hAMSCs regulate EMT in the progression of experimental pulmonary fibrosis through delivering miR-181a-5p targeting TGFBR1

Stem Cell Research & Therapy, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 5, 2025

Pulmonary fibrosis (PF) is a common and multidimensional devastating interstitial lung disease. The development of novel more effective interventions for PF an urgent clinical need. A previous study has found that miR-181a-5p plays important role in the PF, human amniotic mesenchymal stem cells (hAMSCs) exert potent therapeutic potential on PF. However, whether hAMSCs act by delivering its detailed mechanism still remain unknown. Thus, this was designed to investigate underlying possible bleomycin (BLM)-induced mouse model, co-culture system A549 epithelial transition (EMT) focusing effects collagen deposition, EMT, cell cycle regulation. with different expression levels were constructed. BLM (4 mg/kg) used create while TGF-β1 induce construct EMT model. Furthermore, deposition during assessed vivo vitro. We exerted anti-fibrotic effect BLM-induced Moreover, also protective TGFβ1-induced ameliorated promoting proliferation, reducing apoptosis, attenuating through paracrine effects. regulated targeting TGFBR1. Our findings reveal first time inhibit EMT. Mechanistically, hMASCs achieved

Язык: Английский

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Single-cell RNA-seq reveals immune cell heterogeneity and increased Th17 cells in human fibrotic skin diseases

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 13, 2025

Background Fibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix components. The immune cells are postulated to exert pivotal role in the development fibrotic disease. Single-cell RNA sequencing has been used explore composition functionality present diseases. However, these studies detected gene expression all diseases did not enrich cells. Thus, precise cell atlas remains unknown. In this study, we plan investigate intricate cellular landscape keloid, paradigm Methods CD45 + were enriched fluorescence-activated sorting. was analyze keloid normal scar tissues. Ki-67 staining, scratch experiment, real-time PCR, Western blotting effect Th17 supernatant on fibroblasts. Results Our findings revealed We found that percentage significantly increased keloids compared scars. All subclusters macrophages dendritic (DCs) showed similar proportions between samples samples. upregulated genes M1 macrophages, M2 cDC2 associated with MHC class II protein complex assembly antigen assembly, indicating active keloids. Functional suggested could promote proliferation, collagen expression, migration fibroblasts through interleukin 17A. Importantly, also other diseases, such as hypertrophic scars scleroderma, suggesting broad mechanism for fibrosis. Conclusion summary, built single-cell study. addition, explored function cell-fibroblast interaction These will help understand pathogenesis depth identify potential targets treatment.

Язык: Английский

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Alveolar epithelial cell dysfunction and epithelial-mesenchymal transition in pulmonary fibrosis pathogenesis

Frontiers in Molecular Biosciences, Год журнала: 2025, Номер 12

Опубликована: Апрель 24, 2025

Pulmonary fibrosis (PF) is a progressive and lethal interstitial lung disease characterized by aberrant scar formation destruction of alveolar architecture. Dysfunctional epithelial cells (AECs) play central role in initiating PF, where chronic injury triggers apoptosis disrupts homeostasis, leading to epithelial-mesenchymal transition (EMT). This dynamic reprogramming process causes AECs shed markers adopt mesenchymal phenotype, fueling fibroblast activation pathological extracellular matrix (ECM) deposition. review systematically explores the multi-layered mechanisms driving dysfunction EMT, focusing on core signaling axes such as transforming growth factor-β (TGF-β)/Smad, WNT/β-catenin, NF-κB-BRD4, nuclear factor erythroid 2-related 2 (Nrf2), which regulate EMT fibroblast-ECM interactions. It also highlights emerging regulators, including metabolic reprogramming, exosomal miRNA trafficking, immune-epithelial Furthermore, understanding these essential for developing targeted therapeutic strategies modulate pathways halt or reverse progression, offering critical insights into potential clinical treatments PF.

Язык: Английский

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Development of a Novel Biomarker for the Progression of Idiopathic Pulmonary Fibrosis

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(1), С. 599 - 599

Опубликована: Янв. 2, 2024

The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified validated a new biomarker for IPF progression. To identify candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced compared early controls three lung sample cohorts. Candidate expression was confirmed using immunohistochemistry Western blotting tissue samples from an independent clinical cohort. Biomarker potential enzyme-linked immunosorbent assay serum the retrospective validation verified that final reflected prospective In RNA-seq comparative analysis tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, NUPR1 were up-regulated, ADAMTS8 down-regulated IPF. Only CTSB showed significant differences based on (n = 12; p < 0.001) between groups cohort 78), levels higher progressive group 25) than control 29, mean 7.37 ng/mL vs. 2.70 ng/mL, nonprogressive 24, 2.56 0.001). 129), (mean 8.30 3.00 After adjusting baseline FVC, found independently associated (adjusted OR 2.61, Serum significantly predicted (AUC 0.944, level distinguished non-progression or healthy control.

Язык: Английский

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Adenosine receptor signalling as a driver of pulmonary fibrosis

Pharmacology & Therapeutics, Год журнала: 2023, Номер 249, С. 108504 - 108504

Опубликована: Июль 22, 2023

Pulmonary fibrosis is a debilitating and life-limiting lung condition in which the damage- response mechanisms of mixed-population cells within lungs go awry. The tissue microenvironment drastically remodelled by aberrantly activated fibroblasts deposit ECM components into surrounding tissue, detrimentally affecting function capacity for gas exchange. Growing evidence suggests role adenosine signalling pathology variety organs, including lung, but molecular pathways through this occurs remain largely unknown. This review explores evaluates contribution different receptors to fibrogenesis. Therapeutic targeting also considered, along with clinical observations pointing towards fibrosis. In addition, interaction between other profibrotic pathways, such as TGFβ1 signalling, discussed.

Язык: Английский

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MiR-148a-3p within HucMSC-Derived Extracellular Vesicles Suppresses Hsp90b1 to Prevent Fibroblast Collagen Synthesis and Secretion in Silica-Induced Pulmonary Fibrosis

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(19), С. 14477 - 14477

Опубликована: Сен. 23, 2023

Silicosis is a fatal occupational respiratory disease caused by the prolonged inhalation of respirable silica. The core event silicosis heightened activity fibroblasts, which excessively synthesize extracellular matrix (ECM) proteins. Our previous studies have highlighted that human umbilical cord mesenchymal stem cell-derived vesicles (hucMSC-EVs) hold promise in mitigating and significant role played microRNAs (miRNAs) this process. Delving deeper into mechanism, we found miR-148a-3p was most abundant miRNA differential miRNAs hucMSC-EVs, with gene heat shock protein 90 beta family member 1 (Hsp90b1) as potential target. Notably, miR-148a-3p’s expression downregulated during progression silica-induced pulmonary fibrosis both vitro vivo, but restored after hucMSC-EVs treatment (p < 0.05). Introducing mimics effectively hindered collagen synthesis secretion fibroblasts induced transforming growth factor-β1 (TGF-β1) Confirming our hypothesis, Hsp90b1 indeed targeted miR-148a-3p, significantly reduced TGF-β1-treated upon inhibition Collectively, findings provide compelling evidence links present amelioration silicosis, suggesting its therapeutic specifically targeting Hsp90b1, thereby inhibiting fibroblast activities. This study sheds light on opening avenues for innovative interventions molecular pathways fibrosis.

Язык: Английский

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Daphnetin Alleviates Bleomycin-Induced Pulmonary Fibrosis through Inhibition of Epithelial-to-Mesenchymal Transition and IL-17A

Cells, Год журнала: 2023, Номер 12(24), С. 2795 - 2795

Опубликована: Дек. 8, 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there no cure for IPF, the development of drugs with improved efficacy in treatment IPF required. Daphnetin, natural coumarin derivative, has immunosuppressive, anti-inflammatory, antioxidant activities. However, its antifibrotic effects have not yet been elucidated. In this study, we investigated daphnetin on associated molecular mechanism. We examined splenocytes cultured Th17 conditions, epithelial cells, mouse model bleomycin (BLM)-induced fibrosis. identified that inhibited IL-17A production developing cells. also found suppressed epithelial-to-mesenchymal transition (EMT) TGF-β-treated BEAS2B cells through regulation AKT phosphorylation. BLM-treated mice, oral administration attenuated histopathology mechanical functions. Our findings clearly demonstrated EMT both vitro vivo, thereby protecting against BLM-induced Taken together, these results suggest potent therapeutic by modulating differentiation TGF-β signaling pathway, thus expect to be drug candidate IPF.

Язык: Английский

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Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases

Medicina, Год журнала: 2023, Номер 59(9), С. 1552 - 1552

Опубликована: Авг. 26, 2023

New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme regulates dephosphorylation serine threonine residues from many proteins, is observed in multiple diseases, including lung cancer, smoke-induced chronic obstructive disease, alpha-1 antitrypsin deficiency, asthma, idiopathic fibrosis. Loss PP2A responses linked mechanisms associated with progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, mRNA stability. Therefore, chemical restoration may represent treatment these This review outlines the potential impact endogenous exogenous inhibitors PP2A, details possible PP2A-dependent conditions, treatment. Substantial efforts underway therapeutics targeting activity. The development specific activators selectively target holoenzymes could improve our understanding function lead restoring normal within lung.

Язык: Английский

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Protective effects of methylprednisolone–cyclophosphamide treatment on bleomycin-induced pulmonary fibrosis

Cytokine, Год журнала: 2023, Номер 166, С. 156188 - 156188

Опубликована: Апрель 21, 2023

Methylprednisolone (MP) and cyclophosphamide (CTX) combination treatment has shown great benefits in improving pulmonary fibrosis (PF) high safety. Currently, the mechanism underlying effects of MP-CTX on PF remains unclear. This study determined modulation inflammation, oxidative stress, T-cell immunity PF.PF rat models were induced by bleomycin stimulation. MP (3 mg/kg) (MP: 3 mg/kg; CTX: 8 administered + CTX groups, respectively. Transmission electron microscopy, hematoxylin eosin staining, Ashcroft score, Masson trichrome staining performed to measure lung morphology PF. Enzyme-linked immunosorbent assay quantitative polymerase chain reaction quantify inflammatory factors. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) levels using commercial kits. α-Smooth muscle actin (SMA) collagen I western blotting immunohistochemistry. The count was evaluated flow cytometry.MP-CTX reduced injury, deposition, α-SMA a bleomycin-induced model. Additionally, decreased MDA factors (tumor necrosis factor-α, interleukin-1β, interleukin-6) but increased activities SOD GSH-PX. Furthermore, changed types tissues, such as increasing CD4+CD25+Foxp3+ cell count.MP-CTX improved degree reducing inflammation stress immunity. These findings provide novel insights into mechanisms

Язык: Английский

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Advances in understanding the role of interleukins in pulmonary fibrosis (Review)

Experimental and Therapeutic Medicine, Год журнала: 2024, Номер 29(2)

Опубликована: Ноя. 28, 2024

Pulmonary fibrosis (PF) is a progressive, irreversible disease characterized by heterogeneous interstitial lung tissue damage. It originates from persistent or repeated epithelial injury and leads to the activation differentiation of fibroblasts into myofibroblasts. Interleukins (ILs) are group lymphokines crucial for immunomodulation that implicated in pathogenesis PF. However, different types ILs exert disparate effects on In present review, based effect PF, classified three categories: i) Promotors PF; ii) inhibitors iii) those dual Several can promote PF provoking inflammation, initiating proliferation transdifferentiation cells, exacerbating injury, while other inhibit through suppressing expression inflammatory factors, modulating Th1/Th2 balance autophagy. The review summarizes association focusing roles mechanisms underlying

Язык: Английский

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