Lipopolysaccharide (LPS), the major outer surface membrane component of Gram-negative bacteria, is one of the main etiological factors in the pathogenesis of several lung diseases, such as chronic obstructive pulmonary disease. The respiratory epithelium and the macrophages comprise the dynamic interface between the outside environment and the host response to bacterial infection via cytokine secretion. In the present study, the mechanisms of LPS induced‑inflammatory response in human lung cells and macrophages were investigated. The effects of LPS exposure on cytokine production, inflammation‑related transcription factors and intracellular signaling pathway activation were assessed in human lung mucoepidermoid carcinoma H292 cells and human macrophage THP‑1 cells. The results demonstrated that LPS markedly increased the expression of interleukin (IL)‑6, IL‑8, tumor necrosis factor (TNF)‑α, matrix metallopeptidase (MMP)‑9 and tissue inhibitor of metalloproteinases‑1 in H292 cells, while it increased the production of IL‑6, IL‑8 and TNF‑α in differentiated THP‑1 cells. In addition, LPS exposure activated nuclear factor (NF)‑κB and activator protein (AP)‑1 signaling in H292 cells, while it activated NF‑κB and signal transducer and activator of transcription (STAT) 3 signaling in THP‑1 cells. Furthermore, treatment with NF‑κB, AP‑1 or STAT3 inhibitors significantly decreased the LPS‑mediated expression of IL‑8 and TNF‑α in these cells, suggesting that these pathways might serve crucial roles in LPS‑induced cytokine expression. In conclusion, LPS stimulation of H292 and THP‑1 cells induced cytokine expression and NF‑κB, mitogen‑activated protein kinase and Janus kinase/STAT3 pathway activation with subsequent nuclear translocation of NF‑κB, AP‑1 and STAT3, which demonstrated potential of the use of NF‑κB, AP‑1 and STAT3 in therapies for conditions and diseases associated with chronic inflammation.

The present work adopted a systems pharmacology-based approach to provide new insights into the active compounds and therapeutic targets of Bufei Yishen formula (BYF) for the treatment of chronic obstructive pulmonary disease (COPD). In addition, we established a rat model of cigarette smoke- and bacterial infection-induced COPD to validate the mechanisms of BYF action that were predicted in systems pharmacology study. The systems pharmacology model derived 216 active compounds from BYF and 195 potential targets related to various diseases. The compound-target network showed that each herbal drug in the BYF formula acted on similar targets, suggesting potential synergistic effects among these herbal drugs. The ClueGo assay, a Cytoscape plugin, revealed that most targets were related to activation of MAP kinase and matrix metalloproteinases. By using target-diseases network analysis, we found that BYF had great potential to treatment of multiple diseases, such as respiratory tract diseases, immune system and cardiovascular diseases. Furthermore, we found that BYF had the ability to prevent COPD and its comorbidities, such as ventricular hypertrophy, in vivo. Moreover, BYF inhibited the inflammatory cytokine and hypertrophic factors expression, protease-antiprotease imbalance and the collagen deposition, which may be the underlying mechanisms of action of BYF.

Diosgenin (DG), a well-known steroidal sapogenin, is present abundantly in medicinal herbs such as Dioscorea rhizome, Dioscorea villosa, Trigonella foenum-graecum, Smilax China, and Rhizoma polgonati. DG is utilized as a major starting material for the production of steroidal drugs in the pharmaceutical industry. Due to its wide range of pharmacological activities and medicinal properties, it has been used in the treatment of cancers, hyperlipidemia, inflammation, and infections. Numerous studies have reported that DG is useful in the prevention and treatment of neurological diseases. Its therapeutic mechanisms are based on the mediation of different signaling pathways, and targeting these pathways might lead to the development of effective therapeutic agents for neurological diseases. The present review mainly summarizes recent progress using DG and its derivatives as therapeutic agents for multiple neurological disorders along with their various mechanisms in the central nervous system. In particular, those related to therapeutic efficacy for Parkinson’s disease, Alzheimer’s disease, brain injury, neuroinflammation, and ischemia are discussed. This review article also critically evaluates existing limitations associated with the solubility and bioavailability of DG and discusses imperatives for translational clinical research. It briefly recapitulates recent advances in structural modification and novel formulations to increase the therapeutic efficacy and brain levels of DG. In the present review, databases of PubMed, Web of Science, and Scopus were used for studies of DG and its derivatives in the treatment of central nervous system diseases published in English until December 10, 2019. Three independent researchers examined articles for eligibility. A total of 150 articles were screened from the above scientific literature databases. Finally, a total of 46 articles were extracted and included in this review. Keywords related to glioma, ischemia, memory, aging, cognitive impairment, Alzheimer, Parkinson, and neurodegenerative disorders were searched in the databases based on DG and its derivatives.

Traditional Chinese medicine (TCM) has been used to treat chronic obstructive pulmonary disease (COPD) for many years. This study aimed to evaluate the efficacy and safety of the comprehensive therapy based on the three common TCM patterns in stable COPD patients. A four-center, open-label randomized controlled method was conducted. A total of 352 patients were divided into the trial group (n = 176, treated with conventional Western medicine and Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules, and Yi-Qi Zi-Shen granules based on the TCM patterns respectively) and the control group (n = 176, treated with conventional Western medicine). The frequency and duration of acute exacerbation, lung function, clinical symptoms, 6-minute walking distance (6MWD), dyspnea scale and quality of life were observed during a 6-month treatment period and at a further 12-month follow-up. A total of 306 patients completed the study fully. The full analysis set (FAS) population was 350 and the per-protocol analysis set (PPS) population was 306. After the 6-month treatment and 12-month follow-up, there were significant differences between the trial and control group in the following: frequency of acute exacerbation (FAS: P = 0.000; PPS: P = 0.000); duration of acute exacerbation (FAS: P = 0.000; PPS: P = 0.001); FEV1 (FAS: P = 0.007; PPS: P = 0.008); symptoms (FAS: P = 0.001; PPS: P = 0.001); 6MWD (FAS: P = 0.045; PPS: P = 0.042); dyspnea scale (FAS: P = 0.002; PPS: P = 0.004); and physical domain (FAS: P = 0.000; PPS: P = 0.000), psychological domain (FAS: P = 0.008; PPS: P = 0.011), social domain (FAS: P = 0.001; PPS: P = 0.000) and environment domain (FAS: P = 0.015; PPS: P = 0.009) of the WHOQOL-BREF questionnaire. There were no differences between the trial and control group in FVC, FEV1% and adverse events. Based on the TCM patterns, Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules and Yi-Qi Zi-Shen granules have beneficial effects on measured outcomes in stable COPD patients over the 6-month treatment and 12-month follow-up, with no relevant between-group differences in adverse events. This trial was registered at Chinese Clinical Trial Register Center, ChiCTR-TRC-11001406.

Jinshui Huanxian formula (JHF), a traditional Chinese medicine (TCM), has been demonstrated to attenuate idiopathic pulmonary fibrosis (IPF). The active compounds and underlying mechanisms of JHF, however, are unclear. The purpose of This study was to aimed to identify the active compounds and pharmacological mechanism of JHF by integrating serum pharmacochemistry with a network pharmacology strategy. JHF was orally administered to a rat model with bleomycin (BLM)-induced pulmonary fibrosis (PF). The pharmacodynamic effects and compounds present in the serum were identified. The targets and biological mechanisms of these compounds were revealed using network analysis and validated using in vitro experiments. JHF could significantly ameliorate BLM-induced PF by preventing extracellular matrix collagen deposition. Twenty-seven compounds that were found to be enriched in the serum samples collected 1 h after oral administration with JHF were identified as the candidate active compounds, and their 423 potential targets were identified as JHF targets. primarily related to the advanced glycation and products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway, phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB or AKT) signaling pathway, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, etc. The 423 targets, 1145 IPF-related genes and their overlapped genes were applied to analyze, respectively. The results showed that these genes were primarily related to the advanced glycation end-products-receptor for advanced glycation end-products (AGE-RAGE) signaling pathway, lipid and atherosclerosis pathology, phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB or AKT) signaling pathway, and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance. Furthermore, the affinity between serum JHF compounds and the main proteins in the above important pathways was investigated through molecular docking. As a result, Molecular docking analysis showed that, tangeretin, isosinensetin, and peimine were found to could bind to EGFR and AKT, and their inhibitory effect on EGFR and AKT were validated in fibroblast cell induced by transforming growth factor (TGF)TGF-β. The results indicated that suppression of fibroblast activation by inhibiting the EGFR/PI3K/AKT signaling pathway might be an important mechanism of JHF may to treat PF. JHF may suppress fibroblast activation by inhibiting the EGFR/PI3K/AKT signaling pathway to ameliorate PF. Tangeretin, isosinensetin, and peimine may be the active compounds in JHF involved in the treatment of that have therapeutic effects on IPF.

The epithelial-mesenchymal transition (EMT) is an important pathological process in the occurrence of pulmonary fibrosis. Changes in histone methylation modifications of key genes play an important role in this process. As a histone methyltransferase, the regulatory mechanism and role of SET domain bifurcated 1 (SETDB1) in pulmonary fibrosis remain unclear. We found that SETDB1 inhibited EMT and that cells attenuated the expression of SETDB1 to relieve this inhibition during transforming growth factor-β (TGF-β)-induced EMT. Silencing SETDB1 expression significantly enhanced the mesenchymal phenotype induced by TGF-β and the expression and deposition of fibronectin and significantly reduced the expression of E-cadherin. The decrease in E-cadherin expression and the induction of EMT led to increased lipid reactive oxygen species (ROS) and ferrous ions, which induced ferroptosis. Chromatin immunoprecipitation (ChIP) results showed that SETDB1 regulates the expression of Snai1 by catalyzing the histone H3 lysine 9 trimethylation (H3K9me3) of Snai1, the main transcription factor that initiates the process of EMT, and thus, indirectly regulates E-cadherin. Surprisingly, when examining the effect of overexpressed SETDB1 on EMT, we found that overexpressed SETDB1 alleviated EMT and also caused ferroptosis. We suggest that the overexpression of SETDB1 partially reverses the mesenchymal phenotype to an epithelial state, while those cells that fail to reverse are depleted by ferroptosis. In conclusion, the histone methylase SETDB1 regulates Snai1 epigenetically, driving EMT gene reprogramming and ferroptosis in response to TGF-β. However, there are unexplored links between the epigenetic reprogramming and transcriptional processes that regulate EMT in a TGF-β-dependent manner.