Discovery of N-Substituted Acetamide Derivatives as Promising P2Y14R Antagonists Using Molecular Hybridization Based on Crystallographic Overlay.

P2Y14 receptor (P2Y14R) is activated by uridine 5'-diphosphate-glucose, which is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y14R antagonists and the crystallographic overlap study between the reported P2Y14R antagonist compounds 6 and 9, a series of N-substituted-acetamide derivatives were designed, synthesized, and identified as novel and potent P2Y14R antagonists. The most potent antagonist, compound I-17 (N-(1H-benzo[d]imidazol-6-yl)-2-(4-bromophenoxy)acetamide, IC50 = 0.6 nM) without zwitterionic character, showed strong binding ability to P2Y14R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In vitro and in vivo evaluation demonstrated that compound I-17 had satisfactory inhibitory activity on the inflammatory response of monosodium urate (MSU)-induced acute gouty arthritis. I-17 decreased inflammatory factor release and cell pyroptosis through the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/gasdermin D (GSDMD) signaling pathway. Thus, compound I-17, with potent P2Y14R antagonistic activity, in vitro and in vivo efficacy, and favorable bioavailability (F = 75%), could be a promising lead compound for acute gouty arthritis.

Duck compound probiotics fermented diet alters the growth performance by shaping the gut morphology, microbiota and metabolism.

Dietary absorption and digestion are influenced by the microbiota, morphology, and digestive enzymes of intestines, and fermentation is a popular and effective technique to enhance animal rearing growth performance. This study aims to explore the pivotal role of Muscovy duck probiotics fermented feedstuff (FF) in altering the growth performance by reshaping gut morphology, microorganisms and metabolism. The findings showed that FF considerably raised the levels of fatty acids (FA) and small peptides (7-19AA) in the diet. Further feeding trial data reveals that FF greatly increased the Muscovy duck average daily gain (ADG) but had no effect on their daily feed intake (DFI), and the FCR significantly dropped (P < 0.05). Additionally, it was evident that FF improved the integrity of the intestinal mucosa in Muscovy duck by increasing villus height, villus height-to-crypt depth ratio, and lowering crypt depth. Then, in comparison to the control group (NC), there was a significant increase in the gene expression of the mucosal tight junction proteins Occludin, Claudin-1, and Zo-1 in the intestine of Muscovy duck. Additionally, there was higher expression of the mucosal transport channels SGLT-1, PepT1, AQP2, AQP3, and AQP10 in the similarly colon site, jejunum, and duodenum. Furthermore, in AB-PAS/PAS-stained duodenum, jejunum, ileum, and similarly colon site, FF markedly increased relative mucus output and goblet cells while decreasing epithelial cell apoptosis. Following 16S sequencing data indicated that the intestinal microbiota was altered and the diversity and richness of gut microbes was greatly enhanced by FF. Particularly, the boost of core probiotics, such as Rothia of duodenum, Limosilactobacillus and Lentilactobacillus of jejunum, Lactococcus and Rothia of ileum, Ligilactobacillus and Entocuccus of similarly colon site, Gallibacterium of caecum. And reduced potentially pathogenic bacteria (Campylobacter, Prevotellaceae, Clostridia-vadinBB60, and Oscillospira). Nontargeted metabolomics assay for intestinal content confirmed an increased organic acids (oxidanesulfonic acid, cholic acid, gallic acid, coumaric acid, pipecollc acid, 13s-hydroxyoctadecadienoic acid) and glycosides metabolites (5-hydroxydantrolene, 3-hydroxyguanfacine glucuronide, acetylleucine, astragalin, xanthosine, taxiphylin, sinapine, denudatine, penylalanyl-tyrosine and phenylalanyl-valine). These findings demonstrated that FF, a viable option to improve Muscovy duck growth performance through reconstructed intestinal morphology, microorganisms, and metabolism, subsequently promoted the gut health and increased diet digestion and absorption. The study that is being presented offers scientific proof that FF might be a useful strategy for improving Muscovy duck growth performance.

A comprehensive review of natural product-derived compounds acting on P2X7R: The promising therapeutic drugs in disorders.

BACKGROUND: The P2X7 receptor (P2X7R) is known to play a significant role in regulating various pathological processes associated with immune regulation, neuroprotection, and inflammatory responses. It has emerged as a potential target for the treatment of diseases. In addition to chemically synthesized small molecule compounds, natural products have gained attention as an important source for discovering compounds that act on the P2X7R. PURPOSE: To explore the research progress made in the field of natural product-derived compounds that act on the P2X7R. METHODS: The methods employed in this review involved conducting a thorough search of databases, include PubMed, Web of Science and WIKTROP, to identify studies on natural product-derived compounds that interact with P2X7R. The selected studies were then analyzed to categorize the compounds based on their action on the receptor and to evaluate their therapeutic applications, chemical properties, and pharmacological actions. RESULTS: The natural product-derived compounds acting on P2X7R can be classified into three categories: P2X7R antagonists, compounds inhibiting P2X7R expression, and compounds regulating the signaling pathway associated with P2X7R. Moreover, highlight the therapeutic applications, chemical properties and pharmacological actions of these compounds, and indicate areas that require further in-depth study. Finally, discuss the challenges of the natural products-derived compounds exploration, although utilizing compounds from natural products for new drug research offers unique advantages, problems related to solubility, content, and extraction processes still exist. CONCLUSION: The detailed information in this review will facilitate further development of P2X7R antagonists and potential therapeutic strategies for P2X7R-associated disorders.

Degradation selectivity for bamboo fiber and parenchyma lignin-carbohydrates complexes (LCC) esters.

The degradation of lignin-carbohydrate complex (LCC) esters has been proven to be crucial for the selective separation of lignocellulosic components. This study utilized Raman microspectroscopy to image the preferential degradation of lignin and LCC esters from the bamboo wall during successive NaOH (0.2 to 5.0 % w/w), H2SO4 (1 to 8 % v/v), and NaClO2 (5 to 20 min) treatments. Raman imaging showed that lignin and LCC esters were selectively removed from the middle lamella of fibers and the secondary wall of parenchyma during NaOH and NaClO2 treatments. In contrast, H2SO4 primarily caused the simultaneous removal of lignin and LCC esters from the fiber wall under harsh conditions (8 %), while the middle lamella of parenchyma was less affected, both morphologically and topochemically. Raman spectral analysis indicated that the band intensity at 1605 cm-1 for lignin and at 1173 cm-1 for LCC esters decreased by >87.0 % in the highly lignified parenchyma secondary wall after a 5.0 % NaOH treatment, while the decrease was <67 % in the fiber wall. Interestingly, a strong linear correlation was observed between LCC esters and carbohydrates in the parenchyma (R2 > 0.912). These findings provide important insights into the graded and classified utilization of bamboo resources.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Associations of Intracranial Artery Length and Branch Number on Time-of-Flight MRA With Cognitive Impairment in Hypertensive Older Males.

BACKGROUND: Hypertension-induced impairment of the cerebral artery network contributes to cognitive impairment. Characterizing the structure and function of cerebral arteries may facilitate the understanding of hypertension-related pathological mechanisms and lead to the development of new indicators for cognitive impairment. PURPOSE: To investigate the associations between morphological features of the intracranial arteries distal to the circle of Willis on time-of-flight MRA (TOF-MRA) and cognitive performance in a hypertensive cohort. STUDY TYPE: Prospective observational study. POPULATION: 189 hypertensive older males (mean age 64.9 ± 7.2 years). FIELD STRENGTH/SEQUENCE: TOF-MRA sequence with a 3D spoiled gradient echo readout and arterial spin labeling perfusion imaging sequence with a 3D stack-of-spirals fast spin echo readout at 3T. ASSESSMENT: The intracranial arteries were segmented from TOF-MRA and the total length of distal arteries (TLoDA) and number of arterial branches (NoB) were calculated. The mean gray matter cerebral blood flow (GM-CBF) was extracted from arterial spin labeling perfusion imaging. The cognitive level was assessed with short-term and long-term delay-recall auditory verbal learning test (AVLT) scores, and with montreal cognitive assessment. STATISTICAL TESTS: Univariable and multivariable linear regression were used to analyze the associations between TLoDA, NoB, GM-CBF and the cognitive assessment scores, with P < 0.05 indicating significance. RESULTS: TLoDA (r = 0.314) and NoB (r = 0.346) were significantly correlated with GM-CBF. Multivariable linear regression analyses showed that TLoDA and NoB, but not GM-CBF (P = 0.272 and 0.141), were significantly associated with short-term and long-term delay-recall AVLT scores. These associations remained significant after adjusting for GM-CBF. DATA CONCLUSION: The TLoDA and NoB of distal intracranial arteries on TOF-MRA are significantly associated with cognitive impairment in hypertensive subjects. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Fabrication and characterization of ZnGa1.01Te2.13/g-C3N4 heterojunction with enhanced photocatalytic activity.

The extensive consumption of fossil fuels increases CO2 concentration in the atmosphere, resulting in serious global warming problems. Meanwhile, the problem of water contamination by organic substances is another significant global challenge. We have successfully synthesized ZnGa1.01Te2.13/g-C3N4 (ZGT/GCN) composites for the first time as effective photocatalysts for both pollutant degradation and CO2 reduction. ZGT/GCN composites were synthesized by a simple hydrothermal method. The prepared photocatalysts were characterized by XRD, SEM, TEM-EDS, DRS, BET, PL, and XPS. The ZGT/GCN heterojunction exhibited considerably enhanced photocatalytic activity in the degradation of crystal violet (CV) as well as in the photoreduction of CO2 when compared to pure ZGT and GCN semiconductors. The optimal rate constant for CV degradation was obtained with the ZGT-80%GCN composite (0.0442 h-1), which is higher than the constants obtained with individual ZGT and GCN by 7.75 and 1.63 times, respectively. Moreover, the CO2 reduction yields into CH4 by ZGT-80%GCN was 1.013 µmol/g in 72 h, which is 1.21 and 1.08 times larger than the yields obtained with ZGT and GCN. Scavenger and ESR tests were used to propose the photocatalytic mechanism of the ZGT/GCN composite as well as the active species in the CV degradation.

Effects of haloxyfop-p-methyl on the developmental toxicity, neurotoxicity, and immunotoxicity in zebrafish.

Pesticides are extensively used in agricultural production, and their residues in soil, water, and agricultural products have become a threat to aquatic ecosystem. In this study, the toxicity of haloxyfop-p-methyl, an aryloxyphenoxypropionate herbicide was studied using the model animal zebrafish. The development of zebrafish larvae was affected by haloxyfop-p-methyl including spinal deformities, decreased body length, slow heart rate, and large yolk sac area. Behavior analysis revealed that behavior activity of larvae was weakened significantly including shortened displacement distance, reduced swimming speed, increased angular speed winding degrees, in accordance with higher AChE activity. Besides, exposure to haloxyfop-p-methyl could induce oxidative stress companied by the increased intents of ROS, MDA and increased activities of CAT and SOD. In immunotoxicity, haloxyfop-p-methyl not only reduced the innate immune cells such as neutrophils and macrophages, but also affected T cells mature in thymus. Furthermore, haloxyfop-p-methyl could induce neutrophils apoptosis, accompanied with the upregulation of the expression of proapoptotic protein such as Bax and P53 and the downregulation of the expression of antiapoptotic protein Bcl-2. In addition, haloxyfop-p-methyl could induce the expression of Jak, STAT and proinflammatory cytokine genes (IFN-γ, TNF-α, and IL-8). These results indicate that haloxyfop-p-methyl induces developmental toxicity, neurotoxicity, and immunotoxicity in zebrafish, providing a perspective on the toxicological mechanism of haloxyfop-p-methyl in teleosts.

Molecular level insight into the different interaction intensity between microplastics and aromatic hydrocarbon in pure water and seawater.

The interaction of MPs and aromatic hydrocarbons in seawater and pure water was examined using experimental measurements, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations in light of the potential health risks posed by microplastic (MPs)-associated aromatic hydrocarbon pollutants. Isothermal studies and MD simulations suggested that MPs have a stronger affinity for aromatic hydrocarbons in seawater. To uncover the mechanism, MPs' surface characteristics and their intermolecular interactions with aromatic hydrocarbons were examined. According to the research, MPs in seawater have less compact structure, bigger pores, and a higher specific surface area, all of which contribute to more sorption sites. Analysis of the intermolecular interaction indicated that MPs have a greater ability for molecular interactions in seawater and the interaction energy between MPs and aromatic hydrocarbons in seawater is higher. Additionally, seawater cations may act as bridges, which also accelerate sorption in seawater. In summary, this study provides a molecular-level understanding of MPs-aromatic hydrocarbons interaction and demonstrates that the interaction is stronger in seawater.

Degradation of sulfamethoxazole in water by AgNbO3 photocatalyst mediated by persulfate.

In this paper, silver niobate (AgNbO3) material was synthesized by a solid-state reaction. AgNbO3 was characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), UV-visible diffuse reflectance spectroscopy (DRS), and Brunauer-Emmett-Teller (BET) measurement. The photocatalytic activity of AgNbO3 was investigated in degradation of sulfamethoxazole (SMX) under visible light, which is a widely used antibiotic with significant threats towards health and aquatic organisms. Persulfate (PS) oxidant was found to improve the efficiency of the proposed photocatalytic removal of SMX by AgNbO3. The different operational parameters in the AgNbO3/PS/Vis system were investigated. The best photocatalytic performance was achieved with 0.5 g L-1 AgNbO3, 1.0 mM PS, and pH = 5.0 as the optimal conditions, achieving 98% of SMX degradation after 8 h of visible-light irradiation. Scavenger and electron spin resonance (ESR) experiments were carried out to identify the major reactive species in the SMX degradation and to propose the photocatalytic mechanism by the AgNbO3/PS/Vis system. The photodecomposition was found to be majorly caused by holes and ˙O2 - species, with ˙OH and SO4˙- radicals contributing to improve the photocatalytic process. The AgNbO3 catalyst was stable and reusable with efficient photocatalytic activity in three successive recycling experiments and its XRD patterns remained virtually unchanged. The reported process of PS activation by the AgNbO3 photocatalyst is promising for visible-light application in remediation of antibiotic-contaminated water.

Landscape of somatic alterations in large-scale solid tumors from an Asian population.

Extending the benefits of tumor molecular profiling for all cancer patients requires a comprehensive analysis of tumor genomes across distinct patient populations worldwide. In this study, we perform deep next-generation DNA sequencing (NGS) from tumor tissues and matched blood specimens from over 10,000 patients in China by using a 450-gene comprehensive assay, developed and implemented under international clinical regulations. We perform a comprehensive comparison of somatically altered genes, the distribution of tumor mutational burden (TMB), gene fusion patterns, and the spectrum of various somatic alterations between Chinese and American patient populations. Here, we show 64% of cancers from Chinese patients in this study have clinically actionable genomic alterations, which may affect clinical decisions related to targeted therapy or immunotherapy. These findings describe the similarities and differences between tumors from Chinese and American patients, providing valuable information for personalized medicine.

Histone Deacetylase Inhibitors (HDACi) Promote KLF5 Ubiquitination and Degradation in Basal-like Breast Cancer.

Basal-like breast cancer (BLBC) accounts for approximately 15% of all breast cancer cases, and patients with BLBC have a low survival rate. Our previous study demonstrated that the KLF5 transcription factor promotes BLBC cell proliferation and tumor growth. In this study, we demonstrated that the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA), increased KLF5 acetylation at lysine 369 (K369), downregulated KLF5 protein expression levels, and decreased cell viability in BLBC cell lines. HDACi target KLF5 for proteasomal degradation by promoting KLF5 protein ubiquitination. K369 acetylation of KLF5 decreases the binding between KLF5 and its deubiquitinase, BAP1. These findings revealed a novel mechanism by which HDACi suppress BLBC, and a novel crosstalk between KLF5 protein acetylation and ubiquitination.

[Retracted] MicroRNA­101 inhibits the proliferation and invasion of bladder cancer cells via targeting c­FOS.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the Transwell cell migration assay data shown in Fig. 5A were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 14: 2651-2656, 2016; DOI: 10.3892/mmr.2016.5534].

Central versus ambulatory blood pressure for predicting mortality and cardiovascular events in hemodialysis patients: a multicenter cohort study.

OBJECTIVE: Studies in the general population suggest that central blood pressure (BP) may be superior to peripheral BP in risk assessment. Although ambulatory brachial BP is recognized as the most reliable BP measurement in the dialysis population, there is no comparison of office central BP with ambulatory BP regarding risk stratification in these patients. METHODS: In a multicenter prospective study of dialysis patients, central BP was measured noninvasively on a midweek nondialysis day, with interdialytic ambulatory BP and predialysis BP also collected. The primary outcomes were a composite of major adverse cardiovascular events (MACE) and all-cause mortality. Agreement between central and ambulatory BP was assessed using Cohen's Kappa index and Bland--Altman plot. Linear and nonlinear Cox regression models were used to determine the association of BP parameters with outcomes. RESULTS: A total of 368 patients were recruited and 366 underwent central BP measurement. Central BP had a moderate agreement with ambulatory BP in defining hypertension (κ = 0.42) with wide limits of agreement in Bland--Altman analysis. After a median follow-up of 51.5 months, central pulse pressure, ambulatory SBP and ambulatory pulse pressure were associated with all-cause mortality, whereas all BP parameters, except for predialysis DBP, were significant predictors of MACE. However, whenever evaluated in a stepwise variable selection Cox model, only ambulatory pulse pressure, but not any central BP, was determined as the best candidate for prediction of both all-cause mortality and MACE. Nonlinear Cox models revealed no significant nonlinear trend of the association between central BP and outcomes. CONCLUSION: Central BP is predictive of all-cause mortality and cardiovascular events in dialysis patients but its prognostic value does not outperform ambulatory peripheral BP. Our data support the superiority of ambulatory BP in the dialysis population.

Effects of chlorobromoisocyanuric acid on embryonic development and immunotoxicity of zebrafish.

Although chlorobromoisocyanuric acid has been widely used in agriculture, its deleterious toxicity on aquatic organisms remains rare. In this study, zebrafish were exposed to chlorobromoisocyanuric acid (0, 30, 40, and 50 mg/L) from 10 to 96 h post-fertilization (hpf). We found a significant reduction in immune cell numbers (neutrophils and macrophages) and the area of thymus at 96 hpf. The expression of immune-related genes and pro-inflammatory cytokines genes were upregulated. Besides, chlorobromoisocyanuric acid triggered neutrophils cell apoptosis. The mRNA and protein levels of pro-apoptotic p53 pathway and the Bax/Bcl-2 ratio further indicated the underlying mechanism. Furthermore, the oxidative stress was observed that the accumulation of reactive oxygen species and malondialdehyde significantly increased. Subsequently, the antioxidant agent astaxanthin significantly attenuated the level of oxidative stress and the dysregulation of inflammatory response. In summary, our results showed that chlorobromoisocyanuric acid induced developmental defects and immunotoxicity of zebrafish, partly owing to oxidative stress and cell apoptosis.

First principles study on modulating electronic and optical properties with h-BN intercalation in AlN/MoS2heterostructure.

The van der Waals (vdW) heterostructures formed by stacking layered two-dimensional materials can improve the performance of materials and provide more applications. In our paper, six configurations of AlN/MoS2vdW heterostructures were constructed, the most stable structure was obtained by calculating the binding energy. On this basis, the effect of external vertical strain on AlN/MoS2heterostructure was analyzed, the calculated results show that the optimal interlayer distance was 3.593 Å and the band structure was modulated. Then the h-BN intercalation was inserted into the AlN/MoS2heterostructure, by fixing the distance between h-BN and AlN or MoS2, two kinds of models were obtained. Furthermore, the electronic properties of AlN/MoS2heterostructure can be regulated by adding h-BN intercalation layer and adjusting its position. Finally, the optical properties show that the absorption coefficient of AlN/MoS2heterostructure exhibits enhancement characteristic compared with that of the individual monolayers. Meantime, compared with AlN/MoS2, the AlN/h-BN/MoS2shows a redshift effect and the light absorption peak intensity increased, which indicated that h-BN intercalation layer can be used to regulate the electronic and optical properties of AlN/MoS2heterostructure.

C-X-C Motif Chemokine Ligand 16 Is a Potent Predictor of Outcomes in Dialysis Patients.

INTRODUCTION: C-X-C motif chemokine ligand 16 (CXCL16) is an inflammatory marker that has been found to be predictive of outcomes in patients with cardiovascular disease. Our previous work has also demonstrated its relation to cardiac injury in dialysis patients. However, it is yet unclear whether there is an association between CXCL16 and adverse outcomes in dialysis patients. We aimed to evaluate its prognostic value along with several traditional inflammatory markers in the current study. METHODS: This is a multicenter longitudinal study of prevalent dialysis patients. Circulating inflammatory markers including CXCL16, C-reactive protein (CRP), tumor necrosis factor-α, and interleukin-6 (IL-6) were measured using a multiplex assay. The primary outcomes were all-cause mortality and a composite of major adverse cardiovascular events (MACEs). The associations between biomarkers and outcomes were analyzed using Cox proportional hazards regression models. RESULTS: Of the 366 participants with available plasma samples, the average age was 52.5 (±12.1) years, and there were 160 (43.7%) female participants. For all-cause mortality, logarithmically transformed CXCL16, IL-6, and CRP were independent predictors after adjustment for covariates. When the 3 markers were included in the same model, CXCL16 was the only one remaining its significance. For MACEs, logarithmically transformed CXCL16 and IL-6 were significant predictors when analyzed separately and CXCL16 was an independent predictor even after adjustment for IL-6. When the biomarkers were analyzed as categorical variables, only CXCL16 was associated with both outcomes. Adding CXCL16 to established risk factors improved risk prediction as revealed by Net Reclassification Index (NRI). CONCLUSION: Using a multimarker approach, we determined that CXCL16 is a potent predictor of all-cause mortality and cardiovascular events in dialysis patients. Our data suggest CXCL16 may improve risk stratification and could be a potential interventional target.

Effects of sulfometuron-methyl on zebrafish at early developmental stages.

Sulfometuron methyl (SM) is a widely used herbicide and thus leading to accumulation in the environment. The toxicity assessments of SM in model organisms are currently rare. In the present study, zebrafish were utilized for evaluating the detrimental effects of SM in aquatic vertebrates. Zebrafish embryos were exposed to 0, 10, 20, and 40 mg/L SM from 5.5 to 72 h post-fertilization (hpf), respectively. Consequently, SM exposure resulted in increasing the mortality rate and reducing hatching rate in larval zebrafish at 10, 20, and 40 mg/L SM-treated groups. The reduced numbers of immune cells (neutrophils and macrophages) were observed after SM exposure by a dose-dependent manner. The inflammatory responses (TLR4, MYD88, IL-1ß, IL-6, IL-8, IFN-γ, IL-10, and TGF-ß) were measured to estimate immune responses. Anti-inflammatory factors (IL-10 and TGF-ß) were down-regulated in all the treated groups and significantly altered at 40 mg/L exposure group. Additionally, behavioral tests suggested that SM treatment significantly increased the total distance, average speed, and maximum acceleration of larval zebrafish during light-dark transition and subsequently enzymology test displayed the same trend to locomotor behaviors. The content significantly increased in oxidative stress, as reflected in ROS level in all the treated groups. The numbers of cell apoptosis were significantly increased at 20, and 40 mg/L and the highest concentration group induced the substantial increment (P < 0.001) of apoptosis-related genes including p53, Bax/Bcl-2, caspase-9, and caspase-3. In summary, our results demonstrated that exposure to SM caused toxicity of development, immune system, locomotor behavior, oxidative stress, and cell apoptosis at the early developmental stages of zebrafish.

Urinary sodium and potassium excretion and cerebrovascular health: a multimodal imaging study.

PURPOSE: Dietary sodium and potassium intake are associated with stroke, but the potential mechanisms are unclear. We aimed to study the association between sodium and potassium intake and subclinical cerebrovascular health in hypertensive older males using multimodal magnetic resonance imaging. METHODS: A total of 189 hypertensive male subjects without previous cardiovascular or cerebrovascular disease were included. Daily urinary sodium and potassium excretion were estimated from a fasting spot urine sample using a formula approach. A dedicated cerebrovascular health imaging protocol including vessel wall imaging, angiography, arterial spin labeling imaging and T2-weighted fluid-attenuated inversion recovery imaging was performed to study intracranial atherosclerosis, vascular rarefaction (defined as fewer discernible vessels on angiography), brain perfusion and small vessel disease, respectively. RESULTS: The mean age was 64.9 (± 7.2) years. The average daily urinary and potassium excretion was 4.7 (± 1.4) g/L and 2.1 (± 0.5) g/L, respectively. Increased urinary sodium excretion was associated with decreased cerebral blood flow and elevated urinary potassium excretion was associated with reduced prevalence of intracranial plaque. The associations remained significant after adjusting for covariates, even including blood pressure control. Quadratic regression analysis indicated a marginally significant U-shaped association between urinary sodium intake and white matter hyperintensity, which lost significance in fully adjusted models. No significant association of urinary sodium and potassium excretion with other cerebrovascular health measures was noted. CONCLUSION: We concluded that in hypertensive older males without overt cardiovascular disease, increased sodium intake and reduced potassium intake are associated with impaired subclinical cerebrovascular health.