenesis pathways. Pearson correlation analysis revealed significant correlation between the top ten intestinal bacteria at the genus level and markedly enriched DEGs, also more were detected under high density situations. In conclusion, CHL has great potential as a novel protein source in the intensive farming of shrimp.

Assessment of psychometric properties of the union physio-psycho-social assessment questionnaire (UPPSAQ-70) in a large sample of general hospital psychiatric outpatients.

OBJECTIVE: To evaluate the psychometric properties of the Union Physio-Psycho-Social Assessment Questionnaire (UPPSAQ-70) among general hospital psychiatric outpatients. METHODS: A total of 2000 participants responded to the survey. Factor analyses were used to test the construct validity of the scale. Convergent validity was evaluated by the correlation between UPPSAQ-70 and symptoms measured using the Chinese versions of Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Patient Health Questionnaire-15 (PHQ-15), Somatic Symptom Disorder - B Criteria Scale (SSD-12) and Pittsburgh Sleep Quality Index (PSQI). RESULTS: The nine-factor model was supported (χ2 = 8816.395, df = 2309, χ2/df = 3.818, RMSEA = 0.053, CFI = 0.929). The UPPSAQ-70 showed significant correlation with the SAS (r = 0.396, P < .001), SDS (r = 0.451, P < .001), PHQ-15 (r = 0.381, P < .001), SSD-12 (r = 0.324, P < .001) and PSQI (r = 0.220, P < .001). UPPSAQ-70 and its subscales showed good internal consistency with Cronbach's alpha coefficients ranging from 0.79 to 0.96. CONCLUSIONS: The UPPSAQ-70 was a rating scale with good construct validity and reliability, which can measure overall health in the biological, psychological, and social domains for Chinese psychiatric outpatients, but its convergent validity still requires further empirical research.

Treatment expectations of patients and clinicians: a cross-sectional study.

Importance: Understanding treatment expectations of patients and their clinicians is of great importance in improving personalized medical services and enhancing patient safety systems. Objective: To investigate treatment expectations of patients and their clinicians and compare differences between both, by using a pair of validated structured assessment tools covering three key aspects/dimensions of clinical interests. Design setting and participants: This single-center cross-sectional study was conducted at Peking Union Medical College Hospital in China. The study enrolled patients aged 16 years and older receiving inpatient care and their clinicians. Patient recruitment was conducted from March 2023 to November 2023. Assessments: In addition to demographic and clinical characteristics, this study employed two validated structured assessment tools to evaluate treatment expectations among patients and their clinicians: the Hospitalized Patients' Expectations for Treatment Scale-Patient version (HOPE-P) and its counterpart, the Hospitalized Patients' Expectations for Treatment Scale-Clinician version (HOPE-C). Results: A total of 233 patients (mean [SD] age, 52.3 [15.1] years; 108 [46.4%] female) along with their clinicians, who numbered 75 in total were enrolled in this study. The distribution of total scores for HOPE-P and HOPE-C displayed similar patterns, with most scores concentrated in the higher range (above 50% of the full score). The mean HOPE-P total score was higher than that of HOPE-C (mean [SD] score, 38.78 [4.86] vs 37.49 [4.32]; t = 3.12, P = 0.002). In Dimension 2, the HOPE-P score was higher than HOPE-C (23.67 [3.20] vs 21.72 [3.03]; t = 6.98, P < 0.001). However, in Dimensions 1 and 3, HOPE-P scored lower than HOPE-C (13.37 [2.44] vs 13.84 [1.73]; t = -2.384, P < 0.018; 1.74 [1.14] vs 1.94 [1.00]; t = -2.00, P = 0.047). Certain demographic and clinical characteristics led to variations in patients' treatment expectations, including marital status, monthly family income, and smoking history. Conclusions and relevance: This cross-sectional study revealed significant differences between patients' and doctors' treatment expectations. Notably, it highlighted the need for clinicians to focus on rationalizing patients' expectations concerning treatment outcomes. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2300075262.

ß-Methylation of Primary Alcohols with Methanol Catalyzed by a Metal-Ligand Bifunctional Iridium Catalyst.

The development of efficient methods for the direct introduction of a methyl group into molecules is becoming increasingly important. Herein, the ß-methylation of primary alcohols with methanol has been accomplished under environmentally benign conditions using [Cp*Ir(2,2'-bpyO)(H2O)] as a catalyst. It was found that functional groups in the ligand are crucially important for the activity of the iridium complex. Furthermore, the mechanistic research and application potential of our catalytic system are also presented.

Legacy and novel brominated flame retardants in outdoor settled dusts and pine needles in a megacity of Eastern China: Interpretation of plant uptake.

Brominated flame retardants, considered emerging contaminants, are widespread and persist in the environment. This study investigated the contamination of legacy and novel brominated flame retardants in paired outdoor settled dusts and pine needles sampled from a megacity in the Eastern China. The measured total concentrations of PBDEs (∑27PBDEs) in outdoor settled dusts and pine needles were in the range of 77.4-345.2 ng/g dw and 20.7-120.0 ng/g dw, respectively, and equivalent ranges for novel brominated flame retardants (∑11NBFRs) were 25.7-1917.2 ng/g dw and 9.4-38.7 ng/g dw, respectively. BDE-209 and DBDPE dominated PBDEs and NBFRs profiles, respectively, in both dusts and pine needles. Outdoor settled dusts exhibited greater potentials to accumulate high-brominated PBDE homologues and EH-TBB while pine needles tended to accumulate low-brominated PBDE homologues, BTBPE and TBC. The plant uptake of BFRs was interpreted by McLachlan's framework on the assumption that the levels of BFRs in outdoor settled dusts and particle phase of air were positively correlated. The accumulation of PBDEs in pine needles was dominated by equilibrium partitioning between the vegetation and the gas phase when log KOA values <10 and by particle-bound deposition when log KOA values >13. However, NBFRs exhibited more complicated accumulation behavior. The predicted 50th percentile of the estimated daily intakes of ∑27PBDEs via outdoor settled dusts exposure for adults and children were 3.5 × 10-2 and 1.4 × 10-1 ng/kg body weight (bw)/day, respectively, and equivalent values for ∑11NBFRs were 1.6 × 10-2 ng/kg bw/day and 6.3 × 10-2 ng/kg bw/day, respectively. The calculated hazard index (HI) values were far <1, indicating exposure of BFRs via outdoor settled dust intake would not pose potential non-carcinogenic health risks to both adults and children.

Liraglutide ameliorates high glucose-induced vascular endothelial injury through TRIB3/NF-κB signaling pathway.

As one of the most commonly used antidiabetic medications clinically, liraglutide is involved in the protection of vascular endothelium, and whether it can relieve high glucose-induced vascular endothelial damage was unknown. This study aims to address the response of liraglutide (LIRA) on human umbilical vein endothelial cells, as well as to elucidate its possible underlying mechanism. We established a vascular endothelial cell injury model by exposing human umbilical vein endothelial cells (HUVECs) to high glucose, and used LIRA pretreatment before HG treatment to address the endothelial protective effect of LIRA. Our results suggest that LIRA prevented HG-induced HUVEC apoptosis, oxidative stress, inflammasome activation, and pyroptosis. Furthermore, silencing of tribbles homolog 3 (TRIB3) could markedly reduce HG-induced HUVEC apoptosis, ROS level, the expressions of TXNIP, cleaved caspase3, NLRP3, and caspase1, indicating TRIB3 inhibition protected HUVECs against HG-induced vascular endothelial injury. In addition, LIRA restrained NF-κB/IκB-α signaling pathway activation in HUVECs. Thus, LIRA appears to mitigate HG-induced apoptosis, oxidative stress, inflammasome activation, and pyroptosis in HUVECs via regulating the TRIB3/NF-κB/IκB-α signaling pathway. Our study provides new insight into the mechanisms underlying the protective activity of LIRA against the vascular endothelial injury in diabetic vascular complication.

Understanding the Role of Technology Anxiety in the Adoption of Digital Health Technologies (DHTs) by Older Adults with Chronic Diseases in Shanghai: An Extension of the Unified Theory of Acceptance and Use of Technology (UTAUT) Model.

The unprecedented rapid growth of digital health has brought new opportunities to the health field. However, elderly patients with chronic diseases, as an important potential beneficiary group, are affected by the digital divide, leading to unsatisfactory usage of digital health technologies (DHTs). Our study focused on the factors influencing the adoption of DHTs among this vulnerable group. To extend the UTAUT theory, technology anxiety and several demographic predictors were included to address the age characteristics of the respondents. An on-site survey was conducted in general, district, and community hospitals in Shanghai (n = 309). Facilitating conditions negatively influenced technology anxiety. Technology anxiety hindered behavioural intention. Social influence had a significant but negative impact on behavioural intention. Education, whether older adults have had experience with DHTs and previous smartphone usage experiences were significantly associated with technology anxiety. The findings provide valuable information for multiple stakeholders, including family members of elderly users, product designers, and policymakers. Ameliorating facilitating conditions, improving devices' usage experience, encouraging attempts and focusing on groups with lower educational levels can help to reduce technology anxiety and promote DHT acceptance and use in older age groups.

CD4+ T-cell subsets are associated with chronic stress effects in newly diagnosed anxiety disorders.

Aim: Prior research has indicated a connection between CD4+ T cells and the development of anxiety, but the specific CD4+ T cell subsets linked to anxiety disorders remain uncertain. Our study seeks to investigate the relationship between distinct CD4+ T cell subsets and anxiety, as well as to explore whether CD4+ T cell subsets mediate the effect of chronic psychological stress on anxiety. Methods: 56 eligible matched participants were recruited in Peking Union Medical College Hospital. The diagnosis was made based on DSM-5 diagnostic criteria. The severity of anxiety and depression symptoms was assessed using the Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale, respectively. The Life Events Scale (LES) evaluated the chronic stress level. CD4+ T cell subsets were characterized using multiparametric flow cytometry. To assess the impact of CD4+ T cells on the effect of chronic psychological stress on anxiety, Partial Least Squares Structural Equation Modeling (PLS-SEM) analysis was employed. Results: We discovered fifteen notably distinct CD4+ T-cell subsets in anxiety disorder patients compared to healthy controls. Multiple linear regression analysis unveiled an association between anxiety severity and CD27+CD45RA- Th cells, CD27+CD28+ Tregs, and the total Life Events Scale (LES) score. The PLS-SEM analysis demonstrated that CD4+ T cell subsets and LES could explain 80.2% of the variance in anxiety. Furthermore, it was observed that CD27+CD28+ Th/Treg cells acted as inverse mediators of the effects of LES on anxiety (P = 0.031). Conclusions: Drug naïve anxiety disorder patients exhibited significant alterations in numerous CD4+ T-cell subsets. Specifically, the memory subset of CD27+CD45RA- Th cells and the naïve subset of CD27+CD28+ Treg cells were found to be independent factors associated with the severity of anxiety. Additionally, the CD27+CD28+ Th and Treg cell subsets played a significant mediating role in the influence of long-term psychological stress on anxiety.

Prognostic significance of pyrimidine metabolism-related genes as risk biomarkers in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), as a malignancy derived from liver tissue, is typically associated with poor prognosis. Increasing evidence suggests a connection between pyrimidine metabolism and HCC progression. The purpose of this study was to establish a model applied to the prediction of HCC patients' overall survival. Transcriptomic data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) website. Pyrimidine metabolism-related genes (PMRGs) were collected from the Gene Set Enrichment Analysis (GSEA) website. Differential gene expression analysis was carried out on the HCC data, followed by an intersection of the differentially expressed genes (DEGs) and PMRGs. Subsequently, a prognostic model incorporating nine genes was established using univariate/multivariate Cox regression and Least absolute shrinkage and selection operator (LASSO) regression. Survival analysis demonstrated that the high-risk group defined by this model had considerably shorter overall survival than the low-risk group in both TCGA and Gene Expression Omnibus (GEO) datasets. Receiver operating characteristic (ROC) analysis indicated the good predictive capability of the model. CIBERSORT and single sample gene set enrichment analysis (ssGSEA) algorithms revealed significantly higher levels of Macrophages M0 and lower levels of natural killer (NK)_cells in the high-risk group compared to the low-risk group. The immunophenoscore (IPS) and the tumor immune dysfunction and exclusion (TIDE) score demonstrated that the model could significantly differentiate patients who would be more suitable for immunotherapy. Moreover, the CellMiner database was utilized to predict anti-tumor drugs significantly associated with the model genes. Collectively, the potential prognostic significance of pyrimidine metabolism in HCC was revealed in this study. The prognostic model aids in evaluating the survival time and immune status of HCC patients.

Selective N-Alkylation of Aminobenzenesulfonamides with Alcohols for the Synthesis of Amino-(N-alkyl)benzenesulfonamides Catalyzed by a Metal-Ligand Bifunctional Ruthenium Catalyst.

[(p-Cymene)Ru(2,2'-bpyO)(H2O)] was proven to be an efficient catalyst for the synthesis of amino-(N-alkyl)benzenesulfonamides via selective N-alkylation of aminobenzenesulfonamides with alcohols. It was confirmed that functional groups in the bpy ligand are crucial for the activity of catalysts. Furthermore, the utilization of this catalytic system for the preparation of a biologically active compound was presented.

Formulation and Characterization of Triamcinolone Acetonide Acetate-Loaded Microspheres Prepared by a Static Mixing Technique.

PURPOSE: Reproducibility and scale-up production of microspheres through spray drying present significant challenges. In this study, biodegradable microspheres of Triamcinolone Acetonide Acetate (TAA) were prepared using a novel static mixing method by employing poly( lactic-co-glycolic acid) (PLGA) as the sustained-release carrier. METHODS: TAA-loaded microspheres (TAA-MSs) were prepared using a static mixing technique. The PLGA concentration, polyvinyl alcohol concentration (PVA), phase ratio of oil/water, and phase ratio of water/solidification were optimized in terms of the particle size, drug loading (DL), and encapsulation efficiency (EE) of TAA-MSs. The morphology of TAA-MSs was examined using Scanning Electron Microscopy (SEM), while the physicochemical properties were evaluated through X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC), and Fourier Transform Infrared Spectroscopy (FT-IR). The in vitro release of TAA-MSs was compared to that of the pure drug (TAA) using a water-bath vibration method in the medium of pH 7.4 at 37°C. RESULTS: The formulation composition and preparation condition for the preparation of TAA-MSs were optimized as follows: the PLGA concentration was 1%, the phase ratio of oil(dichloromethane) /water (PVA solution) was 1:3, the phase ratio of water (PVA solution)/solidification was 1:2. The optimized TAA-MSs displayed spherical particles with a size range of 30-70 µm, and DL and EE values of 27.09% and 98.67%, respectively. Moreover, the drug-loaded microspheres exhibited a significant, sustained release, with 20% of the drug released over a period of 28 days. The XRD result indicated that the crystalline form of TAA in microspheres had been partly converted into the amorphous form. DSC and FT-IR results revealed that some interactions between TAA and PLGA occurred, indicating that the drug was effectively encapsulated into PLGA microspheres. CONCLUSION: TAA-loaded PLGA microspheres have been successfully prepared via the static mixing technique with enhanced EE and sustained-release manner.

Crafting Docetaxel-Loaded Albumin Nanoparticles Through a Novel Thermal-Driven Self-Assembly/Microfluidic Combination Technology: Formulation, Process Optimization, Stability, and Bioavailability.

Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges. Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated. Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX. Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.

Decoding hotline's information with text-mining: A protocol for improving tobacco control in Shanghai.

Tobacco consumption in China remains the primary cause of preventable mortality, with Shanghai being particularly affected by issues related to secondhand smoke exposure. This study explores the role of the public service hotline 12345, a grassroots initiative in Shanghai, in capturing public sentiment and assessing the effectiveness of anti-smoking regulations. Our research aims to accurately and deeply understand the implementation and feedback of smoking control policies: by identifying high-frequency points and prominent issues in smoking control work based on the smoking control work order data received by the health hotline 12320. The results of this study will assist government enforcement agencies in improving smoking monitoring and clarify the direction for improving smoking control measures. Text-mining techniques were employed to analyze a dataset comprising 78011 call sheets, all related to tobacco control and collected from the hotline between 1 January 2015 and 31 December 2019. This methodological approach aims to uncover prevalent themes and sentiments in the public discourse on smoking and its regulation, as reflected in the hotline interactions. Our study identified hotspots and the issues of greatest concern to citizens. Additionally, it provided recommendations to enforcement agencies to enhance their capabilities, optimize the allocation of human resources for smoking control monitoring, reduce enforcement costs and support for anti-smoking campaigns, thereby contributing to more effective tobacco control policies in the region.

Occurrence and profiles of perfluoroalkyl substances in wastewaters of chemical industrial parks and receiving river waters: Implications for the environmental impact of wastewater discharge.

A total of 17 groups of wastewaters from the chemical industrial parks and matched receiving river waters were collected in the east of China. The measured total concentrations of 21 analyzed PFAS analogues (∑21PFAS) in the influents and effluents of the wastewater treatment plants (WWTPs) were in the range of 0.172-20.6 µg/L (mean: 18.2 µg/L, median: 3.9 µg/L) and 0.167-93.6 µg/L (mean: 10.8 µg/L, median: 1.12 µg/L), respectively, which were significantly higher than those observed in the upstream (range: 0.0158-7.05 µg/L, mean: 1.09 µg/L, median: 0.482 µg/L) and downstream (range: 0.0237-1.82 µg/L, mean: 0.697 µg/L, median: 0.774 µg/L) receiving waters. Despite the concentrations and composition profiles of PFAS varied in the water samples from different sampling sites, PFOA was generally the major PFAS analogue in the research areas, mainly due to the history of PFOA production and usage as well as the specific exemptions. The calculated concentration ratios of the short-chain PFCAs and PFSAs to their respective predecessors (PFOA and PFOS) in most of the samples far exceeded 1, indicating a shift from legacy PFOA and PFOS to short-chain PFAS in the research areas. Correlation network analysis and the calculated concentration ratios of PFAS in the effluents versus influents indicated transformation may have occurred during the water treatment processes and PFAS could not be efficiently removed in the WWTPs. Wastewater discharge of chemical industrial parks is a vital source of PFAS dispersed into the aquatic environment.

SGLT2 inhibition, venous thrombolism, and death due to cardiac causes: a mediation Mendelian randomization study.

Objective: To investigate the causal role of venous thrombolism mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in death due to cardiac causes using Mendelian randomization (MR). Methods: A two-sample two-step MR was used to determine (1) the causal effects of SGLT2 inhibition on death due to cardiac causes; (2) the causal effects of venous thrombolism on death due to cardiac causes; and (3) the mediation effects of venous thrombolism. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Additionally, employing MR to investigate the causal association between SGLT2 inhibition and cardiac arrest as well as coronary heart disease (CHD). Results: SGLT2 inhibition was associated with a lower risk of death due to cardiac causes (odds ratio [OR] = 0.983, [95% CI = 0.972, 0.993], P = 0.0016). Venous thrombolism was associated with death due to cardiac causes ([OR] = 1.031, [95% CI = 1.005, 1.057], P = 0.0199). Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on death due to cardiac causes through venous thrombolism [ß = -0.0015, (95% CI = -0.0032 -0.0002), P = 0.042], with a mediated proportion of 8.9% (95% CI = 1.2%, 18.7%) of the total. Furthermore, SGLT2 inhibition was linked to a lower risk of cardiac arrest ([OR] = 0.097, [95% CI = 0.013, 0.742], P = 0.025). SGLT2 inhibition was linked to a lower risk of CHD ([OR] = 0.957, [95% CI = 0.932, 0.982], P = 0.0009). Conclusions: Our study identified the causal roles of SGLT2 inhibition in venous thrombolism. SGLT2 inhibition may influence death due to cardiac causes through venous thrombolism. Additionally, SGLT2 inhibition was associated with reduced risk of cardiac arrest and CHD.

G-Quadruplex-Programmed Versatile Nanorobot Combined with Chemotherapy and Gene Therapy for Synergistic Targeted Therapy.

Developing synergistic targeted therapeutics to improve treatment efficacy while reducing side effects has proven promising for anticancer therapies, but how to conveniently modulate multidrug cooperation remains a challenge. Here, a novel synergistic strategy using a G-quadruplex-programmed versatile nanorobot (G4VN) containing two subunits of DNAzyme (DzG4) and ligand-drug conjugates (LDCs) is proposed to precisely target tumors and then execute both gene silencing and chemotherapy. As the core module of this nanorobot, a well-designed G4 responding to a high level of K+ in tumor microenvironment smartly kills three birds with one stone, which makes two TfR aptamers proximate to improve their efficiency of targeting tumor cells, and in situ activates a split 10-23 DNAzyme to downregulate target mRNA expression, meanwhile promotes the cell uptake of a GSH-responsive LDCs to enhance drug efficacy. Such a design enables a potently synergistic anticancer therapy with low side effects in vivo, showing great promise for broad applications in precision disease treatment.

Cardiac-specific PFKFB3 overexpression prevents diabetic cardiomyopathy via enhancing OPA1 stabilization mediated by K6-linked ubiquitination.

Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.

SGLT2 inhibition, plasma proteins, and heart failure: a proteome-wide Mendelian Randomization and colocalization study.

Objective: To investigate the causal contributions of Sodium-glucose cotransporter 2 (SGLT2) inhibition on Heart Failure (HF) and identify the circulating proteins that mediate SGLT2 inhibition's effects on HF. Methods: Applying a two-sample, two-step Mendelian Randomization (MR) analysis, we aimed to estimate: (1) the causal impact of SGLT2 inhibition on HF; (2) the causal correlation of SGLT2 inhibition on 4,907 circulating proteins; (3) the causal association of SGLT2 inhibition-driven plasma proteins on HF. Genetic variants linked to SGLT2 inhibition derived from the previous studies. The 4,907 circulating proteins were derived from the deCODE study. Genetic links to HF were obtained through the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium. Results: SGLT2 inhibition demonstrated a lower risk of HF (odds ratio [OR] = 0.44, 95% CI [0.26, 0.76], P = 0.003). Among 4,907 circulating proteins, we identified leucine rich repeat transmembrane protein 2 (LRRTM2), which was related to both SGLT2 inhibition and HF. Mediation analysis revealed that the impact of SGLT2 inhibition on HF operates indirectly through LRRTM2 [ß = -0.20, 95% CI (-0.39, -0.06), P = 0.02] with a mediation proportion of 24.6%. Colocalization analysis provided support for the connections between LRRTM2 and HF. Conclusion: The study indicated a causative link between SGLT2 inhibition and HF, with plasma LRRTM2 potentially serving as a mediator.