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Acta Histochemica Dec 2023Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no...
OBJECTIVE
Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no definitive treatment options. In recent years, scientists have gradually paid attention to the influence of angiogenesis on IPF. Because IPF is a progressive with microvascular remodeling disorder, scientists have postulated that angiogenesis may also be one of the initiating and contributing factors of the disease. Bupleurum is a common natural Chinese herbal medicine with antibacterial, anti-inflammatory, anti-tumor and other pharmacological effects. As the most important active monomer of Bupleurum, Saikosaponin-d (SSd) is a new discovery with anti-pulmonary fibrosis (PF) activity. This study attempts to investigate the role of SSd in the interference of PF through regulation of angiogenesis in IPF through Angiopoietin (Angpt) /Tie receptor 2 (Tie2) pathway.
METHODS
Randomly, we allocated C57BL/6 mice into four groups (n = 20 in each group). Afterwards, establishment of IPF model was accomplished via intratracheal administration of bleomycin (BLM, 5 mg/kg), while corresponding drug intervention was given accordingly. On 3rd, 7th, 14th and 28th days after modeling, we performed histopathological examination through staining. Meanwhile, immunohistochemistry (IHC) of PF and the expression of related factors were observed, while Ang/Tie2 pathway was assessed by ELISA with the effect of SSd on angiogenesis related proteins in IPF being explored with IHC and Western Blot technique.
RESULTS
Our results showed that SSd could reduce inflammation and PF levels in lung tissue of experimental mice, while levels of angiogenesis-related factors, namely Tie-2, Ang-1 and ANGPT2 (Ang-2), fibrosis- associated factors like Alpha-smooth muscle actin (α-SMA), collagen-I and hydroxyproline in SSd and dexamethasone (DXM) mice were significantly reduced at each time point compared to BLM (p < 0.01). Additionally, we discovered substantial decreased expressions of Ang-1, Ang-2, Tie-2, α-SMA and collagen-I at protein level in SSd and DXM mice at each time point compared to BLM (p < 0.05). Besides, insignificant differences were observed between SSd and DXM groups (p > 0.05).
CONCLUSION
This study has demonstrated that SSd could down-regulate the expression of ANG-1, Ang-2 and Tie2 in the Ang/Tie2 pathway, and may reduce lung inflammation and PF in BLM-induced mice via inhibition of angiogenesis.
Topics: Mice; Animals; Angiopoietins; Mice, Inbred C57BL; Lung; Idiopathic Pulmonary Fibrosis; Collagen Type I; Bleomycin
PubMed: 37837833
DOI: 10.1016/j.acthis.2023.152100 -
Applied and Environmental Microbiology Jan 2022Bleomycin (BLM) is a widely used chemotherapeutic drug. BLM-treated cells showed an elevated rate of mutations, but the underlying mechanisms remained unclear. In this...
Bleomycin (BLM) is a widely used chemotherapeutic drug. BLM-treated cells showed an elevated rate of mutations, but the underlying mechanisms remained unclear. In this study, the global genomic alterations in BLM-treated cells were explored in the yeast Saccharomyces cerevisiae. Using genetic assay and whole-genome sequencing, we found that the mutation rate could be greatly elevated in S. cerevisiae cells that underwent Zeocin (a BLM member) treatment. One-base deletion and T-to-G substitution at the 5'-GT-3' motif represented the most striking signature of Zeocin-induced mutations. This was mainly the result of translesion DNA synthesis involving Rev1 and polymerase ζ. Zeocin treatment led to the frequent loss of heterozygosity and chromosomal rearrangements in the diploid strains. The breakpoints of recombination events were significantly associated with certain chromosomal elements. Lastly, we identified multiple genomic alterations that contributed to BLM resistance in the Zeocin-treated mutants. Overall, this study provides new insights into the genotoxicity and evolutional effects of BLM. Bleomycin is an antitumor antibiotic that can mutate genomic DNA. Using yeast models in combination with genome sequencing, the mutational signatures of Zeocin (a member of the bleomycin family) are disclosed. Translesion-synthesis polymerases are crucial for the viability of Zeocin-treated yeast cells at the sacrifice of a higher mutation rate. We also confirmed that multiple genomic alterations were associated with the improved resistance to Zeocin, providing novel insights into how bleomycin resistance is developed in cells.
Topics: Bleomycin; Cell Division; Genomics; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 34731050
DOI: 10.1128/AEM.01703-21 -
Ugeskrift For Laeger Aug 2015Cutaneous metastases occur in up to 9% of all patients with cancer and may cause discomfort and stigmatization. Electrochemotherapy is a local treatment using electric... (Review)
Review
Cutaneous metastases occur in up to 9% of all patients with cancer and may cause discomfort and stigmatization. Electrochemotherapy is a local treatment using electric pulses to permeabilize cell membranes, enabling chemotherapy, such as bleomycin, to enter the cells and increase the cytotoxic effect by at least 300-fold. Electrochemotherapy is an efficient, once only treatment for cutaneous metastases with an objective response of 62-99%. Electrochemotherapy can reduce discomfort such as ulceration, oozing, bleeding and pain. Adverse events depend on the size of treatment area, but are very limited.
Topics: Antibiotics, Antineoplastic; Bleomycin; Electrochemotherapy; Humans; Neoplasm Metastasis; Skin Neoplasms
PubMed: 26321586
DOI: No ID Found -
Indian Pediatrics Feb 2015
Topics: Antibiotics, Antineoplastic; Bleomycin; Child, Preschool; Humans; Injections, Intralesional; Lymphangioma; Male; Tongue
PubMed: 25691206
DOI: 10.1007/s13312-015-0602-5 -
Molecules (Basel, Switzerland) Jun 2016Pingyangmycin is an anticancer drug known as bleomycin A5 (A5), discovered in the Pingyang County of Zhejiang Province of China. Bleomycin (BLM) is a mixture of mainly...
Pingyangmycin is an anticancer drug known as bleomycin A5 (A5), discovered in the Pingyang County of Zhejiang Province of China. Bleomycin (BLM) is a mixture of mainly two compounds (A2 and B2), which is on the World Health Organization's list of essential medicines. Both BLM and A5 are hydrophilic molecules that depend on transporters or endocytosis receptors to get inside of cells. Once inside, the anticancer activities rely on their abilities to produce DNA breaks, thus leading to cell death. Interestingly, the half maximal inhibitory concentration (IC50) of BLMs in different cancer cell lines varies from nM to μM ranges. Different cellular uptake, DNA repair rate, and/or increased drug detoxification might be some of the reasons; however, the molecules and signaling pathways responsible for these processes are largely unknown. In the current study, we purified the A2 and B2 from the BLM and tested the cytotoxicities and the molecular mechanisms of each individual compound or in combination with six different cell lines, including a Chinese hamster ovary (CHO) cell line defective in glycosaminoglycan biosynthesis. Our data suggested that glycosaminoglycans might be involved in the cellular uptake of BLMs. Moreover, both BLM and A5 shared similar signaling pathways and are involved in cell cycle and apoptosis in different cancer cell lines.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Apoptosis Regulatory Proteins; Bleomycin; CHO Cells; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Chromatography, High Pressure Liquid; Cricetulus; ErbB Receptors; Gene Expression; Humans; Inhibitory Concentration 50; Molecular Structure; Phosphorylation; Signal Transduction; Spectrometry, Mass, Electrospray Ionization
PubMed: 27376254
DOI: 10.3390/molecules21070862 -
Journal of B.U.ON. : Official Journal... 2020To investigate the influence of bleomycin (BLM) on the proliferation and apoptosis of brain glioma cells through transforming growth factor-β (TGF-β)/Smads signaling...
PURPOSE
To investigate the influence of bleomycin (BLM) on the proliferation and apoptosis of brain glioma cells through transforming growth factor-β (TGF-β)/Smads signaling pathway.
METHODS
The U87 brain glioma cells were cultured in vitro and reacted with different concentrations of BLM (5 and 10 mU/mL), and the cell growth status of each group was observed under a microscope. The cell proliferation activity was detected using Cell Counting Kit-8 (CCK-8) assay, the percentage of 5-Ethynyl-2'-deoxyuridine (EdU)-positive cells in each group was determined via EdU staining, and the apoptosis of U87 cells was tested by means of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to measure the messenger ribonucleic acid (mRNA) levels of genes related to proliferation, apoptosis and the TGF-β/Smads signaling pathway. Finally, western blotting assay was performed to analyze the expression of the TGF-β/Smads signaling pathway.
RESULTS
In the 5 mU/mL BLM group, the glioma cells were in a poor growth status, with a low density, while the 10 mU/mL BLM group exhibited the poorest growth status and the lowest density, and the morphological structure trended toward normal. It was discovered via CCK-8 assay and EdU staining that the number of cells and proliferation activity were decreased markedly in the 10 mU/mL BLM group. According to TUNEL staining, 10 mU/mL BLM group had remarkably increased apoptotic cells, while negative control (NC) group had fewer apoptotic cells. The gene assay results revealed that the gene expressions of Bcl-2 and TGF-β1 declined notably in the 10 mU/mL BLM group but rose in the NC group, and the gene expression trends of Caspase-3 and Smad4 were the opposite. The protein assay results manifested that the expressions of TGF-β1 was obviously reduced, while that of Smad4 was evidently raised in the 10 mU/mL BLM group.
CONCLUSION
BLM at an appropriate concentration can inhibit the proliferation and promote apoptosis of brain glioma cells by repressing the TGF-β/Smads signaling pathway, thus ameliorating and treating brain glioma and other related diseases.
Topics: Antibiotics, Antineoplastic; Apoptosis; Bleomycin; Cell Proliferation; Glioma; Humans; Signal Transduction; Transforming Growth Factor beta1
PubMed: 32521909
DOI: No ID Found -
Cells Dec 2022DNA damage is the major cause of senescence and apoptosis; however, the manner by which DNA-damaged cells become senescent remains unclear. We demonstrate that DNA...
DNA damage is the major cause of senescence and apoptosis; however, the manner by which DNA-damaged cells become senescent remains unclear. We demonstrate that DNA damage leads to a greater level of senescence rather than apoptosis in DBC1-deficient cells. In addition, we show that BLM becomes degraded during DNA damage, which induces p21 expression and senescence. DBC1 binds to and shields BLM from degradation, thus suppressing senescence. ML216 promotes DBC1-BLM interaction, which aids in the preservation of BLM following DNA damage and suppresses senescence. ML216 enhances pulmonary function by lowering the levels of senescence and fibrosis in both aged mice and a mouse model of bleomycin-induced idiopathic pulmonary fibrosis. Our data reveal a unique mechanism preventing DNA-damaged cells from becoming senescent, which may be regulated by the use of ML216 as a potential treatment for senescence-related diseases.
Topics: Animals; Mice; Bleomycin; DNA; DNA Damage; DNA Helicases; Idiopathic Pulmonary Fibrosis; Lung
PubMed: 36611939
DOI: 10.3390/cells12010145 -
British Journal of Cancer Oct 2018Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity,... (Review)
Review
Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity, long-term complications and even death in extreme cases. There is a lack of evidence or consensus on how to prevent and monitor bleomycin toxicity. We surveyed 63 germ cell cancer physicians from 32 cancer centres across the UK to understand their approach to using bleomycin. Subsequent guideline development was based upon current practice, best available published evidence and expert consensus. We observed heterogeneity in practice in the following areas: monitoring; route of administration; contraindications to use; baseline and follow-up investigations performed, and advice given to patients. A best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours has been developed and includes recommendations regarding baseline investigations, the use of pulmonary function tests, route of administration, monitoring and patient advice. It is likely that existing heterogeneity in clinical practice of bleomycin prescribing has significant economic, safety and patient experience implications. The development of an evidence-based consensus guideline was supported by 93% of survey participants and aims to address these issues and homogenise practice across the UK.
Topics: Antibiotics, Antineoplastic; Bleomycin; Clinical Trials as Topic; Consensus; Evidence-Based Medicine; Humans; Male; Neoplasms, Germ Cell and Embryonal; Respiratory Function Tests; Testicular Neoplasms; United Kingdom
PubMed: 30356125
DOI: 10.1038/s41416-018-0300-x -
International Journal of Molecular... Feb 2023Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the...
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the two FDA-approved drugs for IPF treatment; however, the exact pathophysiological mechanisms of fibrosis progression and response to therapy are still poorly understood. In this work, the molecular fingerprint of fibrosis progression and response to nintedanib treatment have been investigated by mass spectrometry-based bottom-up proteomics in paraffin-embedded lung tissues from bleomycin-induced (BLM) pulmonary fibrosis mice. Our proteomics results unveiled that (i) samples clustered depending on the tissue fibrotic grade (mild, moderate, and severe) and not on the time course after BLM treatment; (ii) the dysregulation of different pathways involved in fibrosis progression such as the complement coagulation cascades, advanced glycation end products (AGEs) and their receptors (RAGEs) signaling, the extracellular matrix-receptor interaction, the regulation of actin cytoskeleton, and ribosomes; (iii) Coronin 1A (Coro1a) as the protein with the highest correlation when evaluating the progression of fibrosis, with an increased expression from mild to severe fibrosis; and (iv) a total of 10 differentially expressed proteins (-value ≤ 0.05 and Fold change ≤-1.5 or ≥1.5), whose abundance varied in the base of the severity of fibrosis (mild and moderate), were modulated by the antifibrotic treatment with nintedanib, reverting their trend. Notably, nintedanib significantly restored lactate dehydrogenase B (Ldhb) expression but not lactate dehydrogenase A (Ldha). Notwithstanding the need for further investigations to validate the roles of both Coro1a and Ldhb, our findings provide an extensive proteomic characterization with a strong relationship with histomorphometric measurements. These results unveil some biological processes in pulmonary fibrosis and drug-mediated fibrosis therapy.
Topics: Mice; Animals; Bleomycin; Proteomics; Lung; Idiopathic Pulmonary Fibrosis; Fibrosis
PubMed: 36901840
DOI: 10.3390/ijms24054410 -
Cells Jan 2023A progressive fibrosing phenotype is critical in several lung diseases. It is irreversible and associated with early patient mortality. Growing evidence has revealed...
A progressive fibrosing phenotype is critical in several lung diseases. It is irreversible and associated with early patient mortality. Growing evidence has revealed pulmonary macrophages' role as modulators of the fibrotic processes. The proportion, phenotype, and function of alveolar (AM) and interstitial macrophages (IM) at the early stages of bleomycin-induced pulmonary fibrosis have not been clearly described. In this way, our study aimed to characterize these macrophage populations and investigate the effect on fibroblast activation. C57BL/6 mice were intratracheally injected with bleomycin and were sacrificed at day 3, 5, and 7 for the performance of flow cytometry and fluorescent-activated cell sorting analysis for protein and gene expression quantification. After bleomycin administration, the proportion of IM was significantly higher than that of AM, which showed a decay during the inflammatory phase, and peaked at day 7. At day 7 of the inflammatory phase, AM started shifting their phenotype from M1-like towards M2, while IM showed a M2-like phenotype. Conditioned medium derived from IM sorted at day 7 induced fibroblast activation and differentiation in myofibroblasts in vitro. Our findings indicate that IM are the largest macrophage population at the early stages of experimental pulmonary fibrosis and are secreted mediators able to activate fibroblasts, pointing to macrophage modulation as a potential therapeutic strategy to restrain progressive fibrosing lung disorders.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Mice, Inbred C57BL; Macrophages; Fibroblasts
PubMed: 36766744
DOI: 10.3390/cells12030402