JOURNAL OF APPLIED TOXICOLOGY
·
2025
·
IF 2.8
Chenxi Yan,Guilan Li,Lian Huang,Zhaohui Zhang
Beryllium (Be) is a recognised environmental toxicant associated with pulmonary fibrosis. Epithelial–mesenchymal transition (EMT), a critical process in cell phenotype conversion, plays a key role in its pathophysiology. Methyltransferase-like 3 (METTL3), a major N6-methyladenosine methyltransferase, regulates gene expression and cellular functions. However, its role in Be-induced EMT remains unclear. In this study, human bronchial epithelial cell line (16HBE cells) were exposed to varying concentrations of beryllium sulphate (BeSO 4 ) to assess changes in METTL3 expression. METTL3 overexpression vectors were constructed, and quantitative reverse transcription-polymerase chain reaction, western blotting and immunofluorescence were used to detect METTL3, EMT markers and Wingless/Integrated (Wnt)/β-catenin pathway proteins. The Wnt/β-catenin pathway inhibitor ICG-001 was also employed to explore the role of the Wnt/β-catenin pathway in BeSO 4 -induced EMT. The study demonstrated that BeSO 4 suppressed METTL3 expression, induced EMT and activated the Wnt/β-catenin pathway in 16HBE cells. Both METTL3 overexpression and ICG-001 pretreatment mitigated BeSO 4 -induced EMT and Wnt/β-catenin pathway activation. These findings suggest that METTL3 inhibits BeSO 4 -induced EMT by suppressing the Wnt/β-catenin pathway, offering novel mechanistic insights into beryllium toxicity and a potential therapeutic target for Be-related pulmonary fibrosis.
研究领域:
细胞生物学
·
毒理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Toxicology Research
·
2022
·Vol. 11
·期 4
·605-615
·
IF 2.68
Deng Weihua,Sun Zhanbing,Chen Shaoxiong,Li Guilan,Liu Xiuli,Huang Lian,Zhang Zhaohui
BackgroundBeryllium and its compounds are carcinogenicity, but the mechanisms through which this occurs have yet to be clarified. Accumulating evidence exists that long noncoding RNAs (lncRNAs) play an important role in occurrence and development of cancer.Aims and MethodsTo explore the carcinogenic mechanism of beryllium, human bronchial epithelial cells (16HBE) were treated with 50 μM beryllium sulfate (BeSO4) for 45 passages (~23 weeks). The expression levels of lncRNA SNHG7, SNHG11, SNHG15, MIR22HG, GMPS, and SIK1 were detected at passage 0 (P0), 15 (P15), 25 (P25), 35 (P35), and 45 (P45).ResultsThe results indicated that enhanced cell proliferation, extensive clones in soft agar, protein expressions of up-regulated matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 2 (MMP2), proliferating cell nuclear antigen (PCNA), cyclin D1, and down-regulated p53 were all observed at the 45th passage in 16HBE cells. Thus, BeSO4-transformed 16HBE cells (T-16HBE) were established. Meanwhile, the study found that the expression of lncRNA SNHG11 was elevated during malignant transformation. Knockdown of SNHG11 in T-16HBE cells blocked cell proliferation, invasion, and migration, and decreased the protein levels of MMP9, MMP2, PCNA, cyclin D1, but increased p53.ConclusionsThe studies revealed that SNHG11 acts as an oncogene in the malignant transformation of 16HBE cells induced by BeSO4, which signifies progress in the study of the carcinogenic mechanism of beryllium.
研究领域:
癌症生物学
·
分子生物学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2024
·
IF 2.7
Xiaodong Liu,Tianyi Jiang,Huiyun Jin,Chenxi Yan,Yuqi Tong,Jiaquan Ding,Yaqi Li,Lian Huang,Zhaohui Zhang
Beryllium sulfate (BeSO 4 ) can cause inflammation through the mechanism, which has not been elucidated. Mitochondrial DNA (mtDNA) is a key contributor of inflammation. With mitochondrial damage, released mtDNA can bind to specific receptors (e.g., cGAS) and then activate related pathway to promote inflammatory responses. To investigate the mechanism of mtDNA in BeSO 4 -induced inflammatory response in 16HBE cells, we established the BeSO 4 -induced 16HBE cell inflammation model and the ethidium bromide (EB)-induced ρ 0 16HBE cell model to detect the mtDNA content, oxidative stress-related markers, mitochondrial membrane potential, the expression of the cGAS-STING pathway, and inflammation-related factors. Our results showed that BeSO 4 caused oxidative stress, decline of mitochondrial membrane potential, and the release of mtDNA into the cytoplasm of 16HBE cells. In addition, BeSO 4 induced inflammation in 16HBE cells by activating the cGAS-STING pathway. Furthermore, mtDNA deletion inhibited the expression of cGAS-STING pathway, IL-10, TNF-α, and IFN-β. This study revealed a novel mechanism of BeSO 4 -induced inflammation in 16HBE cells, which contributes to the understanding of the molecular mechanism of beryllium and its compounds-induced toxicity.
研究领域:
毒理学
·
细胞生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2023
·
IF 3.3
Xiuli Liu,Guilan Li,Shaoxiong Chen,Huiyun Jin,Xiaodong Liu,Linfang Zhang,Zhaohui Zhang
Beryllium sulfate (BeSO 4 ) can result to lung injuries, such as leading to lipid peroxidation and autophagy, and the treatment of beryllium disease has not been well improved. Ferroptosis is a regulated cell death process driven by iron-dependent and lipid peroxidation, while ferritinophagy is a process mediated by nuclear receptor coactivator 4 (NCOA4), combined with ferritin heavy chain 1 (FTH1) degradation and release Fe 2+ , which regulated intracellular iron metabolism and ferroptosis. Hydrogen sulfide (H 2 S) has the effects of antioxidant, antiautophagy, and antiferroptosis. This study aimed to investigate the effect of H 2 S on BeSO 4 -induced ferroptosis and ferritinophagy in 16HBE cells and the underlying mechanism. In this study, BeSO 4 -induced 16HBE cell injury model was established based on cellular level and pretreated with deferoxamine (DFO, a ferroptosis inhibitor), sodium hydrosulfide (NaHS, a H 2 S donor), or NCOA4 siRNA and, subsequently, performed to detect the levels of lipid peroxidation and Fe 2+ and the biomarkers of ferroptosis and ferritinophagy. More importantly, our research found that DFO, NaHS, or NCOA4 siRNA alleviated BeSO 4 -induced ferroptosis and ferritinophagy by decreasing the accumulation of Fe 2+ and lipid peroxides. Furthermore, the relationship between ferroptosis, ferritinophagy, H 2 S, and beryllium disease is not well defined; therefore, our research is innovative. Overall, our results provided a new theoretical basis for the prevention and treatment of beryllium disease and suggested that the application of H 2 S, blocking ferroptosis, and ferritinophagy may be a potential therapeutic direction for the prevention and treatment of beryllium disease.
研究领域:
毒理学
·
细胞生物学
·
药理学
·
肺科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Toxicology Research
·
2024
·Vol. 13
·期 3
·
IF 2.2
Jin Huiyun,Liu Yanping,Lei Yuandi,Li Guilan,Huang Lian,Zhang Zhaohui
BackgroundChronic beryllium disease is characterized by granulomas and pulmonary fibrosis. Recent studies have shown that microRNAs (miRNAs) and circular RNAs (circRNAs) play critical roles in the pathogenesis and development of many diseases. However, the role of miRNAs and circRNAs in pulmonary fibrosis induced by beryllium sulfate (BeSO4) has not been elucidated.MethodsPrevious studies demonstrated hsa-miR-663b was down-regulated in the 150 μmol/L BeSO4-treated 16HBE cells, while hsa_circ_ 0004214 was up-regulated. Here we found epithelial-mesenchymal transition (EMT) involved in pulmonary fibrosis induced by BeSO4 (4, 8, and 12 mg/kg·BW) in SD rats.ResultsElevated expression of hsa-miR-663b blocked the EMT progression of 16HBE cells induced by 150 μmol/L BeSO4. Notably, the overexpression of hsa-miR-663b decreased the expression of leukemia inhibitory factor (LIF), which was predicted as a target gene of hsa-miR-663b by bioinformatics tools. Furthermore, elevated miR-663b inhibited the activation of the downstream Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway induced by BeSO4 in 16HBE cells. Previous study suggested that hsa_circ_0004214 had binding sites for hsa-miR-663b. The results indicated hsa_circ_0004214 alleviated the BeSO4-induced EMT via JAK-STAT pathway in 16HBE cells.ConclusionsCollectively, the overexpression of hsa-miR-663b and knockdown of hsa_circ_0004214 attenuated the EMT induced by BeSO4 through the inhibition of JAK-STAT signaling pathway. The aberrant expressed hsa-miR-663b and hsa_circ_0004214 stimulated by BeSO4 may exert an important function in the toxic mechanism of beryllium exposure to 16HBE cells, providing the potential therapeutic targets in chronic beryllium disease.
研究领域:
分子生物学
·
毒理学
·
肺科学
·
基因组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2021
·Vol. 42
·期 2
·230-243
·
IF 3.446
Yan-ping Liu,Xiao-yan Yuan,Xun-ya Li,Ye Wang,Zhan-bing Sun,Wei-hua Deng,Yuan-di Lei,Lian Huang,Tian-yi Jiang,Zhao-hui Zhang
Beryllium and its compounds are systemic toxicants that are widely applied in many industries. Hydrogen sulfide has been found to protect cells. The present study aimed to determine the protective mechanisms involved in hydrogen sulfide treatment of 16HBE cells following beryllium sulfate-induced injury. 16HBE cells were treated with beryllium sulfate doses ranging between 0 and 300 μM BeSO 4 . Additionally, 16HBE cells were subjected to pretreatment with either a 300 μM dose of sodium hydrosulfide (a hydrogen sulfide donor) or 10 mM DL-propargylglycine (a cystathionine- γ -lyase inhibitor) for 6 hr before then being treated with 150 μM beryllium sulfate for 48 hr. This study illustrates that beryllium sulfate induces a reduction in cell viability, increases lactate dehydrogenase (LDH) release, and increases cellular apoptosis and autophagy in 16HBE cells. Interestingly, pretreating 16HBE cells with sodium hydrosulfide significantly reduced the beryllium sulfate-induced apoptosis and autophagy. Moreover, it increased the mitochondrial membrane potential and alleviated the G2/M-phase cell cycle arrest. However, pretreatment with 10 mM DL-propargylglycine promoted the opposite effects. PI3K/Akt/mTOR and Nrf2/ARE signaling pathways are also activated following pretreatment with sodium hydrosulfide. These results indicate the protection provided by hydrogen sulfide in 16HBE cells against beryllium sulfate-induced injury is associated with the inhibition of apoptosis and autophagy through the activation of the PI3K/Akt/mTOR and Nrf2/ARE signaling pathways. Therefore, hydrogen sulfide has the potential to be a promising candidate in the treatment against beryllium disease.
研究领域:
毒理学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2020
·Vol. 41
·期 8
·1275-1285
·
IF 2.997
Shan Yi,Yan-ping Liu,Xun-ya Li,Xiao-yan Yuan,Ye Wang,Ying Cai,Yuan-di Lei,Lian Huang,Zhao-hui Zhang
Beryllium and its compounds are systemic toxicants that mainly accumulate in the lungs. As a regulator of gene expression, microRNAs (miRNAs) were involved in some lung diseases. This study aimed to analyze the levels of some inflammatory cytokine and the differential expressions of miRNAs in human bronchial epithelial cells (16HBE) induced by beryllium sulfate (BeSO 4 ) and to further explore the biological functions of differentially expressed miRNAs. The profile of miRNAs in 16HBE cells was detected using the high-throughput sequencing between the control groups ( n = 3) and the 150 μmol/L of BeSO 4 -treated groups ( n = 3). Bioinformatics analysis of differentially expressed miRNAs was performed, including the prediction of target genes, Gene Ontology (GO) analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to verify some damage-related miRNAs. We found that BeSO 4 can increase the levels of some inflammatory cytokine such as interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). And BeSO 4 altered miRNAs expression of 16HBE cells and a total of 179 differentially expressed miRNAs were identified, including 88 upregulated miRNAs and 91 downregulated miRNAs. The target genes predicted by 28 dysregulated miRNAs were mainly involved in the transcription regulation, signal transduction, MAPK, and VEGF signaling pathway. The qRT-PCR verification results were consistent with the sequencing results. miRNA expression profiling in 16HBE cells exposed to BeSO 4 provides new insights into the toxicity mechanism of beryllium exposure.
研究领域:
毒理学
·
分子生物学
·
生物信息学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2022
·
IF 4.46
Shaoxiong Chen,Zhanbing Sun,Weihua Deng,Guilan Li,Xiuli Liu,Zhaohui Zhang
Beryllium and its compounds can cause pulmonary interstitial fibrosis through mechanisms that are not yet clear. Long non-coding RNA (lncRNA) is implicated in various diseases. The molecular toxicity of beryllium sulfate (BeSO 4 ) was investigated through the RNA-seq analysis of the lncRNA and mRNA whole-transcriptome of BeSO 4 -treated 16HBE cells. A total of 1014 lncRNAs (535 upregulated and 479 downregulated) and 4035 mRNAs (2224 upregulated and 1811 downregulated) were found to be significantly dysregulated (|logFC| ≥> 2.0, p < 0.05) in the BeSO 4 -treated groups when compared with the control group. Five differentially expressed lncRNAs and mRNAs were verified by qRT-PCR. KEGG analysis showed that lncRNA regulates the ECM receiver interaction and PI3K/AKT signaling pathways, etc. In addition, H19:17, lnc-C5orf13–1:1, lnc-CRYAA-17:1, lnc-VSTM5–1:11, and lnc-THSD7A-7:1 may regulate BeSO 4 -induced 16HBE cytotoxicity through ceRNA mechanism. The results of this study will provide some theoretical support for the study of the toxic mechanism of beryllium and its compounds.
研究领域:
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
Toxicology Research
·
2021
·Vol. 10
·期 5
·1013-1021
·
IF 3.524
Liu Yan-ping,Cai Ying,Lei Yuan-di,Yuan Xiao-yan,Wang Ye,Yi Shan,Li Xun-ya,Huang Lian,Long Ding-xin,Zhang Zhao-hui
Circular RNAs (circRNAs), is a novel type of endogenous non-coding RNAs (ncRNAs) participated in the pathogenesis of many diseases. Beryllium is one of the carcinogenesis elements. However, the mechanism and function of circRNAs in human bronchial epithelial cells (16HBE) induced by beryllium sulfate (BeSO4) was rarely reported. Therefore, the high-throughput RNA sequencing analysis was performed to detect the circRNA profiles between control groups and BeSO4-induced groups. Furthermore, circRNA-miRNA-mRNA network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and PPI network analysis were used for bioinformatics analysis. CircRNA sequencing analysis revealed that 36 circRNAs were up-regulated and 35 circRNAs were down-regulated in the BeSO4-exposed groups. The selected circRNAs were verified by real-time fluorescent quantitative PCR (qRT-PCR). Hsa_circ_0004214 and hsa_circ_0003586 were validated to be up-regulated, hsa_circ_0047958, hsa_circ_0001944, and hsa_circ_0008982 were down-regulated. The circRNA-miRNA-mRNA network annotated the key signaling pathway including cellular senescence, TNF signaling pathway, NF-kappa B signaling pathway, HIF-1 signaling pathway, and Hippo signaling pathway. The PPI network indicated the most circRNAs might participate in the BeSO4 toxicity by acting as a sponge for the miR-663b through JAK–STAT signaling pathway. In summary, our study suggests that circRNAs may play roles in the mechanism of beryllium toxicity.
研究领域:
分子生物学
·
毒理学
·
生物信息学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）