RESUMO
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with high mortality and limited effective therapy. Herein, we reported that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), used in depression and anxiety treatment, also exhibited therapeutic activities in IPF. Fluvoxamine inhibited cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), restrained the activation of their downstream targets, including PERK/ eIF2α/ c-Myc/ miR-9-5p/ TBPL1 and TBK1/ YAP/ JNK1/2/ Bnip3/ CaMKII/ cofilin signaling, thus attenuated the activation and migration of fibroblasts upon TGF-ß1 challenge. Fluvoxamine dose-dependently improved pulmonary function, decreased the expression of inflammatory factors, reduced excessive production of extracellular matrix, and thus alleviated bleomycin (BLM)-induced lung fibrosis in mice. Moreover, fluvoxamine at a dose of 10 mg/ kg showed similar efficacy as pirfenidone (PFD) at a dose of 30 mg/kg in a mice model of lung fibrosis. In summary, our results suggest that fluvoxamine is an effective anti-fibrotic agent for IPF.
Assuntos
Antifibróticos , Fluvoxamina , Fibrose Pulmonar Idiopática , Animais , Camundongos , Bleomicina , Fibroblastos/metabolismo , Fluvoxamina/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Nucleotidiltransferases , Fator de Crescimento Transformador beta1/metabolismo , Antifibróticos/uso terapêuticoRESUMO
Based on a typical ozone ï¼O3ï¼ pollution process in Jinan City from June 16 to 26, 2021, the variation characteristics of O3 and its precursor volatile organic compounds ï¼VOCsï¼ during different pollution periods ï¼clean period ï¼CPï¼, pollution rise period ï¼PRPï¼, heavy pollution period ï¼HPPï¼, and pollution decline period ï¼PDPï¼ï¼ in the urban area were analyzed. Both positive matrix factorization ï¼PMFï¼ and an observation-based model ï¼OBMï¼ were used to identify the main sources of VOCs, O3 production mechanisms, and sensitive species. The results showed that the average value of ρï¼O3-8hï¼ during the HPP period in the urban area was ï¼246.67±11.24ï¼ µg·m-3, and ρï¼O3-1hï¼ had a peak value of 300 µg·m-3. The volume fractions of VOCs and NO2 concentration were affected by the decrease in planetary boundary layer and wind speed, which were 76.99%-145.36% and 127.78%-141.18% higher than those in the other three periods, respectively, and were the main reasons for the aggravation of O3 pollution. Alkanes, oxygenated volatile organic compounds ï¼OVOCsï¼, and halogenated hydrocarbons accounted for 43.81%, 20.98%, and 17.43% of VOCs in urban areas, respectively. All of them showed significant growth during the HPP period, with acetone, propane, and ethane being the top three species by volume in each stage and isopentane showing the highest growth during the HPP period. Alkene, alkanes, and aromatic hydrocarbons accounted for 40.19%, 28.06%, and 21.92% of the ozone generation potential ï¼OFPï¼. 1-butene, toluene, isopentane, and isoprene were the species with higher OFP. Isoprene had the highest OFP during the PRP phase, and 1-butene had the highest OFP during the HPP phase. The volume fraction of isopentane significantly increased OFP. The correlation coefficient between VOCs and CO preliminarily indicated that motor vehicle exhaust and oil and gas volatilization were the main sources of VOCs during the HPP period. Further use of PMF revealed that solvent use sources, combustion sources, motor vehicle exhaust+oil and gas volatilization sources, industrial emission sources, and plant sources were important sources of VOCs in urban areas. The contribution of motor vehicle exhaust+oil and gas volatilization sources in the HPP period to VOCs was 3.09-14.72 times higher than that in other periods. The contribution of solvent use sources to VOCs was approximately 2.50 times higher than that in the CP and PRP periods. The main sources of VOCs volume fraction increase were motor vehicle exhaust, oil and gas volatilization sources, and solvent use sources. Potential sources and concentration weight analysis found that VOCs were also affected by the transmission of VOCs to Binzhou and Dongying in the northeast direction. The OBM results indicated that the main pathway of O3 formation in urban areas was the reaction of peroxide hydroxyl radicals ï¼HO2·ï¼ and methyl peroxide radicals ï¼CH3O2·ï¼ with NO, and the net ozone generation rate during the HPP phase [Pï¼O3ï¼net] was 24×10-9 h-1. Based on the sensitivity experiment results, the alkene components of 1-butene, propylene, cis-2-butene, and ethylene were the dominant species for O3 production.
RESUMO
Companies increasingly implement digital transformation strategies to promote efficiency. Nevertheless, there are few concerns about employees' acceptance of the changes, especially the executives' adaptability, which is an important part of digital transformation strategy implementation. By utilizing the "searching-matching" in keywords of the annual reports of public listed companies in China, we measured the degree of corporate digital transformation to analysis its influence on the turnover rate of the Chairman and CEO. We found that digital transformation decreases the possibility of Chairman and CEO's turnover. Derived from the dynamic managerial capital theory, we demonstrated that executives' social network and political connections both have a moderate effect on the relationship between digital transformation and the turnover rate of executives. These findings will contribute to the digital transformation research by integrating with executives' dynamic managerial capital which is attained through social networks and political connections.