ABSTRACT
BACKGROUND: Pulmonary fibrosis, a progressive and fatal lung disease with no effective treatment medication, is characterized by lung remodeling and fibroblastic foci caused by an oxidative imbalance with an overloading deposition of collagen. Trichodelphinine A, a hetisine-type C20-diterpenoid alkaloid, was found anti-fibrotic activity in vitro, but its effect and mechanism on pulmonary fibrosis still unknown. PURPOSE: Our study aimed to investigate and validate the anti-fibrotic properties of trichodelphinine A in pulmonary fibrosis animals induced by bleomycin (BLM), and its mechanism whether via NOX4-ARG1/TGF-ß signaling pathway. METHODS: The anti-fibrotic effects of trichodelphinine A were evaluated using BLM-induced rats through indicators of lung histopathology and collagen synthesis. Dynamic metabolomics evaluated the metabolic disorder and therapeutic effect of trichodelphinine A. The interaction between trichodelphinine A and NOX4 receptor was confirmed using CETSA and molecular dynamics experiments. Molecular biology experiments were conducted in NOX4 gene knockout mice to investigate the intervention effect of trichodelphinine A. RESULTS: Trichodelphinine A could suppress histopathologic changes, collagen deposition and proinflammatory cytokine release pulmonary fibrosis in bleomycin induced rats. Dynamic metabolomics studies revealed that trichodelphinine A could correct endogenous metabolic disorders of arachidonic acid, arginine and proline during fibrosis development, which revealed that the regulation of oxidative stress and amino acid metabolism targeting NOX4 and ARG1 may be the main pharmacological mechanisms of trichodelphinine A on pulmonary fibrosis. We further determined that trichodelphinine A inhibited over oxidative stress and collagen deposition by suppressing Nrf2-keap1 and ARG1-OAT signaling pathways, respectively. Molecular dynamics studies showed that trichodelphinine A was directly binds with NOX4, in which PHE354 and THR355 residues of NOX4 are critical binding sites for trichodelphinine A. Mechanistic validation in cells or mice with NOX4 knockout or silencing suggested that the anti-fibrotic effects of trichodelphinine A depended on inhibition of NOX4 to suppress ARG1/OAT activation and TGF-ß/Smads signaling pathway. CONCLUSION: Collectively, our findings indicate a powerful anti-fibrotic function of trichodelphinine A in pulmonary fibrosis via targeting NOX4. NOX4 mediates the activation of ARG1/OAT to regulate arginase-proline metabolism, and promotes TGF-ß/Smads signaling pathway, thereby affecting the collagen synthesis in pulmonary fibrosis, which is a novel finding and indicates that inhibition of NOX4 is a novel therapeutic strategy for pulmonary fibrosis.
ABSTRACT
Wide-range flexible pressure sensors are in difficulty in research while in demand in application. In this paper, a wide-range capacitive flexible pressure sensor is developed with the foaming agent ammonium bicarbonate (NH4HCO3). By controlling the concentration of NH4HCO3 doped in the polydimethylsiloxane (PDMS) and repeating the curing process, pressure-sensitive dielectrics with various porosity are fabricated to expand the detection range of the capacitive pressure sensor. The shape and the size of each dielectric is defined by the 3D printed mold. To improve the dielectric property of the dielectric, a 1% weight ratio of multi-walled carbon nanotubes (MWCNTs) are doped into PDMS liquid. Besides that, a 5% weight ratio of MWCNTs is dispersed into deionized water and then coated on the electrodes to improve the contact state between copper electrodes and the dielectric. The laminated dielectric layer and two electrodes are assembled and tested. In order to verify the effectiveness of this design, some reference devices are prepared, such as sensors based on the dielectric with uniform porosity and a sensor with common copper electrodes. According to the testing results of these sensors, it can be seen that the sensor based on the dielectric with various porosity has higher sensitivity and a wider pressure detection range, which can detect the pressure range from 0 kPa to 1200 kPa and is extended to 300 kPa compared with the dielectric with uniform porosity. Finally, the sensor is applied to the fingerprint, finger joint, and knee bending test. The results show that the sensor has the potential to be applied to human motion detection.
