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Necroptosis is the major cause of death in alveolar epithelial cells (AECs) during acute lung injury (ALI). Here, we report a previously unrecognized mechanism for necroptosis. We found an accumulation of mitochondrial citrate (citratemt) in lipopolysaccharide (LPS)-treated AECs because of the downregulation of Idh3α and citrate carrier (CIC, also known as Slc25a1). shRNA- or inhibitor–mediated inhibition of Idh3α and Slc25a1 induced citratemt accumulation and necroptosis in vitro. Mice with AEC-specific Idh3α and Slc25a1 deficiency exhibited exacerbated lung injury and AEC necroptosis. Interestingly, the overexpression of Idh3α and Slc25a1 decreased citratemt levels and rescued AECs from necroptosis. Mechanistically, citratemt accumulation induced mitochondrial fission and excessive mitophagy in AECs. Furthermore, citratemt directly interacted with FUN14 domain-containing protein 1 (FUNDC1) and promoted the interaction of FUNDC1 with dynamin-related protein 1 (DRP1), leading to excessive mitophagy-mediated necroptosis and thereby initiating and promoting ALI. Importantly, necroptosis induced by citratemt accumulation was inhibited in FUNDC1-knockout AECs. We show that citratemt accumulation is a novel target for protection against ALI involving necroptosis.

Necroptosis, a recently described form of programmed cell death, is the main way of alveolar epithelial cells (AECs) death in acute lung injury (ALI). While the mechanism of how to trigger necroptosis in AECs during ALI has been rarely evaluated. Long optic atrophy protein 1 (L-OPA1) is a crucial mitochondrial inner membrane fusion protein, and its deficiency impairs mitochondrial function. This study aimed to investigate the role of L-OPA1 deficiency-mediated mitochondrial dysfunction in AECs necroptosis. We comprehensively investigated the detailed contribution and molecular mechanism of L-OPA1 deficiency in AECs necroptosis by inhibiting or activating L-OPA1. First, our data showed that L-OPA1 expression was downregulated in the lungs and AECs under the lipopolysaccharide (LPS) challenge. Furthermore, inhibition of L-OPA1 aggravated the pathological injury, inflammatory response, and necroptosis in the lungs of LPS-induced ALI mice. In vitro, inhibition of L-OPA1 induced necroptosis of AECs, while activation of L-OPA1 alleviated necroptosis of AECs under the LPS challenge. Mechanistically, inhibition of L-OPA1 aggravated necroptosis of AECs by inducing mitochondrial fragmentation and reducing mitochondrial membrane potential. While activation of L-OPA1 had the opposite effects. In summary, these findings indicate for the first time that L-OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of AECs, and exacerbates ALI in mice.

Our previous study showed that triggering receptors expressed on myeloid cell-1 (TREM-1) was upregulated in bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. However, the role of TREM-1 in the development of PF and its underlying mechanism remain unclear. Herein, we report that the prophylactical blockade of TREM-1 using a decoy peptide dodecapeptide (LR12) exerted protective effects against BLM-induced PF in mice, with a higher survival rate, attenuated tissue injury, and less extracellular matrix deposition. Interestingly, therapeutic blockade of TREM-1 at the early stage of fibrosis also attenuated BLM-induced PF, suggesting a non-inflammatory effect. More importantly, we observed that TREM-1 blockade with LR12 significantly reduced the expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lungs of PF mice. Notably, TREM-1 was upregulated in alveolar epithelial cells (AECs) and correlated with the levels of senescence markers in BLM-treated mice. In vitro, activating TREM-1 with an agonistic antibody exacerbated BLM-induced senescence in MLE12 cells, a murine AEC cell line. Furthermore, prophylactic or therapeutic blockade of TREM-1 protected MLE12 cells from senescence induced by BLM or H

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory immune receptor potentiating acute lung injury (ALI). However, the mechanism of TREM-1-triggered inflammation response remains poorly understood. Here, we showed that TREM-1 blocking attenuated NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome activation and glycolysis in LPS-induced ALI mice. Then, we observed that TREM-1 activation enhanced glucose consumption, induced glycolysis, and inhibited oxidative phosphorylation in macrophages. Specifically, inhibition of glycolysis with 2-deoxyglucose diminished NLRP3 inflammasome activation of macrophages triggered by TREM-1. Hypoxia-inducible factor-1α (HIF-1α) is a critical transcriptional regulator of glycolysis. We further found that TREM-1 activation facilitated HIF-1α accumulation and translocation to the nucleus

Rationale: Dysregulation of arachidonic acid (ARA) metabolism results in inflammation; however, its role in acute lung injury (ALI) remains elusive. In this study, we addressed the role of dysregulated ARA metabolism in cytochromes P450 (CYPs) /cyclooxygenase-2 (COX-2) pathways in the pathogenesis of lipopolysaccharide (LPS)-induced ALI in mice. Methods: The metabolism of CYPs/COX-2-derived ARA in the lungs of LPS-induced ALI was investigated in C57BL/6 mice. The COX-2/sEH dual inhibitor PTUPB was used to establish the function of CYPs/COX-2 dysregulation in ALI. Primary murine macrophages were used to evaluate the underlying mechanism of PTUPB involved in the activation of NLRP3 inflammasome in vitro. Results: Dysregulation of CYPs/COX-2 metabolism of ARA occurred in the lungs and in primary macrophages under the LPS challenge. Decrease mRNA expression of Cyp2j9, Cyp2j6, and Cyp2j5 was observed, which metabolize ARA into epoxyeicosatrienoic acids (EETs). The expressions of COX-2 and soluble epoxide hydrolase (sEH), on the other hand, was significantly upregulated. Pre-treatment with the dual COX-2 and sEH inhibitor, PTUPB, attenuated the pathological injury of lung tissues and reduced the infiltration of inflammatory cells. Furthermore, PTUPB decreased the pro-inflammatory factors, oxidative stress, and activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in LPS-induced ALI mice. PTUPB pre-treatment remarkably reduced the activation of macrophages and NLRP3 inflammasome in vitro. Significantly, both preventive and therapeutic treatment with PTUPB improved the survival rate of mice receiving a lethal dose of LPS. Conclusion: The dysregulation of CYPs/COX-2 metabolized ARA contributes to the uncontrolled inflammatory response in ALI. The dual COX-2 and sEH inhibitor PTUPB exerts anti-inflammatory effects in treating ALI by inhibiting the NLRP3 inflammasome activation.

Background Uncontrolled inflammation is an important factor in the occurrence and development of acute lung injury (ALI). Fibroblast growth factor-inducible 14 (Fn14), a plasma membrane-anchored receptor, takes part in the pathological process of a variety of acute and chronic inflammatory diseases. However, the role of Fn14 in ALI has not yet been elucidated. This study aimed to investigate whether the activation of Fn14 exacerbated lipopolysaccharide (LPS)-induced ALI in mice. Methods In vivo, ALI was induced by intratracheal LPS-challenge combined with/without Fn14 receptor blocker aurintricarboxylic acid (ATA) treatment in C57BL/6J mice. Following LPS administration, the survival rate, lung tissue injury, inflammatory cell infiltration, inflammatory factor secretion, oxidative stress, and NLRP3 inflammasome activation were assessed. In vitro, primary murine macrophages were used to evaluate the underlying mechanism by which Fn14 activated the NLRP3 inflammasome. Lentivirus was used to silence Fn14 to observe its effect on the activation of NLRP3 inflammasome in macrophages. Results In this study, we found that Fn14 expression was significantly increased in the lungs of LPS-induced ALI mice. The inhibition of Fn14 with ATA downregulated the protein expression of Fn14 in the lungs and improved the survival rate of mice receiving a lethal dose of LPS. ATA also attenuated lung tissue damage by decreasing the infiltration of macrophages and neutrophils, reducing inflammation, and suppressing oxidative stress. Importantly, we found that ATA strongly inhibited the activation of NLRP3 inflammasome in the lungs of ALI mice. Furthermore, in vitro, TWEAK, a natural ligand of Fn14, amplified the activation of NLRP3 inflammasome in the primary murine macrophage. By contrast, inhibition of Fn14 with shRNA decreased the expression of Fn14, NLRP3, Caspase-1 p10, and Caspase-1 p20, and the production of IL-1β and IL-18. Furthermore, the activation of Fn14 promoted the production of reactive oxygen species and inhibited the activation of Nrf2-HO-1 in activated macrophages. Conclusions Our study first reports that the activation of Fn14 aggravates ALI by amplifying the activation of NLRP3 inflammasome. Therefore, blocking Fn14 may be a potential way to treat ALI.

Citrate has a prominent role as a substrate in cellular energy metabolism. Recently, citrate has been shown to drive inflammation. However, the role of citrate in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Here, we aimed to clarify whether extracellular citrate aggravated the LPS-induced ALI and the potential mechanism. Our findings demonstrated that extracellular citrate aggravated the pathological lung injury induced by LPS in mice, characterized by up-regulation of pro-inflammatory factors and over-activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in the lungs. In vitro, we found that citrate treatment significantly augmented the expression of NLRP3 and pro-IL-1β and enhanced the translocation of NF-κB/p65 into the nucleus. Furthermore, extracellular citrate plus adenosine-triphosphate (ATP) significantly increased the production of reactive oxygen species (ROS) in primary murine macrophages. Inhibiting the production of ROS with a ROS scavenger N-acetyl-L-cysteine (NAC) attenuated the activation of NLRP3 inflammasome. Altogether, we conclude that extracellular citrate may serve as a damage-associated molecular pattern (DAMP) and aggravates LPS-induced ALI by activating the NLRP3 inflammasome.

Alveolar epithelial cell death, inflammation, and oxidative stress are typical features of acute lung injury (ALI). Aloperine (Alo), an alkaloid isolated from Sophora alopecuroides, has been reported to display various biological effects, such as anti-inflammatory, immunoregulatory, and anti-oxidant properties. In this study, we investigated the effects and mechanisms of Alo in treating a lipopolysaccharide (LPS)-induced ALI in a murine model.The effects of Alo in LPS-induced ALI were investigated in C57BL/6 mice. The RIPK1 inhibitor (Nec-1) and the RIPK3 inhibitor (GSK'872) were used to evaluate the relationship of necroptosis, NF-κB activation, and PDC subunits in LPS-treated mouse alveolar epithelial cells (MLE-12). Then the effects of Alo on necroptosis, inflammation, and oxidative stress of LPS-stimulated MLE-12 cells were evaluated.Alo significantly attenuated histopathological lung injuries and reduced lung wet/dry ratio in LPS-induced ALI mice. Alo also remarkedly reduced total protein and neutrophils recruitment in bronchoalveolar lavage fluid of ALI mice. Meanwhile, Alo ameliorated the LPS-induced necroptosis in the lungs of ALI mice. The RIPK3 inhibitor GSK'872, but not the RIPK1 inhibitor Nec-1, reversed LPS-induced p65 phosphorylation and translocation to the nucleus in MLE-12 cells. GSK'872 also reversed the LPS-induced increase in ROS and binding of RIPK3 and PDC subunits in MLE-12 cells. Moreover, Alo down-regulated the levels of p-RIPK1, p-RIPK3, p-MLKL, p-p65, the translocation of p65 to the nucleus, and reduced the expression of IL-6 and IL-8 in LPS-stimulated MLE-12 cells. Alo also inhibited the binding of RIPK3 and PDC-E1α, PDC-E1β, PDC-E2, and PDC-E3 and the ROS production in LPS-treated MLE-12 cells.The present study validated the beneficial effects of Alo on LPS-induced ALI , suggesting Alo may be a new drug candidate against ALI.

Arachidonic acid can be metabolized to prostaglandins and epoxyeicosatrienoic acids (EETs) by cyclooxygenase-2 (COX-2) and cytochrome P450 (CYP), respectively. While protective EETs are degraded by soluble epoxide hydrolase (sEH) very fast. We have reported that dual inhibition of COX-2 and sEH with specific inhibitor PTUPB shows anti-pulmonary fibrosis and renal protection. However, the effect of PTUPB on cecal ligation and puncture (CLP)-induced sepsis remains unclear. The current study aimed to investigate the protective effects of PTUPB against CLP-induced sepsis in mice and the underlying mechanisms. We found that COX-2 expressions were increased, while CYPs expressions were decreased in the liver, lung, and kidney of mice undergone CLP. PTUPB treatment significantly improved the survival rate, reduced the clinical scores and systemic inflammatory response, alleviated liver and kidney dysfunction, and ameliorated the multiple-organ injury of the mice with sepsis. Besides, PTUPB treatment reduced the expression of hypoxia-inducible factor-1α in the liver, lung, and kidney of septic mice. Importantly, we found that PTUPB treatment suppressed the activation of NLRP3 inflammasome in the liver and lung of septic mice. Meanwhile, we found that PTUPB attenuated the oxidative stress, which contributed to the activation of NLRP3 inflammasome. Altogether, our data, for the first time, demonstrate that dual inhibition of COX-2 and sEH with PTUPB ameliorates the multiple organ dysfunction in septic mice.

Gluconic metabolic reprogramming, immune response, and inflammation are intimately linked. Glycolysis involves in the pathologic progress in acute and chronic inflammatory diseases. However, the involvement of glycolysis in the acute lung injury (ALI) is still unclear. This study investigated the role of glycolysis in an animal model of ALI. First, we found that lactate content in serum was remarkably increased in ALI patients and a murine model induced by intratracheal administration of lipopolysaccharide (LPS). The key proteins involving in glycolysis were robustly elevated, including HK2, PKM2, and HIF-1α. Intriguingly, inhibition of glycolysis by 2-deoxyglucose (2-DG) pronouncedly attenuated the lung tissue pathological injury, accumulation of neutrophil, oxidative stress, expression of proinflammatory factors in the lung of ALI mice induced by LPS. The 2-DG treatment also strongly suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome. Furthermore, we investigated the role of glycolysis in the inflammatory response of primary murine macrophages activated by LPS in vitro. We found that the 2-DG treatment remarkably reduced the expression of proinflammatory factors induced by LPS, including tumor necrosis factor-α messenger RNA (mRNA), pro-interleukin (IL)-1β mRNA, pro-IL-18 mRNA, NLRP3 mRNA, caspase-1 mRNA, and IL-1β protein. Altogether, these data provide a novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in ALI. This study suggests glycolytic inhibition as an effective anti-inflammatory strategy in treating ALI.

Breast lesions classified as BI-RADS-US 3 are probably benign and observation was recommended, while a considerable number of BI-RADS-US 4 lesions were benign, resulting in excessive biopsies. We focus exclusively on BI-RADS-US 3 and 4 lesions and hypothesize that improved diagnostic performance can be achieved by integrating real-time elastography (strain ratio) into the BI-RADS-US classification system. From April 2010 to September 2015, 1071 lesions were included in the final analysis. After the conventional ultrasound examination, the BI-RADS-US (2013) classification was used to evaluate the lesions. Then the strain ratios were calculated, and the final diagnosis was made on the basis of histological results. The sensitivity, specificity, accuracy, PPV and NPV were calculated and the AUCs were compared. Additionally, an analysis of the diagnostic performance expressed by the pretest and posttest probability of disease (POD) was performed in BI-RADS-US 3 and 4A lesions. With the cutoff point of 2.98, the sensitivity, specificity and accuracy of the strain ratio method were 86.9 %, 86.6 % and 82.6 %, respectively. In BI-RADS-US 3 lesions, a suspicious strain ratio significantly modified the POD from 1.3 % to a posttest POD of 29.8 %. In BI-RADS-US 4A lesions, a suspicious strain ratio significantly modified the POD from 8.5 % to a posttest POD of 48.7 %. Ultrasonographic elastography (strain ratio) yields additional diagnostic information in the evaluation of BI-RADS-US 3 and 4 breast lesions. The strain ratios should be integrated into the BI-RADS-US classification system and into daily practice. Herdbefunde der Brust, die mit BI-RADS-US Kategorie 3 bewertet wurden, sind vermutlich gutartig und eine Kontrolle wurde empfohlen, während solche mit BI-RADS-US Kategorie 4 in beträchtlichem Maße gutartig waren, was zu übermäßigen Biopsien führte. Unser Fokus gilt ausschließlich den Herdbefunden der BI-RADS-US Kategorie 3 und 4 und wir vermuten, dass die diagnostische Leistung durch Aufnahme der Echtzeit-Elastografie (Strain-Ratio) in die BI-RADS-US-Befund-Kategorien verbessert werden kann. Von April 2010 bis September 2015 wurden 1071 Herdbefunde in die Endanalyse aufgenommen. Nach Durchführung der konventionellen Sonografie wurden die BI-RADS-US-Kategorien (2013) zur Bewertung der Herdbefunde angewandt. Dann wurden die Strain-Ratios berechnet, die Enddiagnose wurde histologisch gesichert. Sensitivität, Spezifität, Genauigkeit, PPW und NPW wurden berechnet und die AUCs wurden verglichen. Zusätzlich wurde bei den BI-RADS-US 3 und 4A Herdbefunden eine Analyse der diagnostischen Leistung mittels Prätest- und Posttest-POD („probability of disease“) durchgeführt. Bei einem Grenzwert von 2,98 erzielte die Strain-Ratio-Methode eine Sensitivität von 86,9 %, eine Spezifität von 86,6 % und eine Genauigkeit von 82,6 %. Bei BI-RADS-US 3-Herdbefunden führte eine auffällige Strain-Ratio zu einer signifikanten Veränderung der POD von 1,3 % auf 29,8 % (Posttest). Bei BI-RADS-US 4A-Herdbefunden veränderte eine auffällige Strain-Ratio die POD signifikant von 8,5 % auf 48,7 % (Posttest). Die Ultraschall-Elastografie (Strain-Ratio) liefert zusätzliche diagnostische Informationen bei der Bewertung von Herdbefunden der Brust bei BI-RADS-US Kategorien 3 und 4. Die Strain-Ratio sollte in die BI-RADS-US-Befund-Kategorien und in die tägliche Praxis aufgenommen werden.

On the basis of results of our previous studies and the findings of other scholars, the most common histologic type of false-positive diagnosis with strain elastography (SE) was papilloma. The objectives of our study were to evaluate whether SE could contribute to conventional ultrasound differentiation between benign and malignant papillary lesions and between papillary lesions and other common benign breast lesions. Data on 89 papillary lesions at our hospital, including 74 benign and 15 malignant papillary lesions, were included in our study. In addition, 198 non-papillary benign tumors were selected as the control group, including 126 fibroadenomas and 72 cases of fibrocystic mastopathy. All patients gave written informed consent. All patients with breast lesions underwent conventional ultrasound and SE examination. Breast Imaging Recording and Data System (BI-RADS) category and SE score were compared with respect to sensitivity, specificity and accuracy in differentiating between benign and malignant papillary lesions. We then explored the possibility of using BI-RADS combined with SE to differentiate papillary lesions from non-papillary benign tumors. For differentiating between benign and malignant papillary lesions, the area under the receiver operating characteristic curve (AUC) of BI-RADS was 0.568, whereas the AUC values of SE score, strain ratio and BI-RADS combined with SE were 0.517, 0.584 and 0.509, respectively (p > 0.05). For differentiating between papillary lesions and non-papillary benign lesions, the AUC of BI-RADS combined with SE was 0.835, which was higher than the values for BI-RADS (0.775) and SE (SE score: 0.648, strain ratio: 0.661) (p

To evaluate the additive diagnostic performance of ultrasound elastography (UE) to ultrasound (US) with the 2003 or 2013 Breast Imaging Reporting and Data System (BI-RADS)-US classification systems for the differentiation of benign and malignant breast lesions.From June 2010 to December 2012, 738 women with 770 breast lesions were recruited into this retrospective study. Breast lesions were evaluated separately by US, UE, and both. US assessment was based on the 2003 or 2013 BI-RADS-US, and UE assessment was based on a previously reported 5-point scale. Diagnostic performance of US, UE, and both was compared.Before category 4 lesions were subdivided, the area under the receiver operating characteristic curve (AUC) for US, UE, and both were, respectively, 0.735, 0.877, 0.878 (P .01). When subcategories of 4 lesions were considered, the AUC for US, UE, and both were, respectively, 0.865, 0.877, and 0.883 (P.05). Adding UE to analysis of 4A lesions can decrease the percentages of malignancy to 2.56%.When the 2003 BI-RADS was considered, UE could give US some help in differentiating breast lesions. However, when the 2013 BI-RADS was considered, UE gave little help to US, although it reduced unnecessary biopsies of benign category 4A lesions.

Highlights • NLRP3 inflammasome inhibition reduces TREM-1 expression in the lungs of mice with ALI. • Activation of NLRP3 inflammasome up-regulates TREM-1 expression in murine macrophages via HMGB1 and IL-18. • NLRP3 inflammasome activation induces TREM-1 expression, contributing to the inflammatory network in the lungs of ALI mice., NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome and triggering receptor expressed on myeloid cells-1 (TREM-1) are considered critical orchestrators of the inflammatory response in acute lung injury (ALI). However, few assumptions are based on the relationship between them. Here, we investigated the effect of NLRP3 inflammasome activation on the TREM-1 expression in lipopolysaccharide (LPS)-induced ALI and macrophages. We found that inhibition of the NLRP3 inflammasome reduced the TREM-1 expression and pathological lung injury in mice with ALI. Then, primary murine macrophages were used to dissect the underlying mechanistic events of the activation NLRP3 inflammasome involved in the TREM-1 expression. Our results demonstrated that the conditioned medium (CM) from NLRP3 inflammasome-activated-macrophages up-regulated the TREM-1 expression in macrophages, while this effect was reversed by an NLRP3 inflammasome inhibitor MCC950. Furthermore, neutralizing antibodies anti-IL-18 and anti-HMGB1 reduced the TREM-1 expression induced by NLRP3 inflammasome activation. Mechanistically, we found that CM from NLRP3 inflammasome-activated-macrophages increased the level of inhibitor κB kinase protein phosphorylation (p-IκBα) and reactive oxygen species (ROS) content, and promoted IκBα protein degradation in macrophages. While the inhibition of nuclear factor kappa-B (NF-κB) and scavenging ROS eliminated the up-regulation of TREM-1 induced by the NLRP3 inflammasome activation in macrophages. In summary, our study confers NLRP3 inflammasome as a new trigger of TREM-1 signing, which allows additional insight into the pathological of the inflammatory response in ALI.

Vasoactive intestinal peptide (VIP) is one of the most abundant neuropeptides in the lungs with various biological characters. We have reported that VIP inhibited the expressions of TREM-1 and IL-17A, which are involved in the initiation and amplification of inflammation in acute lung injury (ALI). However, the overall effect of VIP on ALI remains unknown. The aim of this study is to investigate the therapeutic effect of VIP mediated by lentivirus (Lenti-VIP) on lipopolysaccharide (LPS)-induced murine ALI. We found that the expression of intrapulmonary VIP peaked at day7 after the intratracheal injection of Lenti-VIP. Lenti-VIP increased the respiratory rate, lung compliance, and tidal volume, while decreased airway resistance in ALI mice, detected by Buxco system. Lenti-VIP significantly reduced inflammatory cell infiltration and maintained the integrity of the alveolar septa. Lenti-VIP also remarkably decreased the total protein level, the number of neutrophil and lactate dehydrogenase activity in the bronchoalveolar lavage fluid of LPS-induced ALI mice. In addition, Lenti-VIP down-regulated pro-inflammatory tumor necrosis factor (TNF)-α mRNA and protein expression, while up-regulated anti-inflammatory interleukin-10 mRNA and protein expression in lungs of ALI mice. Furthermore, we observed that VIP reduced the TNF-α expression in murine macrophages under LPS stimulation through protein kinase C and protein kinase A pathways. Together, our findings show that in vivo administration of lentivirus expressing VIP exerts a potent therapeutic effect on LPS-induced ALI in mice via inhibiting inflammation.

Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening of pulmonary function. No effective therapeutic strategy for pulmonary fibrosis has been established. Aucubin is a natural constituent with a monoterpene cyclic ring system. The potency of aucubin in protecting cellular components against inflammation, oxidative stress, and proliferation effects is well documented. In this study, we investigated the protective effect of aucubin against pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM), and aucubin was administered for 21 days after BLM injection. We found that aucubin decreased the breathing frequency and increased the lung dynamic compliance of BLM-stimulated mice detected by Buxco pulmonary function testing system. Histological examination showed that aucubin alleviated BLM-induced lung parenchymal fibrotic changes. Aucubin also reduced the intrapulmonary collagen disposition and inflammatory injury induced by BLM. In addition, aucubin reduced the expression of pro-fibrotic protein transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) of pulmonary fibrosis mice induced by BLM. Furthermore, the effect of aucubin on the proliferation and differentiation of fibroblast was investigated in vitro. Aucubin inhibited the mRNA and protein expression of Ki67 and proliferating cell nuclear antigen (PCNA) induced by TGF-β1 and reduced the cell proliferation in a murine fibroblast cell NIH3T3. Aucubin also reduced the collagen syntheses and α-SMA expression induced by TGF-β1 in fibroblast. Our results indicate that aucubin inhibits inflammation, fibroblast proliferation, and differentiation, exerting protective effects against BLM-induced pulmonary fibrosis in a mouse model. This study provides an evidence that aucubin may be a novel drug for pulmonary fibrosis.

Non-mass breast lesions on ultrasound (US) are areas without an associated mass. The purpose of this study was to evaluate whether combining B-mode US with color Doppler US and strain elastography (SE) improves US differentiation between benign and malignant non-mass breast lesions and the decision for biopsy. In this prospective study, three different radiologists analyzed the US images of 77 non-mass lesions independently and recorded Breast Imaging Reporting and Data System (BI-RADS) categories for four data sets. The image characteristics and BI-RADS categories of the four data sets were analyzed by another radiologist. The final diagnosis was made on the basis of pathologic findings. Values for area under the receiver operating curve (AUC), sensitivity, specificity and accuracy were compared among the data sets. The AUC of B-mode US combined with both color Doppler US and SE was greater than that of B-mode US alone (0.666 vs. 0.828) (p = 0.011). The specificity of making the decision for biopsy increased from 6.5% to 38.7% when B-mode US was combined with color Doppler and SE, without a statistically significant change in sensitivity (p < 0.001). Combined use of color Doppler and SE could improve the diagnostic value of B-mode US in distinguishing benign from malignant non-mass breast lesions and the specificity of making the decision for biopsy of non-mass breast lesions.

Accumulating evidence indicates that angiotensin (1-7) [Ang-(1-7)] protects against idiopathic pulmonary fibrosis (IPF) in animal experiments. However, whether Ang-(1-7) effectively inhibits epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1) remains unclear. The aim of this study is to examine the eff ;ects of Ang-(1-7) on TGF-β1-induced EMT in human alveolar epithelial cells. We found that angiotensin-converting enzyme 2 (ACE2) /Ang-(1-7)/MasR were decreased in the lungs of mice with IPF induced by bleomycin, and were negatively correlated with Tgfb1 mRNA expression. In vitro, our data showed that exogenous Ang-(1-7) restored the expression of E-cadherin and decreased the expressions of α-SMA and Vimentin induced by TGF-β1 in A549 cells. Ang-(1-7) also reduced TGF-β1-induced migration and synthesis of the extracellular matrix, such as collagen Ⅰ and collagen Ⅲ. Mechanistically, we observed that Ang-(1-7) directly inhibited TGF-β1-induced phosphorylation of Smad2 and Smad3, and suppressed the expression of the downstream target gene of TGF-β1-Smad signaling, including ZEB1, ZEB2, TWIST, and SNAIL1. Additionally, phosphorylation of mTOR induced by TGF-β1 also been suppressed by Ang-(1-7) treatment in A549 cells. Interestingly, we found that TGF-β1 strongly suppressed the expression of ACE2 in A549 cells through inhibiting SIRT1. In conclusion, our findings indicate that Ang-(1-7) directly inhibits TGF-β1-induced EMT in alveolar epithelial cells via disruption of TGF-β1-Smad signaling pathway, contributing to the protective effect against IPF.

This article, based on changes in the pattern of study of contemporary art network of visual arts, contemporary art in the space environment of the network visual arts, visual arts language of visual media, interactive cyberspace realm of art, information and digital communication art platform for contemporary art pattern the basic structure of the reorganization. Through integration of the modern network multi-media production technology and visual vision production method, the traditional art like Painting, Architecture art and Dace could form a new form of art performance and visual language, and enriched the modern context of art dialogue and culture space, which is the new construction of network visual art to the modern art pattern. Compared with the real world, it is virtual and transcendent, however, Network of Visual art provided a real situation of visual experience and psychological experience to a expanding real situation. By the use of network visual space and various visual information, the thinking way and expression platform of modern digital art creation have been extended and expanded.

Background This study aimed to confirm whether strain ratio should be added after evaluation of lesions with 5-point elasticity scoring for differentiating benign and malignant breast lesions on ultrasonographic elastography(UE). Materials and Methods From June 2010 to March 2012, 1080 consecutive female patients with breast lesions were recruited into a multicenter retrospective study, which involved 8 centers across China. Each institutional ethic review board approved the study, and all the patients gave written informed consent. All the patients underwent the UE procedure and the strain ratios were calculated and the final diagnosis was made by histological findings. The sensitivity, specificity, accuracy, PPV and NPV were calculated for each of the two evaluation systems and the areas under the ROC curve were compared. Results The strain ratios of benign lesions (mean, 2.6±2.0) and malignant lesions (mean,7.9±5.8) were significantly different (p 0.05). The strain ratio method shows better a diagnosis performance of the lesions with elasticity score 3 and 4. Conclusions Although the two UE methods have similar diagnostic performance, separate calculation of the strain ratios seems compulsory, especially for the large solid breast lesions and the lesions with elasticity score 3 and 4.

To evaluate the additive value of ultrasound strain elastography (USE) to BI-RADS for the differentiation of benign and malignant breast small lesions.Breast masses (≤2 cm) with histological diagnosis examined by ultrasonography and USE in our department from April 2004 to December 2009 were reviewed. Conventional B-mode ultrasound findings were classified according to the BI-RADS classification. USE findings were classified according to the 5-point scale. Histological diagnosis was used as the reference standard.401 (246 benign (61.3%), 155 malignant (38.7%)) from 370 consecutive patients were included in the study. Sensitivity and specificity were 90.3%, 68.3% for BI-RADS; 72.3%, 91.9% for USE. The sensitivity of BI-RADS was better than that of USE (P0.05), while the specificity of USE was better than that of BI-RADS (P0.05). A revised BI-RADS combined with USE results was proposed in this study. Sensitivity and specificity were 83.9% and 87.8% for revised BI-RADS. The diagnostic performance of revised BI-RADS was better than BI-RADS (P0.05).USE could give BI-RADS some help in the differentiation of benign and malignant breast small lesions. The addition of elastography to BI-RADS could improve the diagnostic performance in2 cm lesions.

The purpose of this study was to analyze the ultrasonic elastography features of phyllodes tumors of the breast comparing with fibroadenomas. A retrospective database was queried for the patients diagnosed as phyllodes tumors and fibroadenomas at Sun Yat-sen Memorial Hospital from January 2008 to August 2012. Three hundred and fifty lesions from 323 consecutive patients were included in the study. All the cases were examined by conventional ultrasonography and ultrasound elastography. Ultrasound elastography was used to calculate strain ratio of the lesions with bilateral breast tissue at the same depth as reference. There were 36 phyllodes tumors (27 benign, 8 borderline, 1 malignant) and 314 fibroadenomas (158 the pericanalicular type, 103 the intracanalicular type, 53 other special types). The strain ratio for phyllodes tumors (3.19 ± 2.33) was significantly higher than for fibroadenomas (1.69 ± 0.88) (p