Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis DOI Creative Commons

Quan Wang,

Xinyue Liu,

Yuan Han

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 8(1), P. 256 - 269

Published: Dec. 28, 2024

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays vital role in (PF). However, the impact selective PDE10A inhibitors on tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited novel carbonyl sulfide (COS)/hydrogen (H2S)-donor hybrid inhibitor called COS-2080 with well-defined mechanism H2S-releasing action. It exhibited highly potent inhibitory activity excellent PDE subfamily selectivity. Moreover, demonstrated significant antifibrotic effects by inhibiting cell proliferation mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation COS-2080-DPI has been developed using ultrasonic spray freeze drying (USFD) technique, demonstrating efficacy mice bleomycin-induced PF at dosage approximately 600 times lower than pirfenidone. This remarkable TGF-β1-induced FMT could be primarily attributed to its inhibition Smad2/Smad3 phosphorylation. effectively attenuated MRC-5 cells activating cAMP/protein kinase (PKA)/CREB potentially increasing levels p53 protein. Our findings suggest confers protective effect impeding TGF-β cAMP/PKA/CREB/p53 axis.

Language: Английский

circGRHPR inhibits aberrant epithelial-mesenchymal transformation progression of lung epithelial cells associated with idiopathic pulmonary fibrosis DOI Creative Commons
Wensi Wu, Zhi Wang, Huiying Zhang

et al.

Cell Biology and Toxicology, Journal Year: 2024, Volume and Issue: 40(1)

Published: Jan. 25, 2024

Abstract Air pollution has greatly increased the risk of idiopathic pulmonary fibrosis (IPF). Circular RNAs (circRNAs) have been found to play a significant role in advancement IPF, but there is limited evidence correlation between circRNAs and lung epithelial cells (LECs) IPF. This research aimed explore influence on regulation EMT progression LECs, with objective elucidating its mechanism establishing association Our results suggested that downregulation circGRHPR peripheral blood clinical cases was associated diagnosis Meanwhile, we downregulated transforming growth factor-beta1 (TGF-β1)–induced A549 Beas-2b cells. It valid model study abnormal IPF-associated LECs vitro. The overexpression inhibited TGF-β1-induced LECs. Furthermore, as sponge miR-665, released expression E3 ubiquitin-protein ligase NEDD4-like (NEDD4L), thus promoting downstream factor beta receptor 2 (TGFBR2) ubiquitination. helpful reduce response TGF-β1 signaling. In summary, circGRHPR/miR-665/NEDD4L axis by TGFBR2 ubiquitination, which provides new ideas potential targets for treatment Graphical headlights 1. Downregulation 2. inhibits 3. ubiquitination

Language: Английский

Citations

5
Design and Synthesis of Novel Ultralong-Acting Peptides as EDP-EBP Interaction Inhibitors for Pulmonary Fibrosis Treatment DOI
Yixiang Wang,

Fanghan Xue,

Wei Cheng

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6624 - 6637

Published: April 8, 2024

The increased remodeling of the extracellular matrix (ECM) in pulmonary fibrosis (PF) generates bioactive ECM fragments called matricryptins, which include elastin-derived peptides (EDPs). interaction between EDPs and their receptors, including elastin-binding protein (EBP), plays a crucial role exacerbating fibrosis. Here, we present

Language: Английский

Citations

5
Novel therapeutic strategies and drugs for idiopathic pulmonary fibrosis DOI

Zezhou Shi,

Min Zhou, Jingfang Zhai

et al.

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(10)

Published: July 3, 2024

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease of unknown etiology. Currently, drugs used to treat IPF in clinical practice exhibit severe side effects and limitations. To address these issues, this paper discusses the therapeutic preclinical targeted (such as STAT3 TGF-β/Smad pathway inhibitors, chitinase PI3K phosphodiesterase etc.) natural products on IPF. Through summary current research progress, it found that possess multitarget effects, stable efficacy, low nondrug dependence. Furthermore, we discuss significant prospects product molecules combating by influencing immune system, expecting analytical data will aid development new or investigation active ingredients for potential treatments future.

Language: Английский

Citations

5
Investigation of the protective effect of cilostazol on acute lung injury-mediated inflammation and in silico molecular modelling studies of inflammatory signalling pathway: a repurposing study DOI

Pranaya L. Misar,

Kishor Otari

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Language: Английский

Citations

0
BI 1015550 Improves Silica-Induced Silicosis and LPS-Induced Acute Lung Injury in Mice DOI Creative Commons
Yuming Liu, Jing Zhang,

Yayue Hu

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(6), P. 1311 - 1311

Published: March 14, 2025

Silicosis is an interstitial lung disease (ILD) caused by prolonged inhalation of silica particles. Acute injury (ALI) a critical clinical syndrome involving bilateral infiltration and acute hypoxic respiratory failure. However, there currently no effective treatment for these two diseases. Previous research has established that cyclic adenosine monophosphate (cAMP) pivotal in the pathogenesis silicosis injury. Phosphodiesterase 4 (PDE4) hydrolase enzyme cAMP, BI 1015550, as inhibitor PDE4B, expected to be candidate drug treating both. 1015550 shown certain anti-inflammatory anti-fibrotic properties systemic sclerosis-associated (SSc-ILD) idiopathic pulmonary fibrosis (IPF), but lack on In this research, we successfully synthesized autonomously demonstrated it could significantly improve inflammation silica-induced mouse model. Furthermore, found also alleviate Lipopolysaccharide (LPS)-induced The mechanism action may involve regulation cAMP-related signaling pathways.

Language: Английский

Citations

0
Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease DOI Creative Commons

Yasuhiko Nishioka,

Jun Araya,

Yoshiya Tanaka

et al.

Inflammation and Regeneration, Journal Year: 2024, Volume and Issue: 44(1)

Published: July 19, 2024

Abstract Background Interstitial lung diseases (ILDs) are a diverse group of conditions characterized by inflammation and fibrosis in the lung. In some patients with ILD, progressive fibrotic phenotype develops, which is associated an irreversible decline function poor prognosis. Main body The pathological mechanisms that underlie this process culminate fibroblast activation, proliferation, differentiation into myofibroblasts, deposit extracellular matrix proteins result fibrosis. Upstream epithelial cell injury immune activation known initiators progression, multiple types involved. Recent years have seen increase our understanding complex interrelated processes drive progression part due to advent single-cell RNA sequencing technology integrative multiomics analyses. Novel been identified, represent new targets for drugs currently clinical development. These include phosphodiesterase 4 inhibitors other molecules act on intracellular cyclic adenosine monophosphate signaling, as well autotaxin-lysophosphatidic acid axis $$\alpha_v$$ α v integrins. Here, we review current knowledge recent developments regarding including potential therapeutic targets. Conclusion Knowledge ILD has expanded, role alveolar endothelial cells, system, fibroblasts better elucidated. Drugs target novel hold promise expanding future armamentarium ILD.

Language: Английский

Citations

2
Nerandomilast Improves Bleomycin-Induced Systemic Sclerosis-Associated Interstitial Lung Disease in Mice by Regulating the TGF-β1 Pathway DOI
Yuming Liu, Zhigang Liu, Xiaohe Li

et al.

Inflammation, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Language: Английский

Citations

2
Emerging opportunities to treat idiopathic pulmonary fibrosis: Design, discovery, and optimizations of small-molecule drugs targeting fibrogenic pathways DOI
Wenxin Luo, Yilin Gu,

Siyu Fu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 260, P. 115762 - 115762

Published: Aug. 25, 2023

Language: Английский

Citations

4
Insights into the selective mechanism of PDE2/9a inhibitors from silico aspects DOI
Pengfei Song, Shizun Wang,

Rongye Han

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 18

Published: March 25, 2024

The selective design of competitive enzyme inhibitors is an extremely difficult task but necessary work for certain types systems, such as the phosphodiesterase (PDE) system addressed in this article. In PDE family, PDE2A and PDE9 respectively target central nervous heart failure, share many conserved amino acids at their binding sites. Therefore, gaining a deep understanding mechanisms PDE2A/9A crucial designing highly drugs. study, various computer-aided drug (CADD) methods, including molecular docking, dynamics simulations (MD), free energy calculations, are employed to explore PDE2A/9A. Overall, our research results indicate strategy PDE2A, which involves incorporating hydrophobic or aromatic moieties into structure better accommodate pocket PDE2A. Additionally, it recommended introduce functional groups capable forming connections with residues, Phe830 Gln812 Ala452 Tyr424 PDE9A, enhance selectivity targeting This achievement anticipated pave way development innovative small molecules

Language: Английский

Citations

0
Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis DOI Creative Commons

Quan Wang,

Xinyue Liu,

Yuan Han

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 8(1), P. 256 - 269

Published: Dec. 28, 2024

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays vital role in (PF). However, the impact selective PDE10A inhibitors on tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited novel carbonyl sulfide (COS)/hydrogen (H2S)-donor hybrid inhibitor called COS-2080 with well-defined mechanism H2S-releasing action. It exhibited highly potent inhibitory activity excellent PDE subfamily selectivity. Moreover, demonstrated significant antifibrotic effects by inhibiting cell proliferation mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation COS-2080-DPI has been developed using ultrasonic spray freeze drying (USFD) technique, demonstrating efficacy mice bleomycin-induced PF at dosage approximately 600 times lower than pirfenidone. This remarkable TGF-β1-induced FMT could be primarily attributed to its inhibition Smad2/Smad3 phosphorylation. effectively attenuated MRC-5 cells activating cAMP/protein kinase (PKA)/CREB potentially increasing levels p53 protein. Our findings suggest confers protective effect impeding TGF-β cAMP/PKA/CREB/p53 axis.

Language: Английский

Citations

0