Targeting F-Box Protein Fbxo3 Attenuates Lung Injury Induced by Ischemia-Reperfusion in Rats

Background: Increasing evidence suggests that Fbxo3 signaling has an important impact on the pathophysiology of the inflammatory process. Fbxo3 protein inhibition has reduced cytokine-driven inflammation and improved disease severity in animal model of Pseudomonas-induced lung injury. However, it remains unclear whether inhibition of Fbxo3 protein provides protection in acute lung injury induced by ischemia-reperfusion (I/R). In this study, we investigated the protective effects of BC-1215 administration, a Fbxo3 inhibitor, on acute lung injury induced by I/R in rats.Methods: Lung I/R injury was induced by ischemia (40 min) followed by reperfusion (60 min). The rats were randomly assigned into one of six experimental groups (n = 6 rats/group): the control group, control + BC-1215 (Fbxo3 inhibitor, 0.5 mg/kg) group, I/R group, or I/R + BC-1215 (0.1, 0.25, 0.5 mg/kg) groups. The effects of BC-1215 on human alveolar epithelial cells subjected to hypoxia-reoxygenation (H/R) were also examined.Results: BC-1215 significantly attenuated I/R-induced lung edema, indicated by a reduced vascular filtration coefficient, wet/dry weight ratio, lung injury scores, and protein levels in bronchoalveolar lavage fluid (BALF). Oxidative stress and the level of inflammatory cytokines in BALF were also significantly reduced following administration of BC-1215. Additionally, BC-1215 mitigated I/R-stimulated apoptosis, NF-κB, and mitogen-activated protein kinase activation in the injured lung tissue. BC-1215 increased Fbxl2 protein expression and suppressed Fbxo3 and TNFR associated factor (TRAF)1–6 protein expression. BC-1215 also inhibited IL-8 production and NF-κB activation in vitro in experiments with alveolar epithelial cells exposed to H/R.Conclusions: Our findings demonstrated that Fbxo3 inhibition may represent a novel therapeutic approach for I/R-induced lung injury, with beneficial effects due to destabilizing TRAF proteins

RhoGDIβ-induced hypertrophic growth in H9c2 cells is negatively regulated by ZAK

We found that overexpression of RhoGDIβ, a Rho GDP dissociation inhibitor, induced hypertrophic growth and suppressed cell cycle progression in a cultured cardiomyoblast cell line. Knockdown of RhoGDIβ expression by RNA interference blocked hypertrophic growth. We further demonstrated that RhoGDIβ physically interacts with ZAK and is phosphorylated by ZAK in vitro, and this phosphorylation negatively regulates RhoGDIβ functions. Moreover, the ZAK-RhoGDIβ interaction may maintain ZAK in an inactive hypophosphorylated form. These two proteins could negatively regulate one another such that ZAK suppresses RhoGDIβ functions through phosphorylation and RhoGDIβ counteracts the effects of ZAK by physical interaction. Knockdown of ZAK expression in ZAK- and RhoGDIβ-expressing cells by ZAK-specific RNA interference restored the full functions of RhoGDIβ

ZAK negatively regulates RhoGDIβ-induced Rac1-mediated hypertrophic growth and cell migration

RhoGDIβ, a Rho GDP dissociation inhibitor, induced hypertrophic growth and cell migration in a cultured cardiomyoblast cell line, H9c2. We demonstrated that RhoGDIβ plays a previously undefined role in regulating Rac1 expression through transcription to induce hypertrophic growth and cell migration and that these functions are blocked by the expression of a dominant-negative form of Rac1. We also demonstrated that knockdown of RhoGDIβ expression by RNA interference blocked RhoGDIβ-induced Rac1 expression and cell migration. We demonstrated that the co-expression of ZAK and RhoGDIβ in cells resulted in an inhibition in the activity of ZAK to induce ANF expression. Knockdown of ZAK expression in ZAK-RhoGDIβ-expressing cells by ZAK-specific RNA interference restored the activities of RhoGDIβ

Comparative Proteomic Analysis of Peritoneal Dialysate from Chronic Glomerulonephritis Patients

Peritoneal dialysis (PD) frequently contributes to peritoneal damage which cannot be easily identified without invasive techniques, implying the urgent need for biomarkers and revealing mechanisms. Chronic glomerulonephritis (CGN) is one of the leading causes of receiving dialysis treatment. Here, we attempted to analyze the peritoneal dialysate collected from CGN patients when they receive continuous ambulatory peritoneal dialysis (CAPD) treatment for the first time and after a year to reveal the protein changes that resulted from PD. Proteins were displayed by two-dimensional gel electrophoresis (2DE). Altered gel spots were digested followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for protein identification. Eight proteins were found to have differential expression levels between two groups. Their differential expressions were validated by Western blots in other sets of peritoneal dialysates. Proteins identified with higher levels in the first-time dialysate suggested their dominant appearance in CGN patients, while those that showed higher levels in peritoneal dialysate collected after one year may result from initial peritoneal inflammation or changes in the permeability of the peritoneum to middle-sized proteins. All the identified proteins may provide a perceptiveness of peritoneal changes caused by PD and may function as potential biomarkers or drug targets

Lumbar-peritoneal shunt for idiopathic normal pressure hydrocephalus and secondary normal pressure hydrocephalus

Objectives: Normal-pressure hydrocephalus is a clinical syndrome consisting of dilated cerebral ventricles with the clinical triad of gait disturbance, cognitive impairment and/or urinary dysfunction. Lumbar-peritoneal (LP) shunt could improve idiopathic normal pressure hydrocephalus (iNPH) while its effectiveness on secondary NPH (sNPH) is elusive. We compared the clinical results of the patients who received LP shunt surgery between iNPH and sNPH. Materials and Methods: We retrospectively analyzed the patients who received LP shunt surgery in a single center from January 1, 2017, to June 30, 2017. Patients selected for LP shunt placement had at least two of three cardinal symptoms of iNPH. The symptoms should persist for more than 3 months with compatible brain magnetic resonance imaging findings. All patients were followed up with iNPH grading scale (iNPHGS) and Modified Rankin Scale (MRS) for evaluation. Results: Thirty-three patients (23 male and 10 female patients) with mean age 76-year-old completed follow-up in this study, and 17 patients received lumbar drainage tests and intracranial pressure measurements. Both iNPH (n = 22) and sNPH (n = 11) groups did not have major complications such as infection, nerve root injury, or shunt failure. Both groups have significant improvement in iNPHGS and MRS. Interestingly, we found the correlation between both opening intracranial pressure and pressure gradient difference to the improvement percentage from LP shunt. Conclusion: The safety and effectiveness for sNPH patients who received LP shunt placement are equivalent to the iNPH patients. Lumbar drainage test provides prerequisite outcome prediction and should be considered to identify NPH patients planned to receive LP shunt

Additional file 1 of Targeting Rev-Erbα to protect against ischemia-reperfusion-induced acute lung injury in rats

Additional file 1: Supplementary Figure S1. The effect of varying doses of SR9009 on pulmonary edema. Lung weight gain (A); vascular filtration coefficient (Kf)(B); lung weight/body weight (LW/BW) (C); wet/dry (W/D) weight ratio (D); protein concentration in bronchoalveolar lavage fluid (BALF)(E); and pulmonary artery pressure (F) increased significantly in the ischemia-reperfusion (IR) group. The increase in these parameters was significantly attenuated by treatment with SR9009 in dose-dependent manner. Data are expressed as mean ± SD (n = 6 per group). *p < 0.05, **p < 0.01, ***p < 0.001 compared to control group; #p < 0.05, ##p < 0.01, ###p < 0.001 compared to IR grou

Correction: Wen-I Liao, et al. Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury. Int. J. Mol. Sci. 2017, 18, 1771

The authors would like to make a correction to their published paper [1][...

Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury

Annexin A1 (AnxA1) is an endogenous protein that modulates anti-inflammatory processes, and its therapeutic potential has been reported in a range of inflammatory diseases. The effect of AnxA1 on ischemia-reperfusion (IR)-induced lung injury has not been examined. In this study, isolated, perfused rat lungs were subjected to IR lung injury induced by ischemia for 40 min, followed by reperfusion for 60 min. The rat lungs were randomly treated with vehicle (phosphate-buffered saline), and Ac2-26 (an active N-terminal peptide of AnxA1) with or without an N-formyl peptide receptor (FPR) antagonist N-Boc-Phe-Leu-Phe-Leu-Phe (Boc2). An in vitro study of the effects of Ac2-26 on human alveolar epithelial cells subjected to hypoxia-reoxygenation was also investigated. Administration of Ac2-26 in IR lung injury produced a significant attenuation of lung edema, pro-inflammatory cytokine production recovered in bronchoalveolar lavage fluid, oxidative stress, apoptosis, neutrophil infiltration, and lung tissue injury. Ac2-26 also decreased AnxA1 protein expression, inhibited the activation of nuclear factor-κB and mitogen-activated protein kinase pathways in the injured lung tissue. Finally, treatment with Boc2 abolished the protective action of Ac2-26. The results indicated that Ac2-26 had a protective effect against acute lung injury induced by IR, which may be via the activation of the FPR

Sclareol ameliorate lipopolysaccharide-induced acute lung injury through inhibition of MAPK and induction of HO-1 signaling. International Immunopharmacology

[[abstract]]Sclareol is a natural fragrance compound that is used widely in the cosmetic and food industries. This study examined the effect of sclareol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Mice were treated with sclareol 1 h before an intratracheal (I.T.) LPS challenge to induce an ALI model. The effects on lung tissue and lung injury were evaluated 6 h after LPS induction. Pretreatment with sclareol noticeably improved the LPS-induced histological alterations and edema in lung tissue. Sclareol also inhibited the release of pro-inflammatory mediators. Differences in nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and IL-10 were found in the bronchoalveolar lavage fluid (BALF) 6 h after LPS-induced lung injury. This study also found a reduced number of total cells and reduced protein concentrations in the BALF. There were also changes in the pulmonary wet/dry (W/D) weight ratio, antioxidant enzyme activity, and myeloperoxidase activity in lung tissues. Sclareol effectively blocked the phosphorylation of mitogen-activated protein kinases (MAPKs) and impeded the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The compound boosted the expression of heme oxygenase-1 (HO-1) and inhibited the breakdown of nuclear factor-kappa B (NF-κB) and inhibitor of kappa B (IκBα). To the best of the authors' knowledge, this study is the first to demonstrate that sclareol effectively inhibits acute lung edema, and the results suggest that sclareol may be a potential agent for the treatment of ALI. The potential therapeutic benefits may include the attenuation of LPS-induced pulmonary inflammation due to sclareol's effects on several pathways, including NF-κB, MAPKs and HO-1, as well as the regulation of antioxidant enzyme activity