-
Biomedicine & Pharmacotherapy =... Jun 2024Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell...
Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell aging is oxidative stress and it is known to have a role in idiopathic pulmonary fibrosis. In this paper, the protective effect of the E-CG-01 (3,4-lacto-cycloastragenol) molecule in terms of its antioxidant properties was evaluated in the bleomycin induced mice lung fibrosis model. Bleomycin sulfate was administered as a single dose (2.5 U/kg body weight) intratracheally to induce lung fibrosis. E-CG-01 was administered intraperitoneally in three different doses (2 mg/kg/day, 6 mg/kg/day, and 10 mg/kg/day) for 14 days, starting three days before the bleomycin administration. Fibrosis was examined by Hematoxylin-Eosin, Masson Trichrome, and immunohistochemical staining for TGF-beta1, Type I collagen Ki-67, and gama-H2AX markers. Activity analysis of catalase and Superoxide dismutase enzymes, measurement of total oxidant, total glutathione, and Malondialdehyde levels. In histological analysis, it was determined that all three different doses of the molecule provided a prophylactic effect against the progression of fibrosis compared to the bleomycin control group. However, it was observed that only the molecule applied in the high dose decreased the total oxidant stress level. Lung weight ratio increased in the BLM group but significantly reduced with high-dose E-CG-01. E-CG-01 at all doses reduced collagen deposition, TGF-β expression, and Ki-67 expression compared to the BLM group. Intermediate and high doses of E-CG-01 also significantly reduced alveolar wall thickness and edema formation. These findings suggest that E-CG-01 has potential therapeutic effects in mitigating lung fibrosis through its antioxidant properties.
PubMed: 38943992
DOI: 10.1016/j.biopha.2024.117016 -
International Immunopharmacology Jun 2024Silicosis is a progressive disease characterized by interstitial fibrosis resulting from inhalation of silica particles, and currently lacks specific treatment. Hydrogen...
Hydrogen combined with tetrandrine attenuates silica-induced pulmonary fibrosis via suppressing NF-kappaB/NLRP3 signaling pathway-mediated epithelial mesenchymal transition and inflammation.
Silicosis is a progressive disease characterized by interstitial fibrosis resulting from inhalation of silica particles, and currently lacks specific treatment. Hydrogen (H) has demonstrated antioxidative, anti-inflammatory, and anti-fibrotic properties, yet its efficacy in treating silicosis remains unexplored. In this study, rats exposed to silica were administered interventions of H combined with tetrandrine, and euthanized at 14, 28, and 56 days post-intervention. Lung tissues and serum samples were collected for analysis. Histological examination, MDA assay, enzyme-linked immunosorbent assay, hydroxyproline assay, and Western blotting were employed to assess the impact of H combined with tetrandrine on pulmonary fibrosis. The results revealed that this combination significantly alleviated inflammation in silicosis-afflicted rats, effectively suppressed levels of MDA, TNF-α, and IL-1β expression, and inhibited epithelial-mesenchymal transition (EMT), thereby ameliorating pulmonary fibrosis. Notably, protein expression level of E-cadherin was increased,however protein expression levels of vimentin and α-SMA were reduced, and TGF-β were reduced, alongside a significant decrease in hydroxyproline content. Furthermore, H combined with tetrandrine downregulated protein expression of NF-κB p65, NF-κB p-p65, Caspase-1, ASC, and NLRP3. These findings substantiate the hypothesis that H combined with tetrandrine mitigates inflammation associated with silicosis and suppresses the EMT process to ameliorate fibrosis via the NF-κB/NLRP3 signaling pathway. However, the pressure of airway opening was not assessed in this study and dynamic readings of lung physiological function were not obtained, which is a major limitation of this study.
PubMed: 38943976
DOI: 10.1016/j.intimp.2024.112563 -
International Immunopharmacology Jun 2024Idiopathic pulmonary fibrosis (IPF) is considered to be associated with aging. Both ER stress and the unfolded protein response (UPR) have been associated with pulmonary...
Idiopathic pulmonary fibrosis (IPF) is considered to be associated with aging. Both ER stress and the unfolded protein response (UPR) have been associated with pulmonary fibrosis via key mechanisms including AEC apoptosis, EMT, altered myofibroblast differentiation, and M2 macrophage polarization. A relationship between ER stress and aging has also been demonstrated in vitro, with increased p16 and p21 levels seen in lung epithelial cells of older IPF patients. The mechanism underlying ER stress regulation of IPF fibroblasts is still unclear. In this study, we aimed to delineate ER stress regulation in IPF-derived fibroblasts. Here, we found that ER stress markers (p-eIF2α, p-IREα, ATF6) and fibrosis markers (α-SMA and Collagen-I) were significantly increased in lung tissues of IPF patients and bleomycin-induced mouse models. Notably, the expression of PGC-1α was decreased in fibroblasts. In vivo experiments were designed using an AAV-6 vector mediated conditional PGC-1α knockout driven by a specific α-SMA promoter. Ablation of PGC-1α expression in fibroblasts promoted ER stress and supported the development of pulmonary fibrosis in a bleomycin-induced mouse model. In another experimental group, mice with conditional knockout of PGC-1α in fibroblasts and injected intraperitoneally with 4-PBA (an endoplasmic reticulum stress inhibitor) were protected from lung fibrosis. We further constructed an AAV-6 vector mediated PGC-1α overexpression model driven by a specific Collagen-I promoter. Overexpression of PGC-1α in fibroblasts suppressed ER stress and attenuated development of pulmonary fibrosis in bleomycin-induced mouse models. Taken together, this study identified PGC-1α as a promising target for developing novel therapeutic options for the treatment of lung fibrosis.
PubMed: 38943974
DOI: 10.1016/j.intimp.2024.112514 -
Journal of Natural Products Jun 2024Four new -terphenyl derivatives, talaroterphenyls A-D (-), together with three biosynthetically related known ones (-), were obtained from the mangrove sediment-derived...
Four new -terphenyl derivatives, talaroterphenyls A-D (-), together with three biosynthetically related known ones (-), were obtained from the mangrove sediment-derived sp. SCSIO 41412. Compounds - are rare -terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that - were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (-). These -terphenyls (-) and 36 marine-derived terphenyl analogues (-) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and -, , , , and showed notable activities with IC values of 0.40-16 μM. The binding pattern of -terphenyl inhibitors - with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized -terphenyl , as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.
PubMed: 38943602
DOI: 10.1021/acs.jnatprod.4c00422 -
The Journal of Antimicrobial... Jun 2024Mycobacterium abscessus has emerged as an opportunistic pathogen responsible for lung infections, especially in cystic fibrosis patients. In spite of the production of...
OBJECTIVES
Mycobacterium abscessus has emerged as an opportunistic pathogen responsible for lung infections, especially in cystic fibrosis patients. In spite of the production of the broad-spectrum β-lactamase BlaMab, the carbapenem imipenem is recommended in the initial phase of the treatment of pulmonary infections. Here, we determine whether the addition of vaborbactam, a second-generation β-lactamase inhibitor belonging to the boronate family, improves the activity of β-lactams against M. abscessus.
METHODS
The activity of β-lactams, alone or in combination with vaborbactam, was evaluated against M. abscessus CIP104536 by determining MICs, time-killing and intramacrophage activity. Kinetic parameters for the inhibition of BlaMab by vaborbactam were determined by spectrophotometry.
RESULTS
The combination of vaborbactam (8 mg/L) with β-lactams decreased more than 8 times the MIC of amoxicillin (from >1024 to 128 mg/L) and 2 times the MICs of meropenem (from 16 to 8 mg/L) and imipenem (from 4 to 2 mg/L). The reduction of the MICs was less than that obtained with avibactam at 4 mg/L for amoxicillin (from >1024 to 16 mg/L, more than 64 times less) and for meropenem (from 16 to 4 mg/L, 4 times less). In vitro and intracellularly, M. abscessus was not killed by the meropenem/vaborbactam combination, in spite of significant in vitro inhibition of BlaMab by vaborbactam.
CONCLUSIONS
Inhibition of BlaMab by vaborbactam decreases the MIC of β-lactams, including that of meropenem. As meropenem/vaborbactam is clinically available, this combination offers an alternative therapeutic option that should be evaluated for the treatment of pulmonary infections due to M. abscessus.
PubMed: 38943535
DOI: 10.1093/jac/dkae181 -
Journal of Cystic Fibrosis : Official... Jun 2024Data on the impact of liver transplantation (LT) in cystic fibrosis (CF) on lung function and exacerbations are limited. The objective of this study was to summarize the...
BACKGROUND
Data on the impact of liver transplantation (LT) in cystic fibrosis (CF) on lung function and exacerbations are limited. The objective of this study was to summarize the literature on lung function, nutritional status, survival, and complications following LT in people with CF.
METHODS
Three databases were searched until September 2023, to identify the impact of LT in CF. Lung transplant prior to LT and simultaneous liver-lung transplant were excluded. Pooled hazard ratios were calculated using random-effects models.
RESULTS
Thirty studies were included in this review, with 3 and 9 studies included in meta-analyses for nutritional status and lung function, respectively. Eighty-three percent of the studies used data that was more than a decade old. There was a significant increase in percent-predicted forced expiratory volume with mean change of 7.16 % (2.13, 12.19; p = 0.005) one year post-LT. Pulmonary exacerbations decreased in the short-term, however there was no significant change in body mass index (BMI). One-year survival post-LT ranged between 75 and 100 %, while five-year survival was lower at 64-89 %.
CONCLUSION
Existing data suggest that LT improves lung function in the short term and does not increase the likelihood of pulmonary exacerbations, despite ongoing immunosuppression in the setting of chronic lung infection.
PubMed: 38942722
DOI: 10.1016/j.jcf.2024.06.012 -
Life Sciences Jun 2024Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals with COPD who smoke compared to those who do not smoke. Matrix metalloproteinases (MMPs) play a crucial role in the pathophysiology of respiratory diseases by promoting inflammation and tissue degradation. Furthermore, MMPs are involved in key processes like epithelial-to-mesenchymal transition (EMT), metastasis, and invasion in lung cancer. While EMT has traditionally been associated with the progression of lung cancer, recent research highlights its active involvement in individuals with COPD. Current evidence underscores its role in orchestrating airway remodeling, fostering airway fibrosis, and contributing to the potential for malignant transformation in the complex pathophysiology of COPD. The precise regulatory roles of diverse MMPs in steering EMT during COPD progression needs to be elucidated. Additionally, the less-understood aspect involves how these MMPs bi-directionally activate or regulate various EMT-associated signaling cascades during COPD progression. This review article explores recent advancements in understanding MMPs' role in EMT during COPD progression and various pharmacological approaches to target MMPs. It also delves into the limitations of current MMP inhibitors and explores novel, advanced strategies for inhibiting MMPs, potentially offering new avenues for treating respiratory diseases.
PubMed: 38942362
DOI: 10.1016/j.lfs.2024.122874 -
American Journal of Respiratory and... Jun 2024
PubMed: 38941619
DOI: 10.1164/rccm.202406-1123LE -
American Journal of Respiratory and... Jun 2024
PubMed: 38941617
DOI: 10.1164/rccm.202405-1008LE -
Sarcoidosis, Vasculitis, and Diffuse... Jun 2024Any test that provides sufficient prognostic information to guide treatment decisions in idiopathic pulmonary fibrosis (IPF) is not available. The aim of our study was...
BACKGROUND AND AIM
Any test that provides sufficient prognostic information to guide treatment decisions in idiopathic pulmonary fibrosis (IPF) is not available. The aim of our study was to determine the predictive factors of mortality in patients with IPF treated with antifibrotics.
METHODS
Patients with diagnosis of IPF who were treated with antifibrotics between 2016 - 2021 were included in the study. Demographic, clinical and laboratory characteristics of the patients was derived from hospital records retrospectively. Kaplan Meier and multivariate cox regression analysis were achieved for detection of mortality predictors.
RESULTS
Study population was composed of 119 IPF patients with a male predominance of 80.7% (n=96). Mean age of the patients was 67.9 ± 7.07 years. On univariate analysis, sex was not a significant predictor of mortality (HR 1.79; 95% CI: 0.87 - 3.69, p =0.11). BMI ≤ 26,6 m2/kg, DLCO ≤ 3.11 ml/mmHg/min, age over 62 years, 6DWT ≤ 382 meters, NLR ≤ 2.67 and PDW ≤ 16.7% were found to be significant for predicting mortality. On multivariate cox regression analysis four parameters remained significant for prediction of mortality: RDW > 14%, NLR ≤ 2.67, BMI ≤ 26,6 m2/kg and DLCO ≤ 3.11 ml/mmHg/min (respectively, HR: 2.0. 95% CI: 1.02 - 3.91, p=0.44; HR: 2.68. 95% CI: 1.48 - 4.85, p=0.001, HR: 2.07. 95% CI: 1.14 - 3.76, p=0.02, HR: 3.46. 95% CI: 1.85 - 6.47, p<0.001). A scoring system with these parameters discriminated patients with worse prognosis with a sensitivity of 89.1 % and a specificity of 65.8 % when total point was over 2 (AUC0.83, p<0.001). Conclusions In this study, DLCO, BMI, RDW and NLR levels significantly predicted mortality in IPF patients. Along with GAP index, scoring system with these simple parameters may give information about the prognosis of an IPF patient treated with antifibrotics.
PubMed: 38940720
DOI: 10.36141/svdld.v41i2.13779