lignans and Pulmonary-Fibrosis

Topics: Animals; Collagen; Lignans; Mice; Polycyclic Compounds; Pulmonary Fibrosis

Schisandra chinensis decoction derived from the book of Waitai Miyao (Tao Wang, Tang dynasty) is often used in the treatment of idiopathic pulmonary fibrosis (IPF), which is included in the Grand Ceremony of Chinese formulae (Huairen Peng, 1994). Schisandrae Chinensis Fructus (Sch) is one of the most important herbs in this formula. According to the "Shennong's Herbal Classicherbal" of the Han Dynasty, Sch has sour taste, warm nature, which has the effect of tonifying qi and curing cough. In addition, according to the "Compendium of Materia Medica" of the Ming Dynasty, Sch is used to treat cough and asthma, which has the effect of moistening the lung and tonifying the kidney. However, the active ingredients of Sch absorption into the plasma and its pharmacological mechanism of treatment for IPF still remained unclear.. Our research aimed at identifying the absorbed active ingredients and metabolized of Sch in rat plasma and the mechanism of anti-IPF based on serum pharmacochemistry.. First, the rats were divided into control group and Sch group. Sch sample was orally administrated to the rats for seven days. The blood samples were drawn into an Eppendorf tube after the last dosing. The ultrahigh performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS) was applied to identify the absorption components and metabolites of Sch in rat plasma. Second, the network pharmacology combined with molecular docking analysis was further investigated to illuminate its potential mechanism of treatment for IPF by the biological targets regulating related pathways. Finally, the mechanism of action was verified by experimental in vitro and in vivo.. A total of 78 compounds, consist of 13 prototype lignans and 65 metabolites (including isomers) were identified. Network pharmacology study and molecular docking analysis indicated that schisandrol A (L1) play an anti-fibrosis role by regulating the TGF-β signaling pathway. Experimental in vitro and in vivo verified that the schisandrol A could inhibiting pulmonary fibrosis through TGF-β signaling pathway. The effect and mechanism of schisandrol A inhibiting pulmonary fibrosis were reported for the first time.. In this study, the absorption active ingredients of Sch in rat plasma were combined with the network pharmacology investigation and experimental in vitro and in vivo to elucidate its biological mechanism of treatment for IPF. The results provided a theoretical support for understanding the bioactive compounds and the pharmacological mechanism of Sch.

Topics: Animals; Chromatography, High Pressure Liquid; Cyclooctanes; Female; Fruit; Lignans; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Network Pharmacology; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Schisandra; Signal Transduction; Transforming Growth Factor beta

In this study, we evaluated the in vivo effect of arctigenin (ATG) on bleomycin-induced pulmonary fibrosis in mice and assessed the role of antioxidant activity. Hematoxylin and eosin (H&E) staining, the results of Masson's trichrome, and Sirius red staining showed that bleomycin induced obvious pathological changes and collagen deposition in the lung tissue of mice, which were effectively inhibited by ATG. Specifically, based on immunohistochemistry and western blot results, ATG inhibited the expression of fibrosis markers, such as collagen, fibronectin, and

Topics: Animals; Antioxidants; Bleomycin; Collagen; Fibrosis; Furans; Glutathione; Lignans; Lung; Mice; Pulmonary Fibrosis

Pulmonary fibrosis (PF) is an epithelial/fibroblastic crosstalk disorder of the lungs with highly complex etiopathogenesis. Limited treatment possibilities are responsible for poor prognosis and mean survival rate of 3 to 5 years of PF patients after definite diagnosis. Once thought to be an irreversible disorder, recent evidences have brought into existence the concept of organ fibrosis reversibility due to plastic nature of fibrotic tissues. These findings have kindled interest among the scientific community and given a new direction for research in the arena of fibrosis for developing new anti-fibrotic therapies. The current study is designed to evaluate the anti-fibrotic effects of Honokiol (HNK), a neolignan active constituent from Magnolia officinalis. This study has been conducted in TGF-β1 induced in vitro model and 21 day in vivo murine model of Bleomycin induced PF. The findings of our study suggest that HNK was able to inhibit fundamental pathways of epithelial to mesenchymal transition (EMT) and TGF-β/Smad signaling both in vitro and in vivo. Additionally, HNK also attenuated collagen deposition and inflammation associated with fibrosis. We also hypothesized that HNK interfered with IL-6/CD44/STAT3 axis. As hypothesized, HNK significantly mitigated IL-6/CD44/STAT3 axis both in vitro and in vivo as evident from outcomes of various protein expression studies like western blotting, immunohistochemistry and ELISA. Taken together, it can be concluded that HNK reversed pulmonary fibrotic changes in both in vitro and in vivo experimental models of PF and exerted anti-fibrotic effects majorly by attenuating EMT, TGF-β/Smad signaling and partly by inhibiting IL-6/CD44/STAT3 signaling axis.

Topics: Animals; Biphenyl Compounds; Bleomycin; Bronchoalveolar Lavage Fluid; Cell Line; Cell Movement; Collagen; Cytokines; Epithelial-Mesenchymal Transition; Humans; Hyaluronan Receptors; Interleukin-6; Lignans; Lung; Mice; Pulmonary Fibrosis; Signal Transduction; Smad Proteins; STAT3 Transcription Factor; Transforming Growth Factor beta

Hypertrophic scars (HSs) are a progressive fibroproliferation disorder caused by abnormal tissue repair after deep skin injury, and are characterized by continuous activation of fibroblasts and excessive deposition of extracellular matrix. Arctigenin (ATG), a phytomedicine derived from certain plants, displays antifibrotic effects in certain diseases, such as oral submucous fibrosis and peritoneal fibrosis. In the present study, to determine the antifibrotic potential of ATG in HS, a bleomycin (BLM)‑induced skin fibrosis murine model was established. C57BL/6 mice were randomly divided into Control group, BLM group and BLM+ATG group. At 1 day post‑bleomycin induction, the BLM+ATG group was intraperitoneally injected with 3 mg/kg/day ATG for 28 consecutive days. Pathological changes in the skin tissues were observed by hematoxylin and eosin staining. Collagen content was determined using a Sircol Collagen assay kit. Immunofluorescence staining was performed to detect the expression of TGF‑β1 and α‑SMA. The expression changes of various factors were detected by reverse transcription‑quantitative PCR, western blotting and ELISA. Compared with the BLM group, ATG treatment significantly alleviated skin fibrosis by reducing dermal thickness, collagen content and expression levels of extracellular matrix‑related genes (collagen type I α1 chain, collagen type I α2 chain, connective tissue growth factor and plasminogen activator inhibitor‑1) in BLM‑induced fibrotic skin. ATG also inhibited the transformation of fibroblasts into myofibroblasts in vivo and decreased the expression of TGF‑β1 in BLM‑induced fibrotic skin. Furthermore, the contents of proinflammatory cytokines, including IL‑1β, IL‑4, IL‑6, TNF‑α and monocyte chemoattractant protein‑1, were significantly decreased in the BLM+ATG group compared with the BLM group. Redox imbalance and oxidative stress were also reversed by ATG in BLM‑induced fibrotic skin, as demonstrated by the upregulation of antioxidants (glutathione and superoxide dismutase) and downregulation of oxidants (malondialdehyde) in the BLM+ATG group compared with the BLM group. Moreover, the results indicated that the antioxidant effect of ATG may occur via activation of the nuclear factor erythroid‑2‑related factor 2/heme oxygenase‑1 signaling pathway. Collectively, the present study indicated that ATG could ameliorate skin fibrosis in a murine model of HS, which was partly mediated by reducing inflammation and oxidative stress. Therefore,

Topics: Animals; Antioxidants; Bleomycin; Cicatrix, Hypertrophic; Cytokines; Disease Models, Animal; Extracellular Matrix; Female; Fibroblasts; Fibrosis; Furans; Inflammation; Lignans; Malondialdehyde; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Pulmonary Fibrosis; Superoxide Dismutase; Transforming Growth Factor beta1

Pulmonary fibrosis, a progressive and lethal lung disease, is a major therapeutic challenge for which new therapeutic strategies are warranted. Schisandrin B (Sch B) and Glycyrrhizic acid (GA) are the principal active ingredients of Schisandra chinensis and Glycyrrhiza glabra respectively, which have been reported to protect against lung injures. The present study was aimed at exploring the combinatorial therapeutic effects on bleomycin-induced pulmonary fibrosis. Lung fibrotic injuries were induced in mice by a single intratracheal instillation of 5mg/kg bleomycin (BLM). Then, these mice were administered with Sch B (100mg/kg) or/and GA (75mg/kg) for 28days. BLM-triggered structure distortion, collagen overproduction, excessive inflammatory infiltration, pro-inflammatory cytokine release, and oxidative stress damages in lung tissues were attenuated to a higher degree by combinatorial treatment than by treatment of the individual agents. The expression of TGF-β1 and the phosphorylation of its downstream target, Smad2 were enhanced by BLM, but weakened by Sch B or/and GA. Furthermore, the significant overexpression of NADPH oxidase 4 (NOX4) was observed in BLM-induced pulmonary fibrosis, which was inhibited by Sch B or/and GA. Our study reveals that the synergistic protection by Sch B and GA against BLM-induced pulmonary fibrosis is correlated to its anti-inflammatory, anti-oxidative and anti-fibrotic properties, involving inhibition of TGF-β1/Smad2 signaling pathways and overexpression of NOX4.

Topics: Animals; Anti-Inflammatory Agents; Bleomycin; Cyclooctanes; Cytokines; Drug Synergism; Glycyrrhizic Acid; Lignans; Lung; Male; Mice; NADPH Oxidase 4; Polycyclic Compounds; Pulmonary Fibrosis; Signal Transduction; Smad2 Protein

Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed's therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated.. We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis.. Irradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS-fed mice had decreased fibrosis compared to those fed 0%FS. Lung OH-Proline content ranged from 96.5 ± 7.1 to 110.2 ± 7.7 μg/ml (Mean ± SEM) in all irradiated FS-fed mouse groups, as compared to 138 ± 10.8 μg/ml for mice on 0%FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS-fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS-fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0%FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS-fed mice.. Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Bronchoalveolar Lavage Fluid; Cachexia; Cytokines; Diet; Drug Evaluation, Preclinical; Female; Flax; Lignans; Lung; Mice; Mice, Inbred C57BL; Oxidative Stress; Oxygen; Phytotherapy; Plant Preparations; Pulmonary Fibrosis; Radiation Pneumonitis; Radiation-Protective Agents; Radiotherapy; Random Allocation; Seeds; Weight Loss