Frontiers in Immunology
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2025
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IF 5.9
Maolin Chu,Suna Jiang,Jiawei Xue,Wenjing Li,Guanhua Jing,Hongying Li,Juan Zhang,Wanhai Xu
Introduction: Premature senescence of renal tubular epithelial cells (RTECs) can be caused by oxidative stress related to calcium oxalate (CaOx) kidney stones (KSs), but the role and mechanisms of cellular senescence of RTECs in the pathogenesis of kidney stones have not been fully determined. Macrophages, the most prevalent leucocyte found in nephrolithiasis, have been implicated in the pathogenesis of kidney stones.Methods: Using oxalate (Ox) induction to simulate the hyperoxaluria microenvironment in vivo, fisetin was administered to human renal proximal tubular epithelial cells (HK-2 cells). The senescence of HK-2 cells was evaluated by detecting SA-β-gal staining, expression of senescence markers p16 and p53, and levels of senescence-associated secretory phenotype (SASP) molecules. THP-1 cells were differentiated into macrophages (M0-MΦs) using PMA induction, and macrophages in different polarization states (M1-like phenotype, M2-like phenotype) were treated with the supernatant from HK-2 cell culture. siRNA gene knockdown technology was applied to evaluate the activity of the LXN/Rps3/p53 pathway during oxalate-induced senescence in HK-2 cells. A rat model of calcium oxalate crystal-induced kidney injury was established, and the rats were divided into following groups: PBS, oxalate, oxalate + fisetin, oxalate + transfection with LXN-knockdown adeno-associated virus (AAV-shLXN), and oxalate + fisetin + AAV-shLXN, Histological assessment was performed using HE staining and Von Kossa staining of kidney tissues. The expression levels of LXN, Rps3, p53, iNOS, and CD163 in renal tissues were evaluated by immunohistochemical staining.Results: The onset of RTEC senescence was increased after treatment with oxalate, and the increase in RTEC senescence was reduced by fisetin treatment. Interestingly, the changes in proinflammatory M1-like phenotype polarization induced by culture medium from HK-2 cells treated with Ox+/-fisetin were consistent with the proportion of senescent HK-2 cells cultured. Furthermore, reducing cellular LXN/Rps3/p53 signaling significantly decreased SASP factors in the culture medium and simultaneously abolished M1-like phenotype macrophage polarization. More importantly, silencing renal LXN reduced RTEC senescence and M1-like phenotype macrophage polarization and consequently decreased intrarenal CaOx crystal deposition in a rat kidney stone model.Discussion: Our results demonstrate that kidney macrophage phenotype changes are related, at least in part, to RTEC senescence, and a strategy to modulate the cellular senescence of RTECs is promising as a new target for immunotherapy to treat nephrolithiasis and other age-related diseases.
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高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-20
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IF 11.4
Fei Xiaobin,Zhu Changhao,Liu Peng,Liu Songbai,Ren Likun,Lu Rishang,Hou Junyi,Gao Yongjia,Wang Xing,Pan Yaozhen
Background Pancreatic cancer (PC) is a highly malignant gastrointestinal tumor, which is characterized by difficulties in early diagnosis, early metastasis, limited therapeutic response and a grim prognosis. Therefore, it is imperative to explore potential therapeutic targets for PC. Currently, although the involvement of the Pellino E3 Ubiquitin Protein Ligase 1 (PELI1) in the human growth of some malignant tumors has been demonstrated, its association with PC remains uncertain. Methods Bioinformatics, qRT-PCR, Western blot and IHC were used to detect the expression of PELI1 in pancreas or PC tissues and cells at mRNA and protein levels. The effects of PELI1 on the proliferation and metastatic ability of pancreatic cancer in vitro and in vivo were investigated using CCK8, cloning formation, EdU, flow cytometry, IHC, Transwell assay, wound healing, nude mice subcutaneous tumorigenesis and intrasplenic injection to construct a liver metastasis model. The interactions of PELI1 with proteins as well as the main functions and pathways were investigated by protein profiling, Co-IP, GST-pull down, Immunofluorescence techniques, immunohistochemical co-localization and enrichment analysis. The rescue experiment verified the above experimental results. Results The mRNA and protein expression levels of PELI1 in PC tissues were upregulated and were associated with poor prognosis of patients, in vitro and in vivo experiments confirmed that PELI1 can affect the proliferation and metastatic ability of PC cells. Co-IP, GST-pull down, and other experiments found that PELI1 interacted with Ribosomal Protein S3 (RPS3) through the FHA structural domain and promoted the polyubiquitination of RPS3 in the K48 chain, thereby activates the PI3K/Akt/GSK3β signaling pathway. Moreover, ubiquitinated degradation of RPS3 further reduces Tumor Protein P53 (p53) protein stability and increases p53 degradation by MDM2 Proto-Oncogene (MDM2). Conclusion PELI1 is overexpressed in PC, which increased ubiquitination of RPS3 proteins and activates the PI3K/Akt/GSK3β signaling pathway, as well as reduces the protective effect of RPS3 on p53 and promotes the degradation of the p53 protein, which facilitates the progression of PC and leads to a poor prognosis for patients. Therefore, PELI1 is a potential target for the treatment of PC.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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生物信息学
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细胞生物学
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高影响因子
ENVIRONMENTAL POLLUTION
·
2022
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IF 9.988
Lin-Lin Hu,Hong-Ge Li,Xiao-Mei Li,Yi Xu,Ya-Qin Pang,Bin Wang,Jun-Li Wang,Shao-Chen Sun
Nonylphenol (NP) belongs to the metabolites of commercial detergents, which acts as an environmental endocrine disruptor . NP is reported to have multiple toxicity including reproductive toxicity. In present study, we reported the protective effects of melatonin on the NP-exposed oocyte quality. We set up a mouse in vivo model of NP exposure (500 μg/L), by daily drinking and continued feeding for 4 weeks; and we gave a daily dose of melatonin (30 mg/kg) to the NP-exposed mice. Melatonin supplementation restores the development ability of oocytes exposed to NP, and this was due to the reduction of ROS level and DNA damage by melatonin. Melatonin could rescue aberrant mitochondria distribution, mitochondria membrane potential, which also was reflected by ATP content and mtDNA copy number. Moreover, melatonin could restore the RPS3 expression to ensure the ribosome function for protein synthesis , and reduced GRP78 protein level to protect against ER stress and ER distribution defects. We also found that vesicle protein Rab11 from Golgi apparatus was protected by melatonin at the spindle periphery of oocytes of NP-exposed mice, which further moderated LAMP2 for lysosome function. Our results indicate that melatonin protects oocytes from NP exposure through its effects on the reduction of oxidative stress and DNA damage, which might be through its amelioration on the organelles in mice.
研究领域:
生殖毒理学
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内分泌学
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细胞生物学
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分子生物学
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高影响因子
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