The aged extracellular matrix and the profibrotic role of senescence-associated secretory phenotype

AJP Cell Physiology, Год журнала: 2023, Номер 325(3), С. C565 - C579

Опубликована: Июль 24, 2023

Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal lung disease that primarily found in the elderly population, several studies have demonstrated aging major risk factor for IPF. IPF characterized by presence of apoptosis-resistant, senescent fibroblasts generate excessively stiff extracellular matrix (ECM). The ECM profoundly affects cellular functions tissue homeostasis, aberrant closely associated with development fibrosis. Aging progressively alters components accumulation cells promote age-related dysfunction through expression factors linked to a senescence-associated secretary phenotype (SASP). There growing evidence SASP affect various cell behaviors influence turnover autocrine and/or paracrine signaling mechanisms. Since life expectancy increasing worldwide, it important elucidate how dynamics via thereby promotes In this review, we will focus on molecular properties its regulatory Furthermore, pathophysiological process remodeling altered from aged lungs be highlighted. Finally, recent attempts target alteration modulate introduced.

Язык: Английский

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Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

Aging and Disease, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Cellular senescence is characterized by the permanent arrest of cell proliferation and a response to endogenous exogenous stress. The continuous accumulation senescent cells (SnCs) in body leads development aging age-related diseases (such as neurodegenerative diseases, cancer, metabolic cardiovascular osteoarthritis). In face growing challenge several compounds have received widespread attention for their potential target SnCs. As result, senolytics (compounds that selectively eliminate SnCs) senomorphics alter intercellular communication modulate behavior become hot research topics field anti-aging. addition, strategies such combination therapies immune-based approaches also made significant progress anti-aging therapy. this article, we discuss latest on targeting SnCs gain deeper understanding mechanism action impact different with aim providing more effective references therapeutic ideas clinical treatment ever-grave challenges diseases.

Язык: Английский

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Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities

Annals of Intensive Care, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 5, 2024

Abstract Whereas aging is a whole-organism process, senescence cell mechanism that can be triggered by several stimuli. There increasing evidence critical conditions activate programs irrespective of patient’s age. In this review, we briefly describe the basic pathways and consequences their activation in critically ill patients. The available suggests paradigm which beneficial short term rendering cells resistant to apoptosis, but also detrimental late phase inducing pro-inflammatory pro-fibrotic state. Senescence therapeutic target. use drugs eliminate senescent (senolytics) or senescence-associated phenotype (senomorphics) will require monitoring these responses identification windows improve outcome

Язык: Английский

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Senescence and tissue fibrosis: opportunities for therapeutic targeting

Trends in Molecular Medicine, Год журнала: 2024, Номер unknown

Опубликована: Июнь 1, 2024

Язык: Английский

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Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(1)

Опубликована: Янв. 1, 2025

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: first establishes a vulnerable bronchoalveolar epithelium, second triggers mechanisms reprogram distal epithelia to initiate perpetuate profibrotic phenotype. While vulnerability most often driven by common or rare variants, subsequent injury results in persistent changes cell biology disrupt tissue homeostasis activate fibroblasts. The dynamic can best be contextualized temporally, including stages vulnerability, early disease, progressive lung fibrosis. These dimensions highlight critical adversely epithelial function, fibroblasts, lead remodeling. Together better recognition conceptual approach should novel therapeutics directed at etiologic temporal drivers will ultimately transform care patients from palliative curative.

Язык: Английский

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Celastrol Pyrazine Derivative Alleviates Silicosis Progression via Inducing ROS-Mediated Apoptosis in Activated Fibroblasts

Molecules, Год журнала: 2024, Номер 29(2), С. 538 - 538

Опубликована: Янв. 22, 2024

Silicosis is a complex occupational disease without recognized effective treatment. Celastrol, natural product, has shown antioxidant, anti-inflammatory, and anti-fibrotic activities, but the narrow therapeutic window high toxicity severely limit its clinical application. Through structural optimization, we have identified highly efficient low-toxicity celastrol derivative, CEL-07. In this study, systematically investigated potential underlying mechanisms of CEL-07 in silicosis fibrosis. By constructing mouse model analyzing with HE, Masson, Sirius Red, immunohistochemical staining, significantly prevented progress inflammation fibrosis, it effectively improved lung respiratory function mice. Additionally, markedly suppressed expression inflammatory factors (IL-6, IL-1α, TNF-α, TNF-β) fibrotic (α-SMA, collagen I, III), promoted apoptosis fibroblasts by increasing ROS accumulation. Moreover, bioinformatics analysis combined experimental validation revealed that inhibited pathways associated (PI3K-AKT JAK2-STAT3) apoptosis-related proteins. Overall, these results suggest may serve as candidate for treatment silicosis.

Язык: Английский

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Current senolytics: Mode of action, efficacy and limitations, and their future

Mechanisms of Ageing and Development, Год журнала: 2023, Номер 217, С. 111888 - 111888

Опубликована: Ноя. 29, 2023

Senescence is a cellular state characterized by its near-permanent halted cell cycle and distinct secretory phenotype. Although senescent cells have variety of beneficial physiological functions, progressive accumulation these due to aging or other conditions has been widely shown provoke deleterious effects on the normal functioning same higher-level biological organizations. Recently, erasing in vivo, using senolytics, could ameliorate diseases identified with an elevated number cells. Since then, researchers struggled develop new senolytics each different selectivity potency. In this review, we gathered classified proposed discussed their mechanisms action. Moreover, highlight heterogeneity regarding effect sizes, type specificity as well comment exploited strategies improve features. Finally, suggest some prospective routes for novel methods ablation

Язык: Английский

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Inflammasome activation and metabolic remodelling in p16‐positive aging cells aggravates high‐fat diet‐induced lung fibrosis by inhibiting NEDD4L‐mediated K48‐polyubiquitin‐dependent degradation of SGK1

Clinical and Translational Medicine, Год журнала: 2023, Номер 13(6)

Опубликована: Июнь 1, 2023

Chronic changes caused by a high-fat diet (HFD) may be associated with weakened lung function in obese patients. However, few studies have focused on the role of senescent cells HFD-induced pulmonary fibrosis. This study aimed to determine whether (i) obesity causes accumulation aging lungs, (ii) p16 epithelial or fibroblasts exacerbates long-term senescence-associated fibrosis (SAPF) and (iii) deletion clearance ameliorates SAPF through inactivation inflammasome metabolic remodelling.Twelve-month old male mice p16INK4a (hereafter p16) knockout (p16-- ) wild-type (WT), ApoE (ApoE-- ApoE-- p16-- were fed HFD induce obesity, effects treatment senolytic drug ABT263 SGK1 specific inhibitor EMD638683 fibrosis, inflammaging, gene expression, integrin-inflammasome signalling metabolism examined. A549 IMR-90 transduced p16-overexpressing adenovirus, treated palmitic oleic acids (P&O) steatosis vitro.We found that promoted expression increase lung. P16 alleviated secretory phenotype (SASP) HFD-fed mice, as well P&O-treated cells. RNA sequencing bioinformatics analyses revealed inhibited activation pathway cellular glycolysis. Mass spectrometry, co-immunoprecipitation GST pull-down assays demonstrated bound N-terminal SGK1, thereby interfering interaction between E3 ubiquitin ligase NEDD4L subsequently inhibiting K48-polyubiquitin-dependent degradation mediated NEDD4L-Ubch5 complex. was alleviate pathway.P16 integrin- cell glycolysis binding N- terminal intefering K48- polyubiquitin- dependent could used potential drugs treat

Язык: Английский

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Procyanidin C1 inhibits bleomycin‐induced pulmonary fibrosis in mice by selective clearance of senescent myofibroblasts

The FASEB Journal, Год журнала: 2024, Номер 38(13)

Опубликована: Июнь 21, 2024

Abstract Pulmonary fibrosis is a formidable challenge in chronic and age‐related lung diseases. Myofibroblasts secrete large amounts of extracellular matrix induce pro‐repair responses during normal wound healing. Successful tissue repair results termination myofibroblast activity via apoptosis; however, some myofibroblasts exhibit senescent phenotype escape apoptosis, causing over‐repair that characterized by pathological fibrotic scarring. Therefore, the removal using senolytics an important method for treatment pulmonary fibrosis. Procyanidin C1 (PCC1) has recently been discovered as senolytic compound with very low toxicity few side effects. This study aimed to determine whether PCC1 could improve promoting apoptosis investigate mechanisms involved. The showed attenuates bleomycin (BLM)‐induced mice. In addition, we found inhibited deposition promoted increasing PUMA expression activating BAX signaling pathway. Our findings represent new management emphasize potential senotherapeutic agent fibrosis, providing hope patients worldwide. advance our understanding diseases highlight importance addressing cellular senescence treatment.

Язык: Английский

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Cordyceps sinensis ameliorates idiopathic pulmonary fibrosis in mice via inhibiting mitochondrion‐mediated oxidative stress

MedComm – Future Medicine, Год журнала: 2024, Номер 3(3)

Опубликована: Июль 19, 2024

Abstract Idiopathic pulmonary fibrosis (IPF) represents a chronic interstitial lung disease with an unclear underlying mechanism and currently lacks definitive treatment. Cordyceps sinensis (CS), renowned for its pharmacological properties in traditional Chinese medicine extensive use treatment, holds promise as therapeutic agent IPF. However, the specific role of CS treating IPF remains unclear. In this study, we aimed to assess efficacy unravel potential mechanisms. Our results demonstrate that treatment effectively mitigated inflammation collagen deposition bleomycin‐induced mice. Proteomics analysis revealed regulation mitochondrial oxidative phosphorylation may serve protective against Further investigation unveiled could suppress excessive production reactive oxygen species tissues induced by bleomycin through moderating expression activity complexes, thus safeguarding integrity function mitochondria. Overall, our findings not only underscore effectiveness preventing but also highlight mitochondrial‐mediated stress promising target

Язык: Английский

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