Deficiency of thrombospondin-2 alleviates intimal hyperplasia in mice by modulating vascular smooth muscle cell proliferation and migration.

Thrombospondin-2 (Tsp2), a glycoprotein in the extracellular matrix, plays a critical role in the maintenance of vascular homeostasis. However, its role in the pathogenesis of cardiovascular disorders such as intimal hyperplasia is not fully elucidated. This study, therefore, aims to explore the effect of Tsp2 on intimal hyperplasia and its associated underlying mechanisms. Intimal hyperplasia (IH) was established using a modified wire-mediated femoral artery injury model. Immunofluorescence and qPCR identified upregulated Tsp2 expression in the injured femoral artery compared with the uninjured femoral artery. Similarly, TSP2 expression was also increased in human samples from the atherosclerotic femoral artery and colocalized with vascular smooth muscle cells (VSMCs). Compared with the wild-type littermates, Tsp2 knockout mice displayed a mitigated IH in the injured femoral artery, as demonstrated by a decreased neointimal area and intimal/median ratio. Primary mouse VSMCs were cultured to explore the mechanism by which Tsp2 influenced IH in vitro. PDGF-stimulated VSMCs presented an elevated Tsp2 expression and enhanced migration and proliferation. However, Tsp2 knockdown by siRNA blocked the increased migration and proliferation of VSMCs. Further analysis identified an association between Notch3 and IH when the intracellular domain of Notch3 (Nicd3) was upregulated in PDGF-stimulated VSMCs and femoral arteries with IH in human tissues. Along with the overexpression and downregulation of Tsp2, the Nicd3 expression was also up and downregulated accordingly. Tsp2 was associated with IH and may serve as a therapeutic target for IH. Downregulation of Tsp2 could mitigate the progression of IH by modulating the proliferation and migration of VSMCs.

Distinguishing Sanghuangporus from sanghuang-related fungi: a comparative and phylogenetic analysis based on mitogenomes.

The Chinese medicinal fungi "Sanghuang" have been long recognized for their significant and valued medicinal properties, as documented in ancient medical literature. However, in traditional folk medicine, various macrofungi sharing similar appearance, habitat, and therapeutic effects with Sanghuang were erroneously used. These Sanghuang-like fungi mainly belong to the Porodaedalea, Phellinus, and Inonotus genera within the Hymenochaetaceae family. Despite the establishment of the Sanghuangporus genus and the identification of multiple species, the emerging taxonomic references based on morphological, ITS, and mycelial structural features have been inadequate to differentiate Sanghuangporus and Sanghuang-like fungi. To address this limitation, this study presents the first comparative and phylogenetic analysis of Sanghuang-related fungi based on mitogenomes. Our results show that Sanghuangporus species show marked convergence in mitochondrial genomic features and form a distinct monophyletic group based on phylogenetic analyses of five datasets. These results not only deepen our understanding of Sanghuang-like fungi but also offer novel insights into their mitochondrial composition and phylogeny, thereby providing new research tools for distinguishing members of the Sanghuangporus genus. KEY POINTS: • Sanghuangporus, Inonotus, and Porodaedalea are monophyly in sanghuang-like species. • Mitogenome-based analysis exhibits high resolution in sanghuang-like genus. • The mitogenomes provide strong evidence for reclassifying Phellinus gilvus S12 as Sanghuangporus vaninii.

Unsupervised machine learning cluster analysis to identification EVAR patients clinical phenotypes based on radiomics.

OBJECTIVE: This study used unsupervised machine learning (UML) cluster analysis to explore clinical phenotypes of endovascular aortic repair (EVAR) for abdominal aortic aneurysm (AAA) patients based on radiomics. METHOD: We retrospectively reviewed 1785 patients with infra-renal AAA who underwent elective EVAR procedures between January 2010 and December 2020. Pyradiomics was used to extract the radiomics features. Statistical analysis was applied to determine the radiomics features that related to severe adverse events (SAEs) after EVAR. The selected features were used for UML cluster analysis in training set and validation in test set. Comparison of basic characteristics and radiomics features of different clusters. The Kaplan-Meier analysis was conducted to generate the cumulative incidence of freedom from SAEs rate. RESULT: A total of 1180 patients were enrolled. During the follow-up, 353 patients experienced EVAR-related SAEs. In total, 1223 radiomics features were extracted from each patient, of which 23 radiomics features were finally preserved to identify different clinical phenotypes. 944 patients were allocated to the training set. Three clusters were identified in training set, in which patients had identical clinical characteristics and morphological features, while varied considerably of selected radiomics features. This encouraging performance was further approved in the test set. In addition, each cluster was well differentiated from other clusters and Kaplan-Meier analysis showed significant differences of freedom from SAEs rate between different clusters both in the training (p = .0216) and test sets (p = .0253). CONCLUSION: Based on radiomics, UML cluster analysis can identify clinical phenotypes in EVAR patients with distinct long-term outcomes.

Deep Learning Prediction for Distal Aortic Remodeling After Thoracic Endovascular Aortic Repair in Stanford Type B Aortic Dissection.

PURPOSE: This study aimed to develop a deep learning model for predicting distal aortic remodeling after proximal thoracic endovascular aortic repair (TEVAR) in patients with Stanford type B aortic dissection (TBAD) using computed tomography angiography (CTA). METHODS: A total of 147 patients with acute or subacute TBAD who underwent proximal TEVAR at a single center were retrospectively reviewed. The boundary of aorta was manually segmented, and the point clouds of each aorta were obtained. Prediction of negative aortic remodeling or reintervention was accomplished by a convolutional neural network (CNN) and a point cloud neural network (PC-NN), respectively. The discriminatory value of the established models was mainly evaluated by the area under the receiver operating characteristic curve (AUC) in the test set. RESULTS: The mean follow-up time was 34.0 months (range: 12-108 months). During follow-up, a total of 25 (17.0%) patients were identified as having negative aortic remodeling, and 16 (10.9%) patients received reintervention. The AUC (0.876) by PC-NN for predicting negative aortic remodeling was superior to that obtained by CNN (0.612, p=0.034) and similar to the AUC by PC-NN combined with clinical features (0.884, p=0.92). As to reintervention, the AUC by PC-NN was significantly higher than that by CNN (0.805 vs 0.579; p=0.042), and AUCs by PC-NN combined with clinical features and PC-NN alone were comparable (0.836 vs 0.805; p=0.81). CONCLUSION: The CTA-based deep learning algorithms may assist clinicians in automated prediction of distal aortic remodeling after TEVAR for acute or subacute TBAD. CLINICAL IMPACT: Negative aortic remodeling is the leading cause of late reintervention after proximal thoracic endovascular aortic repair (TEVAR) for Stanford type B aortic dissection (TBAD), and possesses great challenge to endovascular repair. Early recognizing high-risk patients is of supreme importance for optimizing the follow-up interval and therapy strategy. Currently, clinicians predict the prognosis of these patients based on several imaging signs, which is subjective. The computed tomography angiography-based deep learning algorithms may incorporate abundant morphological information of aorta, provide with a definite and objective output value, and finally assist clinicians in automated prediction of distal aortic remodeling after TEVAR for acute or subacute TBAD.

Predictive Value of Laboratory Indicators for Endoleak During Short-Term Follow-Up After EVAR.

BACKGROUND: The aim of this study was to explore the predictive value of endoleak in short-term follow-up after endovascular aortic repair (EVAR) of abdominal aortic aneurysm (AAA) via perioperative laboratory indicators. METHODS: A retrospective study included 200 consecutive patients who received standard EVAR treatment for AAA and were followed-up for 1 year. Binary logistic regression analysis was used to evaluate the correlation of the level and changes of perioperative laboratory indicators with the endoleak events during the follow-up. The receiver operating characteristic (ROC) curve was used to assess the predictive value of laboratory indicators for endoleak. RESULTS: A total of 45 cases of endoleak events occurred during follow-up. Binary logistic regression analysis showed that postoperative fibrinogen decrease, perioperative lymphocyte difference and lymphocyte monocyte ratio (LMR) difference were independent risk factors for short term endoleak. The area under the ROC curve (AUC) of postoperative fibrinogen was 0.596, the cut-off value was 284 mg/dl, and the corresponding specificity and sensitivity were 0.644 and 0.568. The AUC of the lymphocyte difference was 0.622, the cut-off value was -0.45 × 109/L, and the corresponding specificity and sensitivity were 0.651 and 0.568. The AUC of the LMR difference was 0.597, the cut-off value was -1.719, and the corresponding specificity and sensitivity were 0.631 and 0.614. CONCLUSIONS: Decrease of postoperative fibrinogen, increase of lymphocyte difference and LMR difference were independent predictive factors for endoleak in short-term follow-up after EVAR for AAA.

Endovascular treatment of type B aortic dissection in patients with end-stage renal disease.

OBJECTIVES: This study aimed to evaluate the postoperative and intermediate outcomes of thoracic endovascular aortic repair (TEVAR) in patients with end-stage renal disease (ESRD). METHODS: We retrospectively reviewed patients with type B aortic dissection (TBAD) undergoing TEVAR at our single center from January 2010 to December 2020. Patients with pre-existing ESRD were enrolled as the study group. One hundred consecutive patients from September 2013 to March 2015 without ESRD were included as the control group. The primary and secondary outcomes were adverse events and survival, respectively. Kaplan-Meier curves of survival and freedom from adverse events were calculated and analyzed using the log-rank univariate test. Multivariable analysis was used to isolate the effects of ESRD. RESULTS: A total of 39 patients with ESRD and TBAD underwent TEVAR during the study period. The median follow-up time of patients with and without ESRD was 45 and 46 months, respectively. There was significant difference between the survival at 4 years of patients with and without ESRD (72.8% vs 94.9%; p = 0.011). Meanwhile, the incidence of adverse events was significantly higher in patients with ESRD (p = 0.026). Multivariable logistic regression analysis showed that ESRD (OR, 2.46; p = 0.049) and peripheral artery disease (OR, 4.11; p = 0.002) were the predictors of adverse events. CONCLUSIONS: The rates of adverse events and survival expectancy were poor in patients with ESRD and TBAD.

A radiomics model for predicting the outcome of endovascular abdominal aortic aneurysm repair based on machine learning.

OBJECTIVE: This study aimed to develop a radiomics model to predict the outcome of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA), based on machine learning (ML) algorithms. METHODS: We retrospectively reviewed 711 patients with infra-renal AAA who underwent elective EVAR procedures between January 2016 and December 2019 at our single center. The radiomics features of AAA were extracted using Pyradiomics. Pearson correlation analysis, analysis of variance (ANOVA), least absolute shrinkage, and selection operator (LASSO) regression were applied to determine the predictors for EVAR-related severe adverse events (SAEs). Eighty percent of patients were classified as the training set and the remaining 20 percent of patients were classified as the test set. The selected features were used to build a radiomics model in training set using different ML algorithms. The performance of each model was assessed using the area under the curve (AUC) from the receiver operating characteristic (ROC) curve in the test set. RESULTS: A total of 493 patients were enrolled in this study, the mean follow-up time was 32 months. During the follow-up, 156 (31.6%) patients experienced EVAR-related SAEs. A total of 1223 radiomics features were extracted from each patient, of which 30 radiomics features were finally identified. The quantitative performance assessment and the ROC curves indicated that the logistics regression (LR) model had better predictive value than others, with accuracy, 0.86; AUC, 0.93; and F1 score, 0.91. The Rad-score waterfall plot showed that the overall amount of error was small both in the training set and in the test set. Calibration curve showed that the calibration degree of the training set and the test set were good (p > 0.05). Decision curve analysis (threshold 0.32) demonstrated that the model had good clinical applicability. CONCLUSION: Our radiomics model could be used as an efficient and adjunctive tool to predict the outcome after EVAR.

The First Five Mitochondrial Genomes for the Family Nidulariaceae Reveal Novel Gene Rearrangements, Intron Dynamics, and Phylogeny of Agaricales.

The family Nidulariaceae, consisting of five genera including Cyathus, is a unique group of mushrooms commonly referred to as bird's nest fungi due to their striking resemblance to bird's nests. These mushrooms are considered medicinal mushrooms in Chinese medicine and have received attention in recent years for their anti-neurodegenerative properties. However, despite the interest in these mushrooms, very little is known about their mitochondrial genomes (mitogenomes). This study is the first comprehensive investigation of the mitogenomes of five Nidulariaceae species with circular genome structures ranging in size from 114,236 bp to 129,263 bp. Comparative analyses based on gene content, gene length, tRNA, and codon usage indicate convergence within the family Nidulariaceae and heterogeneity within the order Agaricales. Phylogenetic analysis based on a combined mitochondrial conserved protein dataset provides a well-supported phylogenetic tree for the Basidiomycetes, which clearly demonstrates the evolutionary relationships between Nidulariaceae and other members of Agaricales. Furthermore, phylogenetic inferences based on four different gene sets reveal the stability and proximity of evolutionary relationships within Agaricales. These results reveal the uniqueness of the family Nidulariaceae and its similarity to other members of Agaricales; provide valuable insights into the origin, evolution, and genetics of Nidulariaceae species; and enrich the fungal mitogenome resource. This study will help to expand the knowledge and understanding of the mitogenomes in mushrooms.

A new classification and strategies for endovascular treatment of celiac artery aneurysms.

BACKGROUND: Endovascular treatment is being increasingly used for celiac artery aneurysms (CAAs), but systematic endovascular treatment strategies have not been defined yet. This study intended to investigate the strategies of endovascular management of CAAs according to a single-center experience. METHODS: Anatomically, CAAs were classified into two types: Type I CAAs located in the main trunk of celiac artery. Type II CAAs located on the branches of the celiac artery. Type I and Type II CAAs can be further divided into two different subtypes according to fusiform (a) or saccular or (b) morphology: type Ia, type Ib, type IIa, and type IIb. Patient demographics, clinical manifestations, aneurysm characteristics, endovascular intervention procedures, and perioperative and follow-up outcomes were reviewed and analyzed. RESULTS: Between August 2012 and August 2020, 18 consecutive patients (12 men; mean age, 56.8 ± 14.5 years) with CAAs were identified and treated with endovascular procedures. There were seven patients with type Ia, three patients with type Ib, four patients with type IIa, and four patients with type IIb CAAs. One patient died of hemorrhagic shock due to a ruptured aneurysm. Technical success was achieved in 16 patients (88.9%). The mean follow-up period was 51.7 ± 19.4 months. No hepatic or intestinal ischemia or death developed perioperatively or during the follow-up period. No aneurysmal expansion was detected on CTA surveillance, except for one patient who was diagnosed with an endoleak during the follow-up and received reintervention. CONCLUSIONS: The endovascular strategy based on the novel classification of CAAs was safe and effective, with a favorable mid-term clinical outcome.

Circular RNA expression profile and its potential regulative role in human abdominal aortic aneurysm.

BACKGROUND: This study aimed to identify the differentially expressed circular RNAs (circRNAs) between human abdominal aortic aneurysm (AAA) and the control group. METHODS: High-throughput sequencing was applied to determine the circRNA expression profiles of 4 paired aortic samples. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out to testify 6 randomly selected dysregulated circRNAs. Kyoto Encyclopedia of Genes and Genomes and Gene ontology (GO) analysis were conducted for functional annotation of the parental genes. Additionally, interaction networks between circRNA and 5 putative microRNA (miRNA) partners were constructed. RESULTS: Finally, 411 differentially expressed circRNAs were discovered, including 266 downregulated and 145 upregulated circRNAs. Compared with the control group, the expression level of hsa (Homo sapiens) _circ_0005360 (LDLR) and hsa_circ_0002168 (TMEM189) were proved significantly lower in the AAA group by qRT-PCR. Regarding upregulated circRNAs, the most enriched GO molecular function, biological process and cellular component terms were poly(A) RNA binding, negative regulation of transcription from RNA polymerase II promoter and nucleoplasm, respectively. Moreover, circRNA/miRNA interaction networks showed that hsa_circ_0005360/miR-181b and hsa_circ_0002168/miR-15a axis might have a regulative role in human AAA. CONCLUSIONS: This study revealed new circRNAs potentially related to the pathogenesis of AAA. Further experimental studies are warranted to clarify the potential molecular mechanisms.

The real-world incidence and predictors of sac regression in patients with infrarenal abdominal aortic aneurysm after standard EVAR.

OBJECTIVE: Sac regression (SR) is a surrogate marker of satisfied endovascular aneurysm repair (EVAR). This research aims to investigate the incidence and predictors of SR in a Chinese population. DESIGN: Single centre retrospective cohort study. METHODS: Consecutive patients with infrarenal abdominal aortic aneurysms (AAAs) who underwent standard EVAR were retrospectively reviewed. SR was defined as sac shrinkage > 5 mm on computed tomography images, while major SR (MaSR) was ≥ 10 mm sac shrinkage. The cumulative rate was calculated by Kaplan-Meier analysis and predictors were identified by the Cox regression model. RESULTS: A total of 469 patients (median age, 71 years old) were included. The majority of them (86.6 %) were male. With a median time of 13.6 months, SR was detected in 129 (27.5 %) patients after the index EVAR. Compared with never smokers, current smokers were more likely to experience SR (adjusted HR 2.630, p < .001), while former smokers did not show any significant difference. Multivariate Cox regression also showed that maximal aneurysm diameter (adjusted HR 1.012, p = 0.035) and female (adjusted HR 1.675, p = .045) were independent predictors of SR. A total of 51 (10.9 %) patients had MaSR at a median time of 15.4 months after EVAR. In multivariate analysis, maximal aneurysm diameter and Zenith stent graft were independently associated with MaSR. CONCLUSION: In Chinese population, the incidence of SR and MaSR was 27.5 % and 10.9 % after EVAR, respectively. Maximal aneurysm diameter and female were independent predictors of SR. Compared with never smokers, it was more likely to have SR in current smokers.

Fully automatic segmentation of abdominal aortic thrombus in pre-operative CTA images using deep convolutional neural networks.

BACKGROUND: Endovascular aortic aneurysm repair (EVAR) is currently established as the first-line treatment for anatomically suitable abdominal aortic aneurysm (AAA). OBJECTIVE: To establish a deep convolutional neural networks (DCNN) model for fully automatic segmentation intraluminal thrombosis (ILT) of abdominal aortic aneurysm (AAA) in pre-operative computed tomography angiography (CTA) images. METHODS: We retrospectively reviewed 340 patients of AAA with ILT at our single center. The software ITKSNAP was used to draw AAA and ILT region of interests (ROIs), respectively. Image preprocessing and DCNN model build using MATLAB. Randomly divided, 80% of patients was classified as training set, 20% of patients was classified as test set. Accuracy, intersection over union (IOU), Boundary F1 (BF) Score were used to evaluate the predictive effect of the model. RESULTS: By training in 34760-35652 CTA images (n= 204) and validation in 6968-7860 CTA images (n=68), the DCNN model achieved encouraging predictive performance in test set (n= 68, 6898 slices): Global accuracy 0.9988 ± 5.7735E-05, mean accuracy 0.9546 ± 0.0054, ILT IOU 0.8650 ± 0.0033, aortic lumen IOU 0.8595 ± 0.0085, ILT weighted IOU 0.9976 ± 0.0001, mean IOU 0.9078 ± 0.0029, mean BF Score 0.9829 ± 0.0011. Our DCNN model achieved a mean IOU of more than 90.78% for segmentation of ILT and aortic lumen. It provides a mean relative volume difference between automatic segmentation and ground truth (P> 0.05). CONCLUSION: An end-to-end DCNN model could be used as an efficient and adjunctive tool for fully automatic segmentation of abdominal aortic thrombus in pre-operative CTA image.

Therapeutic or prophylactic anticoagulation in acute isolated distal deep vein thrombosis: protocol for a prospective, multicentre, single-blind, randomised controlled trial (TOP-IDDVT).

INTRODUCTION: The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic isolated distal deep vein thrombosis (IDDVT). In real-world clinical practice, both therapeutic and prophylactic anticoagulation are used for acute IDDVT. However, therapeutic anticoagulation is associated with higher risk of bleeding than prophylactic anticoagulation. Thus, this study aims to assess the efficacy and safety in patients with first acute symptomatic IDDVT treated with therapeutic or prophylactic anticoagulation using rivaroxaban. METHODS AND ANALYSIS: This study is a prospective, multicentre, single-blind, randomised controlled trial. Outpatients with a first, acute, symptomatic, objectively confirmed IDDVT in four centres from 1 August 2021 are recruited. Eligible patients are randomised in a 1:1 ratio to receive prophylactic anticoagulation (rivaroxaban 10 mg once a day for 3 months) or therapeutic anticoagulation (rivaroxaban 20 mg once a day for 3 months). All patients are followed for 6 months. The primary efficacy outcome is radiographically confirmed recurrent venous thromboembolism. The primary safety outcome is the incidence of major or clinically relevant non-major bleeding events. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Zhongshan Hospital Fudan University (B2021-175R). Study results will be disseminated through peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04967573.

Genomic and Metabolomic Analyses of the Medicinal Fungus Inonotus hispidus for Its Metabolite's Biosynthesis and Medicinal Application.

Inonotus hispidus mushroom is a traditional medicinal fungus with anti-cancer, antioxidation, and immunomodulatory activities, and it is used in folk medicine as a treatment for indigestion, cancer, diabetes, and gastric illnesses. Although I. hispidus is recognized as a rare edible medicinal macrofungi, its genomic sequence and biosynthesis potential of secondary metabolites have not been investigated. In this study, using Illumina NovaSeq combined with the PacBio platform, we sequenced and de novo assembled the whole genome of NPCB_001, a wild I. hispidus isolate from the Aksu area of Xinjiang Province, China. Comparative genomic and phylogenomic analyses reveal interspecific differences and evolutionary traits in the genus Inonotus. Bioinformatics analysis identified candidate genes associated with mating type, polysaccharide synthesis, carbohydrate-active enzymes, and secondary metabolite biosynthesis. Additionally, molecular networks of metabolites exhibit differences in chemical composition and content between fruiting bodies and mycelium, as well as association clusters of related compounds. The deciphering of the genome of I. hispidus will deepen the understanding of the biosynthesis of bioactive components, open the path for future biosynthesis research, and promote the application of Inonotus in the fields of drug research and functional food manufacturing.

Deficiency of ITGAM Attenuates Experimental Abdominal Aortic Aneurysm in Mice.

Background Integrin αM (CD11b), which is encoded by the Integrin Subunit Alpha M (ITGAM) gene, is not only a surface marker of monocytes but also an essential adhesion molecule. In this study, we investigated the effect of CD11b on experimental abdominal aortic aneurysm and the potential underlying mechanisms. Methods and Results The incidence of abdominal aortic aneurysm was not significantly lower in ITGAM(-/-) mice than in control mice. Nevertheless, knockout of CD11b reduced the maximum abdominal aortic diameter, macrophage infiltration, matrix metalloproteinase-9 expression, and elastin and collagen degradation. Additionally, lower expression of IL-6 was found in both the peripheral blood and abdominal aortas of ITGAM(-/-) mice, indicating a biological correlation between CD11b and the inflammatory response in abdominal aortic aneurysm. In vitro, the number of ITGAM(-/-) bone marrow-derived macrophages (BMDMs) that adhered to endothelial cells was significantly lower than the number of wild-type BMDMs. Moreover, the CD11b monoclonal antibody and CD11b agonist leukadherin-1 decreased and increased the number of adherent wild-type BMDMs, respectively. Through RNA sequencing, genes associated with leukocyte transendothelial migration were found to be downregulated in ITGAM(-/-) BMDMs. Furthermore, immunoprecipitation-mass spectrometry analysis predicted that the Akt pathway might be responsible for the impaired transmigratory ability of ITGAM(-/-) BMDMs. The reduced activation of Akt was then confirmed, and the Akt agonist SC79 partially rescued the transendothelial migratory function of ITGAM(-/-) BMDMs. Conclusions CD11b might promote the development and progression of abdominal aortic aneurysm by mediating the endothelial cells adhesion and transendothelial migration of circulating monocytes/macrophages.

Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation.

OBJECTIVE: Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms. APPROACHES AND RESULTS: In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration. CONCLUSIONS: Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.

Molecular characterization of thioredoxin reductase in waterflea Daphnia magna and its expression regulation by polystyrene microplastics.

Global scale concerns regarding rise in microplastics pollution in the environment have recently aroused. Ingestion of microplastics by biota, including freshwater zooplankton has been well studied, however, despite keystone species in freshwater food webs, the molecular response (e.g. oxidative defense) of zooplankton in response to microplastics is still in its infancy. The thioredoxin (TRx) system has a vital function in cellular antioxidative defense via eliminating the excessive generation of reactive oxygen species (ROS). Therefore, it is necessary to investigate the effects of thioredoxin reductase (TRxR), due to its triggering the TRx catalysis cascade. The present study identified TRxR in Daphnia magna (Dm-TRxR) for the first time, and found that the full-length cDNA was 1862 bp long, containing an 1821-bp open reading frame. Homologous alignments showed the presence of conserved catalytic domain CVNVGC and the seleocysteine (SeCys) residue (U) located in the N- and C- terminal portions. Subsequently, the expression of Dm-TRxR, together with permease, arginine kinase (AK), was investigated by approach of quantitative real-time PCR after exposure to four (1.25-µm) polystyrene (PS) microbeads concentrations: 0 (control), 2, 4 and 8 mg L-1 for 10 days. Dm-TRxR, permease and AK mRNA were significantly upregulated after exposure to 2, 4 mg L-1 of PS, but then declined in the presence of 8 mg L-1 PS. The gene expression results suggested that oxidative defense, energy production and substance extra cellular transportation were significantly regulated by microplastic exposure. Collectively, the present study will advance our knowledge regarding the biological effects of microplastic pollution on zooplankton, and builds a foundation for freshwater environmental studies on mechanistic and biochemical responses to microplastics.