Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июль 31, 2023

Abstract Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical regarding cell activities and metabolism. Typical cues in organisms include hydrostatic pressure, fluid shear stress, tensile force, extracellular matrix stiffness or tissue elasticity, viscosity. Mechanotransduction has been expected trigger multiple such as embryonic development, repair regeneration. However, prolonged excessive stimulation can result pathological multi-organ fibrosis, tumorigenesis, cancer immunotherapy resistance. Although associations between normal homeostasis diseases have identified, regulatory mechanisms among different are not yet comprehensively illustrated, no effective therapies currently available targeting cue-related signaling. This review systematically summarizes characteristics typical conditions with updated evidence. The key effectors responding stimulations listed, Piezo channels, integrins, Yes-associated protein (YAP) /transcriptional coactivator PDZ-binding motif (TAZ), transient receptor potential vanilloid 4 (TRPV4). We also reviewed signaling pathways, therapeutic targets cutting-edge clinical applications related cues.

Язык: Английский

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Tangeretin attenuates bleomycin-induced pulmonary fibrosis by inhibiting epithelial-mesenchymal transition via the PI3K/Akt pathway

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Сен. 15, 2023

Background: Pulmonary fibrosis (PF) is a terminal pathological change in variety of lung diseases characterized by excessive deposition extracellular matrix, for which effective treatment lacking. Tangeretin (Tan), flavonoid derived from citrus, has been shown to have wide range pharmacological effects. This study aimed investigate the role and potential mechanisms Tan on pulmonary fibrosis. Methods: A model was established administering bleomycin through tracheal drip, followed or pirfenidone gavage. HE Masson staining were employed assess extent Subsequently, Western blot, enzyme-linked immunosorbent assay (ELISA), RNA sequencing, immunohistochemistry techniques uncover protective mechanism PF mice. Furthermore, A549 cells stimulated with TGF-β1 induce epithelial-mesenchymal transition (EMT) demonstrate effectiveness mitigating PF. Results: significantly ameliorated bleomycin-induced fibrosis, improved fibrotic changes, collagen lungs, reduced inflammation oxidative stress. The KEGG pathway enrichment analysis revealed higher number enriched genes PI3K/Akt pathway. Additionally, can inhibit EMT process related Conclusion: Taken together, above research results indicate that suppresses inflammation, stress, BLM-induced via agent

Язык: Английский

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Mesenchymal stem cells reversibly de-differentiate myofibroblasts to fibroblast-like cells by inhibiting the TGF-β-SMAD2/3 pathway

Molecular Medicine, Год журнала: 2023, Номер 29(1)

Опубликована: Апрель 25, 2023

Abstract Background Myofibroblasts (MFB), one of the major effectors pathologic fibrosis, mainly derived from activation fibroblast to myofibroblast transition (FMT). Although MFBs were historically considered terminally differentiated cells, their potential for de-differentiation was recently recognized and implied with therapeutic value in treating fibrotic diseases, instance, idiopathic pulmonary fibrosis (IPF) post allogeneic hematopoietic stem cell transplantation bronchiolitis obliterans (BO). During past decade, several methods reported block or reverse MFB differentiation, among which mesenchymal cells (MSC) have demonstrated but undetermined values. However, MSC-mediated regulation FMT underlying mechanisms remained largely undefined. Method By identifying TGF-β1 hypertension as pivotal landmark during pro-fibrotic FMT, TGF-β1-induced MSC co-culture models established utilized investigate regulations by on vitro. Methods including RNA sequencing (RNA-seq), Western blot, qPCR flow cytometry used. Result Our data revealed that readily induced invasive signatures identified tissues initiated differentiation normal FB. reversibly de-differentiated into a group FB-like selectively inhibiting TGF-β-SMAD2/3 signaling. Importantly, these proliferation-boosted sensitive could be re-induced MFB. Conclusion findings highlighted reversibility through signaling, may explain MSC's inconsistent clinical efficacies BO other diseases. These are still further deteriorate phenotypes unless microenvironment is corrected.

Язык: Английский

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Pathology of idiopathic pulmonary fibrosis with particular focus on vascular endothelium and epithelial injury and their therapeutic potential

Pharmacology & Therapeutics, Год журнала: 2024, Номер unknown, С. 108757 - 108757

Опубликована: Ноя. 1, 2024

Язык: Английский

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In situ tailored confining microenvironment for lung cancer spheroids

Materials Today Bio, Год журнала: 2025, Номер 31, С. 101602 - 101602

Опубликована: Фев. 20, 2025

The mechanical properties and physical confinement of the extracellular matrix (ECM) are crucial roles in regulating tumor growth progression. Extensive efforts have been dedicated to replicating characteristics tissue by developing two-dimensional (2D) three-dimensional (3D) vitro models. However, it remains a significant challenge modulate local microenvironment around specific cells according culture progress. In this study, we develop 3D platform for multicellular lung cancer spheroids using gelatin-based hydrogel with adjustable density stiffness. Then, utilizing two-photon mediated bioprinting technique, construct confining microstructures micrometer accuracy enclose selected within matrix. Diverse transcriptional profilings observed response increased ECM stiffness compared additional stress. addition, changed stress can regulate contrary impacts on cell cycle-related pathways. Our model not only allows modifications overall but also facilitates localized adjustments throughout evolution. This approach serves as valuable tool investigating progression understanding cell-ECM interactions.

Язык: Английский

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Is pulmonary fibrosis a precancerous disease?

European Journal of Radiology, Год журнала: 2023, Номер 160, С. 110723 - 110723

Опубликована: Фев. 2, 2023

Язык: Английский

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N‐Phenyl‐2‐Pyridone‐Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three‐Pronged Action

Angewandte Chemie International Edition, Год журнала: 2024, Номер unknown

Опубликована: Авг. 21, 2024

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone (P5), thus targeting multiple mechanisms for treating non-small cell lung cancer idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford with half-life of 8.3 hours without the generation other by-products, not only achieves good cytotoxicity toward cells decreases levels hypoxia-inducible factor 1α (HIF-1α) protein, but also inhibits transforming growth β1 (TGF-β1) induced fibrosis in vitro. vivo experiments demonstrated efficacy inhibiting tumor relieving fibrosis, while exhibiting biocompatibility. Many lines evidence reveal these two diseases, could downregulate HIF-1α relieve hypoxia is critical issue photodynamic therapy (PDT). Unlike combination therapies, agents are given independent formulations, our work demonstrates single molecule prodrugs be developed as new platforms treatment cancers related diseases.

Язык: Английский

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High-Fat Diet Related Lung Fibrosis-Epigenetic Regulation Matters

Biomolecules, Год журнала: 2023, Номер 13(3), С. 558 - 558

Опубликована: Март 18, 2023

Pulmonary fibrosis (PF) is an interstitial lung disease characterized by the destruction of pulmonary parenchyma caused excessive extracellular matrix deposition. Despite well-known etiological factors such as senescence, aberrant epithelial cell and fibroblast activation, chronic inflammation, PF has recently been recognized a metabolic abnormal lipid signature was observed both in serum bronchoalveolar lavage fluid (BALF) patients mice model. Clinically, observational studies suggest significant link between high-fat diet (HFD) manifested high intake saturated fatty acids (SFAs) meat increases risk fibrosis. However, possible mechanisms HFD remain unclear. In current review we emphasize diversity effects epigenetic dysregulation induced on fibrotic injury, activation inflammation. Finally, discuss potential ways for to improve their conditions prospect targeted therapy based regulation scientific researchers or drug developers.

Язык: Английский

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Biomimetic Human Lung Alveolar Interstitium Chip with Extended Longevity

ACS Applied Materials & Interfaces, Год журнала: 2023, Номер 15(30), С. 36888 - 36898

Опубликована: Июль 18, 2023

Determining the mechanistic causes of lung diseases, developing new treatments thereof, and assessing toxicity whether from chemical exposures or engineered nanomaterials would benefit significantly a preclinical human alveolar interstitium model physiological relevance. The existing models have limitations because they fail to replicate key anatomical characteristics alveoli. Thus, chip was developed imitate microenvironmental factors including an electrospun nanofibrous membrane as analogue basement for co-culture epithelial cells with fibroblasts embedded in 3D collagenous gels, physiologically relevant interstitial matrix stiffness, fluid flow, breathing-like mechanical stretch. biomimetic substantially improved barrier function compared transwell models. Moreover, having gel made collagen I-fibrin blend sustained integrity further enhanced barrier, resulting longevity that extended beyond eight weeks. assessment multiwalled carbon nanotube on line animal study.

Язык: Английский

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Retrospective study of 540 cats with respiratory diseases in Japan (2003–2020)

Veterinary Medicine and Science, Год журнала: 2024, Номер 10(3)

Опубликована: Апрель 23, 2024

Abstract Background Few epidemiological studies on respiratory medicine and the relationship between clinical signs various diseases in cats have been reported. Objectives This retrospective study aimed to investigate prevalence breed predisposition feline Japan determine association signs, duration type of diseases. Methods The medical records with were examined obtain information age, sex, breed, final diagnosis, duration. odds ratios (ORs) 95% confidence intervals calculated evaluate predispositions. Mann–Whitney U , Kruskal–Wallis Dunn's tests used assess signs. Results included 540 615 diagnoses. American Shorthair was predisposed bronchopneumonia (BP; OR: 5.0) pulmonary tumour (PT; 3.6), while Russian Blue exhibited a inflammatory lower airway (OR: 3.4), BP 6.1) interstitial lung 11.1). Similarly, Scottish Fold displayed PTs 5.8). among nasal diseases, nasopharyngeal tracheal/bronchial differed significantly ( p = 0.001, 0.012, < 0.0001, respectively). Conclusions results suggest that some popular breeds are especially Shorthair, breeds. characteristics occurrence, each disease will aid diagnosing, treating, preventing elucidating pathophysiology disease.

Язык: Английский

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