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Su Yuan,1,2 Biao Zuo,2,3 Si-Cong Zhou,1,2 Meng Wang,2,3 Kai-Yue Tan,2,3 Zhi-Wei Chen,2,3 Wen-Fu Cao1– 3 1Department of Combination of Chinese and Western Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, People’s Republic of China; 3College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Wen-Fu Cao, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, People’s Republic of China, Email caowenfu20220401@163.comPurpose: Our study aims to reveal the pharmacological mechanism of Astragaloside IV in the treatment of pulmonary fibrosis(PF) through network pharmacology and experimental validation.Methods: We first determined the in vivo anti-pulmonary fibrosis effect of Astragaloside IV by HE, MASSON staining, and lung coefficients, then used network pharmacology to predict the signaling pathways and molecularly docked key pathway proteins, and finally validated the results by in vivo and in vitro experiments.Results: In in vivo experiments, we found that Astragaloside IV improved body weight (P < 0.05), increased lung coefficients (P < 0.05), and reduced lung inflammation and collagen deposition in mice with pulmonary fibrosis. The network pharmacology results showed that Astragaloside IV had 104 cross-targets with idiopathic pulmonary fibrosis, and the results of KEGG enrichment analysis indicated that cellular senescence could be an important pathway for Astragaloside IV in the treatment of pulmonary fibrosis. Astragaloside IV also bound well to senescence-associated proteins, according to molecular docking results. The results of both in vivo and in vitro experiments showed that Astragaloside IV significantly inhibited senescence protein markers such as P53, P21, and P16 and delayed cellular senescence (P < 0.05). In in vivo experiments, we also found that Astragaloside IV reduced the production of SASPs (P < 0.05), and in in vitro experiments, Astragaloside IV also reduced the production of ROS. In addition, by detecting epithelial-mesenchymal transition(EMT)-related marker protein expression, we also found that Astragaloside IV significantly inhibited the development of EMT in both in vivo and in vitro experiments (P < 0.05).Conclusion: Our research found that Astragaloside IV could alleviate bleomycin-induced PF by preventing cellular senescence and EMT.Keywords: astragaloside IV, pulmonary fibrosis, network pharmacology, cellular senescence, epithelial-mesenchymal transition

AimGut microbiota is of crucial importance to cardiac health. Astragaloside IV (AS-IV) is a main active ingredient of Huangqi, a traditional edible and medicinal herb that has been shown to have beneficial effects on cardiac fibrosis (CF). However, it is still uncertain whether the consumption of AS-IV alleviates cardiac fibrosis through the gut microbiota and its metabolites. Therefore, we assessed whether the anti-fibrosis effect of AS-IV is associated with changes in intestinal microbiota and fecal metabolites and if so, whether some specific gut microbes are conducive to the benefits of AS-IV.MethodsMale C57BL-6J mice were subcutaneously injected with isoprenaline (ISO) to induce cardiac fibrosis. AS-IV was administered to mice by gavage for 14 days. The effects of AS-IV on cardiac function, myocardial enzyme, cardiac weight index (CWI), and histopathology of ISO-induced CF mice were investigated. Moreover, 16S rRNA sequencing was used to establish gut-microbiota profiles. Fecal-metabolites profiles were established using the liquid chromatograph-mass spectrometry (LC-MS).ResultsAS-IV treatment prevented cardiac dysfunction, ameliorated myocardial damage, histopathological changes, and cardiac fibrosis induced by ISO. AS-IV consumption increased the richness of Akkermansia, Defluviitaleaceae_UCG-011, and Rikenella. AS-IV also modulated gut metabolites in their feces. Among 141 altered gut metabolites, amino acid production was sharply changed. Furthermore, noticeable correlations were found between several specific gut microbes and altered fecal metabolites.ConclusionsAn increase of Akkermansia, Defluviitaleaceae_UCG-011, and Rikenella abundance, and modulation of amino acid metabolism, may contribute to the anti-fibrosis and cardiac protective effects of Astragaloside IV.

170 p. This project investigated the mechanochemical synthesis of nanograined Fe-Si based alloys, the thermal stability of the nanograins, sintering and the magnetic properties of sintered products. Initially, synthesis and thermal stability of a set of nanostructured alloys based on the Fe75Si25 composition with ternary additions of Al, Cu and Nb were investigated. The milling conditions required to achieve nanograined and fully alloyed powder were first determined. Thermal stability investigations showed that Al and Nb additions inhibited grain growth more effectively than Cu. However, the Nb containing alloy formed the second phase Fe2Nb which is undesirable for soft magnetic applications. Hence Al was chosen as the promising ternary additive for further detailed studies on sintering and magnetic properties. DOCTOR OF PHILOSOPHY (MSE)

Epithelial barrier function studies often attribute alterations in barrier function to induced changes in tight junctional (TJ) complexes. The occurrence of spontaneous and cytokine-induced, focal cell detachment in cell layers of the human gingival epithelial cell line, Gie-3B11, highlights the danger of this assumption without confirmatory experimentation. Gie-3B11 cell layers manifest morphological polarity, TJ complexes and barrier function after confluence but fail to then maintain a stable epithelial barrier. Transepithelial electrical resistance rises to over 100 ohms x cm(2) a few days after seeding cell layers at a confluent density, but then spontaneously declines, with simultaneous, inverse changes in transepithelial (14)C-D-mannitol diffusion rates. This barrier decline correlates with the appearance of focal cell detachment/hole formation in cell layers. Both barrier compromise (decreased electrical resistance; increased (14)C-D-mannitol leak) and hole formation are accelerated and exaggerated by exposing cell layers to proinflammatory cytokines. Both are inhibited by increasing the basal-lateral medium compartment volume, suggesting that cell layers are secreting factor(s) across their basal-lateral surfaces that are causal to hole formation. The molecular mechanism of cell death/detachment here is not as significant as the implications of hole formation for the correct interpretation of barrier function studies. Barrier changes in any epithelial model should be attributed to induced changes in TJ complexes only after thorough investigation.