Andrographolide ameliorates bleomycin-induced pulmonary fibrosis by suppressing cell proliferation and myofibroblast differentiation of fibroblasts via the TGF-ß1-mediated Smad-dependent and -independent pathways.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no effective medication. Andrographolide (Andro), extracted from Chinese herbal Andrographis paniculata, could attenuate bleomycin (BLM)-induced pulmonary fibrosis via inhibition of inflammation and oxidative stress, however, the anti-fibrotic mechanisms have not been clarified. Myofibroblasts are the primary cell types responsible for the accumulation of extracellular matrix (ECM) in fibrotic diseases, and targeting fibroblast proliferation and differentiation is an important therapeutic strategy for the treatment of IPF. Hence, this study aimed to investigate the effects of Andro on the fibroblast proliferation and differentiation in the in vivo and in vitro models. The results showed that Andro improved pulmonary function and inhibited BLM-induced fibroblast proliferation and differentiation and ECM deposition in the lungs. In vitro, Andro inhibited proliferation and induced apoptosis of TGF-ß1-stimulated NIH 3T3 fibroblasts and primary lung fibroblasts (PLFs). Andro also inhibited TGF-ß1-induced myofibroblast differentiation and ECM deposition in both cells. We also found that Andro suppressed TGF-ß1-induced Smad2/3 and Erk1/2 activation, suggesting that Smad2/3 and Erk1/2 inactivation mediates Andro-induced effects on TGF-ß1-induced fibroblast proliferation and differentiation. These results indicated that Andro has novel and potent anti-fibrotic effects in lung fibroblasts via inhibition of the proliferation and myofibroblast differentiation of fibroblasts and subsequent ECM deposition, which are modulated by TGF-ß1-mediated Smad-dependent and -independent pathways.

Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis.

Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.

Spontaneous ventilation anaesthesia: total intravenous anaesthesia with local anaesthesia or thoracic epidural anaesthesia for thoracoscopic bullectomy.

OBJECTIVES: At present, few data exist regarding the comparisons of perioperative outcomes and recurrence of spontaneous ventilation (SV) video-assisted thoracic surgery (VATS) bullectomy using total intravenous anaesthesia (TIVA) with local anaesthesia (LA) or thoracic epidural anaesthesia (TEA). We evaluated the feasibility and safety of TIVA with LA in the management of primary spontaneous pneumothorax (PSP). METHODS: We conducted a single-institution retrospective analysis of patients undergoing VATS bullectomy between July 2011 and May 2015; 240 patients were included for analysis. Preoperative, intraoperative and postoperative variables of patients undergoing VATS bullectomy using TIVA-TEA (n = 140) were compared with those using TIVA-LA (n = 100). RESULTS: Baseline demographics were similar between groups. No patients in either group required conversion to thoracotomy. Three patients (TIVA-TEA: 2; TIVA-LA: 1) required conversion to intubated general anaesthesia. Both groups had comparable surgical duration, estimated blood loss, peak EtCO2 and lowest intraoperative SpO2 level. Postoperatively, thoracic drainage volume, duration of chest tube drainage and hospitalization cost did not differ between groups. The incidence of postoperative complications between groups was not significant (2% for TIVA-TEA vs 2% for TIVA-LA, P = 1.00). Pneumothorax recurrence rate was 3% in TIVA-TEA cases (n = 4) and 2% in TIVA-LA cases (n = 2). CONCLUSIONS: SV-VATS bullectomy using TIVA with LA or TEA is technically feasible and safe. Both groups have comparable short-term outcomes and recurrence rates; TIVA-LA seems a valid alternative to TIVA-TEA for the surgical management of PSP under SV.