Non-coding RNA Research
·
2024
·
IF 5.9
Zixuan Yang,Lei Shi,Minhui Zheng,Minbo Hou,Mengdi Zhou,Naying Su,Hui Lang,Liyuan Zhao,Mengyun Gu,Naping Tang,Yan Chang
Background Drug-induced liver injury (DILI) is a leading cause of drug development failures during clinical trials and post-market introduction. Current biomarkers, such as ALT and AST, lack the necessary specificity and sensitivity needed for accurate detection. Exosomes, which protect LncRNAs from RNase degradation, could provide reliable and easily accessible options for biomarkers. Materials and methods RNA-sequencing was used to identify differentially expressed LncRNAs (DE-LncRNAs), followed by isolation of LncRNAs from plasma exosomes in this study. Exosome characterization was conducted by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). Bioinformatics analysis included functional enrichment and co-expression network analysis. Five rat models were established, and quantitative real-time PCR was used to verify the specificity and sensitivity of two candidate exosomal LncRNAs. Results The APAP-induced hepatocellular injury model was successfully established for RNA-sequencing, leading to the identification of several differentially expressed exosomal LncRNAs. Eight upregulated exosomal DE-LncRNAs were selected for validation. Among them, NONRATT018001.2 (p < 0.05) and MSTRG.73954.4 (p < 0.05) exhibited a more than 2-fold increase in expression levels. In hepatocellular injury and intrahepatic cholestasis models, both NONRATT018001.2 and MSTRG.73954.4 showed earlier increases compared to serum biomarkers ALT and AST. However, no histological changes were observed until the final time point. In the fatty liver model, NONRATT018001.2 and MSTRG.73954.4 increased earlier than ALT and AST at 21 days. By the 7th day, minor steatosis was evident in liver tissue, while the expression levels of the two candidate exosomal LncRNAs exceeded 2 and 4 times, respectively. In the hepatic fibrosis model, NONRATT018001.2 and MSTRG.73954.4 showed increases at every time point. By the 49th day, hepatocellular necrosis and fibrosis were observed in the liver tissue, with NONRATT018001.2 showing an increase of more than 8 times. The specificity of the identified exosomal DE-LncRNAs was verified using a myocardial injury model and they showed no significant differences between the case and control groups. Conclusion NONRATT018001.2 and MSTRG.73954.4 hold potential as biomarkers for distinguishing different types of organ injury induced by drugs, particularly enabling early prediction of liver injury. Further experiments, such as siRNA interference or gene knockout, are warranted to explore the underlying mechanisms of these LncRNAs.
研究领域:
分子生物学
·
肝脏病学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
·
IF 14.5
Yu-Meng Sun,Shun-Xin Zhu,Xiao-Tong Chen,Qi Pan,Yan An,Tian-Qi Chen,Heng-Jing Huang,Ke-Jia Pu,Jun-Yi Lian,Wen-Long Zhao,Wen-Tao Wang,Yue-Qin Chen
Liquid-to-solid phase transition of proteins with prion-like domains (PLDs) has been associated with neurodegenerative diseases and aging. High protein concentration is one important aspect triggering the transition; however, several prion-like proteins, including fibrillarin (FBL), an important phase-separated protein in the nucleolus for pre-rRNA processing, show relatively high expression levels in certain cells, especially cancer cells, without obvious phase transitions and growth arrest. How cells maintain prion-like protein proteostasis is still unknown. Here, we attempt to answer the question, with FBL as an example. We find that lncRNA DNAJC3-AS1 can buffer the behavior of FBL condensation and maintain the state and function of fibrillar component/dense fibrillar component (FC/DFC) units in human cell lines through two mechanisms, not only facilitating FBL condensation but also inhibiting excessive aggregation by binding multiple PLDs and partially blocking their interactions. We propose that lncRNAs could supply buffered systems to sustain functional phase states of prion-like proteins.
研究领域:
分子生物学
·
细胞生物学
·
遗传学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2020
·
IF 4.872
Yuhao Wu,Junke Wang,Tianxin Zhao,Yuexin Wei,Lindong Han,Lianju Shen,Chunlan Long,Shengde Wu,Guanghui Wei
Di-(2-ethylhexyl) phthalate (DEHP), one of the most commonly used endocrine-disrupting chemicals, has been shown to cause reproductive dysfunction in humans and animal models. However, very few studies have investigated the impact of DEHP at the post-transcriptional level in mouse testes, and the underlying mechanisms remain unclear. In the present research, TM3 Leydig cells were treated with 200 µM phthalic acid mono-2-ethylhexyl ester (MEHP, bio-metabolite of DEHP), and then the mRNA and lncRNA sequencing of TM3 Leydig cells was performed. Mice were exposed prepubertally to 0 or 500 mg DEHP/kg/day. RNA sequencing of mouse testes was performed to verify the RNA-seq results in vitro . The expression patterns of relevant genes and proteins were verified using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. DEHP and MEHP exposure led to testicular damage and accelerated cell aging via ROS accumulation. RNA sequencing analyses indicated that FOXO signaling and longevity regulation pathways were activated in resistance to ROS accumulation. FOXO signaling and longevity regulation pathway-related genes and proteins were also activated. By constructing a competing endogenous RNA (ceRNA) network, we observed that the ceRNA network might play a role in regulating FOXO signaling and longevity regulation pathways in response to excessive ROS accumulation and cell aging. In summary, our data here suggests that the ceRNA network may play a role in regulating FOXO signaling and longevity pathways in response to DEHP exposure in mouse testes.
研究领域:
生殖生物学
·
毒理学
·
分子生物学
·
基因组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
·
2024
·Vol. 27
·期 11
·1611-1628
·
IF 1.6
Pan Chengzhen,Zhang Chi,Lin Zonghan,Liang Zhou,Cui Yinhang,Shang Zhihao,Wei Yuanxun,Chen Feng
Background: Osteoporosis (OP) is an age-related skeletal disease. Kaempferol can regulate bone mesenchymal stem cells (BMSCs) osteogenesis to improve OP, but its mechanism related to disulfidptosis, a newly discovered cell death mechanism, remains unclear. Objective: The study
aimed to investigate the biological function and immune mechanism of disulfidptosis- related ribophorin I (RPN1) in OP and to experimentally confirm that RPN1 is the target for the treatment of OP with kaempferol. Methods: Differential expression analysis was conducted on disulfide-related
genes extracted from the GSE56815 and GSE7158 datasets. Four machine learning algorithms identified disease signature genes, with RPN1 identified as a significant risk factor for OP through the nomogram. Validation of RPN1 differential expression in OP patients was performed using the GSE56116
dataset. The impact of RPN1 on immune alterations and biological processes was explored. Predictive ceRNA regulatory networks associated with RPN1 were generated via miRanda, miRDB, and TargetScan databases. Molecular docking estimated the binding model between kaempferol and RPN1. The targeting
mechanism of kaempferol on RPN1 was confirmed through pathological HE staining and immunohistochemistry in ovariectomized (OVX) rats. Results: RPN1 was abnormally overexpressed in the OP cohort, associated with TNF signaling, hematopoietic cell lineage, and NF-kappa B pathway. Immune
infiltration analysis showed a positive correlation between RPN1 expression and CD8+ T cells and resting NK cells, while a negative correlation with CD4+ naive T cells, macrophage M1, T cell gamma delta, T cell follicular helper cells, activated mast cells, NK cells, and dendritic cells, was
found. Four miRNAs and 17 lncRNAs associated with RPN1 were identified. Kaempferol exhibited high binding affinity (-7.2 kcal/mol) and good stability towards the RPN1. The experimental results verified that kaempferol could improve bone microstructure destruction and reverse the abnormally
high expression of RPN1 in the femur of ovariectomized rats. Conclusion: RPN1 may be a new diagnostic biomarker in patients with OP, and may serve as a new target for kaempferol to improve OP.
研究领域:
医学研究
·
药理学
·
分子生物学
·
免疫学
·
生物信息学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）