CASP8AP2

Caenorhabditis elegans was employed as model to compare reproductive toxicity between pristine and aged polylactic acid microplastics (PLA-MPs). Aged PLA-MPs induced by UV irradiation showed degradation reflected by decrease in size and alteration in morphological surface. Aged PLA-MPs also exhibited some certain changes of chemical properties compared to pristine PLA-MP. Compared with pristine PLA-MPs, more severe toxicity on reproductive capacity and gonad development was detected in 1-100 μg/L aged PLA-MPs. Meanwhile, aged PLA-MPs caused more severe enhancement in germline apoptosis and alterations in expressions of ced-9, ced-4, ced-3, and egl-1 governing cell apoptosis. In addition, aged PLA-MPs resulted in more severe increase in expression of DNA damage related genes (cep-1, mrt-2, hus-1, and clk-2) compared to pristine PLA-MPs, and the alterations in expression of ced-9, ced-4, ced-3, and egl-1 in pristine and aged PLA-MPs could be reversed by RNAi of cep-1, mrt-2, hus-1, and clk-2. Besides this, enhanced germline apoptosis in pristine and aged PLA-MPs exposed animals was also suppressed by RNAi of cep-1, mrt-2, hus-1, and clk-2. Therefore, our results suggested the more severe exposure risk of aged PLA-MPs than pristine PLA-MPs in causing reproductive toxicity, which was associated with the changed physicochemical properties and DNA damage induced germline apoptosis.

Exposure to large-size particulate air pollution (PM2.5 or PM10) has been reported to increase risks of aging-related diseases and human death, indicating the potential pro-aging effects of airborne nanomaterials with ultra-fine particle size (which have been widely applied in various fields). However, this hypothesis remains inconclusive. Here, a meta-analysis of 99 published literatures collected from electronic databases (PubMed, EMBASE and Cochrane Library; from inception to June 2023) was performed to confirm the effects of nanomaterial exposure on aging-related indicators and molecular mechanisms in model animal C. elegans. The pooled analysis by Stata software showed that compared with the control, nanomaterial exposure significantly shortened the mean lifespan [standardized mean difference (SMD) = -2.30], reduced the survival rate (SMD = -4.57) and increased the death risk (hazard ratio = 1.36) accompanied by upregulation of ced-3, ced-4 and cep-1, while downregulation of ctl-2, ape-1, aak-2 and pmk-1. Furthermore, multi-transcriptome data associated with nanomaterial exposure were retrieved from Gene Expression Omnibus (GSE32521, GSE41486, GSE24847, GSE59470, GSE70509, GSE14932, GSE93187, GSE114881, and GSE122728) and bioinformatics analyses showed that pseudogene prg-2, mRNAs of abu, car-1, gipc-1, gsp-3, kat-1, pod-2, acdh-8, hsp-60 and egrh-2 were downregulated, while R04A9.7 was upregulated after exposure to at least two types of nanomaterials. Resveratrol (abu, hsp-60, pod-2, egrh-2, acdh-8, gsp-3, car-1, kat-1, gipc-1), naringenin (kat-1, egrh-2), coumestrol (egrh-2) or swainsonine/niacin/ferulic acid (R04A9.7) exerted therapeutic effects by reversing the expression levels of target genes. In conclusion, our study demonstrates the necessity to use phytomedicines that target hub genes to delay aging for populations with nanomaterial exposure.

Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of the loss of epithelial features concomitant with the acquisition of mesenchymal features. Activation of EMT in cancer facilitates the acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal markers, confers survival advantages for cancer cells in constantly changing environments during metastasis.

RNAseq analysis was performed to assess genome-wide transcriptional changes in cancer cells depleted for histone regulators FLASH, NPAT, and SLBP. Quantitative PCR and Western blot were used for the detection of mRNA and protein levels. Computational analysis was performed on distinct sets of genes to determine the epithelial and mesenchymal score in cancer cells and to correlate FLASH expression with EMT markers in the CCLE collection.

We demonstrate that loss of FLASH in cancer cells gives rise to a hybrid E/M phenotype with high epithelial scores even in the presence of TGFβ, as determined by computational methods using expression of predetermined sets of epithelial and mesenchymal genes. Multiple genes involved in cell-cell junction formation are similarly specifically upregulated in FLASH-depleted cells, suggesting that FLASH acts as a repressor of the epithelial phenotype. Further, FLASH expression in cancer lines is inversely correlated with the epithelial score. Nonetheless, subsets of mesenchymal markers were distinctly up-regulated in FLASH, NPAT, or SLBP-depleted cells.

The ZEB1^low/SNAIL^high/E-cadherin^high phenotype described in FLASH-depleted cancer cells is driving a hybrid E/M phenotype in which epithelial and mesenchymal markers coexist.