YY1-induced LncRNA-TUG1 elevates YOD1 to promote cell proliferation and inhibit bortezomib sensitivity in multiple myeloma.

Taurine upregulated gene 1 (TUG1) has been implicated in the onset and progression of various malignancies. The current study aimed to evaluate the biological function and potential mechanisms of TUG1 in multiple myeloma (MM) progression. TUG1 knockdown in MM cells was investigated in vitro and in vivo to evaluate the role of TUG1. We also predicted the transcription factor (TF) that bound to TUG1 together with the downstream target genes of the TUG1-TF interaction, and evaluated the regulatory mechanism of TUG1 in cell assays. TUG1 knockdown reduced the cell's proliferative and migratory capabilities while increasing apoptosis and bortezomib sensitivity in vitro and inhibiting tumorigenesis in vivo. TUG1 was found in the nucleus of MM cells and was found to be positively regulated by the TF-YY1. Further in vitro mechanistic investigations indicated that the YY1-TUG1 complex targeted YOD1 to regulate MM progression.

A novel drainage strategy using chest tube plus pleural catheter in uniportal upper lobectomy: A randomized controlled trial.

BACKGROUND: In this study we explored whether one pleural catheter plus single chest tube drainage could achieve a noninferior drainage effect when compared with the traditional two chest tubes in uniportal video-assisted thoracoscopic surgery (VATS) for an upper pulmonary lobectomy. METHODS: Patients that underwent an upper pulmonary lobectomy from January to November 2020 were enrolled in this single-center, randomized, open-label, noninferiority trial. Prior to closure, patients were randomized to an intervention group who received an improved drainage strategy involving one pleural catheter with one chest tube (24 Fr), while traditional double chest tube drainage was applied for the control group. RESULTS: A total of 390 patients entered the study, although 190 were excluded for changing nonuniportal surgical approaches or opting for nonlobectomy resections. Finally, 200 patients were randomized (100 in the intervention group and 100 in the control group). The baseline demographic and clinical characteristics were comparable between the groups. The incidence of pneumothorax in the intervention and control groups was similar on postoperative Day 1 (noninferiority, 10% vs. 13%, p = 0.658). In addition, there were no significant differences in secondary outcomes such as incidence of pneumothorax by Day 30, postoperative chest tube/pleural catheter removal time, amount of drainage on Day 1, total amount of drainage after operation, or postoperative hospitalization. A significantly lower pain score was observed in the intervention group (3.33 ± 0.68 vs. 3.68 ± 0.94, p = 0.003). CONCLUSIONS: The new strategy is noninferior to double chest tube drainage after an upper pulmonary lobectomy offers superior pain control, and is recommended for an upper lobectomy by uniportal VATS.

Elevated urbanization-driven plant accumulation and human intake risks of polycyclic aromatic hydrocarbons in crops of peri-urban farmlands.

As an ubiquitous carcinogen, polycyclic aromatic hydrocarbons (PAHs) are closely related to anthropogenic activities. The process of urbanization leads to the spatial interlacing of farmlands and urbanized zones. However, field evidence on the influence of urbanization on the accumulation of PAHs in crops of peri-urban farmlands is lacking. This study comparatively investigated the urbanization-driven levels, compositions, and sources of PAHs in 120 paired plant and soil samples collected from the Yangtze River Delta in China and their species-specific human intake risks. The concentrations of PAHs in crops and soils in the peri-urban areas were 2407.92 ng g-1 and 546.64 ng g-1, respectively, which are significantly higher than those in the rural areas. The PAHs in the root were highly relevant to those in the soils (R2 = 0.63, p < 0.01), and the root bioconcentration factors were higher than 1.0, implying the contributions of root uptake to plant accumulations. However, the translocation factors in the peri-urban areas (1.57 ± 0.33) were higher than those in the rural areas (1.19 ± 0.14), indicating the enhanced influence through gaseous absorption. For the congeners, the 2- to 3-ring PAHs showed a higher plant accumulation potential than the 4- to 6-ring PAHs. Principal component analysis show that the PAHs in the peri-urban plants predominantly resulted from urbanization parameters, such as coal combustion, vehicle emissions, and biomass burning. The mean values of estimated dietary intake of PAHs from the consumption of peri-urban and rural crops were 9116 ng day-1 and 6601.83 ng day-1, respectively. The intake risks of different crops followed the order rice > cabbage > carrot > pea. Given the significant input of PAHs from urban to farmland, the influence of many anthropogenic pollutants arising from rapid urbanization should be considered when assessing the agricultural food safety.

LncRNA LOC146880 promotes esophageal squamous cell carcinoma progression via miR-328-5p/FSCN1/MAPK axis.

We investigated the role of long non-coding RNA (lncRNA) LOC146880 in esophageal squamous cell carcinoma (ESCC). LOC146880 was significantly upregulated in ESCC tissues (n = 21) and cell lines compared to the corresponding controls. Higher LOC146880 expression correlated with poorer overall survival (OS) of ESCC patients. Moreover, CREB-binding protein (CBP) and H3K27 acetylation levels were significantly higher in the LOC146880 promoter in ESCC cell lines than in the controls. LOC146880 silencing inhibited in vitro proliferation, invasion, migration, and epithelial-mesenchymal transition of ESCC cells. LOC146880 silencing also induced G1-phase cell cycle arrest and apoptosis in ESCC cells. Bioinformatics analysis, dual luciferase reporter assays, and RNA immunoprecipitation assays showed that LOC146880 regulates FSCN1 expression in ESCC cells by sponging miR-328-5p. Moreover, FSCN1 expression correlated with activation of the MAPK signaling pathway in ESCC cells and tissues. In vivo xenograft tumor volume and liver metastasis were significantly reduced in nude mice injected with LOC146880-silenced ESCC cells as compared to those injected with control shRNA-transfected ESCC cells. These findings show that the LOC146880/miR-328-5p/FSCN1/MAPK axis regulates ESCC progression in vitro and in vivo. LOC146880 is thus a promising prognostic biomarker and potential therapeutic target in ESCC.

Real-time monitoring of caspase-3/8 activity by self-assembling nanofiber probes in living cells.

Caspase-3/8 are key members of the cysteine-aspartyl protease family with pivotal roles in apoptosis. We have designed and synthesized self-assembling probes, Nap-GFFpYDEVD-AFC and Nap-GFFpYIETD-AFC, with fluorescence 'turn-on' properties for real-time monitoring of Caspase-3/8 activity in living cells.

[A Retrospective Study of Microporous Polysaccharide Hemostatic Powder Combined with Other Repair Materials for Reducing Postoperative Pulmonary Air Leakage during Pulmonary Segmentectomy].

BACKGROUND: Anatomical segmentectomy is more and more widely used in lung nodules and early stage lung cancer. Postoperative lung air leakage is one of the common complications after surgery. This study aimed to explore the effect of the application of repair materials in precise segmentectomy under thoracoscopy in reducing postoperative lung air leakage. METHODS: This study included patients admitted to the Department of Thoracic Surgery of Jiangsu Provincial People's Hospital who were scheduled to undergo thoracoscopic segmentectomy from August 1, 2018 to July 31, 2019. According to the difference of the materials used in the treatment of the inter-segment interface during the operation: patients who used microporous polysaccharide hemostatic powder+fibrin adhesive glue+absorbable polyglycolic acid patch were divided into group A, and the patients with fibrin adhesive+absorbable polyglycolic acid patch were divided into group B. The preoperative basic information of all patients and the daily postoperative chest drainage volume, the indwelling time of the chest drainage tube, the chest radiograph before the chest drainage tube is removed, the chest radiograph after the chest drainage tube is removed, blood routine and postoperative hospital stay were collected and recorded, and the effect of the application of intraoperative repair materials on postoperative lung air leakage was analyzed. RESULTS: There were statistically significant differences in the indwelling time of thoracic drainage tube (P=0.019) and postoperative hospital stay (P=0.017) between the two groups. CONCLUSIONS: Compared with the use of the fibrin glue+absorbability polyglycolic acid patch, the use of microporous polysaccharide hemostatic powder+fibrin glue+absorbability polyglycolic acid patch in the treatment of the inter-segment interface during segmentectomy can better reduce the incidence of postoperative air leakage and shorten the postoperative hospital stay.

Long non-coding RNA CCAT2 as a potential serum biomarker for diagnosis and prognosis of multiple myeloma.

Increasing knowledge of long non-coding RNAs (lncRNAs) has shown that they can be used as circulating tumor markers. Also, considerable evidences have revealed that lncRNAs have important roles in tumor diagnosis and prognosis. The lncRNA CCAT2 has manifested its carcinogenic effect in a variety of tumors, but the serum expression level and clinical value in multiple myeloma (MM) remain to be explored. In our study, the expression of lncRNA CCAT2 is upregulated in the serum and bone marrow of MM patients by using quantitative real-time polymerase chain reaction (qRT-PCR). The high expression level of CCAT2 in the serum of MM patients correlated with International Scoring System (ISS) stages, renal dysfunction, serum ß2-microglobulin (ß2-MG) concentration, and light chain (κ and λ) concentrations. Area under the curve (AUC) of CCAT2 in serum is 0.899. Besides, the sensitivity and specificity were 85.80% and 83%, respectively. Furthermore, combination of CCAT2, IgA, HGB, and ß2-MG significantly improved the MM diagnostic sensitivity and AUC. Here, our present investigation indicates that serum circulating CCAT2 may serve as a potential tumor marker for diagnosis and prognosis of MM.

Cytoprotective Effects Evaluation of a Novel Danshensu Derivative DEX-018 against Oxidative Stress Injury in HUVECs.

Ischemic heart disease (IHD) is one of the most common cardiovascular diseases with high morbidity and mortality. Danshensu (DSS) is widely used in the treatment of coronary heart disease. In this study, the carboxy group of DSS was esterified with edaravone to synthesize the novel DSS derivative DEX-018 to achieve a synergistic protective effect and overcome the structural deficiency of DSS. The pharmacological effect of DEX-018 against tert-butyl hydrogen peroxide (t-BHP) induced oxidative damage in human umbilical vein endothelial cells (HUVECs) was evaluated. The results demonstrated that pretreatment with DEX-018 significantly increased cell viability and superoxide dismutase (SOD) activity and decreased the lactate dehydrogenase (LDH) leakage rate, malondialdehyde (MDA) level and intracellular reactive oxygen species (ROS) level. In addition, DEX-018 inhibited cell apoptosis and reversed the expression of apoptosis-related proteins (Bcl-2, Bax, and caspase-3) in HUVECs stimulated by t-BHP. Further study on the mechanism of DEX-018 revealed that the expression of p-Akt and p-extracellular signal-regulated kinase 1/2 (ERK1/2) was increased, which suggested that DEX-018 may protect HUVECs against t-BHP induced oxidative injury via the Akt and ERK1/2 signaling pathways. To further validate the correlation, CCK8 was used to detect cell viability after treatment with DEX-018 plus Akt inhibitor (MK2206) and phosphadylinositol 3-kinase (PI3K) inhibitor (LY294002). Compared with DEX-018 alone, MK2206 or LY294002 significantly decreased cell viability of HUVECs, indicating that the protective effect of DEX-018 against t-BHP induced oxidative injury was significantly weakened. It was further verified that the antioxidant and anti-apoptotic effects of DEX-018 were partly related to the PI3K-Akt signaling pathway.

NALP3 orchestrates cellular bioenergetics to facilitate non-small cell lung cancer cell growth.

AIMS: Previous work has reported the closely correlation between inflammation and carcinogenesis, while the role of NALP3, the key component of inflammasome activation in NSCLC remains elusive. This study was to unravel the mechanism of NALP3 on modulating NSCLC cancer cell growth. METHODS: IHC and immuno-blot were performed to analyze expression of NALP3 and indicated molecules. CCK-8 and xenograft nude mice assay were used to evaluate cell growth in vitro and in vivo. Bioenergetics assay was performed to measure OXPHOS and aerobic glycolysis. siRNA and shRNA were constructed to knockdown endogenous NALP3 and DNMT1. Co-immunoprecipitation was applied to confirm the interaction between NALP3 and DMAP1. BioProfile FLEX analyzer and Lactate Reagent Kit were used to measure relative level glucose uptake and lactate production. KEY FINDINGS: We reported NALP3 were up-regulated in NSCLC tumor tissues. NALP3 depletion suppressed cancer cell growth in vitro and in vivo. Moreover, data showed depletion of NALP3 promoted cell bioenergetics switch from aerobic glycolysis to OXPHOS. Additionally, we found NALP3 interacted with DMAP1 and alteration of NALP3 increased DNMT1 level. Subsequently, we clarified depletion of DNMT1 significantly suppressed NSCLC cell growth and orchestrated cellular metabolism which was similar to the effects of NALP3 knockdown. Finally, our data showed high NALP3 was associated with poor outcomes, and correlated with TNM stage and differentiation. SIGNIFICANCE: Current study elucidated NALP3 could promote metabolic reprogramming to regulate NSCLC cell growth and suggested that NALP3 may be considered as a novel biomarker and therapeutic target for NSCLC patients.

miR-204-5p regulates cell proliferation, invasion, and apoptosis by targeting IL-11 in esophageal squamous cell carcinoma.

Esophageal cancer (EC) is the world's eighth most common malignant neoplasm and is ranked as the sixth leading cause of death related to cancer. Aberrant microRNA (miRNA) expression has been reported to be associated with esophageal squamous cell carcinoma. However, the molecular mechanism of miR-204-5p in esophageal squamous cell carcinoma (ESCC) is not clear. Therefore, the aim of this study was to investigate the potential role of miR-204-5p in ESCC. In the present study, we found that miR-204-5p could affect ESCC proliferation, invasion, apoptosis, and cell cycle in cell and mouse models. A dual-luciferase reporter assay showed that miR-204-5p expression was negatively correlated with interleukin-11 (IL-11) expression. IL-11 overexpression reversed the suppressive effects of miR-204-5p in the cell lines. These results indicated that miR-204-5p functions as a tumor suppressor by directly targeting IL-11 in ESCC.

A natural AKT inhibitor swertiamarin targets AKT-PH domain, inhibits downstream signaling, and alleviates inflammation.

Swertiamarin (SW), a representative component in Flos Lonicerae Japonicae, has been reported to exert significant activity in preventing infections. In this research, we aim to clarify the details of SW and its target to explore SW's underlying anti-inflammatory mechanisms. An azide labeled SW probe was synthesized for protein target fishing, and the results demonstrated that AKT could be captured specifically. Immunofluorescence colocalization with AKT was implemented by a click reaction of the SW probe and alkynyl CY5. The result showed that AKT was one of the targets of SW. Then, a competitive combination experiment using a set of AKT inhibitors and a membrane translocation experiment confirmed that SW might target the pleckstrin homology (PH) domain of AKT. This specific binding directly deactivated the phosphorylation of AKT on both Ser473 and Thr308, which induced the dephosphorylation of IKK and NF-κB. Finally, proinflammatory cytokines (TNF-α, IL-6, and IL-8) were suppressed both in cells and in acute lung injury animal model by targeting AKT-PH domain. This study demonstrated that SW functions as a natural AKT inhibitor and presents significant anti-inflammatory activity by directly regulating the AKT-PH domain and inhibiting downstream inflammatory molecules.

Autophagy regulates the therapeutic potential of adipose-derived stem cells in LPS-induced pulmonary microvascular barrier damage.

Adipose-derived stem cells (ADSCs) have been shown to be beneficial in some pulmonary diseases, and the paracrine effect is the major mechanism underlying ADSC-based therapy. Autophagy plays a crucial role in maintaining stem cell homeostasis and survival. However, the role of autophagy in mediating ADSC paracrine effects has not been thoroughly elucidated. We examined whether ADSCs participate in lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cell (PMVEC) barrier damage in a paracrine manner and illuminated the role of autophagy in regulating ADSC paracrine effects. PMVECs and ADSCs with or without autophagy inhibition were cocultured without intercellular contact, and the microvascular barrier function was assessed after LPS treatment. ADSC paracrine function was evaluated by detecting essential growth factors for endothelial cells. For in vivo experiments, ADSCs with or without autophagy inhibition were transplanted into LPS-induced lung-injury mice, and lung injury was assessed. ADSCs significantly alleviated LPS-induced microvascular barrier injury. In addition, ADSC paracrine levels of VEGF, FGF, and EGF were induced by LPS treatment, especially in the coculture condition. Inhibiting autophagy weakened the paracrine function and the protective effects of ADSCs on microvascular barrier injury. Moreover, ADSC transplantation alleviated LPS-induced lung injury, and inhibiting autophagy markedly weakened the therapeutic effect of ADSCs on lung injury. Together, these findings show that ADSC paracrine effects play a vital protective role in LPS-induced pulmonary microvascular barrier injury. Autophagy is a positive mediating factor in the paracrine process. These results are helpful for illuminating the role and mechanism of ADSC paracrine effects and developing effective therapies in acute lung injury.

Association of VDR gene TaqI polymorphism with the susceptibility to prostate cancer in Asian population evaluated by an updated systematic meta-analysis.

BACKGROUND: The vitamin D receptor (VDR) plays a key role in vitamin-mediated signaling pathway. Emerging evidence has suggested that the VDR polymorphism may contribute to the risk of prostate cancer (PCa). However, the existing results are not conclusive in Asian population. METHODS: We aim to evaluate the potential role of VDR polymorphisms on PCa of Asian population. PubMed, Scopus, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wang Fang Data, and VIP Periodical were retrieved, and eligible studies (case-control or cohort study) meeting the inclusion criteria were evaluated through an updated meta-analysis using Stata13.0 software. RESULTS: A total of 1,363 cases and 2,101 controls obtained from 13 eligible publications were eventually included in this meta-analysis. Our results show that a significant association of VDR taq1 polymorphism with PCa risk, especially in the Japanese population. In the clinical stage-stratified analysis, the pooled results revealed no significant difference in genetic polymorphisms between the local stage and control groups, whereas there was increased frequency of T allele and TT genotype in the advanced tumor stage group compared with local tumor stage or control groups. Similarly, no significant difference was seen in Gleason <7 and control groups, but the T allele and TT genotype were significantly higher in the Gleason ≥7 group compared with Gleason <7 or control groups. CONCLUSION: The VDR TaqI polymorphism might be associated with PCa risk in Asian population, especially in the Japanese population. Also, PCa patients carrying the T allele or TT genotype were more likely to progress to advanced stage. These results suggest that VDR TaqI polymorphisms may be potential diagnostic biomarkers for PCa susceptibility.

Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis.

Previous findings have identified that tumor necrosis factor-related weak inducer of apoptosis (TWEAK) is associated with lupus nephritis (LN) activity status; however, the mechanism involved remains unclear. The present study aimed to investigate the roles of TWEAK and the nuclear factor (NF)-κB signaling pathway in LN. TWEAK levels in the blood and urine of patients with LN or non-LN systemic lupus erythematosus were measured by ELISA and compared with those in healthy controls. TWEAK expression and NF-κB transcriptional activity in the kidney were detected by western blotting, and Ki-67 and cluster of differentiation (CD) 68 expression were assessed using immunofluorescence. Additionally, human mesangial cells (HMCs) were cultured in vitro and divided into five groups: Normal control, TWEAK stimulus group, TWEAK + TWEAK blocking antibody, TWEAK + NF-κB inhibitor (BAY 11-7082) and TWEAK + combined (blocking antibody + BAY 11-7082). Cell cycle activity and Ki-67 expression in the HMCs were evaluated using flow cytometry, and cell induction of macrophage chemotaxis was determined by a Transwell assay. Levels of the inflammation-associated factors interleukin (IL)-6, monocyte chemotactic protein 1 (MCP-1), chemokine ligand 5 (CCL5), IL-8 and IL-10 were also detected by reverse transcription-quantitative polymerase chain reaction. It was observed that the urine levels of TWEAK in patients with LN were significantly elevated compared with those in the other groups (P<0.05). LN kidneys exhibited markedly increased cell proliferative ability, macrophage infiltration, TWEAK expression and NF-κB transcriptional activity compared with normal kidneys. Furthermore, the results indicated that treatment with recombinant TWEAK notably enhanced NF-κB transcriptional activity and significantly promoted cell proliferation and cell cycle activity (P<0.05), induced macrophage chemotaxis (P<0.05), significantly increased the expression of the chemotactic factors IL-6, IL-8, MCP-1 and CCL5 (P<0.05), and significantly reduced anti-inflammatory cytokine IL-10 mRNA expression in HMCs (P<0.05), relative to normal controls. Accordingly, blocking TWEAK function or inhibiting NF-κB activity reversed these effects. Collectively these data indicate that urine TWEAK may be considered as a novel biomarker of LN activity, and that blocking TWEAK function or NF-κB activity may effectively alleviate glomerular mesangial cell proliferation and macrophage chemotaxis.

Menstrual Disturbances in Premenopausal Women with End-Stage Renal Disease: A Cross-Sectional Study.

OBJECTIVE: To evaluate menstrual disturbances and sex hormonal status in premenopausal women with end-stage renal disease (ESRD). SUBJECTS AND METHODS: The study consisted of 184 patients with ESRD treated with one of four treatment modalities (46/modality): conventional hemodialysis (CHD), continuous ambulatory peritoneal dialysis (CAPD), nocturnal hemodialysis (NHD) and renal transplantation (RT). Blood samples were collected to determine sex hormone levels. Sociodemographic and clinical data were collected from medical records. A questionnaire was administered to analyze menstrual patterns, and the final analysis included 46, 43, 40 and 36 patients in the CHD, CAPD, NHD and RT groups, respectively. RESULTS: The overall prevalence of menstrual disturbances was 64.2% for all four treatment modalities (RT: 50%; NHD: 55%; CAPD: 72.1%, and CHD: 76.1%). Serum prolactin levels were significantly lower (p < 0.01) in the NHD (25.1 ± 10.9 ng/ml) and RT (13.4 ± 5.1 ng/ml) groups than in the CHD group (55.2 ± 10.8 ng/ml). Serum progesterone levels were significantly higher (p < 0.01) in the NHD (25.7 ± 8.3 nmol/l) and RT (30.1 ± 5.9 nmol/l) groups than in the CHD group (17.7 ± 7.3 nmol/l). Moreover, the hormonal status (follicle-stimulating hormone, luteinizing hormone and testosterone) was much closer to normal in the NHD and RT groups compared to the other two groups. CONCLUSIONS: In this study, successful transplantation and NHD partially improved the symptoms of menstrual disturbances. Therefore, we recommend that further studies are necessary to confirm our finding in ESRD patients.

Histone deacetylases inhibitor trichostatin A increases the expression of Dleu2/miR-15a/16-1 via HDAC3 in non-small cell lung cancer.

Histone deacetylases (HDACs) inhibitor is a promising new approach to the treatment of lung cancer therapy via inhibiting cell growth and inducing apoptosis. miR-15a and miR-16-1 are important tumor suppressors through modulating B cell lymphoma 2 (Bcl-2), Cyclin D1, D2, and others. However, whether HDACs inhibitor modulates the expression of miR-15a/16-1 in lung cancer is still unknown. The purpose of our study was to identify a new miRNA-mediated mechanism which plays an important role in the anti-cancer effects of HDACs inhibitor. We found HDACs inhibitors trichostatin A (TSA) and sodium butyrate upregulated the expression of miR-15a/16-1, residing in the host tumor suppressor Dleu2 gene, through increasing the histone acetylation in the region of Dleu2/miR-15a/16-1 promoter in lung cancer cells. Moreover, among class Ι HDACs subtypes, only knockdown of HDAC3 by specific siRNA increased the hyperacetylation of Dleu2/miR-15a/16-1 promoter region and finally resulted in the upregulation of miR-15a/16-1. Furthermore, overexpression of miR-15a/16-1, which were always deleted or downregulated in lung cancer cells, effectively suppressed cell growth and reduced colony formation. Finally, TSA reduced the expression of Bcl-2, an important survival protein in lung cancer cells, partly through upregulation of miR-15a/16-1. Therefore, this offers a therapeutic strategy that lung cancer patients who exhibit low level of miR-15a/16-1 or high activity of HDACs may benefit from HDACs inhibitor-based therapy.

Activation of endothelial intrinsic NF-{kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice.

Although the role of systemic activation of the nuclear factor kappaB (NF-kappaB) pathway in septic coagulation has been well documented, little is known about the contribution of endothelial-specific NF-kappaB signaling in this pathologic process. Here, we used transgenic mice that conditionally overexpress a mutant I-kappaBalpha, an inhibitor of NF-kappaB, selectively on endothelium, and their wild-type littermates to define the role of endothelial-specific NF-kappaB in septic coagulation. In wild-type mice, lipopolysaccharide (LPS) challenge (5 mg/kg intraperitoneally) caused markedly increased plasma markers of coagulation, decreased plasma fibrinogen level, and widespread tissue fibrin deposition, which were abrogated by endothelial NF-kappaB blockade in transgenic mice. Endothelial NF-kappaB blockade inhibited tissue factor expression in endothelial cells, but not in leukocytes. Endothelial NF-kappaB blockade did not inhibit LPS-induced tissue factor expression in heart, kidney, and liver. Endothelial NF-kappaB blockade prevented LPS down-regulation of endothelial protein C receptor (EPCR) and thrombomodulin protein expressions, inhibited tissue tumor necrosis factor-alpha converting enzyme activity, reduced EPCR shedding, and restored plasma protein C level. Our data demonstrate that endothelial intrinsic NF-kappaB signaling plays a pivotal role in septic coagulation and suggests a link between endothelial-specific NF-kappaB activation and the impairment of the thrombomodulin-protein C-EPCR anticoagulation pathway.