Search

Prodigiosin contains a tripyrrole skeleton and shows impressive anticancer potential in multiple cell lines. Numerous studies have been conducted on prodigiosin-induced apoptosis and the related mechanisms. However, few reports have considered the effects of prodigiosin on autophagy and the relationship between apoptosis and autophagy. Here, we examined whether prodigiosin affected apoptosis and autophagy through the extracellular signal-regulated (ERK) signaling pathway in K562 cells, employing cell proliferation, flow cytometry, caspase activity, and western blot analyses. Inhibition of the ERK signaling pathway with PD184352 was conducted to verify the role of this pathway on prodigiosin-mediated processes. Our findings revealed that prodigiosin inhibited the proliferation of K562 cells, increased reactive oxygen species (ROS), induced apoptosis and inhibited autophagy in K562 cells. Additionally, the ROS scavenger, N-Acetyl-L-cysteine (NAC), partially prevented prodigiosin-induced apoptosis but did not reduce prodigiosin-inhibited autophagy in K562 cells. Furthermore, prodigiosin treatment in K562 cells reduced the phosphorylation of c-Jun N-terminal kinases (JNKs) and P38, and activated ERK signaling pathway. When ERK1/2 phosphorylation was blocked by PD184352, prodigiosin-induced apoptosis and the inhibition of autophagy decreased significantly. Taken together, these results demonstrated that the ERK signaling pathway was involved in prodigiosin-induced apoptosis and prodigiosin-inhibited autophagy.

Benzene is a ubiquitous, occupational, and environmental hematotoxic and leukemogen. Damage to hematopoietic stem cells (HSCs) induced by benzene and its metabolites is a key event in bone marrow (BM) depression and leukemogenesis. There are no reports on transcriptome profiles of HSCs following benzene exposure. Here, Smart-seq2 single-cell transcriptome sequencing was used to detect transcriptomic alternations in BM HSCs and peripheral blood HSCs (PBSCs) in male C57B/6 mice exposed to benzene. We found that benzene caused hematotoxicity which was confirmed by routine blood test, pathological examination, and HSCs percentage analysis. A total of 1514 differentially expressed genes (DEGs) in BM HSCs and 1703 DEGs in PBSCs were screened after treatment with benzene. Weighted gene correlation network analysis revealed that pathways in cancer, transcriptional misregulation in cancer, and hematopoietic cell lineage are vital pathways involved in benzene-induced toxicity in BM HSCs, whereas hematopoietic cell lineage and leukocyte transendothelial migration are critical pathways in PBSCs. Of note, there were 164 common DEGs in both HSCs, out of which 53 genes were co-regulated in both types of HSCs. Subsequent pathway analysis of these 53 genes indicated that the most relevant pathways involved neutrophil degranulation and CD93 localized in the core of the network of the 53 genes, which are known to regulate leukemia stem cell self-renewal and quiescence. Our results could enhance our understanding of HSC responses to benzene, facilitate the identification of potential molecular biomarkers and future studies on its mechanism of toxicity toward HSCs.

Widespread occupational and environmental exposure to benzene is unavoidable and poses a public health threat. Studies of potential interventions to prevent or relieve benzene toxicity are, thus, essential. Research has shown l-carnitine (LC) has beneficial effects against various pathological processes and diseases. LC possesses antioxidant activities and participates in fatty acid oxidation (FAO). In this study, we investigated whether 1,4-benzoquinone (1,4-BQ) affects LC levels and the FAO pathway, as well as analyzed the influence of LC on the cytotoxic effects of 1,4-BQ. We found that 1,4-BQ significantly decreased LC levels and downregulated Cpt1a, Cpt2, Crat, Hadha, Acaa2, and Acadvl mRNA expression in K562 cells. Subsequent assays confirmed that 1,4-BQ decreased cell viability and increased apoptosis and caspase-3, -8, and -9 activities. It also induced obvious oxidative stress and DNA damage, including an increase in the levels of reactive oxygen species and malondialdehyde, tail DNA%, and olive tail moment. Additionally, the mitochondrial membrane potential was significantly reduced. Cotreatment with LC (500 μmol/L) relieved these alterations by reducing oxidative stress and increasing the protein expression levels of Cpt1a and Hadha, particularly in the 20 μmol/L 1,4-BQ group. Thus, our results demonstrate that 1,4-BQ causes cytotoxicity, reduces LC levels, and downregulates the FAO genes. In contrast, LC exhibits protective effects against 1,4-BQ-induced apoptosis and DNA damage by decreasing oxidative stress and promoting the FAO pathway.

Benzene, a commonly used chemical, has been confirmed to specifically affect the hematopoietic system as well as overall human health. PTP4A3 is overexpressed in leukemia cells and is related to cell proliferation. We previously found that HIF-1alpha was involved in benzene toxicity and PTP4A3 may be the target gene of HIF-1alpha via ChIP-seq. The aim of this study is to confirm the relationship between HIF-1alpha and PTP4A3 in benzene toxicity, as well as the function of PTP4A3 on cell toxicity induced by 1,4-benzoquinone (1,4-BQ). Our results indicate that HIF-1alpha could regulate PTP4A3 with in vivo and in vitro experiments. A cell line with suppressed PTP4A3 was established to investigate the function of PTP4A3 in 1,4-BQ toxicity in vitro. The results revealed that cell proliferation inhibition was more aggravated in PTP4A3 low-expression cells than in the control cells after 1,4-BQ treatment. The relative oxygen species (ROS) significantly increased in cells with inhibited PTP4A3, while the rise was inferior to the control cells at the 20 &mu, M 1,4-BQ group. An increase in DNA damage was seen in PTP4A3 down-regulated cells at the 10 &mu, M 1,4-BQ group, whereas the results reversed at the concentration of 20 &mu, M. Moreover, the apoptosis rate increased higher in down-regulated PTP4A3 cells after 1,4-BQ exposure. In addition, PI3K/AKT pathway was significantly restrained in cells with inhibited PTP4A3 after 1,4-BQ treatment. Our results indicate that HIF-1alpha may regulate PTP4A3 to be involved in benzene toxicity. Inhibition of PTP4A3 could aggravate cell proliferation suppression and apoptosis by regulating PI3K/AKT pathway after 1,4-BQ treatment.

The gut microbiota comprises a multispecies microbial community and is essential for maintaining health. Benzene is a widespread environmental and occupational pollutant that mainly causes blood and bone marrow abnormalities. However, the effects of benzene on gut microbiota and metabolism have not yet been investigated. In this study, C57BL/6 mice were exposed to 0, 6, 30 and 150 mg/kg benzene by subcutaneous injection for 30 days. We observed that white blood cell levels significantly decreased in the three benzene exposure groups, while red blood cell and hemoglobin levels were only changed remarkably in 30 and 150 mg/kg benzene-treated mice. The results of 16S rRNA sequencing showed that benzene exposure altered the overall structure of the gut microbial communities. In addition, significant enrichments of Actinobacteria (p