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 DLpropargylglycine (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.

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 (BeSO4) 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 BeSO4‐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 BeSO4 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 BeSO4 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 BeSO4 provides new insights into the toxicity mechanism of beryllium exposure.

Inhalation of beryllium and its compounds can cause lung injuries, resulting from inflammation and oxidative stress. Multivesicular bodies (MVB), such as exosomes, are membrane vesicles produced by early and late endosomes that mediate intercellular communications. However, the role of exosomes in beryllium toxicity has not been elucidated. This current study aimed to investigate the functional role of exosomes in lung injury resulting from beryllium sulfate (BeSO 4 ). Here, Sprague-Dawley (SD) rats were exposed to 4, 8, and 12 mg/kg BeSO 4 by nonexposed intratracheal instillation. Murine macrophage (RAW 264.7) cells were pretreated with 50 nmol/L rapamycin (an mTOR signaling pathway inhibitor) for 30 min and then cultured for 24 h with 100 μg/mL exosomes, which had been previously isolated from the serum of 12 mg/kg BeSO 4 -treated SD rats. Compared with those of the controls, exposure to BeSO 4 in vivo increased LDH activity, elevated levels of inflammatory cytokines (IL-10, TNF-α, and IFN-γ) alongside inflammation-related proteins expression (COX-2 and iNOS), and enhanced secretion of exosomes from the SD rat's serum. Moreover, the BeSO 4 -Exos-induced upregulation of LDH activity and inflammatory responses in RAW 264.7 cells can be alleviated following pretreatment with rapamycin. Collectively, these results suggest that serum exosomes play an important role in pulmonary inflammation induced by BeSO 4 in RAW 264.7 cells via the mTOR pathway.

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.

Context Ellagic acid (EA) is a phenolic constituent in certain fruits and has largely been recognized for its role as an antioxidant compound. Objective To evaluate the effect of EA on beryllium sulphate-induced splenic toxicity in rats. Materials and methods Male Sprague-Dawley rats were divided into four groups. The first group was used as control. Group 2 was exposed to BeSO 4 (12 mg/kg, b.w.). Groups 3 and 4 were treated with EA (100 and 300 mg/kg, b.w.) daily for 6 weeks after exposing to BeSO 4 (12 mg/kg, b.w.). Various biochemical and molecular biomarkers were assessed in blood and spleen. Results BeSO 4 -intoxicated rats showed significant higher WBC (6.74 ± 0.20 × 10 9 /L vs. 11.02 ± 1.31 × 10 9 /L, p < 0.05), Neu (1.14 ± 0.11 × 10 9 /L vs. 2.45 ± 0.42 × 10 9 /L, p < 0.05), Lym (3.80 ± 0.83 × 10 9 /L vs. 9.64 ± 1.99 × 10 9 /L, p < 0.05), and PLT (868.4 ± 43.2 × 10 9 /L vs. 1408 ± 77.57 × 10 9 /L, p < 0.05) than normal control animals. Moreover, an increase in MDA with depletion of GSH and SOD activity (all p < 0.05) occurred in the spleen of rats treated with BeSO 4 . Furthermore, BeSO 4 -treated rats displayed significantly higher levels of apoptotic markers (Bax, Caspase-3, PARP) (all p < 0.05). EA administration resulted in a significant reversal of hematological and apoptotic markers in beryllium sulphate-intoxicated rats. Discussion and conclusions Our results suggest EA treatment exerts a significant protective effect on BeSO 4 -induced splenic toxicity in rats.