NF-κB affected the serum levels of TNF-α and IL-1ß via activation of the MAPK/NF-κB signaling pathway in rat model of acute pulmonary microthromboembolism.

Pulmonary thromboembolism caused by thrombi blocking major pulmonary artery and its branches, is a frequently encountered phenomenon and an important cause of high morbidity and mortality in lung diseases and may develop into persistent pulmonary hypertension (PH). Nuclear factor-κB (NF-κB) signaling pathway had been reported participated in the formation and development of PH by promoting inflammatory response. The aim of this study was to investigate the effects of NF-κB activation on the serum levels of tumor necrosis factor α (TNF-α) and interleukin-1ß (IL-1ß) in acute pulmonary microthromboembolism (APMTE) rats. Rats were randomized into five groups. APMTE group received jugular vein injection of autologous thrombus, while control group rats received normal saline injection. Pulmonary hemodynamic parameters were measured through ECHO-guided transthoracic puncture. Pulmonary vascular morphological changes were analyzed by HE. The expression changes of NF-κB and serum TNF-α、IL-1ß levels were detected by enzyme-linked immunosorbent assay. Protein expression of the MAPK/NF-κB signaling pathway including p-IκBα, p-p38 MAPK, p-NF-κB p65, IκBα, p38 MAPK, and NF-κB p65 was determined using western blot analysis. Compared with control group, the expression of NF-κB in lung tissue and the levels of serum TNF-α and IL-1ß rats were higher, a significant reduction in IκBα and elevation in the phosphorylation of IκBα, p38 MAPK, and NF-κB p65 were found in APMTE group rats. And UK administration reversed the APMTE-induced increase in TNF-α, IL-1ß, p-IκBα, p-MAPK, and p-NF-κB protein. Furthermore, the levels of NF-κB, TNF-α, and IL-1ß were positively correlated with mean pulmonary artery. And the levels of TNF-α and IL-1ß were positively correlated with NF-κB. These findings suggest that the activation of MAPK/NF-κB pathway as a critical driver of increasing TNF-α and IL-1ß level in APMTE rats and UK exerted protective effects against APMTE-induced PH may be related to the downregulation of the MAPK/NF-κB signaling pathway.

TOB1 modulates neutrophil phenotypes to influence gastric cancer progression and immunotherapy efficacy.

Introduction: The ErbB-2.1(TOB1) signaling transducer protein is a tumor-suppressive protein that actively suppresses the malignant phenotype of gastric cancer cells. Yet, TOB1 negatively regulates the activation and growth of different immune cells. Understanding the expression and role of TOB1 in the gastric cancer immune environment is crucial to maximize its potential in targeted immunotherapy. Methods: This study employed multiplex immunofluorescence analysis to precisely delineate and quantify the expression of TOB1 in immune cells within gastric cancer tissue microarrays. Univariate and multivariate Cox analyses were performed to assess the influence of clinical-pathological parameters, immune cells, TOB1, and double-positive cells on the prognosis of gastric cancer patients. Subsequent experiments included co-culture assays of si-TOB1-transfected neutrophils with AGS or HGC-27 cells, along with EdU, invasion, migration assays, and bioinformatics analyses, aimed at elucidating the mechanisms through which TOB1 in neutrophils impacts the prognosis of gastric cancer patients. Results: We remarkably revealed that TOB1 exhibits varying expression levels in both the nucleus (nTOB1) and cytoplasm (cTOB1) of diverse immune cell populations, including CD8+ T cells, CD66b+ neutrophils, FOXP3+ Tregs, CD20+ B cells, CD4+ T cells, and CD68+ macrophages within gastric cancer and paracancerous tissues. Significantly, TOB1 was notably concentrated in CD66b+ neutrophils. Survival analysis showed that a higher density of cTOB1/nTOB1+CD66b+ neutrophils was linked to a better prognosis. Subsequent experiments revealed that, following stimulation with the supernatant of tumor tissue culture, the levels of TOB1 protein and mRNA in neutrophils decreased, accompanied by enhanced apoptosis. HL-60 cells were successfully induced to neutrophil-like cells by DMSO. Neutrophils-like cells with attenuated TOB1 gene expression by si-TOB1 demonstrated heightened apoptosis, consequently fostering a malignant phenotype in AGS and HCG-27 cells upon co-cultivation. The subsequent analysis of the datasets from TCGA and TIMER2 revealed that patients with high levels of TOB1 combined neutrophils showed better immunotherapy response. Discussion: This study significantly advances our comprehension of TOB1's role within the immune microenvironment of gastric cancer, offering promising therapeutic targets for immunotherapy in this context.

Evaluating the Effect of Deficit Irrigation on Yield and Water Use Efficiency of Drip Irrigation Cotton under Film in Xinjiang Based on Meta-Analysis.

Water scarcity constrains the sustainable development of Chinese agriculture, and deficit irrigation as a new irrigation technology can effectively alleviate the problems of water scarcity and water use inefficiency in agriculture. In this study, the drip irrigation cotton field under film in Xinjiang was taken as the research object. Meta-analysis and machine learning were used to quantitatively analyze the effects of different farm management practices, climate, and soil conditions on cotton yield and water use efficiency under deficit irrigation, to investigate the importance of the effects of different factors on cotton yield and water use efficiency, and to formulate appropriate optimization strategies. The results showed that deficit irrigation significantly increased cotton water use efficiency (7.39%) but decreased cotton yield (-15.00%) compared with full irrigation. All three deficit irrigation levels (80~100% FI, 60~80% FI, and 40~60% FI; FI: full irrigation) showed a significant decrease in cotton yield and a significant increase in water use efficiency. Under deficit irrigation, cotton yield reduction was the smallest and cotton water use efficiency increased the most when planted with one film, two tubes, a six-row cropping pattern, an irrigation frequency ≥10 times, a nitrogen application of 300~400 kg·ha-1, and a crop density ≥240,000 per hectare, and planted with the Xinluzhong series of cotton varieties; deficit irrigation in areas with average annual temperature >10 °C, annual evapotranspiration >2000 mm, annual precipitation <60 mm, and with loam, sandy soil had the least inhibition of cotton yield and the greatest increase in cotton water use efficiency. The results of the random forest showed that the irrigation amount and nitrogen application had the greatest influence on cotton yield and water use efficiency. Rational irrigation based on optimal management practices under conditions of irrigation not less than 90% FI is expected to achieve a win-win situation for both cotton yield and water use efficiency. The above results can provide the best strategy for deficit irrigation and efficient water use in drip irrigation cotton under film in arid areas.

A Bayesian benchmark concentration analysis for urinary fluoride and intelligence in adults in Guizhou, China.

Environmental fluoride exposure has been linked to numerous cases of fluorosis worldwide. Previous studies have indicated that long-term exposure to fluoride can result in intellectual damage among children. However, a comprehensive health risk assessment of fluorosis-induced intellectual damage is still pending. In this research, we utilized the Bayesian Benchmark Dose Analysis System (BBMD) to investigate the dose-response relationship between urinary fluoride (U-F) concentration and Raven scores in adults from Nayong, Guizhou, China. Our research findings indecate a dose-response relationship between the concentration of U-F and intelligence scores in adults. As the benchmark response (BMR) increased, both the benchmark concentration (BMCs) and the lower bound of the credible interval (BMCLs) increased. Specifically, BMCs for the association between U-F and IQ score were determined to be 0.18 mg/L (BMCL1 = 0.08 mg/L), 0.91 mg/L (BMCL5 = 0.40 mg/L), 1.83 mg/L (BMCL10 = 0.83 mg/L) when using BMRs of 1 %, 5 %, and 10 %. These results indicate that U-F can serve as an effective biomarker for monitoring the loss of IQ in population. We propose three interim targets for public policy in preventing interllectual harm from fluoride exposure.

A nomogram for predicting left atrial thrombus or spontaneous echo contrast in non-valvular atrial fibrillation patients using hemodynamic parameters from transthoracic echocardiography.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a high risk of stroke. This study was designed to investigate the relationship between hemodynamic parameters and left atrial thrombus/spontaneous echo contrast (LAT/SEC) in non-valvular atrial fibrillation (NVAF) patients and establish a predictive nomogram that integrates hemodynamic parameters with clinical predictors to predict the risk of LAT/SEC. Methods: From January 2019 to September 2022, a total of 354 consecutive patients with NVAF were enrolled in this cross-sectional study at the First Affiliated Hospital of Guangxi Medical University. To identify the optimal predictive features, we employed least absolute shrinkage and selection operator (LASSO) regression. A multivariate logistic regression model was subsequently constructed, and the results were visualized with a nomogram. We evaluated the model's performance using discrimination, calibration, and the concordance index (C-index). Results: We observed a 38.7% incidence of SEC/TH in NVAF patients. Independent influencing factors of LAT/SEC were identified through LASSO and multivariate logistic regression. Finally, four indicators were included, namely, previous stroke/transient ischaemic attack (OR = 4.25, 95% CI = 1.57-12.23, P = 0.006), left atrial volume index (LAVI) (OR = 1.04, 95% CI = 1.01-1.06, P = 0.001), S/D ratio (OR = 0.27, 95% CI = 0.11-0.59, P = 0.002), and left atrial acceleration factor (OR = 4.95, 95% CI = 2.05-12.79, P = 0.001). The nomogram, which incorporated these four influencing factors, demonstrated excellent predictive ability. The training set had a C-index of 0.878, while the validation set had a C-index of 0.872. Additionally, the calibration curve demonstrated great consistency between the predicted probabilities and the observed outcomes, and the decision curve analysis confirmed the important clinical advantage of the model for patients with NVAF. Conclusion: Our findings indicate that an enlarged left atrium and abnormal hemodynamic parameters in the left atrial and pulmonary veins are linked to a greater risk of LAT/SEC. Previous stroke/transient ischaemic attack, LAVI, the S/D ratio, and left atrial acceleration factor were independently associated with LAT/SEC in NVAF patients. With the incorporation of these four variables, the developed nomogram effectively predicts the risk of LAT/SEC and outperforms the CHA2DS2-VASc score.

Inhibition of the lncRNA 585189 prevents podocyte injury and mitochondria dysfunction by promoting hnRNP A1 and SIRT1 in diabetic nephropathy.

Podocyte dysfunction has been identified as a crucial pathological characteristic of diabetic nephropathy (DN). However, the regulatory effects of long non-coding RNAs (lncRNAs) in this process have not been fully elucidated. Here, we performed an unbiased RNA-sequencing (RNA-seq) analysis of renal tissues and identified a significantly upregulated long non-coding RNA, ENST00000585189.1 (lncRNA 585189), in patients with DN. Furthermore, lncRNA 585189 was positively correlated with renal insufficiency and was upregulated in both DN patients and high-glucose-induced human podocytes. Gain- and loss-of-function experiments revealed that silencing lncRNA 585189 decreased the production of ROS, rescued aberrant mitochondrial morphology and membrane potential, and alleviated podocyte damage caused by high glucose. Mechanistically, bioinformatics analysis predicted an interaction between lncRNA 585189 and hnRNP A1, which was subsequently confirmed by RIP, pull-down, and EMSA assays. Further investigation revealed that lncRNA 585189 destabilizes the hnRNP A1 protein, leading to the downregulation of its expression. Conversely, hnRNP A1 promoted the expression of lncRNA 585189. Moreover, both RIP and pull-down assays demonstrated a direct interaction between hnRNP A1 and SIRT1, which enhanced SIRT1 mRNA stability. Our findings suggest that lncRNA 585189 suppresses SIRT1 through hnRNP A1, thereby hindering the recovery from mitochondrial abnormalities and podocyte damage. In summary, targeting lncRNA 585189 is a promising strategy for reversing mitochondrial dysfunction and treating DN.

Speckle-Tracking Echocardiography Predicts Adverse Left Ventricular Remodeling After Valve Replacement in Rheumatic Mitral Stenosis.

Background: Rheumatic mitral stenosis(RMS) may leads to left ventricular remodeling (LVR), which can persist even after valve surgery. Identifying markers for early structure and function in patients with rheumatic heart disease who are at risk for adverse LVR after surgery can help determine the optimal timing of intervention. This study aimed to investigate whether preoperative parameters of global left ventricular long-axis strain (LVGLS) and mechanical discretization (MD) could predict postoperative adverse LVR. Methods: A total of 109 adult patients with RMS and 50 healthy controls were enrolled in this study. Baseline clinical features, conventional echocardiography results, LVGLS, and MD were compared between the two groups. Pre- and post-surgery echocardiography measurements were collected, and adverse LVR was defined as a>15% increase in left ventricular end-diastolic volume or >10% decrease in left ventricular ejection fraction. Binary regression analysis was used to determine independent predictors of poor left ventricular remodeling. Results: The variables associated with adverse LVR in this study were LVGLS (P<0.001, odds ratio: 1.996, 95% CI: 1.394-2.856) and MD (P=0.011, odds ratio: 1.031, 95% CI: 1.007-1.055). The poorly reconstructed group had lower absolute values of LVGLS and higher MD than the healthy control group and the non-poorly reconstructed group. A LVGLS cutoff of -15.0% was the best predictor for patients with poorly reconstructed LVR (sensitivity: 75.7%; specificity: 100.0%; AUC: 0.93), and a MD cutoff of 63.8ms was the best predictor (sensitivity: 63.8%; specificity: 98.6%; AUC: 0.88). Conclusion: Speckle tracking echocardiography has potential value for predicting the progression of adverse LVR and for identifying non-responders among patients with RMS undergoing surgery.

Non-invasive arterial blood pressure measurement and SpO2 estimation using PPG signal: a deep learning framework.

BACKGROUND: Monitoring blood pressure and peripheral capillary oxygen saturation plays a crucial role in healthcare management for patients with chronic diseases, especially hypertension and vascular disease. However, current blood pressure measurement methods have intrinsic limitations; for instance, arterial blood pressure is measured by inserting a catheter in the artery causing discomfort and infection. METHOD: Photoplethysmogram (PPG) signals can be collected via non-invasive devices, and therefore have stimulated researchers' interest in exploring blood pressure estimation using machine learning and PPG signals as a non-invasive alternative. In this paper, we propose a Transformer-based deep learning architecture that utilizes PPG signals to conduct a personalized estimation of arterial systolic blood pressure, arterial diastolic blood pressure, and oxygen saturation. RESULTS: The proposed method was evaluated with a subset of 1,732 subjects from the publicly available ICU dataset MIMIC III. The mean absolute error is 2.52 ± 2.43 mmHg for systolic blood pressure, 1.37 ± 1.89 mmHg for diastolic blood pressure, and 0.58 ± 0.79% for oxygen saturation, which satisfies the requirements of the Association of Advancement of Medical Instrumentation standard and achieve grades A for the British Hypertension Society standard. CONCLUSIONS: The results indicate that our model meets clinical standards and could potentially boost the accuracy of blood pressure and oxygen saturation measurement to deliver high-quality healthcare.

Explainable drug side effect prediction via biologically informed graph neural network.

Early detection of potential side effects (SE) is a critical and challenging task for drug discovery and patient care. In-vitro or in-vivo approach to detect potential SEs is not scalable for many drug candidates during the preclinical stage. Recent advances in explainable machine learning may facilitate detecting potential SEs of new drugs before market release and elucidating the critical mechanism of biological actions. Here, we leverage multi-modal interactions among molecules to develop a biologically informed graph-based SE prediction model, called HHAN-DSI. HHAN-DSI predicted frequent and even uncommon SEs of the unseen drug with higher or comparable accuracy against benchmark methods. When applying HHAN-DSI to the central nervous system, the organs with the largest number of SEs, the model revealed diverse psychiatric medications' previously unknown but probable SEs, together with the potential mechanisms of actions through a network of genes, biological functions, drugs, and SEs.

Confidence-based laboratory test reduction recommendation algorithm.

BACKGROUND: We propose a new deep learning model to identify unnecessary hemoglobin (Hgb) tests for patients admitted to the hospital, which can help reduce health risks and healthcare costs. METHODS: We collected internal patient data from a teaching hospital in Houston and external patient data from the MIMIC III database. The study used a conservative definition of unnecessary laboratory tests, which was defined as stable (i.e., stability) and below the lower normal bound (i.e., normality). Considering that machine learning models may yield less reliable results when trained on noisy inputs containing low-quality information, we estimated prediction confidence to assess the reliability of predicted outcomes. We adopted a "select and predict" design philosophy to maximize prediction performance by selectively considering samples with high prediction confidence for recommendations. Our model accommodated irregularly sampled observational data to make full use of variable correlations (i.e., with other laboratory test values) and temporal dependencies (i.e., previous laboratory tests performed within the same encounter) in selecting candidates for training and prediction. RESULTS: The proposed model demonstrated remarkable Hgb prediction performance, achieving a normality AUC of 95.89% and a Hgb stability AUC of 95.94%, while recommending a reduction of 9.91% of Hgb tests that were deemed unnecessary. Additionally, the model could generalize well to external patients admitted to another hospital. CONCLUSIONS: This study introduces a novel deep learning model with the potential to significantly reduce healthcare costs and improve patient outcomes by identifying unnecessary laboratory tests for hospitalized patients.

ROS promote hyper-methylation of NDRG2 promoters in a DNMTS-dependent manner: Contributes to the progression of renal fibrosis.

Renal fibrosis is the common histopathological feature of chronic kidney diseases (CKD), and there is increasing evidence that epigenetic regulation is involved in the occurrence and progression of renal fibrosis. N-myc downstream-regulated gene 2 (NDRG2) is significantly down-regulated in renal fibrosis, the mechanism of which remains unclear. Previous studies have confirmed that the inhibition of NDRG2 expression in tumor cells is related to hyper-methylation, mainly regulated by DNA methyltransferases (DNMTS). Herein, we explored the expression of NDRG2 and its epigenetic regulatory mechanism in renal fibrosis. The results showed that the expression of NDRG2 was significantly inhibited in vivo and in vitro, while the overexpression of NDRG2 effectively alleviated renal fibrosis. Meanwhile, we found that the expression of DNMT1/3A/3B was significantly increased in hypoxia-induced HK2 cells and Unilateral Ureteral Obstruction (UUO) mice accompanied by hyper-methylation of the NDGR2 promoter. Methyltransferase inhibitor (5-AZA-dC) corrected the abnormal expression of DNMT1/3A/3B, reduced the methylation level of NDRG2 promoter and restored the expression of NDRG2. The upstream events that mediate changes in NDRG2 methylation were further explored. Reactive oxygen species (ROS) are important epigenetic regulators and have been shown to play a key role in renal injury due to various causes. Accordingly, we further explored whether ROS could induce DNA-epigenetic changes of the expression of NDRG2 and then participated in the development of renal fibrosis. Our results showed that mitochondria-targeted antioxidants (Mito-TEMPO) could reverse the epigenetic inhibition of NDRG2 in a DNMT-sensitive manner, showing strong ability of DNA demethylation, exhibiting epigenetic regulation and anti-fibrosis effects similar to 5-AZA-dC. More importantly, the anti-fibrotic effects of 5-AZA-dC and Mito-TEMPO were eliminated in HK2 cells with NDRG2 knockdown. These findings highlight that targeting ROS-mediated hyper-methylation of NDRG2 promoter is a potentially effective therapeutic strategy for renal fibrosis, which will provide new insights into the treatment of CKD.

T cells and their products in diabetic kidney disease.

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease and has gradually become a public health problem worldwide. DKD is increasingly recognized as a comprehensive inflammatory disease that is largely regulated by T cells. Given the pivotal role of T cells and T cells-producing cytokines in DKD, we summarized recent advances concerning T cells in the progression of type 2 diabetic nephropathy and provided a novel perspective of immune-related factors in diabetes. Specific emphasis is placed on the classification of T cells, process of T cell recruitment, function of T cells in the development of diabetic kidney damage, and potential treatments and therapeutic strategies involving T cells.

Long noncoding RNA ENST00000436340 promotes podocyte injury in diabetic kidney disease by facilitating the association of PTBP1 with RAB3B.

Dysfunction of podocytes has been regarded as an important early pathologic characteristic of diabetic kidney disease (DKD), but the regulatory role of long noncoding RNAs (lncRNAs) in this process remains largely unknown. Here, we performed RNA sequencing in kidney tissues isolated from DKD patients and nondiabetic renal cancer patients undergoing surgical resection and discovered that the novel lncRNA ENST00000436340 was upregulated in DKD patients and high glucose-induced podocytes, and we showed a significant correlation between ENST00000436340 and kidney injury. Gain- and loss-of-function experiments showed that silencing ENST00000436340 alleviated high glucose-induced podocyte injury and cytoskeleton rearrangement. Mechanistically, we showed that fat mass and obesity- associate gene (FTO)-mediated m6A induced the upregulation of ENST00000436340. ENST00000436340 interacted with polypyrimidine tract binding protein 1 (PTBP1) and augmented PTBP1 binding to RAB3B mRNA, promoted RAB3B mRNA degradation, and thereby caused cytoskeleton rearrangement and inhibition of GLUT4 translocation to the plasma membrane, leading to podocyte injury and DKD progression. Together, our results suggested that upregulation of ENST00000436340 could promote podocyte injury through PTBP1-dependent RAB3B regulation, thus suggesting a novel form of lncRNA-mediated epigenetic regulation of podocytes that contributes to the pathogenesis of DKD.

Deep learn-based computer-assisted transthoracic echocardiography: approach to the diagnosis of cardiac amyloidosis.

Myocardial amyloidosis (CA) differs from other etiological pathologies of left ventricular hypertrophy in that transthoracic echocardiography is challenging to assess the texture features based on human visual observation. There are few studies on myocardial texture based on echocardiography. Therefore, this paper proposes an adaptive machine learning method based on ultrasonic image texture features to identify CA. In this retrospective study, a total of 289 participants (50 cases of myocardial amyloidosis; Hypertrophic cardiomyopathy: 70 cases; Uremic cardiomyopathy: 92 cases; Hypertensive heart disease: 77 cases). We extracted the myocardial ultrasonic imaging features of these patients and screened the features, and four models of random forest (RF), support vector machine (SVM), logistic regression (LR) and gradient decision-making lifting tree (GBDT) were established to distinguish myocardial amyloidosis from other diseases. Finally, the diagnostic efficiency of the model was evaluated and compared with the traditional ultrasonic diagnostic methods. In the overall population, the four machine learning models we established could effectively distinguish CA from nonCA diseases, AUC (RF 0.77, SVM 0.81, LR 0.81, GBDT 0.71). The LR model had the best diagnostic efficiency with recall, F1-score, sensitivity and specificity of 0.21, 0.34, 0.21 and 1.0, respectively. Slightly better than the traditional ultrasonic diagnosis model. In further subgroup analysis, the myocardial amyloidosis group was compared one-by-one with the patients with hypertrophic cardiomyopathy, uremic cardiomyopathy, and hypertensive heart disease groups, and the same method was used for feature extraction and data modeling. The diagnostic efficiency of the model was further improved. Notably, in identifying of the CA group and HHD group, AUC values reached more than 0.92, accuracy reached more than 0.87, sensitivity equal to or greater than 0.81, specificity 0.91, and F1 score higher than 0.84. This novel method based on echocardiography combined with machine learning may have the potential to be used in the diagnosis of CA.

Sulphur dioxide and fluoride co-exposure cause enamel damage by disrupting the Cl-/HCO3- ion transport.

OBJECTIVE: Although there is growing evidence linking the exposure to sulphur dioxide (SO2) and fluoride to human diseases, there is little data on the co-exposure of SO2 and fluoride. Moreover, literature on SO2 and fluoride co-exposure to enamel damage is insufficient. In this work, we concentrate on the concurrent environmental issues of excessive SO2 and fluoride in several coal-consuming regions. METHOD: To identify the toxicity of SO2 and fluoride exposure either separately or together, we used both ICR mice and LS8 cells, and factorial design was employed to assess the type of potential combined action. RESULT: In this study, co-exposure to SO2 and fluoride exacerbated enamel damage, resulting in more severe enamel defects of incisor and the damage occurred earlier. Cl-/HCO3- exchanger expression is increased by SO2 and fluoride in mouse incisor. Consistent with in vivo results, co-exposure of SO2 and fluoride decreased pHi and increased [Cl-]i level by increasing the expression of the Cl-/HCO3- exchanger in LS8 cells. Furthermore, SO2 and F may increase merlin protein expression, and merlin deficiency causes AE2 expression to decrease in vitro. CONCLUSION: Overall, these results indicate that co-exposure to SO2 and fluoride may result in more toxicity both in vitro and in vivo than a single exposure to SO2 and fluoride, suggesting that residents in areas contaminated with SO2 and fluoride may be more likely to suffer enamel damage.

Urokinase-loaded cyclic RGD-decorated liposome targeted therapy for in-situ thrombus of pulmonary arteriole of pulmonary hypertension.

Backgroud: In-situ thrombosis is a significant pathophysiological basis for the development of pulmonary hypertension (PH). However, thrombolytic therapy for in-situ thrombus in PH was often hampered by the apparent side effects and the low bioavailability of common thrombolytic medications. Nanoscale cyclic RGD (cRGD)-decorated liposomes have received much attention thanks to their thrombus-targeting and biodegradability properties. As a result, we synthesized urokinase-loaded cRGD-decorated liposome (UK-cRGD-Liposome) for therapy of in-situ thrombosis as an exploration of pulmonary hypertensive novel therapeutic approaches. Purpose: To evaluate the utilize of UK-cRGD-Liposome for targeted thrombolysis of in-situ thrombus in PH and to explore the potential mechanisms of in-situ thrombus involved in the development of PH. Methods: UK-cRGD-Liposome nanoscale drug delivery system was prepared using combined methods of thin-film hydration and sonication. Induced PH via subcutaneous injection of monocrotaline (MCT). Fibrin staining (modified MSB method) was applied to detect the number of vessels within-situ thrombi in PH. Echocardiography, hematoxylin-eosin (H & E) staining, and Masson's trichrome staining were used to analyze right ventricular (RV) function, pulmonary vascular remodeling, as well as RV remodeling. Results: The number of vessels with in-situ thrombi revealed that UK-cRGD-Liposome could actively target urokinase to in-situ thrombi and release its payload in a controlled manner in the in vivo environment, thereby enhancing the thrombolytic effect of urokinase. Pulmonary artery hemodynamics and echocardiography indicated a dramatical decrease in pulmonary artery pressure and a significant improvement in RV function post targeted thrombolytic therapy. Moreover, pulmonary vascular remodeling and RV remodeling were significantly restricted post targeted thrombolytic therapy. Conclusion: UK-cRGD-Liposome can restrict the progression of PH and improve RV function by targeting the dissolution of pulmonary hypertensive in-situ thrombi, which may provide promising therapeutic approaches for PH.

A novel method for measuring pulmonary artery pressure by high-frequency ultrasound-guided transthoracic puncture in rats.

Objectives: The success of the rat model of pulmonary hypertension (PH) is primarily dependent on the measurement of pulmonary artery pressure. We herein demonstrate a novel method for measuring pulmonary artery pressure through a high-frequency ultrasound-guided transthoracic puncture in rats. The efficacy and time of this novel method are also discussed. Methods: A single subcutaneous injection of monocrotaline (MCT) was used to establish a rat model of PH. Through the heat shaping method, the tip of that puncture cannula was maintained at a certain angle after the needle core was removed. In-plane real-time guided trocar puncture of the right ventricular outflow tract was performed in the short-axis section of the parasternal aorta. The external pressure sensor was used to record the real-time waveform of right ventricular systolic pressure, pulmonary artery systolic pressure, and diastolic pressure. Results: The success rates of which using this novel method in the model group and the control group were 88.5 and 86.7%, respectively. The time of puncture pressure measurement was 164 ± 31 and 235 ± 50 s, respectively. The right ventricular systolic blood pressure, pulmonary systolic blood pressure, and diastolic blood pressure of the model group were higher than those of the control group. Conclusion: The modified method for trocar is helpful for accurately positioning pulmonary artery manometry. The method described in this paper has a high success rate and short operation time. It can simultaneously measure systolic blood pressure, diastolic blood pressure, and mean pressure of the right ventricle and pulmonary artery. It has a broad application prospect in verifying the rat PH model and pulmonary artery pressure monitoring.

Sulphur dioxide and fluoride co-exposure induce incisor hypomineralization and amelogenin upregulation via YAP/RUNX2 signaling pathway.

Sulphur dioxide (SO2) and fluoride are among the most common environmental pollutants affecting human health, and both co-exist in areas predominantly consuming coal. It is vital to analyse the combined toxicity of SO2 and fluoride, and their effects on health and the underlying mechanisms of their co-exposure have not yet been adequately assessed. In the present study, we used ICR mice and LS8 cells to investigate the toxicity of SO2 and fluoride exposure to the enamel, alone or in combination. Factorial design analysis was used to reveal the combined toxicity in vitro and in vivo. Co-exposure to SO2 and fluoride exacerbated enamel injury, resulting in more severe hypomineralization of incisor, and enamel structure disorders in mice, and could induce the accumulation of protein residue in the matrix of the enamel. Amelogenin expression was increased upon exposure to SO2 and fluoride, but enamel matrix proteases were not affected. Consistent with our in vivo results, co-exposure of SO2 and fluoride aggravated amelogenin expression in LS8 cells, and increased the YAP and RUNX2 levels. Co-exposure to SO2 and fluoride resulted in greater toxicity than individual exposure, both in vitro and in vivo, indicating that residents of areas exposed to SO2 and fluoride may have an increased risk of developing enamel damage.

LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease.

Endothelial dysfunction is common in patients with chronic kidney disease (CKD), but the mechanism is unknown. In this study, we found that the circulating ANRIL level was increased and correlated with vascular endothelial dysfunction in patients with CKD, also negatively correlated with plasma brain-derived neurotrophic factor (BDNF) concentration. We constructed the ANRIL knockout mice model, and found that ANRIL deficiency reversed the abnormal expression of BDNF, along with endothelial nitric oxide synthase (eNOS), vascular adhesion molecule 1 (VCAM-1) and Von Willebrand factor (vWF). Meanwhile, mitochondrial dynamics-related proteins, Dynamin-related protein 1 (Drp1) and mitofusins (Mfn2) level were also recovered. In addition, in vitro, serum derived from CKD patients and uremia toxins induced abnormal expression of ANRIL. By making use of the gain- and loss-of-function approaches, we observed that ANRIL mediated endothelial dysfunction through BDNF downregulation. To explore the specific mechanism, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) were used to explore the binding of ANRIL to histone methyltransferase Enhancer of zeste homolog 2 (EZH2). Further experiments found increased EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) levels at the BDNF promoter region. Collectively, we demonstrated that ANRIL mediate BDNF transcriptional suppression through recruitment of EZH2 to the BDNF promoter region, then regulated the proteins expression related to endothelial function and mitochondrial dynamics. This study provides new insights for the study of endothelial dysfunction in CKD.

Chronic Kidney Disease and Cancer: Inter-Relationships and Mechanisms.

Chronic kidney disease (CKD) has been recognized as an increasingly serious public health problem globally over the decades. Accumulating evidence has shown that the incidence rate of cancer was relatively higher in CKD patients than that in general population, which, mechanistically, may be related to chronic inflammation, accumulation of carcinogenic compounds, oxidative stress, impairment of DNA repair, excessive parathyroid hormone and changes in intestinal microbiota, etc. And in patients with cancer, regardless of tumor types or anticancer treatment, it has been indicated that the morbidity and incidence rate of concomitant CKD was also increased, suggesting a complex inter-relationship between CKD and cancer and arousing increasing attention from both nephrologists and oncologists. This narrative review focused on the correlation between CKD and cancer, and underlying molecular mechanisms, which might provide an overview of novel interdisciplinary research interests and the potential challenges related to the screening and treatment of CKD and cancer. A better understanding of this field might be of help for both nephrologists and oncologists in the clinical practice.