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GeroScience Apr 2024As we age, the ability to regenerate and repair skeletal muscle damage declines, partially due to increasing dysfunction of muscle resident stem cells-satellite cells...
As we age, the ability to regenerate and repair skeletal muscle damage declines, partially due to increasing dysfunction of muscle resident stem cells-satellite cells (SC). Recent evidence implicates cellular senescence, which is the irreversible arrest of proliferation, as a potentiator of SC impairment during aging. However, little is known about the role of senescence in SC, and there is a large discrepancy in senescence classification within skeletal muscle. The purpose of this study was to develop a model of senescence in skeletal muscle myoblasts and identify how common senescence-associated biomarkers respond. Low-passage CC myoblasts were treated with bleomycin or vehicle and then evaluated for cytological and molecular senescence markers, proliferation status, cell cycle kinetics, and differentiation potential. Bleomycin treatment caused double-stranded DNA breaks, which upregulated p21 mRNA and protein, potentially through NF-κB and senescence-associated super enhancer (SASE) signaling (p < 0.01). Consequently, cell proliferation was abruptly halted due to G2/M-phase arrest (p < 0.01). Bleomycin-treated myoblasts displayed greater senescence-associated β-galactosidase staining (p < 0.01), which increased over several days. These myoblasts remained senescent following 6 days of differentiation and had significant impairments in myotube formation (p < 0.01). Furthermore, our results show that senescence can be maintained despite the lack of p16 gene expression in CC myoblasts. In conclusion, bleomycin treatment provides a valid model of damage-induced senescence that was associated with elevated p21, reduced myoblast proliferation, and aberrant cell cycle kinetics, while confirming that a multi-marker approach is needed for the accurate classification of senescence within skeletal muscle.
Topics: Bleomycin; Cell Line; Cellular Senescence; Cell Differentiation; Myoblasts; Biomarkers
PubMed: 37751045
DOI: 10.1007/s11357-023-00929-9 -
Dermatology Online Journal Dec 2013A 21-year-old woman presented with a pruritic eruption on her trunk and extremities after receiving bleomycin for treatment of stage III ovarian germ-cell tumor....
A 21-year-old woman presented with a pruritic eruption on her trunk and extremities after receiving bleomycin for treatment of stage III ovarian germ-cell tumor. Physical examination was consistent with bleomycin-induced flagellate erythema. We discuss the pathophysiologic mechanism that produces this dermatitis.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Drug Eruptions; Erythema; Etoposide; Female; Humans; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Young Adult
PubMed: 24365007
DOI: No ID Found -
Advanced Drug Delivery Reviews Jan 2024Pulmonary fibrosis (PF) is a progressive, and life-threatening interstitial lung disease which causes scarring in the lung parenchyma and thereby affects architecture... (Review)
Review
Pulmonary fibrosis (PF) is a progressive, and life-threatening interstitial lung disease which causes scarring in the lung parenchyma and thereby affects architecture and functioning of lung. It is an irreversible damage to lung functioning which is related to epithelial cell injury, immense accumulation of immune cells and inflammatory cytokines, and irregular recruitment of extracellular matrix. The inflammatory cytokines trigger the differentiation of fibroblasts into activated fibroblasts, also known as myofibroblasts, which further increase the production and deposition of collagen at the injury sites in the lung. Despite the significant morbidity and mortality associated with PF, there is no available treatment that efficiently and effectively treats the disease by reversing their underlying pathologies. In recent years, many therapeutic regimens, for instance, rho kinase inhibitors, Smad signaling pathway inhibitors, p38, BCL-xL/ BCL-2 and JNK pathway inhibitors, have been found to be potent and effective in treating PF, in preclinical stages. However, due to non-selectivity and non-specificity, the therapeutic molecules also result in toxicity mediated severe side effects. Hence, this review demonstrates recent advances on PF pathology, mechanism and targets related to PF, development of various drug delivery systems based on small molecules, RNAs, oligonucleotides, peptides, antibodies, exosomes, and stem cells for the treatment of PF and the progress of various therapeutic treatments in clinical trials to advance PF treatment.
Topics: Humans; Pulmonary Fibrosis; Bleomycin; Fibrosis; Lung; Cytokines
PubMed: 38065244
DOI: 10.1016/j.addr.2023.115147 -
Stem Cells Translational Medicine May 2016This authors’ reply to a letter to the editor addresses whether young rodents are appropriate animal models for advanced-age human disease.
This authors’ reply to a letter to the editor addresses whether young rodents are appropriate animal models for advanced-age human disease.
Topics: Animals; Bleomycin; Disease Models, Animal; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pulmonary Fibrosis
PubMed: 27091589
DOI: 10.5966/sctm.2015-0406 -
Scientific Reports Sep 2023Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF,...
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF, their median survival is approximately 3-5 years. PPARγ is an important target for the prevention and treatment of pulmonary fibrosis. Asarinin is a lignan compound that can be extracted from food plant Asarum heterotropoides. In this study, we investigated the therapeutic effects of asarinin in a pulmonary fibrosis model constructed using bleomycin in mice and explored the underlying mechanisms. Intraperitoneal administration of asarinin to mice with pulmonary fibrosis showed that asarinin effectively attenuated pulmonary fibrosis, and this effect was significantly inhibited by the PPARγ inhibitor GW9662. Asarinin inhibited TGF-β1-induced fibroblast-to-myofibroblast transition in vitro, while GW9662 and PPARγ gene silencing significantly inhibited this effect. In addition, asarinin inhibited not only the canonical Smad pathway of TGF-β but also the non-canonical AKT and MAPK pathways by activating PPARγ. Our study demonstrates that asarinin can be used as a therapeutic agent for pulmonary fibrosis, and that PPARγ is its key target.
Topics: Animals; Mice; PPAR gamma; Lignans; Idiopathic Pulmonary Fibrosis; Bleomycin
PubMed: 37679587
DOI: 10.1038/s41598-023-41933-5 -
American Journal of Respiratory Cell... Jul 2023VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T...
VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is upregulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated after VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of patients with IPF. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA upregulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limits the fibrotic innate immune landscape and consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment.
Topics: Humans; Mice; Animals; Idiopathic Pulmonary Fibrosis; Lung; Fibrosis; Bleomycin; Inflammation; Fibroblasts
PubMed: 36450109
DOI: 10.1165/rcmb.2022-0219OC -
Disease Models & Mechanisms Jan 2022Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic...
Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the bleomycin mouse model of IPF, we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids and lipids and extracellular matrix turnover. Energy production was upregulated, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, lactate production and fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Because the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the bleomycin-induced pulmonary fibrosis model. Surprisingly, except for cytidine, we did not detect any significantly differential metabolites or lipids between old and young bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation, which might serve to improve diagnostic and therapeutic options for fibrotic lung diseases in the future.
Topics: Animals; Bleomycin; Fibrosis; Idiopathic Pulmonary Fibrosis; Lipidomics; Lung; Mice; Mice, Inbred C57BL
PubMed: 34845494
DOI: 10.1242/dmm.049105 -
American Journal of Respiratory Cell... May 2022
Topics: Bleomycin; Humans; Myofibroblasts; Pulmonary Fibrosis; p38 Mitogen-Activated Protein Kinases
PubMed: 35238730
DOI: 10.1165/rcmb.2022-0026ED -
Stem Cell Research & Therapy Sep 2023Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease characterized by pulmonary fibrosis and lung dysfunction, ultimately leading...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease characterized by pulmonary fibrosis and lung dysfunction, ultimately leading to respiratory failure. Many preclinical studies have investigated the therapeutic potential of stem cell-derived exosomes in this disease, particularly mesenchymal stem cell-derived exosomes. However, the effects of embryonic stem cell-derived exosomes in IPF remain unclear.
METHODS
We established a bleomycin (BLM)-induced pulmonary fibrosis mice model and administered human embryonic stem cell exosomes (hESC-exo) from the first day after BLM treatment. The effects of hESC-exo were assessed by pulmonary function tests, biochemical analysis, histochemistry, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). RNA-seq was used to screen for the potential therapeutic targets of hESC-exo in fibrotic lungs; the identified signaling axis was characterized using a luciferase assay, qPCR, and WB.
RESULTS
Results indicated hESC-exo administration notably alleviated inflammation, removed deposited collagen, and rescued alveolar architecture in the lungs of BLM-induced mice. In vivo and in vitro tests revealed that hESC-exo-derived miR-17-5p directly bound thrombospondin-2 (Thbs2) to regulate inflammation and fibrosis; thus, hESC-exo protected against BLM toxicity in the lungs via the miR-17-5p/Thbs2 axis.
CONCLUSION
These results suggest a promising new treatment for fibrosis-associated diseases.
Topics: Humans; Animals; Mice; Human Embryonic Stem Cells; Thrombospondins; MicroRNAs; Idiopathic Pulmonary Fibrosis; Inflammation; Bleomycin
PubMed: 37667335
DOI: 10.1186/s13287-023-03449-7 -
Brain Research Bulletin Jun 2023Depression and anxiety are prevalent in patients with idiopathic pulmonary fibrosis (IPF). Recent researchers reveal that intermittent hypoxia (IH) increases the...
Depression and anxiety are prevalent in patients with idiopathic pulmonary fibrosis (IPF). Recent researchers reveal that intermittent hypoxia (IH) increases the severity of bleomycin (BLM)-induced lung injury. However, experimental studies dealing with anxiety- and depression-like behavior in animal models of BLM-induced pulmonary fibrosis in a combination of IH are lacking, hence, this study aimed to investigate that. In this study, 80 C57BL/6J male mice were intratracheally injected with BLM or normal saline at day0 and then exposed to IH (alternating cycles of FiO 21 % for 60 s and FiO 10 % for 30 s, 40 cycles/hour, 8 h/day) or intermittent air (IA) for 21 days. Behavioral tests, including open field test (OFT), sucrose preference test (SPT) and tail suspension test (TST), were detected from day22 to day26. This study found that pulmonary fibrosis developed and lung inflammation were activated in BLM-induced mice, which were potentiated by IH. Significant less time in center and less frequency of entries in the centre arena in OFT were observed in BLM treated mice, and IH exposure further decreased that. Marked decreased percent of sucrose preference in SPT, and significant increased immobility time of the TST were detected in BLM treated mice and IH widen the gaps. The expression of ionized calcium-binding adaptor molecule (Iba1) was activated in the hippocampus of BLM instillation mice and IH enlarged it. Moreover, a positive correlation between hippocampal microglia activation and inflammatory factors was observed. Our results demonstrated that IH exacerbated depressive and anxiety-like behaviors in the BLM-induced pulmonary fibrosis mice. The changes in pulmonary inflammation-hippocampal microglia activation may be a potential mechanism in this phenomenon, which can be researched in future.
Topics: Male; Animals; Mice; Pulmonary Fibrosis; Bleomycin; Mice, Inbred C57BL; Hypoxia; Anxiety; Disease Models, Animal
PubMed: 37094614
DOI: 10.1016/j.brainresbull.2023.04.008