Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase.

Background: Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4'-amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods: An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution (V t), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results: At the end of synthesis, the yield of [18F]FBAT was 2.2-3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125-137 GBq/µmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18, 1.53 ± 0.25, 1.41 ± 0.21, and 1.90 ± 0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution (V t, mL/cm3), and K i (influx rate) of [18F]FBAT were 1.9 ± 0.21- and 1.4 ± 0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain K i of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and V t values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion: An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.

Basic fibroblast growth factor activates ß-catenin/RhoA signaling in pulmonary fibroblasts with chronic obstructive pulmonary disease in rats.

Chronic obstructive pulmonary disease (COPD) is featured by aberrant extracellular matrix (ECM) deposition. Trigger of the ß-catenin/RhoA pathway has been involved in aberrant ECM deposition in several diseases. We investigated WNT signaling activation in primary pulmonary fibroblasts of rats with and without COPD and the function of WNT signaling in pulmonary fibroblast. We evaluated the expression of WNT signaling and the role of ß-catenin, using MRC-5 fibroblasts and primary lung fibroblasts of rats with and without COPD. Lung fibroblasts highly expressed mRNA of genes associated with WNT signaling. Treatment of MRC-5 fibroblasts using basic fibroblast growth factor (bFGF), a composition of the mucus in COPD patients, enhanced ß-catenin, Wnt5a and RhoA expression. The expression in ß-catenin, Wnt5a and RhoA induced by bFGF was higher in fibroblasts of rats with COPD than without COPD, whereas the basal expression was similar. bFGF also activated transcriptionally active and increased total ß-catenin protein expression. Moreover, bFGF enhanced the expression of α-sm-actin and fibronectin, which was abrogated by ß-catenin, Wnt5a and RhoA-specific adenovirus siRNA. The induction of active ß-catenin and then fibronectin turnover in response to bFGF were markedly increased in pulmonary fibroblasts from rat with COPD. ß-Catenin/RhoA pathway results in ECM deposition in lung fibroblasts and myofibroblasts differentiation. ß-catenin/RhoA signaling induced by bFGF is promoted in lung fibroblasts from rats with COPD. The study indicated a crucial role of the WNT signaling in mediating fibroblast morphology and function in COPD.

Mapping a Decade (2014-2024) of Research on Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: A Visual Analysis with CiteSpace and VOSviewer.

Background: Acute Respiratory Distress Syndrome (ARDS) stands as a primary cause of mortality among critically ill patients. Extracorporeal Membrane Oxygenation (ECMO) is increasingly employed in the rescue therapy of ARDS patients. However, the current status of research in the field of ECMO-assisted ARDS remains unclear. Objective: This research aims to categorize and evaluate the literature regarding Extracorporeal Membrane Oxygenation (ECMO) support for Acute Respiratory Distress Syndrome (ARDS), offering a comprehensive analysis of bibliometric properties, research hotspots, and developmental trends within the domain of ECMO-assisted ARDS. Methods: A literature search was conducted for ECMO-assisted support for patients with ARDS in the Web of Science Core Collection (WoSCC) database from 2014 to 2024. We employed visualization tools such as CiteSpace and VOSviewer to explore and assess connections among nations, institutions, researchers, and co-cited journals, authors, references, and keywords. Results: This study included 1739 publications. The United States leads in publication volume with Columbia University at the forefront of ECMO research. Intensive Care Medicine has been identified as the most cited journal in this field. Alain Combes from France stands out as a key contributor, particularly in his 2018 publication in the New England Journal of Medicine, which is the most cited work in the discipline. Furthermore, keyword analysis identified three distinct research phases: examining complications associated with ECMO therapy, exploring optimal strategies for mechanical ventilation under ECMO support, and compiling insights into the application of ECMO in treating COVID-19 patients and in the development of predictive models for patient outcomes. Conclusion: Using bibliometric visualization techniques, this study revealed significant progress in the use of ECMO for treating ARDS respiratory support, evaluated the impact of these findings, and outlined potential areas for future studies.

Chinese Herbal Formulas Miao-Yi-Ai-Tang Inhibits the Proliferation and Migration of Lung Cancer Cells through Targeting ß-Catenin/AXIN and Presents Synergistic Effect with Cisplatin Suppressing Lung Cancer.

OBJECTIVE: Lung cancer is one of the major causes of cancer deaths worldwide, and the five-year survival still remains low despite the improvement of screening, prevention, and treatment methods. Chinese herbal medicines have been widely used for tumor prevention and treatment. Miao-Yi-Ai-Tang (Miao) is a novel herbal formulation and shows a potential anticancer effect. Materials and Methods. Human Small Cell Lung Cancer Cell was used for study in vitro. After treatments by Miao and Cisplatin (DDP), the invasion, migration, proliferation, and apoptosis of cells were detected by transwell, wound healing, CCK-8, and flow cytometry, respectively. The expression of ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of. RESULTS: We found that Miao could inhibit invasion, migration, and proliferation and promote apoptosis of human lung cancer cells. Meanwhile, Miao and DDP presented synergy regulating the proliferation and apoptosis of lung cancer cells. The percentage of lung cancer cells in S and G2 stages was increased markedly by Miao. Besides, the expression of c-myc, AXIN, and ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of. CONCLUSIONS: Chinese herbal formulas Miao could suppress lung cancer through targeting the ß-catenin/AXIN signaling pathway. Therefore, our findings may provide a novel strategy for the prevention and treatment of lung cancer.ß-catenin, AXIN, and c-myc was detected by qRT-PCR and immunohistochemistry staining. Western blotting was applied for measuring the protein expression of.