New-generation advanced PROTACs as potential therapeutic agents in cancer therapy.

Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit the endogenous E3 ubiquitin ligases to facilitate degradation of the proteins of interest (POIs) through the ubiquitin-proteasome system (UPS) in a cyclic catalytic manner. Despite recent endeavors to advance the utilization of PROTACs in clinical settings, the majority of PROTACs fail to progress beyond the preclinical phase of drug development. There are multiple factors impeding the market entry of PROTACs, with the insufficiently precise degradation of favorable POIs standing out as one of the most formidable obstacles. Recently, there has been exploration of new-generation advanced PROTACs, including small-molecule PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, to improve the in vivo efficacy of PROTACs. These improved PROTACs possess the capability to mitigate undesirable physicochemical characteristics inherent in traditional PROTACs, thereby enhancing their targetability and reducing off-target side effects. The new-generation of advanced PROTACs will mark a pivotal turning point in the realm of targeted protein degradation. In this comprehensive review, we have meticulously summarized the state-of-the-art advancements achieved by these cutting-edge PROTACs, elucidated their underlying design principles, deliberated upon the prevailing challenges encountered, and provided an insightful outlook on future prospects within this burgeoning field.

The development of biosensors for alkaline phosphatase activity detection based on a phosphorylated DNA probe.

Alkaline phosphatase (ALP) is a zinc-containing metalloprotein that shows very great significance in clinical diagnosis, which can catalyze the hydrolysis of phosphorylated species. ALP has the potential to serve as a valuable biomarker for detecting liver dysfunction and bone diseases. On the other hand, ALP is an efficient biocatalyst to amplify detection signals in the enzyme-linked assay. It has always been a major research focus to develop novel biosensors that can detect ALP activity with high selectivity and sensitivity. There have been numerous reports on the development of biosensors to determine ALP activity using a phosphorylated DNA probe. Among them, various beneficial strategies, such as λ exonuclease-mediated cleavage reaction, terminal deoxynucleotidyl transferase-triggered DNA polymerization, and Klenow fragment polymerase-catalyzed elongation, are employed to generate amplified and more intuitive signal. This review discusses and summarizes the development and advances of biosensors for ALP activity detection that use a well-designed phosphorylated DNA probe, aiming to provide some guidelines for the design of more sophisticated sensing strategies that exhibit improved sensitivity, selectivity, and adaptability in detecting ALP activity.

Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial.

The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470-0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414-0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579 .

Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities.

A new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 µM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 µM and 5 µM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 µM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 µM, 0.24 µM, and 0.36 µM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnß349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski's rule of five.

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7.

Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3ß, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1ß, IL-6, JAG2, KCNJ2, MALT1, ß-MHC, NF-κB, PCK1, PLCß1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

Clinical advances in TNC delivery vectors and their conjugate agents.

Tenascin C (TNC), a glycoprotein that is abundant in the tumor extracellular matrix (ECM), is strongly overexpressed in tumor tissues but virtually undetectable in most normal tissues. Many TNC antibodies, peptides, aptamers, and nanobodies have been investigated as delivery vectors, including 20A1, α-A2, α-A3, α-IIIB, α-D, BC-2, BC-4 BC-8, 81C6, ch81C6, F16, FHK, Ft, Ft-NP, G11, G11-iRGD, GBI-10, 19H12, J1/TN1, J1/TN2, J1/TN3, J1/TN4, J1/TN5, NJT3, NJT4, NJT6, P12, PL1, PL3, R6N, SMART, ST2146, ST2485, TN11, TN12, TNFnA1A2-Fc, TNfnA1D-Fc, TNfnBD-Fc, TNFnCD-Fc, TNfnD6-Fc, TNfn78-Fc, TTA1, TTA1.1, and TTA1.2. In particular, BC-2, BC-4, 81C6, ch81C6, F16, FHK, G11, PL1, PL3, R6N, ST2146, TN11, and TN12 have been tested in human tissues. G11-iRGD and simultaneous multiple aptamers and arginine-glycine-aspartic acid (RGD) targeting (SMART) may be assessed in clinical trials because G11, iRGD and AS1411 (SMART components) are already in clinical trials. Many TNC-conjugate agents, including antibody-drug conjugates (ADCs), antibody fragment-drug conjugates (FDCs), immune-stimulating antibody conjugates (ISACs), and radionuclide-drug conjugates (RDCs), have been investigated in preclinical and clinical trials. RDCs investigated in clinical trials include 111In-DTPA-BC-2, 131I-BC-2, 131I-BC-4, 90Y-BC4, 131I81C6, 131I-ch81C6, 211At-ch81C6, F16124I, 131I-tenatumomab, ST2146biot, FDC 131I-F16S1PF(ab')2, and ISAC F16IL2. ADCs (including FHK-SSL-Nav, FHK-NB-DOX, Ft-NP-PTX, and F16*-MMAE) and ISACs (IL12-R6N and 125I-G11-IL2) may enter clinical trials because they contain components of marketed treatments or agents that were investigated in previous clinical studies. This comprehensive review presents historical perspectives on clinical advances in TNC-conjugate agents to provide timely information to facilitate tumor-targeting drug development using TNC.

3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines inhibit tubulin polymerisation and act as anticancer agents.

A series of cis-restricted 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines as novel tubulin polymerisation inhibitors was designed based on molecular docking. Compound 9p, exhibited potent antiproliferative activity against HeLa, MCF-7, and A549 cell lines. Mechanism studies indicated that 9p potently inhibited tubulin polymerisation and disrupted the microtubule dynamics of tubulin in HeLa cells. Moreover, 9p could cause G2/M phase cell cycle arrest and apoptosis in HeLa cells. In addition, the prediction of physicochemical properties disclosed that 9p conformed well to the Lipinski's rule of five. The initial results suggest that the 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines could serve as a promising scaffold for the development of novel anticancer drugs.

Research on robust fault-tolerant control of the controllable suspension based on knowledge-data fusion driven.

For the robust fault-tolerant control of the controllable suspension system, a control strategy driven by knowledge-data fusion is proposed. Firstly, the boundary fuzziness between perturbation type uncertainty and gain type fault is analyzed, and then a data-driven method is introduced to avoid the state estimation of system uncertainty and fault. The proximal policy optimization algorithm in reinforcement learning is selected to construct a "data control law", to deal with uncertainty and fault. On the other hand, based on the classical sky-hook control, the "knowledge control law" for system performance optimization is designed, taking into account the nonlinear and non-stationary characteristics of the system. Furthermore, the dependency between robust fault tolerance and performance optimization control is revealed, and the two control laws are fused by numerical multiplication, to realize the performance matching optimization control of robust fault tolerance of controllable suspension system driven by knowledge-data fusion. Finally, the effectiveness and feasibility of the proposed method are verified by the simulation and real-time experiment of non-stationary excitation and near-stationary excitation under the combination of uncertainty and fault.

Overview of nanozymes with phosphatase-like activity.

Nanomaterials with intrinsic enzyme activity, referred to as nanozymes, have attracted substantial attention in recent years. Among them, phosphatase-mimicking nanozymes have become an increasingly important focus for future research, considering that phosphatase is not only one of key enzymes for phosphorous metabolism, which is essential for many biological processes (e.g., cellular regulation and signaling), but also one of extensively used biocatalytic labels in the enzyme-linked assays as well as a powerful tool enzyme in molecular biology laboratories. Nevertheless, compared with extensive oxidoreductase-mimicking nanozymes, there are a very limited number of nanozymes with phosphatase-like activity have been explored at present. The increasing demand of complex and individualized phosphatase-involved catalytic behaviors is pushing the development of more advanced phosphatase-mimicking nanozymes. Thus, we present an overview on recently reported phosphatase-like nanozymes, providing guidelines and new insights for designing more advanced phosphatase-mimicking nanozyme with superior properties.

The ratio of monocyte count and high-density lipoprotein cholesterol mediates the association between urinary tungsten and cardiovascular disease: a study from NHANES 2005-2018.

Tungsten (W) is an emerging contaminant that can damage multiple systems in humans. However, studies of its effects on cardiovascular disease (CVD) are limited. The monocyte count to high-density lipoprotein cholesterol ratio (MHR) is a composite inflammatory index of great concern in recent years, derived from lipid and cell inflammation parameters, that is used to indicate the risk of CVD. This study aimed to investigate the association between urinary W and CVD in the general population and compare the mediating effects of lipids, cell inflammatory parameters, and MHR to find a better target for intervention. We analyzed data from 9137 (≥ 20 years) participants in the National Health and Nutrition Examination Survey (NHANES), from 2005 to 2018. Restricted cubic splines (RCS) and survey-weighted generalized linear models (SWGLMs) were used to assess the relationship between W and CVD. Mediated analyses were used to explore lipids, cell inflammatory parameters, and MHR in the possible mediating pathways between W and CVD. In SWGLM, we found that W enhances the risk of CVD, especially congestive heart failure (CHF), coronary heart disease (CHD), and angina pectoris (AP). Women, higher age groups (≥ 55 years), and those with hypertension were vulnerable to W in the subgroup analysis. Mediation analysis showed that monocyte count (MC), white blood cell count (WBC), high-density lipoprotein cholesterol (HDL), and MHR played a mediating role between W and CVD in proportions of 8.49%, 3.70%, 5.18%, and 12.95%, respectively. In conclusion, our study shows that urinary W can increase the risk of CVD, especially for CHF, CHD, and AP. Women, older age groups, and people with hypertension seem to be more vulnerable to W. In addition, MC, WBC, HDL, and MHR mediated the association between W and CVD, especially MHR, which suggests that we should consider it as a priority intervention target in the future.

The global burden of schizophrenia and the impact of urbanization during 1990-2019: An analysis of the global burden of disease study 2019.

BACKGROUND AND HYPOTHESIS: The burden of schizophrenia is increasing. Assessing the global distribution of schizophrenia and understanding the association between urbanization factors and schizophrenia are crucial. STUDY DESIGN: We conducted a two-stage analysis utilizing public data from GBD (global burden of disease) 2019 and the World Bank. First, the distribution of schizophrenia burden at the global, regional, and national levels as well as temporal trends was analyzed. Then, four composite indicators of urbanization (including demographic, spatial, economic, and eco-environment urbanization) were constructed from ten basic indicators. Panel data models were used to explore the relationship between urbanization indicators and the burden of schizophrenia. RESULTS: In 2019, there were 23.6 million people with schizophrenia, an increase of 65.85% from 1990, and the country with the largest ASDR (age-standardized disability adjusted life years rate) was the United States of America, followed by Australia, and New Zealand. Globally, the ASDR of schizophrenia rose with the sociodemographic index (SDI). In addition, six basic urbanization indicators including urban population proportion, employment in industry/services proportion, urban population density, the population proportion in the largest city, GDP, and PM2.5 concentration were positively associated with ASDR of schizophrenia, with the largest coefficients being urban population density. Overall, demographic, spatial, economic, and eco-environment urbanization all had positive effects on schizophrenia, and the estimated coefficients indicated that demographic urbanization was the most significant influence. CONCLUSIONS: This study provided a comprehensive description of the global burden of schizophrenia and explored urbanization as a factor contributing to the variation in the burden of schizophrenia, and highlighted policy priorities for schizophrenia prevention in the context of urbanization.

Characterization of airborne microplastics at different workplaces of the poly(ethylene:propylene:diene) (EPDM) rubber industry.

Microplastics (MPs) as an emerging air pollutant have received widespread attention, but research on airborne MPs at occupational sites is still limited, especially in the rubber industry. Hence, indoor air samples were collected from three production workshops and an office of a rubber factory producing automotive parts to analyze the characteristics of airborne MPs in different workplaces of this industry. We found MP contamination in all air samples from the rubber industry, and the airborne MPs at all sites mainly showed small-sized (< 100 µm) and fragmented characteristics. The abundance and source of MPs at various locations is primarily related to the manufacturing process and raw materials of the workshop. The abundance of MPs in the air was higher in workplaces where production activities are involved than in office (360 ± 61 n/m3), of which the highest abundance of airborne MPs was in the post-processing workshop (559 ± 184 n/m3). In terms of types, a total of 40 polymer types were identified. The post-processing workshop has the largest proportion of injection-molded plastic ABS, the extrusion workshop has a greater proportion of EPDM rubber than the other locations, and the refining workshop has more MPs used as adhesives, such as aromatic hydrocarbon resin (AHCR).

The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis.

Cholesterol levels are an initiating risk factor for atherosclerosis. Many genes play a central role in cholesterol synthesis, including HMGCR, SQLE, HMGCS1, FDFT1, LSS, MVK, PMK, MVD, FDPS, CYP51, TM7SF2, LBR, MSMO1, NSDHL, HSD17B7, DHCR24, EBP, SC5D, DHCR7, IDI1/2. Especially, HMGCR, SQLE, FDFT1, LSS, FDPS, CYP51, and EBP are promising therapeutic targets for drug development due to many drugs have been approved and entered into clinical research by targeting these genes. However, new targets and drugs still need to be discovered. Interestingly, many small nucleic acid drugs and vaccines were approved for the market, including Inclisiran, Patisiran, Inotersen, Givosiran, Lumasiran, Nusinersen, Volanesorsen, Eteplirsen, Golodirsen, Viltolarsen, Casimersen, Elasomeran, Tozinameran. However, these agents are all linear RNA agents. Circular RNAs (circRNAs) may have longer half-lives, higher stability, lower immunogenicity, lower production costs, and higher delivery efficiency than these agents due to their covalently closed structures. CircRNA agents are developed by several companies, including Orna Therapeutics, Laronde, and CirCode, Therorna. Many studies have shown that circRNAs regulate cholesterol synthesis by regulating HMGCR, SQLE, HMGCS1, ACS, YWHAG, PTEN, DHCR24, SREBP-2, and PMK expression. MiRNAs are essential for circRNA-mediated cholesterol biosynthesis. Notable, the phase II trial for inhibiting miR-122 with nucleic acid drugs has been completed. Suppressing HMGCR, SQLE, and miR-122 with circRNA_ABCA1, circ-PRKCH, circEZH2, circRNA-SCAP, and circFOXO3 are the promising therapeutic target for drug development, specifically the circFOXO3. This review focuses on the role and mechanism of the circRNA/miRNA axis in cholesterol synthesis in the hope of providing knowledge to identify new targets.

Built environment and schizophrenia re-hospitalization risk in China: A cohort study.

BACKGROUND: Built environment exposure, characterized by ubiquity and changeability, has the potential to be the prospective target of public health policy. However, little research has been conducted to explore its impact on schizophrenia. This study aimed to investigate the association between built environmentand and schizophrenia rehospitalization by simultaneously considering substantial built environmental exposures. METHODS: We recruited eligible schizophrenia patients from Hefei, Anhui Province, China between 2017 and 2019. The main outcome for this study was the time interval until the first recurrent hospital admission occurred within one year after discharge. For each included subject, we estimated the built environment exposures, including population density, walkability, land use mix, green and blue space, public transportation accessibility and road traffic indicator. Lasso (Least Absolute Shrinkage and Selection Operator) analysis was used to select the key variables. Multivariable Cox regression model was applied to obtain hazard ratio (HR) and its corresponding 95% confidence intervals (CI). Further, we also evaluated the joint effects of built environment characteristics on rehospitalization for schizophrenia by Quantile g-computation model. RESULTS: A total of 1564 hospitalized schizophrenia patients were enrolled, with 347 patients (22.2%) had a rehospitalization within one-year after discharge. Multivariable Cox regression analysis indicated that the re-hospitalization rate for schizophrenia would be higher in areas with a high population density (HR: 1.10, 95%CI: 1.04-1.16). Nonetheless, compared to the reference (Q1), participants who lived in a neighborhood with the highest walkability and NDVI (Normalized Difference Vegetation Index) (Q4) had a 76% and 47% lower risk of re-hospitalization within one year (HR:0.24, 95%CI: 0.13-0.45; and 0.53, 95%CI:0.32-0.85), respectively. Moreover, quantile-based g-computation analyses revealed that increased walkability and green space significantly eliminated the adverse effects of population density increases on schizophrenia patients, with a HR ratio of 0.61 (95%CI:0.48,0.79) per one quartile change at the same time. CONCLUSION: Our study provides scientific evidence for the significant role of built environment in schizophrenia rehospitalization, suggesting that optimizing the built environment is required in designing and building a healthy city.

Sunshine duration and risks of schizophrenia hospitalizations in main urban area: Do built environments modify the association?

BACKGROUND: Although studies have explored the relationship between sunshine duration and schizophrenia, the evidence was ambiguous. Different built environments may alter the effect of sunlight on schizophrenia, thus the purpose of this study was to investigate the effects of built environments on the sunshine duration-schizophrenia association. MATERIALS AND METHODS: Daily schizophrenia hospitalizations data during 2017-2020 in Hefei's main urban area, China, and corresponding meteorological factors as well as ambient pollutants were collected. The impact of sunshine duration on schizophrenia admissions in urban areas was investigated using a generalized additive model combined with a distributed lagged nonlinear model. Additionally, the various modifying effects of different Building Density, Building Height, Normalized Vegetation Index, and Nighttime Light were also explored between sunshine duration and schizophrenia. RESULTS: We observed that inadequate sunshine duration (<5.3 h) was associated with an increase in schizophrenia hospital admissions, with a maximum relative risk of 1.382 (95 % confidence interval (CI): 1.069-1.786) at 2.9 h. In turn, adequate sunshine duration reduced the risk of schizophrenia hospitalizations. Subgroup analyses indicated females and old patients were particularly vulnerable. In the case of insufficient sunshine duration, significant positive effects were noticed on schizophrenia risk at High-Building Density and High-Nighttime Light. Higher NDVI as well as Building Height were found to be associated with lower risks of schizophrenia. CONCLUSIONS: Given that sunshine duration in various built environments might lead to distinct effects on schizophrenia hospitalizations. Our findings assist in identifying vulnerable populations that reside in particular areas, thus suggesting policymakers provide advice to mitigate the onset of schizophrenia by allocating healthcare resources rationally and avoiding adverse exposures to vulnerable populations timely.

Phenotypic aging mediates the association between blood cadmium and depression: a population-based study.

Depression is a serious public health problem today, especially in middle-aged and older adults. Although the etiology of the disease has not been fully elucidated, environmental factors are increasingly not negligible. Cadmium is widely used in industrial production. The general population may be chronically exposed to low doses of cadmium. This study aimed to investigate the association between blood cadmium and depression and to explore the mediating role of aging indicators in this process. We conducted a cross-sectional study on blood cadmium (N = 7195, age ≥ 20 years) using data from the 2007-2010 National Health and Nutrition Examination Survey (NHANES). Aging indicators (biological and phenotypic age) are calculated by combining multiple biochemical and/or functional indicators. To determine the relationship between blood cadmium concentrations and depressive symptoms, we used weighted multivariate logistic regression and restricted cubic spline functions and employed mediation analysis to explore the possible mediating effects of aging indicators in the process. We found a significant positive association between blood cadmium and depression with an odds ratio (OR) and 95% confidence interval (CI): 1.22 (1.04,1.43). Restricted cubic spline analysis found a linear positive association between blood cadmium and depression. In the fully covariate-adjusted model, we found a positive association between blood cadmium and biological age and phenotypic age with ß and 95% CI: 1.02 (0.65, 1.39) and 2.35 (1.70, 3.01), respectively. In the mediation analysis, we found that phenotypic age mediated 21.32% of the association between blood cadmium and depression. These results suggest that even exposure to low doses of cadmium can increase the risk of depression and that this process may be mediated by phenotypic aging.

Associations of polycyclic aromatic hydrocarbons, water-soluble ions and metals in PM2.5 with liver function: Evidence from schizophrenia cohort.

BACKGROUND: Fine particulate matter (PM2.5) was reported to impact liver function, but the roles of specific PM2.5 chemical components remained to be explored. Besides, severe liver dysfunction in schizophrenia patients deserves attention. OBJECTIVE: To investigate the associations of short-term PM2.5 components with liver function in schizophrenia patients. METHODS: A repeated-measures study based on schizophrenia cohort including 1023 visits (n = 446) was conducted during 2017-2020. Liver function was reflected by 10 indicators including liver enzymes, proteins and bilirubin et al. Monitoring data of PM2.5 and its components, including 16 polycyclic aromatic hydrocarbons (PAHs), 4 water-soluble ions and 10 metals were collected. Linear mixed effect and Bayesian kernel machine regression (BKMR) models were used to evaluate the single and combined effects of PM2.5 components (0-3 day) on liver function in schizophrenia patients. RESULTS: Several PAHs were significantly associated with liver enzymes, while water-soluble ions and metal components had almost no association. Specifically, with per interquartile range (IQR) increased in Fluoranthene, levels of alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) increased by 2.06 %, 5.07 %, 4.94 % and 5.56 %, respectively. An IQR increases in Benzo[a]pyrene was significantly associated with 6.62 %, 3.67 % and 7.83 % increase in ALT, AST and GGT. Almost all PAHs, sulfate, nitrate, ammonium, Sb, Al, As, Pb, Mn and Tl were positively associated with albumin (ALB). Phenanthrene was associated with increased levels of direct bilirubin (DBIL) and total bilirubin (TBIL). The combined effects of significant PM2.5 components on ALP, GGT, ALB, globulin (GLOB), ratio of albumin to globulin (A/G), TBIL and total bile acid (TBA) were found by BKMR, respectively. CONCLUSIONS: Findings highlight the short-term combined effects of PM2.5 components, especially PAHs, on liver function in schizophrenia patients, which contribute to the management of PM2.5 sources including combustion activities and traffic emissions as well as improving schizophrenia comorbidities.

The impact of hazes on schizophrenia admissions and the synergistic effect with the combined atmospheric oxidation capacity in Hefei, China.

OBJECTIVES: Currently, most epidemiological studies on haze focus on respiratory diseases, cardiovascular diseases, etc. However, the relationship between haze and mental health has not been adequately explored. The purpose of this study was to investigate the influence of hazes on schizophrenia admissions and to further explore the potential interaction effect with the combined atmospheric oxidative indices (Ox and Oxwt). METHODS: We collected 5328 cases during the cold season from 2013 to 2015 in Hefei, China. By integrating the Poisson Generalized Linear Models with the Distributed Lag Non-linear Models, the association between haze and schizophrenia admissions was evaluated. The interaction between hazes and two combined oxidation indexes was tested by stratifying hazes and Ox, and Oxwt. RESULTS: Haze was found to be significantly linked to an increased risk of hospitalization for schizophrenia, and a 9-day lag effect on schizophrenia (lag 3-lag 11), with the largest effect on lag 6 (RR = 1.080, 95% confidence interval (CI): 1.046-1.116). Males, females, and <40 y (people under 40 years old) were sensitive to hazes. Furthermore, in the stratified analysis, we found synergies between two combined oxidation indexes and hazes. The interaction relative risk (IRR) and relative excess risk due to interaction (RERI) between Ox and hazes were 1.170 (95% CI: 1.071-1.277) and 0.149 (95% CI: 0.045-0.253), respectively. For Oxwt, the IRR and RERI were 1.179 (95% CI: 1.087-1.281) and 0.159 (95% CI: 0.056-0.263), respectively. It is noteworthy that this synergistic effect was significant in males and <40 y when examining the various subgroups in the interaction analysis. CONCLUSIONS: Our findings suggest that exposure to haze significantly increases the risk of hospitalization for schizophrenia. More significant public health benefits can be obtained by prioritizing haze periods with high combined atmospheric oxidation capacity.

Effects of urban particulate matter on gut microbiome and partial schizophrenia-like symptoms in mice: Evidence from shotgun metagenomic and metabolomic profiling.

BACKGROUND: Epidemiological evidence reported that particulate matter (PM) was associated with increased schizophrenia (SCZ) risk. Disturbance of gut microbiome was involved in SCZ. However, it remains unclear whether PM induces SCZ-like symptoms and how gut microbiome regulates them. Therefore, a multi-omics animal experiment was conducted to verify how urban PM induces SCZ-like behavior and altered gut microbiota and metabolic pathways. METHODS: Using a completely random design, mice were divided into three groups: PM group, control group and MK801 group, which received daily tracheal instillation of PM solution, sterile PBS solution and intraperitoneal injection of MK801 (establish SCZ model), respectively. After a 14-day intervention, feces were collected for multi-omics testing (shotgun metagenomic sequencing and untargeted metabolomic profiling), followed by open field test, tail suspension test, and passive avoidance test. Besides, fecal microbiome of PM group and control group were transplanted into "pseudo-sterile" mice, then behavioral tests were conducted. RESULTS: Similar to MK801 group, mice in PM group showed SCZ-like symptoms, including increased spontaneous activity, excitability, anxiety and decreased learning and spatial memory. PM exposure significantly increased the relative abundance of Verrucomicrobia and decreased that of Fibrobacteres et al. The metabolism pathways of estrogen signaling (estriol, 16-glucuronide-estriol and 21-desoxycortisol) and choline metabolism (phosphocholine) were significantly altered by PM exposure. Verrucomicrobia was negatively correlated with the level of estriol, which was correlated with decreased learning and spatial memory. Fibrobacteres and Deinococcus-Thermus were positively correlated with the level of phosphocholine, which was correlated with increased spontaneous activity, excitability and anxiety. Fecal microbiome transplantation from PM group mice reproduced excitability and anxiety symptoms. CONCLUSIONS: Exposure to PM may affect composition of gut microbiome and alterations of estrogen signaling pathway and choline metabolism pathway, which were associated with partial SCZ-like behaviors. But whether gut microbiome regulates these metabolic pathways and behaviors remains to be determined.

Association between organophosphorus pesticide exposure and depression risk in adults: A cross-sectional study with NHANES data.

Organophosphorus pesticides (OPPs) are widely used pesticides, and previous studies showed that OPPs can increase the risk of central nervous system disorders (e.g., Parkinson's and Alzheimer's disease). However, few studies have comprehensively explored their association with depression in general adults. We analyzed data from 5206 participants aged 20 years or more based on four National Health and Nutrition Examination Survey (NHANES) cycles. OPPs exposure was estimated using measures of urinary concentrations for six OPPs metabolites. Survey-weighted generalized linear regression model (SWGLM) was used to explore the association of OPPs metabolites with depression. Subgroup analyses were performed by age (≦60 years and >60 years) and gender. The weighted quantile sum (WQS) regression model was used to explore the overall association of six OPPs metabolites with depression. In addition, The Bayesian kernel machine regression (BKMR) model was applied to investigate the interaction and joint effects of multiple OPPs metabolites with depression. The SWGLM showed that dimethyl phosphate (DMP) and dimethyl thiophosphate (DMTP), whether taken as continuous or quartile variables, had a positive correlation with depression. Diethyl phosphate (DEP) and dimethyl dithiophosphate (DMDTP) in the highest quartile were positively associated with depression compared to the lowest quartile. In subgroup analysis, we found that the effects of the above chemicals on depression existed in the male and young middle-aged population, while DMP was present in the female. There was a significant combined overall effect of six OPPs metabolites with depression [OR = 1.232, 95%CI: (1.011, 1.504)] in WQS. Furthermore, the BKMR model also showed a positive trend in the overall effect of six OPPs metabolites with depression. In conclusion, our results suggest that exposure to OPPs may increase the risk of depression in US adults. Men and young and middle-aged populations are more vulnerable to OPPs and the mixture of OPPs metabolites may induce depression.