Rosmarinic acid alleviates radiation-induced pulmonary fibrosis by downregulating tRNA N7-Methylguanosine modification-regulated fibroblast to myofibroblast transition through the exosomes pathway
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE249534 | GEO | 2024/09/02
REPOSITORIES: GEO
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Project description:Radiation-induced pulmonary fibrosis (RIPF) is a common complication after radiotherapy in thoracic cancer patients, and there is a lack of effective treatment methods. The aim of this study was to explore the protective effect of rosmarinic acid (RA) on RIPF in mice as well as the underlying mechanism.We found that RA exerted an antifibrotic effect on lung tissues of RIPF mouse models and inhibited the progression of FMT through exosomes derived from lung epithelial cells. Mechanistically, RA reduced the transcription and translation efficiency of SPHK1 in lung fibroblasts by decreasing the tRNA N7-methylguanosine modification and downregulating the expression of tRNAs in lung epithelial cell-derived exosomes after irradiation, as well as inhibiting the interaction of SPHK1 with the NAT10 protein in fibroblasts. Furthermore, exosomes derived from irradiated lung epithelial cells after RA intervention decreased the acetylation and cytoplasmic translocation of PFKFB3, suppressing the FMT process triggered by glycolysis, and ultimately decelerating the progression of RIPF.
2024-09-02 | GSE249531 | GEO
Project description:Radiation-induced pulmonary fibrosis (RIPF) is a common complication after radiotherapy in thoracic cancer patients, and there is a lack of effective treatment methods. The aim of this study was to explore the protective effect of rosmarinic acid (RA) on RIPF in mice as well as the underlying mechanism.We found that RA exerted an antifibrotic effect on lung tissues of RIPF mouse models and inhibited the progression of FMT through exosomes derived from lung epithelial cells. Mechanistically, RA reduced the transcription and translation efficiency of SPHK1 in lung fibroblasts by decreasing the tRNA N7-methylguanosine modification and downregulating the expression of tRNAs in lung epithelial cell-derived exosomes after irradiation, as well as inhibiting the interaction of SPHK1 with the NAT10 protein in fibroblasts. Furthermore, exosomes derived from irradiated lung epithelial cells after RA intervention decreased the acetylation and cytoplasmic translocation of PFKFB3, suppressing the FMT process triggered by glycolysis, and ultimately decelerating the progression of RIPF.
2024-09-02 | GSE249532 | GEO
Project description:Radiation-induced pulmonary fibrosis (RIPF) is a common complication after radiotherapy in thoracic cancer patients, and there is a lack of effective treatment methods. The aim of this study was to explore the protective effect of rosmarinic acid (RA) on RIPF in mice as well as the underlying mechanism.We found that RA exerted an antifibrotic effect on lung tissues of RIPF mouse models and inhibited the progression of FMT through exosomes derived from lung epithelial cells. Mechanistically, RA reduced the transcription and translation efficiency of SPHK1 in lung fibroblasts by decreasing the tRNA N7-methylguanosine modification and downregulating the expression of tRNAs in lung epithelial cell-derived exosomes after irradiation, as well as inhibiting the interaction of SPHK1 with the NAT10 protein in fibroblasts. Furthermore, exosomes derived from irradiated lung epithelial cells after RA intervention decreased the acetylation and cytoplasmic translocation of PFKFB3, suppressing the FMT process triggered by glycolysis, and ultimately decelerating the progression of RIPF.
2024-09-02 | GSE249530 | GEO
Project description:Radiation-induced pulmonary fibrosis (RIPF) is a common complication after radiotherapy in thoracic cancer patients, and there is a lack of effective treatment methods. The aim of this study was to explore the protective effect of rosmarinic acid (RA) on RIPF in mice as well as the underlying mechanism.We found that RA exerted an antifibrotic effect on lung tissues of RIPF mouse models and inhibited the progression of FMT through exosomes derived from lung epithelial cells. Mechanistically, RA reduced the transcription and translation efficiency of SPHK1 in lung fibroblasts by decreasing the tRNA N7-methylguanosine modification and downregulating the expression of tRNAs in lung epithelial cell-derived exosomes after irradiation, as well as inhibiting the interaction of SPHK1 with the NAT10 protein in fibroblasts. Furthermore, exosomes derived from irradiated lung epithelial cells after RA intervention decreased the acetylation and cytoplasmic translocation of PFKFB3, suppressing the FMT process triggered by glycolysis, and ultimately decelerating the progression of RIPF.
2024-09-02 | GSE249533 | GEO
Project description:Cardiomyocyte apoptosis is a key event in the process of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that rosmarinic acid (RA) could attenuate pressure overload-induced cardiac dysfunction via cardiac fibroblasts (CFs), however its effect in DOX-induced cardiotoxicity remains unknown. In the present study, mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to generate DOX-induced cardiotoxicity. Histological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. Neonatal rat cardiomyocytes (CMs) and CFs were used to verify the protective effect of RA in vitro. Conditioned medium derived from RA-treated CFs were prepared to illustrate the effect of RA on paracrine interplay between CFs and CMs. We found that RA significantly alleviated DOX-induced cardiomyocyte apoptosis and cardiac dysfunction in vivo, which, however, had almost negligible beneficial effect on DOX directly induced cardiomyocyte apoptosis in vitro. Mechanistically, CFs-derived Fas L was responsible for DOX-induced cardiomyocyte apoptosis, and RA treatment could decrease Fas L expression in CFs and its release to the conditioned medium by suppressing nuclear factor of activated T cells (NFAT) activation and metalloproteinase 7 (MMP7) expression, and exerted the anti-apoptotic effect on CMs via CFs. Ionomycin, and activator of NFAT, abrogated RA-mediated protective effect on cardiomyocyte apoptosis and cardiac dysfunction. In summary, RA alleviated cardiomyocyte apoptosis by inhibiting the expression and release of Fas L in CFs via a paracrine manner, moreover, NFAT as well as MMP7 inhibition were responsible for the suppression of Fas L. RA could be a powerful new therapeutic agent to mitigate cardiomyocyte apoptosis, thereby improving DOX-induced cardiotoxicity.
| S-EPMC6367577 | biostudies-literature
Project description:Radiofrequency heat ablation is an ideal radical cure for HCC treatment; however, insufficient radiofrequency ablation (IRFA) could lead to a high recurrence rate. N7-methylguanosine (m7G) on tRNAs is a heat-responding modification that is critical for yeast survival under high temperature, while its function and mechanism in HCC recurrence after IRFA are unknown. Here, we found that IRFA significantly up-regulates the level of m7G tRNA modification and its methyltransferase complex components METTL1 and WDR4 in multiple systems including HCC patient-derived xenograft (PDX) mouse, HCC tissues of patients, sublethal-heat-treated models of HCC cell lines and organoids. Functionally, gain- or loss-of function assays showed that METTL1 mediated m7G tRNA modification promotes HCC metastasis under sublethal heat exposure both in vitro and in vivo. Mechanistically, we found that METTL1 and m7G tRNA modification enhance the translation of SLUG and SNAIL in a codon frequency dependent manner under sublethal heat exposure. Overexpression of SLUG and SNAIL rescued the malignant potency of METTL1 knockdown HCC cells after sublethal heat stress. Our study uncovers the important physiological functions of m7G tRNA modification in heat stress responses and HCC recurrence after IRFA and suggests that targeting METTL1-m7G-SLUG and SNAIL axis could be a promising strategy to prevent HCC metastasis after radiofrequency heat ablation treatment.
2022-11-20 | GSE199966 | GEO
Project description:Mutations of tRNA modification enzymes including the tRNA m7G methyltransferase complex component WDR4 were frequently found in patients with neural disorders, while the pathogenic mechanism and therapeutic intervention strategies are poorly explored. In this study, we revealed that patient-derived WDR4 mutation leads to temporal and cell-type-specific neural degeneration, and directly causes neural developmental disorders in mice.
2024-10-15 | GSE229612 | GEO
Project description:The cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, while the underlying mechanisms are poorly understood. N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex METTL1/WDR4 are significantly up-regulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We developed tRNA reduction and cleavage sequencing (TRAC-Seq) to reveal the m7G tRNA methylome inICC cell line and ribosome nascent-chain complex-bound mRNAs sequencing(RNC-seq) and ribosome profiling(Ribo-seq) to study the differential translated genes and reveal the ribosome pausing. A subset of 22 tRNAs is modified at a ‘RAGGU’ motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in the Mettl1 knockdown ICC cell line implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and EGFR signaling pathway genes is particularly affected. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of cancer progression.
2021-08-07 | GSE161319 | GEO
Project description:Methylation of guanosine on position N7 (m7G) on internal RNA positions has been found in all domains of life and have been implicated in human disease. Here, we present m7G Mutational Profiling sequencing (m7G-MaP-seq), which allows high throughput detection of m7G modifications at nucleotide resolution. In our method, m7G modified positions are converted to abasic sites by reduction with sodium borohydride, directly recorded as cDNA mutations through reverse transcription and sequenced. We detect positions with increased mutation rates in the reduced and control samples taking the possibility of sequencing/alignment error into account and use replicates to calculate statistical significance based on log likelihood ratio tests. We show that m7G-MaP-seq efficiently detects known m7G modifications in rRNA with mutational rates up to 25% and we map a previously uncharacterised evolutionarily conserved rRNA modification at position 1581 in Arabidopsis thaliana SSU rRNA. Furthermore, we identify m7G modifications in budding yeast, human and arabidopsis tRNAs and demonstrate that m7G modification occurs before tRNA splicing. We do not find any evidence for internal m7G modifications being present in other small RNA, such as miRNA, snoRNA and sRNA, including human Let-7e. Likewise, high sequencing depth m7G-MaP-seq analysis of mRNA from E. coli or yeast cells did not identify any internal m7G modifications.
| S-EPMC6847341 | biostudies-literature
Project description:PurposeHepatocellular carcinoma (HCC) is a kind of primary liver cancer. It is a common malignant tumor of digestive system that is difficult to predict the prognosis of patients. As an important epigenetic modification, N7 methyl guanosine (m7G) is indispensable in gene regulation. This regulation may affect the development and occurrence of cancer. However, the prognosis of long non coding RNAs (lncRNAs) in HCC is limited, especially how m7G-related lncRNAs regulate the development of HCC has not been reported.MethodsThe Cancer Genome Atlas (TCGA) provides us with the expression data and corresponding clinical information of HCC patients we need. We used a series of statistical methods to screen four kinds of m7G-related lncRNAs related to HCC prognosis and through a series of verifications, the results were in line with our expectations. Finally, we also explored the IC50 difference and correlation analysis of various common chemotherapy drugs.ResultOur study identified four differentially expressed m7g-related lncRNAs associated with HCC prognosis. Survival curve analysis showed that high risk lncRNAs would lead to poor prognosis of HCC patients. M7G signature's AUC was 0.789, which shows that the prognosis model we studied has certain significance in predicting the prognosis of HCC patients. Moreover, our study found that different risk groups have different immune and tumor related pathways through gene set enrichment analysis. In addition, many immune cell functions are significantly different among different risk groups, such as T cell functions, including coordination of type I INF response and coordination of type II INF response. The expression of PDCD1, HHLA2, CTLA-4 and many other immune checkpoints in different risk groups is also different. Additionally, we analyzed the differences of IC50 and risk correlation of 15 chemotherapeutic drugs among different risk groups.ConclusionA novel lncRNAs associated with m7G predicts the prognosis of HCC.
| S-EPMC10120187 | biostudies-literature