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Bioorganic Chemistry Aug 2024Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the...
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.
Topics: Idiopathic Pulmonary Fibrosis; Phosphodiesterase 4 Inhibitors; Animals; Structure-Activity Relationship; Mice; Molecular Structure; Humans; Cyclic Nucleotide Phosphodiesterases, Type 4; Bleomycin; Dose-Response Relationship, Drug; Mice, Inbred C57BL; Male; Benzofurans
PubMed: 38805909
DOI: 10.1016/j.bioorg.2024.107474 -
Journal of Gastroenterology and... May 2024Hydronidone (HDD) is a novel pirfenidone derivative developed initially to reduce hepatotoxicity. Our previous studies in animals and humans have demonstrated that HDD...
BACKGROUND AND AIM
Hydronidone (HDD) is a novel pirfenidone derivative developed initially to reduce hepatotoxicity. Our previous studies in animals and humans have demonstrated that HDD treatment effectively attenuates liver fibrosis, yet the underlying mechanism remains unclear. This study aimed to investigate whether HDD exerts its anti-fibrotic effect by inducing apoptosis in activated hepatic stellate cells (aHSCs) through the endoplasmic reticulum stress (ERS)-associated mitochondrial apoptotic pathway.
METHODS
The carbon tetrachloride (CCl)- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver fibrosis models were used for in vivo studies. In vitro studies were conducted using the human hepatic stellate cell line LX-2. The apoptotic effect of HDD on aHSCs was examined using TUNEL and flow cytometry assays. The small interfering RNA (siRNA) technique was employed to downregulate the expression of interest genes.
RESULTS
HDD treatment significantly promoted apoptosis in aHSCs in both the CCl- and DDC-induced liver fibrosis in mice and LX-2 cells. Mechanistic studies revealed that HDD triggered ERS and subsequently activated the IRE1α-ASK1-JNK pathway. Furthermore, the influx of cytochrome c from the mitochondria into the cytoplasm was increased, leading to mitochondrial dysfunction and ultimately triggering apoptosis in aHSCs. Notably, inhibition of IRE1α or ASK1 by siRNA partially abrogated the pro-apoptotic effect of HDD in aHSCs.
CONCLUSIONS
The findings of both in vivo and in vitro studies suggest that HDD induces apoptosis in aHSCs via the ERS-associated mitochondrial apoptotic pathway, potentially contributing to the amelioration of liver fibrosis.
PubMed: 38804845
DOI: 10.1111/jgh.16635 -
Experimental Cell Research Jun 2024The involvement of γδT cells, Th17 cells, and CD4CD25 regulatory T cells (Tregs) is crucial in the progression of pulmonary fibrosis (PF), particularly in maintaining...
Correlation between the dynamic changes of γδT cells, Th17 cells, CD4CD25 regulatory T cells in peripheral blood and pharmacological interventions against bleomycin-induced pulmonary fibrosis progression in mice.
The involvement of γδT cells, Th17 cells, and CD4CD25 regulatory T cells (Tregs) is crucial in the progression of pulmonary fibrosis (PF), particularly in maintaining immune tolerance and homeostasis. However, the dynamics of these cells in relation to PF progression, especially under pharmacological interventions, remains poorly understood. This study aims to unravel the interplay between the dynamic changes of these cells and the effect of pharmacological agents in a mouse model of PF induced by intratracheal instillation of bleomycin. We analyzed changes in lung histology, lung index, hydroxyproline levels, and the proportions of γδT cells, Th17 cells, and Tregs on the 3rd, 14th, and 28th days following treatment with Neferine, Isoliensinine, Pirfenidone, and Prednisolone. Our results demonstrate that these drugs can partially or dynamically reverse weight loss, decrease lung index and hydroxyproline levels, and ameliorate lung histopathological damage. Additionally, they significantly modulated the abnormal changes in γδT, Th17, and Treg cell proportions. Notably, on day 3, the proportion of γδT cells increased in the Neferine and Prednisolone groups but decreased in the Isoliensinine and Pirfenidone groups, while the proportion of Th17 cells decreased across all treated groups. On day 14, the Neferine group showed an increase in all three cell types, whereas the Pirfenidone group exhibited a decrease. In the Isoliensinine group, γδT and Th17 cells increased, and in the Prednisolone group, only Tregs increased. By day 28, an increase in Th17 cell proportion was observed in all treatment groups, with a decrease in γδT cells noted in the Neferine group. These shifts in cell proportions are consistent with the pathogenesis changes induced by these anti-PF drugs, suggesting a correlation between cellular dynamics and pharmacological interventions in PF progression. Our findings imply potential strategies for assessing the efficacy and timing of anti-PF treatments based on these cellular changes.
Topics: Animals; Bleomycin; Pulmonary Fibrosis; T-Lymphocytes, Regulatory; Th17 Cells; Mice; Pyridones; Male; Prednisolone; Disease Progression; Mice, Inbred C57BL; Disease Models, Animal; Lung; Interleukin-2 Receptor alpha Subunit; Isoquinolines; Benzylisoquinolines
PubMed: 38796136
DOI: 10.1016/j.yexcr.2024.114098 -
The Journal of Heart and Lung... May 2024Chronic lung allograft dysfunction (CLAD) is the leading long-term cause of poor outcomes after transplant and manifests by fibrotic remodeling of small airways and/or...
BACKGROUND
Chronic lung allograft dysfunction (CLAD) is the leading long-term cause of poor outcomes after transplant and manifests by fibrotic remodeling of small airways and/or pleuroparenchymal fibroelastosis. This study evaluated the effect of pirfenidone on quantitative radiographic and pulmonary function assessment in patients with CLAD.
METHODS
We performed a single-center, 6-month, randomized, placebo-controlled trial of pirfenidone in patients with CLAD. Randomization was stratified by CLAD phenotype. The primary outcome for this study was change in radiographic assessment of small airways disease, quantified as percentage of lung volume using parametric response mapping analysis of computed tomography scans (PRM); secondary outcomes included change in forced expiratory volume in 1 second (FEV), change in forced vital capacity (FVC), and change in radiographic quantification of parenchymal disease (PRM). Linear mixed models were used to evaluate the treatment effect on outcome measures.
RESULTS
The goal enrollment of 60 patients was not met due to the coronavirus disease of 2019 pandemic, with 23 patients included in the analysis. There was no significant difference over the study period between the pirfenidone vs placebo groups with regards to the observed change in PRM (+4.2% vs -0.4%; p = 0.22), FEV (-3.5% vs -3.6%; p = 0.97), FVC (-1.9% vs -4.6%; p = 0.41), or PRM (-0.6% vs -2.5%; p = 0.30). The study treatment tolerance and adverse events were generally similar between the pirfenidone and placebo groups.
CONCLUSIONS
Pirfenidone had no apparent impact on radiographic evidence of allograft dysfunction or pulmonary function decline in a single-center randomized trial of CLAD patients that did not meet enrollment goals but had an acceptable tolerance and side-effect profile.
PubMed: 38796045
DOI: 10.1016/j.healun.2024.05.013 -
Phytomedicine : International Journal... Jul 2024Pulmonary fibrosis (PF) is an end-stage change in many interstitial lung diseases, whereas no proven effective anti-pulmonary fibrotic treatments. Forsythoside A (FA)...
BACKGROUND
Pulmonary fibrosis (PF) is an end-stage change in many interstitial lung diseases, whereas no proven effective anti-pulmonary fibrotic treatments. Forsythoside A (FA) derived from Forsythia suspensa (Thunb.) Vahl, has been found to possess lung-protective effect. However, studies on its anti-pulmonary fibrosis effect are limited and its mechanism of action remains unknown.
PURPOSE
This study aimed to explore the underlying mechanism of FA on PF.
METHODS
Male C57BL/6 mice were randomized into normal (CON), model (BLM), pirfenidone (PFD), low- and high-dose FA (FA-L, FA-H, respectively). Except for the CON group, which was injected with the same dose of saline, the model of PF was established by intratracheal instillation of BLM, during which the survival rate and body weight changes of the mice were measured. The lung histopathology was evaluated by Hematoxylin-eosin, Sirius red, and Masson staining. Transcriptome analysis was performed to screen for the differential genes associated with the role of FA in PF. Differential genes in normal and pulmonary fibrosis patients with the GSE2052 dataset were analyzed in the GEO database. The levels of CTGF, α-SMA, MMP-8 in lung and TNF-α in bronchoalveolar lavage fluid (BALF) were detected by ELISA. The levels of HYP in lungs were detected by digestion. The mRNA and protein levels of MMP-7, E-cadherin, CD31, α-SMA, TGF-β1, IL-6, β-catenin, ZO-1, PTPRB, E-cadherin, and vimentin in lungs were detected by RT-qPCR and Western blot. The expression of CD31, α-SMA, TGF-β1 and ZO-1 were detected by immunofluorescence. TGF-β1-stimulated HFL1 cells and human umbilical vein endothelial cells (HUVECs) were used in an attempt to explore the possible role of protein tyrosine phosphatase receptor type B (PTPRB) involved in FA-induced improvement of PF.
RESULTS
The results showed that FA could improve the survival rate and body weight of PF mice. FA could alleviate the symptoms of alveolar wall thickening, inflammatory cell infiltration, blue collagen fiber deposition, collagen fiber type Ⅰ and type Ⅲ in mice with PF. In addition, FA could reduce the levels of HYP, CTGF, α-SMA, TGF-β1, TNF-α, β-catenin and MMP8, and regulate the expression levels of CD31, ZO-1, PTPRB and E-cadherin in lung of mice with PF, inhibiting endothelial-to-mesenchymal transition (EndMT) and fibroblasts proliferation. In the GSE2052 dataset, the expression level of PTPRB is reduced in lung tissue from PF patients, and results from transcriptome sequencing indicate that PTPRB expression is also reduced in PF mice. In addition, the effect of FA on TGF-β1-induced HFL1 or HUVECs cells could be attenuated by the inhibitor of PTPRB, suggesting that the effect of FA on PF is related to PTPRB.
CONCLUSION
This study demonstrated that FA could ameliorate PF by inhibiting lung fibroblast proliferation and EndMT, and that PTPRB might be a target of FA to ameliorate PF, which provided evidence to support FA as a candidate phytochemical for PF.
Topics: Animals; Male; Mice, Inbred C57BL; Pulmonary Fibrosis; Signal Transduction; Lung; Glycosides; Forsythia; Epithelial-Mesenchymal Transition; Mice; Cell Proliferation; Fibroblasts; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Humans; Human Umbilical Vein Endothelial Cells; Disease Models, Animal; Actins; Bleomycin
PubMed: 38788399
DOI: 10.1016/j.phymed.2024.155715 -
BioRxiv : the Preprint Server For... May 2024Although axotomized neurons retain the ability to initiate the formation of growth cones and attempt to regenerate after spinal cord injury, the scar area formed as a...
Although axotomized neurons retain the ability to initiate the formation of growth cones and attempt to regenerate after spinal cord injury, the scar area formed as a result of the lesion in most adult mammals contains a variety of reactive cells that elaborate multiple extracellular matrix and enzyme components that are not suitable for regrowth . Newly migrating axons in the vicinity of the scar utilize upregulated LAR family receptor protein tyrosine phosphatases, such as PTPσ, to associate with extracellular chondroitin sulphate proteoglycans (CSPGs), which have been discovered to tightly entrap the regrowing axon tip and transform it into a dystrophic non-growing endball. The scar is comprised of two compartments, one in the lesion penumbra, the glial scar, composed of reactive microglia, astrocytes and OPCs; and the other in the lesion epicenter, the fibrotic scar, which is made up of fibroblasts, pericytes, endothelial cells and inflammatory cells. While the fibrotic scar is known to be strongly inhibitory, even more so than the glial scar, the molecular determinants that curtail axon elongation through the injury core are largely uncharacterized. Here, we show that one sole member of the entire family of collagens, collagen I, creates an especially potent inducer of endball formation and regeneration failure. The inhibitory signaling is mediated by mechanosensitive ion channels and RhoA activation. Staggered systemic administration of two blood-brain barrier permeable-FDA approved drugs, aspirin and pirfenidone, reduced fibroblast incursion into the complete lesion and dramatically decreased collagen I, as well as CSPG deposition which were accompanied by axonal growth and considerable functional recovery. The anatomical substrate for robust axonal regeneration was provided by laminin producing GFAP and NG2 bridging cells that spanned the wound. Our results reveal a collagen I-mechanotransduction axis that regulates axonal regrowth in spinal cord injury and raise a promising strategy for rapid clinical application.
PubMed: 38766123
DOI: 10.1101/2024.05.07.592424 -
JAMA May 2024Current treatments for idiopathic pulmonary fibrosis slow the rate of lung function decline, but may be associated with adverse events that affect medication adherence....
IMPORTANCE
Current treatments for idiopathic pulmonary fibrosis slow the rate of lung function decline, but may be associated with adverse events that affect medication adherence. In phase 2 trials, pamrevlumab (a fully human monoclonal antibody that binds to and inhibits connective tissue growth factor activity) attenuated the progression of idiopathic pulmonary fibrosis without substantial adverse events.
OBJECTIVE
To assess the efficacy and safety of pamrevlumab for patients with idiopathic pulmonary fibrosis.
DESIGN, SETTING, AND PARTICIPANTS
Phase 3 randomized clinical trial including 356 patients aged 40 to 85 years with idiopathic pulmonary fibrosis who were not receiving antifibrotic treatment with nintedanib or pirfenidone at enrollment. Patients were recruited from 117 sites in 9 countries between July 18, 2019, and July 29, 2022; the last follow-up encounter occurred on August 28, 2023.
INTERVENTIONS
Pamrevlumab (30 mg/kg administered intravenously every 3 weeks; n = 181) or placebo (n = 175) for 48 weeks.
MAIN OUTCOMES AND MEASURES
The primary outcome was absolute change in forced vital capacity (FVC) from baseline to week 48. There were 5 secondary outcomes (including time to disease progression, which was defined as a decline of ≥10% in predicted FVC or death). The exploratory outcomes included patient-reported symptoms. Adverse events were reported.
RESULTS
Among 356 patients (mean age, 70.5 years; 258 [72.5%] were men; 221 [62.1%] were White), 277 (77.8%) completed the trial. There was no significant between-group difference for absolute change in FVC from baseline to week 48 (least-squares mean, -260 mL [95% CI, -350 to -170 mL] in the pamrevlumab group vs -330 mL [95% CI, -430 to -230 mL] in the placebo group; mean between-group difference, 70 mL [95% CI, -60 to 190 mL], P = .29). There were no significant between-group differences in any of the secondary outcomes or in the patient-reported outcomes. In the pamrevlumab group, there were 160 patients (88.4%) with treatment-related adverse events and 51 patients (28.2%) with serious adverse events vs 151 (86.3%) and 60 (34.3%), respectively, in the placebo group. During the study, 23 patients died in each group (12.7% in the pamrevlumab group vs 13.1% in the placebo group).
CONCLUSIONS AND RELEVANCE
Among patients with idiopathic pulmonary fibrosis treated with pamrevlumab or placebo, there was no statistically significant between-group difference for the primary outcome of absolute change in FVC from baseline to week 48.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03955146.
PubMed: 38762797
DOI: 10.1001/jama.2024.8693 -
Journal of Controlled Release :... Jun 2024Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a...
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors β1 (TGF-β1), Smad3 and inflammatory cytokines IL-6, IL-1β and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF.
Topics: Animals; Glycyrrhetinic Acid; Idiopathic Pulmonary Fibrosis; Extracellular Vesicles; Administration, Inhalation; Milk; Mice, Inbred C57BL; Cytokines; Anti-Inflammatory Agents; Bleomycin; Male; Lung; Mice; Humans; Cell Line; Drug Carriers; Smad3 Protein
PubMed: 38754632
DOI: 10.1016/j.jconrel.2024.05.024 -
Scientific Reports May 2024This study aimed to investigate the potential anti-fibrotic activity of vinpocetine in an experimental model of pulmonary fibrosis by bleomycin and in the MRC-5 cell...
This study aimed to investigate the potential anti-fibrotic activity of vinpocetine in an experimental model of pulmonary fibrosis by bleomycin and in the MRC-5 cell line. Pulmonary fibrosis was induced in BALB/c mice by oropharyngeal aspiration of a single dose of bleomycin (5 mg/kg). The remaining induced animals received a daily dose of pirfenidone (as a standard anti-fibrotic drug) (300 mg/kg/PO) and vinpocetine (20 mg/kg/PO) on day 7 of the induction till the end of the experiment (day 21). The results of the experiment revealed that vinpocetine managed to alleviate the fibrotic endpoints by statistically improving (P ≤ 0.05) the weight index, histopathological score, reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. It also alleviated tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators significantly elevated in bleomycin-only induced animals (P ≤ 0.05). Vinpocetine managed to express a remarkable attenuating effect in pulmonary fibrosis both in vivo and in vitro either directly by interfering with the classical TGF-β1/Smad2/3 signaling pathway or indirectly by upregulating the expression of Nrf2 enhancing the antioxidant system, activating PPAR-γ and downregulating the NLRP3/NF-κB pathway making it a candidate for further clinical investigation in cases of pulmonary fibrosis.
Topics: Animals; Vinca Alkaloids; Pulmonary Fibrosis; Transforming Growth Factor beta1; PPAR gamma; Mice; NF-kappa B; Smad3 Protein; Smad2 Protein; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Mice, Inbred BALB C; Alveolar Epithelial Cells; Humans; Bleomycin; Disease Models, Animal; Male; Cell Line; Oxidative Stress
PubMed: 38750140
DOI: 10.1038/s41598-024-61269-y -
Basic & Clinical Pharmacology &... Jul 2024This study investigated the therapeutic benefits of para-hydroxycinnamic acid in mice with bleomycin-induced lung fibrosis. Forty male BALB/c mice were randomly assigned...
This study investigated the therapeutic benefits of para-hydroxycinnamic acid in mice with bleomycin-induced lung fibrosis. Forty male BALB/c mice were randomly assigned to four groups: normal, which received 0.9% normal saline; induced, which received a single dose of bleomycin (5 mg/kg) by oropharyngeal challenge; pirfenidone-treated; and para-hydroxycinnamic acid-treated, which challenged with bleomycin and received a daily oral dose of 300 and 50 mg/kg, respectively, from day 7 to day 21. Tissue pro-fibrotic and inflammatory cytokines, oxidative indicators, pulmonary histopathology, immunohistochemistry of fibrotic proteins and the assessment of gene expression by RT-qPCR were evaluated on day 22 after euthanizing animals. Pirfenidone and para-hydroxycinnamic acid managed to alleviate the fibrotic endpoints by statistically improving the weight index, histopathological score and reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. They also managed to alleviate tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators. para-Hydroxycinnamic acid enhanced the expression of crucial genes associated with oxidative stress, inflammation and fibrosis in vivo. para-Hydroxycinnamic acid has demonstrated similar effectiveness to pirfenidone, suggesting it could be a promising treatment for fibrotic lung conditions by inhibiting the TGF-β1/Smad3 pathway or through its anti-inflammatory and antioxidant properties.
Topics: Animals; Bleomycin; Pulmonary Fibrosis; Male; Oxidative Stress; Mice, Inbred BALB C; Mice; Coumaric Acids; Lung; Pyridones; Inflammation; Cytokines; Disease Models, Animal; Antioxidants; Transforming Growth Factor beta1
PubMed: 38745367
DOI: 10.1111/bcpt.14018