Zymosan A Improved Doxorubicin-Induced Ventricular Remodeling by Evoking Heightened Cardiac Inflammatory Responses and Healing in Mice.

Background Doxorubicin-induced myocardial injury is reflected by the presence of vacuolization in both clinical and animal models. The lack of scar tissue to replace the vacuolizated cardiomyocytes indicates that insufficient cardiac inflammation and healing occurred following doxorubicin injection. Whether improved macrophage activity by zymosan A (zymosan) ameliorates doxorubicin-induced ventricular remodeling in mice is unknown. Methods and Results Mice were intravenously injected with vehicle or doxorubicin (5 mg/kg per week, 4 weeks), and cardiac structure and function were assessed by echocardiography. Two distinct macrophage subsets in hearts following doxorubicin injection were measured at different time points by flow cytometry. Moreover, cardiomyocyte vacuolization, capillary density, collagen content, and ventricular tensile strength were assessed. The therapeutic effect of zymosan (3 mg/kg, single injection) on doxorubicin-induced changes in the aforementioned parameters was determined. At the cellular level, the polarization of monocytes to proinflammatory or reparative macrophages were measured, with or without doxorubicin (0.25 and 0.5 µmol/L). Doxorubicin led to less proinflammatory and reparative macrophage infiltration in the heart in the early phase, with decreased cardiac capillary density and collagen III in the chronic phase. In cell culture, doxorubicin (0.5 µmol/L) repressed macrophage transition toward both proinflammatory and reparative subset. Zymosan enhanced both proinflammatory and reparative macrophage infiltration in doxorubicin-injected hearts, evoking a heightened acute inflammatory response. Zymosan alleviated doxorubicin-induced cardiomyocyte vacuolization in the chronic phase, in parallel with enhanced collagen content, capillary density, and ventricular tensile strength. Conclusions Zymosan improved cardiac healing and ameliorated doxorubicin-induced ventricular remodeling and dysfunction by activating macrophages at an optimal time.

The pathogenesis of aging-induced left atrial appendage thrombus formation and cardioembolic stroke in mice is influenced by inflammation-derived matrix metalloproteinases.

Elderly people without atrial fibrillation (AF) still have a high incidence of cardioembolic stroke, suggesting that thrombus formation within the left atrial appendage (LAA) may also occur in an AF-independent manner. In the present study, we explored the potential mechanisms for aging-induced LAA thrombus formation and stroke in mice. We monitored stroke events in 180 aging male mice (14-24 months) and assessed left atrium (LA) remodeling by echocardiography at different ages. Mice that had stroke were implanted with telemeters to confirm AF. Histological features of LA and LAA thrombi were examined, as well as collagen content, expression of matrix metalloproteinases (MMPs), and leukocyte density in the atria at different ages, in mice with or without stroke. Also, the effects of MMP inhibition on stroke incidence and atrial inflammation were tested. We detected 20 mice (11 %) with stroke, 60 % of which were within 18-19 months of age. Although we did not detect AF in mice with stroke, we detected the presence of LAA thrombi, suggesting that stroke originated from the hearts of these mice. Compared with 18-month-old mice without stroke, 18-month-old stroke mice had enlarged LA with a very thin endocardium, that was associated with less collagen and heightened MMP expression in the atria. During aging, we found that the expression of mRNAs for atrial MMP7, MMP8, and MMP9 peaked at 18 months, which closely correlated with reductions in collagen content and the time-window for cardioembolic stroke in these mice. Treatment of mice with an MMP inhibitor at 17-18 months of age reduced atrial inflammation and remodeling, and stroke incidence. Taken together, our study demonstrates that aging-induced LAA thrombus formation occurs through a mechanism involving upregulation of MMPs and breakdown of collagen, and that treatment with an MMP inhibitor may be effective as a treatment strategy for this heart condition.

Identification of exosomes-related lncRNAs in clear cell renal cell carcinoma based on Bayesian spike-and-slab lasso approach.

Exosomes-related long non-coding RNAs (lncRNAs) have been reported to play significant roles in clear cell renal cell carcinoma (ccRCC). However, there is little known about the relationship between exosomes-related lncRNAs and ccRCC. This study aimed to select optimal prognostic model based on exosomes-related lncRNAs to provide a methodological reference for high-dimensional data. Based on the Cancer Genome Atlas (TCGA) database of 515 ccRCC patients, two risk score models were generated underlying Bayesian spike-and-slab lasso and lasso regression. The optimal model was determined by calculating the area of time-dependent receiver-operating characteristic (ROC) curves in the TCGA and ArrayExpress databases. The immune patterns and sensitivity of immunotherapy between the high and low groups were further explored. Initially, we constructed two risk score models containing 11 and 7 exosomes-related lncRNAs according to Bayesian spike-and-slab lasso and lasso regression respectively. ROC curves revealed that the model constructed by Bayesian spike-and-slab lasso regression was more reliable in predicting survival at 1, 3, and 5 years, yielding an area under the curves (AUCs) of 0.796, 0.732, and 0.742, respectively. Kaplan-Meier (K-M) curves presented that prognosis was poorer in the high-risk score group (P < 0.001). Additionally, the high-risk score group patients were enriched in immune-activating phenotypes and more sensitive to immunotherapy. The exosomes-related lncRNAs model constructed with Bayesian spike-and-slab lasso regression has higher predictive power for ccRCC patients' prognosis, which provides methodological reference for the analysis of high-dimensional data in bioinformatics and guides the tailored treatment of ccRCC patients.

Prognostic Model for Clear-cell Renal Cell Carcinoma Based on Natural Killer Cell-related Genes.

BACKGROUND: Natural killer (NK) cells are a key factor affecting progression and immune surveillance of clear-cell renal cell carcinoma (ccRCC). This study sought to construct a natural killer cell-related prognostic signature (NKRPS) to predict the outcome of ccRCC patients and to furnish guidance for finding appropriate treatment strategies. METHODS: From the TCGA and ArrayExpress databases, transcriptomic profiles and relevant clinical information of ccRCC patients were downloaded for the TCGA cohort (n = 515) and the E-MTAB-1980 cohort (n = 101). With the univariate Cox analysis and LASSO-Cox regression algorithm, a NKRPS was built to evaluate patients' prognosis. Receiver operating characteristic (ROC) curves and calibration curves were drawn to estimate the predictive power of the prognostic model. Then, tumor microenvironment (TME), tumor mutational burden (TMB), sensitization to immune checkpoint inhibitors (ICIs) therapy and targeted drug treatment were analyzed in ccRCC patients. RESULTS: Nine genes (BID, CCL7, CSF2, IL23A, KNSTRN, RHBDD3, PIK3R3, RNF19B and VAV3) were identified to construct a NKRPS. High-risk group displayed undesirable survival compared to low-risk group (P < .05). Moreover, the area under the curve (AUC) of ROC at 1-, 3- and 5-year were 0.766, 0.755, and 0.757, respectively. High-risk group was characterized by superior immune infiltration, higher TMB, and higher expression of 5 ICI-related genes. Additionally, this model enabled to predict the sensitivity of patients to chemotherapy drugs. CONCLUSION: NKRPS had a strong predictive power on prognosis of ccRCC patients, which may facilitate individualized treatment and medical decision making.

The predictive value of changes in left atrial volume index for rehospitalization in heart failure with preserved ejection fraction.

AIMS: Left atrial volume index (LAVI) is an adequate analysis to predicate the left ventricle (LV) filling pressures, providing a powerful predictive marker of LV diastolic dysfunction. LAVI is a dynamic morphophysiological marker, and whether LAVI changes can predicate clinical outcomes in HF with preserved ejection fraction (HFpEF) is unknown. METHODS: HFpEF patients were retrospectively studied from the First Affiliated Hospital of Dalian Medical University. Patients were classified into deteriorated, stable and improved groups according to the change in LAVI. Rehospitalization was defined as the main endpoint, the composite outcome of rehospitalization or all-cause death was defined as the secondary endpoint. RESULTS: A total of 409 patients were included. In this cohort, the percentage of deteriorated, stable, and improved LAVI were 99 (24.2%), 235 (57.4%), and 75 (18.4%), respectively. During the 22 months follow-up period, 168 patients (41.1%) were rehospitalized, 31 patients (7.5%) died and 182 patients (44.5%) experienced a composite outcome. Multivariate Cox regression showed that compared to improved LAVI, those with deteriorated and stable LAVI experienced higher risk of rehospitalization. Logistic regression showed atrial fibrillation (AF) and higher creatinine were independent predictors of deteriorated LAVI, whereas the use of loop diuretics, calcium channel blockers (CCB), and high level of high-density lipoprotein cholesterol (HDL-C) were significantly associated with improved LAVI. CONCLUSIONS: Change in LAVI provides a powerful and dynamic morphophysiological marker of LV filling status and can be used to evaluate the rehospitalization in HFpEF patients.

Identification of a Prognostic Model Based on Immune Cell Signatures in Clear Cell Renal Cell Carcinoma.

Background: Accumulating evidence substantiated that the immune cells were intricately intertwined with the prognosis and therapy of clear cell renal cell carcinoma (ccRCC). We aimed to construct an immune cell signatures (ICS) score model to predict the prognosis of ccRCC patients and furnish guidance for finding appropriate treatment strategies. Methods: Based on The Cancer Genome Atlas (TCGA) database, the normalized enrichment score (NES) of 184 ICSf was calculated using single-sample gene set enrichment analysis (ssGSEA). An ICS score model was generated in light of univariate Cox regression and Least absolute shrinkage and selection operator (Lasso)-Cox regression, which was independently validated in ArrayExpress database. In addition, we appraised the predictive power of the model via Kaplan-Meier (K-M) curves and time-dependent receiver operating characteristic (ROC) curves. Eventually, immune infiltration, genomic alterations and immunotherapy were analyzed between high and low ICS score groups. Results: Initially, we screened 11 ICS with prognostic impact based on 515 ccRCC patients. K-M curves presented that the high ICS score group experienced a poorer prognosis (P < 0.001). In parallel, ROC curves revealed a satisfactory reliability of model to predict individual survival at 1, 3, and 5 years, with area under the curves (AUCs) of 0.744, 0.713, and 0.742, respectively. In addition, we revealed that the high ICS score group was characterized by increased infiltration of immune cells, strengthened BAP1 mutation frequency, and enhanced expression of immune checkpoint genes. Conclusion: The ICS score model has higher predictive power for patients' prognosis and can instruct ccRCC patients in seeking suitable treatment.

Leucine Supplementation in Middle-Aged Male Mice Improved Aging-Induced Vascular Remodeling and Dysfunction via Activating the Sirt1-Foxo1 Axis.

Vascular aging is associated with metabolic remodeling, and most studies focused on fatty acid and glucose metabolism. Based on our metabolomic data, leucine was significantly reduced in the aortas of aged mice. Whether leucine supplementation can reverse aging-induced vascular remodeling remains unknown. To investigate the effectiveness of leucine, male mice at 15 or 18 months were supplemented with leucine (1.5%) for 3 months. All the aged mice, with or without leucine, were sacrificed at 21 months. Blood pressure and vascular relaxation were measured. H&E, Masson's trichrome, and Elastica van Gieson staining were used to assess aortic morphology. Vascular inflammation, reactive oxidative stress (ROS), and vascular smooth muscle cell (VSMC) phenotype were also measured in mouse aortas. Compared with the 21-month-old mice without leucine, leucine supplementation from 15 months significantly improved vascular relaxation, maintained the contractile phenotype of VSMCs, and repressed vascular inflammation and ROS levels. These benefits were not observed in the mice supplemented with leucine starting from 18 months, which was likely due to the reduction in leucine transporters Slc3a2 or Slc7a5 at 18 months. Furthermore, we found benefits from leucine via activating the Sirt1-induced Foxo1 deacetylation. Our findings indicated that leucine supplementation in middle-aged mice improved aging-induced vascular remodeling and dysfunction.

Degradation of polycyclic aromatic hydrocarbons in a coking wastewater treatment plant residual by an O3/ultraviolet fluidized bed reactor.

Coking wastewater treatment plant (CWWTP) represents a typical point source of polycyclic aromatic hydrocarbons (PAHs) to the water environment and threatens the safety of drinking water in downstream regions. To enhance the removal of residual PAHs from bio-treated coking wastewater, a pilot-scale O3/ultraviolet (UV) fluidized bed reactor (O3/UV FBR) was designed and different operating factors including UV irradiation intensity, pH, initial concentration, contact time, and hydraulic retention time (HRT) were investigated at an ozone level of 240 g h(-1) and 25 ± 3 °C. A health risk evaluation and cost analysis were also carried out under the continuous-flow mode. As far as we know, this is the first time an O3/UV FBR has been explored for PAHs treatment. The results indicated that between 41 and 75 % of 18 target PAHs were removed in O3/UV FBR due to synergistic effects of UV irradiation. Both increased reaction time and increased pH were beneficial for the removal of PAHs. The degradation of the target PAHs within 8 h can be well fitted by the pseudo-first-order kinetics (R (2) > 0.920). The reaction rate was also positively correlated with the initial concentrations of PAHs. The health risk assessment showed that the total amount of carcinogenic substance exposure to surface water was reduced by 0.432 g day(-1). The economic analysis showed that the O3/UV FBR was able to remove 18 target PAHs at a cost of US$0.34 m(-3). These results suggest that O3/UV FBR is efficient in removing residuals from CWWTP, thus reducing the accumulation of persistent pollutant released to surface water.

Identification and removal of polycyclic aromatic hydrocarbons in wastewater treatment processes from coke production plants.

Identification and removal of polycyclic aromatic hydrocarbons (PAHs) were investigated at two coke plants located in Shaoguan, Guangdong Province of China. Samples of raw coking wastewaters and wastewaters from subunits of a coke production plant were analyzed using gas chromatography-mass spectrometry (GC/MS) to provide a detailed chemical characterization of PAHs. The identification and characterization of PAH isomers was based on a positive match of mass spectral data of sample peaks with those for PAH isomers in mass spectra databases with electron impact ionization mass spectra and retention times of internal reference compounds. In total, 270 PAH compounds including numerous nitrogen, oxygen, and sulfur heteroatomic derivatives were positively identified for the first time. Quantitative analysis of target PAHs revealed that total PAH concentrations in coking wastewaters were in the range of 98.5 ± 8.9 to 216 ± 20.2 µg/L, with 3-4-ring PAHs as dominant compounds. Calculation of daily PAH output from four plant subunits indicated that PAHs in the coking wastewater came mainly from ammonia stripping wastewater. Coking wastewater treatment processes played an important role in removing PAHs in coking wastewater, successfully removing 92 % of the target compounds. However, 69 weakly polar compounds, including PAH isomers, were still discharged in the final effluent, producing 8.8 ± 2.7 to 31.9 ± 6.8 g/day of PAHs with potential toxicity to environmental waters. The study of coking wastewater herein proposed can be used to better predict improvement of coke production facilities and treatment conditions according to the identification and removal of PAHs in the coke plant as well as to assess risks associated with continuous discharge of these contaminants to receiving waters.