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Pulmonary nodules are usually considered to be associated with malignant tumors and benign lesions, such as granuloma, pulmonary lymph nodes, fibrosis, and inflammatory lesions. Clinical cases of pulmonary nodules associated with hemophagocytic lymphohistiocytosis have rarely been reported. Therefore, when patients develop pulmonary nodules, the possibility of developing hemophagocytic lymphohistiocytosis is often not considered. We report the first case of familial hemophagocytic lymphohistiocytosis with recurrent pulmonary nodules as the first symptom. Our findings will hopefully provide new ideas for the diagnosis and treatment of pulmonary nodules in the future.

In this work, a novel electrospun nanofiber (PAN/TpBD; 2,4,6‐triformylphloroglucinol [Tp] and benzidine [BD]; polyacrylonitrile [PAN]) was fabricated via a facile electrospinning method and utilized as adsorbent in thin film microextraction (TFME) of phthalate esters (PAEs) (dimethyl phthalate, diethyl phthalate, diallyl phthalate, dibutyl phthalate, and dioctyl phthalate) in biodegradable plastics. The prepared PAN/TpBD combines the strong stability of nanofibers with increased exposure sites for covalent organic frameworks and enhanced interactions with the target, thus improving the enrichment effect on the target. The extraction efficiency of PAN/TpBD reached above 80%. Based on PAN/TpBD, a TFME‐high‐performance liquid chromatography method was established, and the experimental parameters were optimized. Under the optimal extraction conditions, the PAEs of this method varied linearly in the range of 10–10 000 µg/L with low detection limits (0.69–2.72 µg/L). The intra‐day and inter‐day relative standard deviation values of the PAEs were less than 8.04% and 8.73%, respectively. The adsorbent can achieve more than 80% recovery of the five targets after six times reuse. The developed method was successfully applied for the determination of trace PAEs in biodegradable plastics with recoveries ranging from 80.1% to 113.4% and relative standard deviations were less than 9.45%. The as‐synthesized PAN/TpBD adsorbent exhibited great potential in PAE analysis. [ABSTRACT FROM AUTHOR]

Cardiac ischemia, hypoxia, arrhythmias, and heart failure share the common electrophysiological changes featured by the elevation of intracellular Ca2+ (Ca2+ overload) and inhibition of the inward rectifier potassium (IK1) channel. IK1 channel agonists have been considered a new type of anti‐arrhythmia and cardioprotective agents. We predicted using a drug repurposing strategy that tetramisole (Tet), a known anthelminthic agent, was a new IK1 channel agonist. The present study aimed to experimentally identify the above prediction and further demonstrate that Tet has cardioprotective effects. Results of the whole‐cell patch clamp technique showed that Tet at 1–100 μmol/L enhanced IK1 current, hyperpolarized resting potential (RP), and shortened action potential duration (APD) in isolated rat cardiomyocytes, while without effects on other ion channels or transporters. In adult Sprague–Dawley (SD) rats in vivo, Tet showed anti‐arrhythmia and anticardiac remodeling effects, respectively, in the coronary ligation‐induced myocardial infarction model and isoproterenol (Iso, i.p., 3 mg/kg/day, 10 days) infusion‐induced cardiac remodeling model. Tet also showed anticardiomyocyte remodeling effect in Iso (1 μmol/L) infused adult rat ventricular myocytes or cultured H9c2 (2‐1) cardiomyocytes. Tet at 0.54 mg/kg in vivo or 30 μmol/L in vitro showed promising protections on acute ischemic arrhythmias, myocardial hypertrophy, and fibrosis. Molecular docking was performed and identified the selective binding of Tet with Kir2.1. The cardioprotection of Tet was associated with the facilitation of IK1 channel forward trafficking, deactivation of PKA signaling, and inhibition of intracellular calcium overload. Enhancing IK1 may play dual roles in anti‐arrhythmia and antiventricular remodeling mediated by restoration of Ca2+ homeostasis. [ABSTRACT FROM AUTHOR]

Background: TGF-β1 is a key cytokine involved in both airway inflammation and airway remodeling in asthma because of its anti-inflammatory and profibrotic effect. In our previous study, we found that knockdown of cytosolic β-catenin alleviated the profibrogenic effect of TGF-β1 without influencing its anti-inflammatory effect. However, the exact role of targeting β-catenin in asthma is not yet fully demonstrated. In the present study, we investigated the effect and mechanism of targeting β-catenin in OVA-challenged asthmatic rats with airway inflammation and remodeling features. Methods: We integrated experimental asthma model and asthma related cell model to explore the effect of targeting β-catenin on airway inflammation and remodeling of asthma. Results: Blocking β-catenin with ICG001, a small molecule inhibitor of β-catenin/TCF via binding to cAMP-response elementbinding protein, attenuated airway inflammation by increasing levels of anti-inflammation cytokines IL-10, IL-35 and decreasing levels of T helper (Th)2 cells and Th17 cytokine. Suppressing β-catenin by ICG001 inhibited airway remodeling via reducing the level of TGF-β1 and the expressions of Snail, MMP-7, MMP-9 and, up-regulating expression of E-cadherin, down-regulating expressions of α-SMA and Fn. Inhibition of β-catenin with ICG001 suppressed TGF-β1 induced proliferation and activation of CCC-REPF-1, blocked TGF-β1 induced epithelial–mesenchymal transition (EMT) of RLE-6TN. Conclusion: Blockade of β-catenin/TCF not only prevents TGF-β1 induced EMT and profibrogenic effects involved in pathological remodeling of airway, but also alleviates airway inflammation in asthma by balancing pro-inflammatory and anti-inflammatory cytokine. In conclusion, targeting β-catenin specifically via inhibition of β-catenin/TCF might be a new therapeutic strategy for asthma. The reviews of this paper are available via the supplemental material section. [ABSTRACT FROM AUTHOR]

Background: TGF-β1 is a key cytokine involved in both airway inflammation and airway remodeling in asthma because of its anti-inflammatory and profibrotic effect. In our previous study, we found that knockdown of cytosolic β-catenin alleviated the profibrogenic effect of TGF-β1 without influencing its anti-inflammatory effect. However, the exact role of targeting β-catenin in asthma is not yet fully demonstrated. In the present study, we investigated the effect and mechanism of targeting β-catenin in OVA-challenged asthmatic rats with airway inflammation and remodeling features. Methods: We integrated experimental asthma model and asthma related cell model to explore the effect of targeting β-catenin on airway inflammation and remodeling of asthma. Results: Blocking β-catenin with ICG001, a small molecule inhibitor of β-catenin/TCF via binding to cAMP-response elementbinding protein, attenuated airway inflammation by increasing levels of anti-inflammation cytokines IL-10, IL-35 and decreasing levels of T helper (Th)2 cells and Th17 cytokine. Suppressing β-catenin by ICG001 inhibited airway remodeling via reducing the level of TGF-β1 and the expressions of Snail, MMP-7, MMP-9 and, up-regulating expression of E-cadherin, down-regulating expressions of α-SMA and Fn. Inhibition of β-catenin with ICG001 suppressed TGF-β1 induced proliferation and activation of CCC-REPF-1, blocked TGF-β1 induced epithelial–mesenchymal transition (EMT) of RLE-6TN. Conclusion: Blockade of β-catenin/TCF not only prevents TGF-β1 induced EMT and profibrogenic effects involved in pathological remodeling of airway, but also alleviates airway inflammation in asthma by balancing pro-inflammatory and anti-inflammatory cytokine. In conclusion, targeting β-catenin specifically via inhibition of β-catenin/TCF might be a new therapeutic strategy for asthma. The reviews of this paper are available via the supplemental material section. [ABSTRACT FROM AUTHOR]

TGF- β is a key profibrotic factor, but targeting TGF- β to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF- β signaling by preventing downstream profibrotic interaction of β -catenin with T cell factor (TCF), thereby enhancing the interaction of β -catenin with Foxo, a transcription factor that controls differentiation of TGF- β induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF- β In iTregs derived from EL4 T cells treated with recombinant human TGF- β 1 (rhTGF- β 1) in vitro , inhibition of β -catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of β -catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of β -catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3 gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF- β 1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF- β 1 treatment alone. Coadministration of rhTGF- β 1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF- β 1. Together, our results show that diversion of β -catenin from TCF- to Foxo-mediated transcription inhibits the β -catenin/TCF-mediated profibrotic effects of TGF- β while enhancing the β -catenin/Foxo-mediated anti-inflammatory effects. Targeting β -catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure., (Copyright © 2018 by the American Society of Nephrology.)

Objective: To explore the therapeutic effects and mechanism of Bacillus Calmette-Guerin (BCG) vaccine on airway remodeling in rats., Methods: Forty male Wistar rats were randomly divided into 5 groups of control, asthma,BCG vaccine, dexamethasone and BCG vaccine plus dexamethasone (n = 8 each). The animals were then sensitized and challenged by ovalbum in to establish the asthmatic model. A subcutaneous injection of BCG vaccine 0.025 mg was administered for the BCG vaccine group and an intraperitoneal injection of dexamethasone 0.5 mg/kg for the dexamethasone group.In BCG vaccine plus dexamethasone group, the rats received a subcutaneous injection of BCG vaccine (0.025 mg) plus an intraperitoneal injection of dexamethasone (0.25 mg/kg). All treatments were offered at half an hour pre-atomization. The control rats received an aerosol inhalation of normal saline instead of ovalbum. The parameters of airway morphological changes and the degree of airway remodeling were analyzed with computer graphics. The levels of transforming growth factor beta 1 (TGF-β1) in bronchoalveolar lavage fluid (BALF) and the expressions of E-cadherin, α-smooth muscle actin (α-SMA) and fibronectin in lung tissue and sera were detected., Results: In asthmatic rats, the thickness of airway wall and smooth muscle were more significant than those of the control group ((95.01 ± 0.48), (43.86 ± 0.51) vs (25.96 ± 0.42), (15.14 ± 0.18) µm). Compared with the control group, the levels of TGF-β1 in BALF and sera were significantly higher ((10.05 ± 0.26), (75.67 ± 1.17) vs (1.53 ± 0.18), (22.24 ± 0.35) µg/L), the expression of E-cadherin significantly decreased (0.26 ± 0.03 vs 0.45 ± 0.04), while α-SMA and fibronectin significantly increased (0.54 ± 0.06,0.56 ± 0.06 vs 0.32 ± 0.04, 0.35 ± 0.06) (all P < 0.01); Notably, compared with the asthmatic group, the thickness of airway wall and smooth muscle ((58.46 ± 2.43),(49.51 ± 1.44), (49.63 ± 1.42) and (25.84 ± 0.54), (25.44 ± 0.40), (25.62 ± 1.17) µm) significantly decreased by the treatments of BCG vaccine, dexamethasone or BCG vaccine plus dexamethasone, the levels of TGF-β1 in BALF and sera ((3.42 ± 0.18), (3.27 ± 0.34), (3.39 ± 0.26) and (37.61 ± 0.22), (35.65 ± 0.49), (36.22 ± 0.71) µg/L) significantly decreased, the expressions of E-cadherin (0.29 ± 0.04, 0.32 ± 0.04, 0.31 ± 0.03) significantly increased and α-SMA and fibronectin (0.40 ± 0.06, 0.35 ± 0.06, 0.40 ± 0.05 and 0.47 ± 0.03, 0.43 ± 0.06, 0.47 ± 0.04) significantly declined (all P < 0.01). Western blot showed the similar results., Conclusions: BCG vaccine alleviates airway epithelial cell injury and epithelial mesenchymal transition induced by TGF-β1 through immunoregulation. It also reduces asthmatic airway remodeling with a combination of dexamethasone.

Matrix metalloproteinases (MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial-mesenchymal transition (EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT) and pericyte-myofibroblast transdifferentiation. Interstitial macrophage infiltration has also been shown to correlate with the severity of kidney fibrosis in various chronic kidney diseases. MMPs secreted by macrophages, especially MMP-9, has been shown by us to be profibrotic by induction of tubular cells EMT. EMT is mainly induced by transforming growth factor-β (TGF-β). However, MMP-9 was found by us and others to be up-regulated by TGF-β1 in kidney tubular epithelial cells and secreted by activated macrophages, resulting in EMT and ultimately kidney fibrosis. Therefore, MMP-9 may serve as a potential therapeutic target to prevent kidney fibrosis in chronic kidney disease. This review, by a particular focus on EMT, seeks to provide a comprehensive understanding of MMPs, especially MMP-9, in kidney fibrosis.

A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early- and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early- and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis.