Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure.

Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity.

Sodium butyrate alleviates lead-induced neuroinflammation and improves cognitive and memory impairment through the ACSS2/H3K9ac/BDNF pathway.

Lead is an environmentally widespread neurotoxic pollutant. Although the neurotoxicity of lead has been found to be closely associated with metabolic disorders, the effects of short-chain fatty acids on the neurotoxicity of lead and its mechanisms have not yet been explored. In this study, the results of open field tests and Morris water maze tests demonstrated that chronic lead exposure caused learning and memory deficits and anxiety-like symptoms in mice. The serum butyric acid content of lead-treated mice decreased in a dose-dependent manner, and oral administration of butyrate significantly improved cognitive memory impairment and anxiety symptoms in lead-exposed mice. Moreover, butyrate alleviated neuroinflammation caused by lead exposure by inhibiting the STAT3 signaling in microglia. Butyrate also promoted the expression of acetyl-CoA synthetase ACSS2 in hippocampal neurons, thereby increasing the content of acetyl-CoA and restoring the expression of both histone H3K9ac and the downstream BDNF. We also found that the median butyric acid concentration in high-lead exposure humans was remarkably lower than that in the low-lead exposure humans (45.16 µg/L vs. 60.92 µg/L, P < 0.01), and that butyric acid significantly mediated the relationship of lead exposure with the Montreal cognitive assessment scores, with a contribution rate of 27.57 %. In conclusion, our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced neurotoxicity.

Stanniocalcin 1 promotes lung metastasis of breast cancer by enhancing EGFR-ERK-S100A4 signaling.

Lung metastasis is the leading cause of breast cancer-related death. The tumor microenvironment contributes to the metastatic colonization of tumor cells in the lungs. Tumor secretory factors are important mediators for the adaptation of cancer cells to foreign microenvironments. Here, we report that tumor-secreted stanniocalcin 1 (STC1) promotes the pulmonary metastasis of breast cancer by enhancing the invasiveness of tumor cells and promoting angiogenesis and lung fibroblast activation in the metastatic microenvironment. The results show that STC1 modifies the metastatic microenvironment through its autocrine action on breast cancer cells. Specifically, STC1 upregulates the expression of S100 calcium-binding protein A4 (S100A4) by facilitating the phosphorylation of EGFR and ERK signaling in breast cancer cells. S100A4 mediates the effect of STC1 on angiogenesis and lung fibroblasts. Importantly, S100A4 knockdown diminishes STC1-induced lung metastasis of breast cancer. Moreover, activated JNK signaling upregulates STC1 expression in breast cancer cells with lung-tropism. Overall, our findings reveal that STC1 plays important role in breast cancer lung metastasis.

NLRP3 activation in microglia contributes to learning and memory impairment induced by chronic lead exposure in mice.

Lead (Pb)-induced microglial activation and neuroinflammation has been considered as one of the main pathological events of Pb neurotoxicity. The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. However, the relationship between chronic Pb exposure and neurogenic NLRP3 inflammasome is unclear. Therefore, the aim of this study was to characterize the role of NLRP3 inflammasome activation during the chronic Pb exposure using in vitro and in vivo models. Our results showed that chronic Pb exposure induce learning and memory impairment in mice, mainly related to the activation of microglia and NLRP3 inflammasome. This phenomenon was reversed in mice by treating with the NLRP3 inhibitor MCC950 and using NLRP3-/- mice. In addition, Pb caused the activation of NLRP3 inflammasome, the production of mitochondrial ROS (mtROS), and mitochondrial Ca2+ overload in BV2 cells. Amelioration of mtROS abolished Pb-induced NLRP3 inflammasome activation. Moreover, after regulation of Ca2+ redistribution, mtROS and NLRP3 inflammasome activation was restored. In conclusion, NLRP3 inflammasome activation in microglia plays a vital role in Pb neurotoxicity, by a novel mechanism of enhancing mtROS production and Ca2+ redistribution.

Lactobacillus plantarum WSJ-06 alleviates neurobehavioral injury induced by lead in mice through the gut microbiota.

Chronic lead exposure can result in cognitive dysfunction and behavioral disorders. However, the current treatments for alleviating lead poisoning have many side effects. Previous studies have suggested that probiotics may have the potential to ameliorate neurotoxicity caused by lead exposure. This study determines the alleviating effects of Lactobacillus plantarum WSJ-06 on neurological disorders induced by chronic lead exposure from the perspective of the gut microbiota and serum metabolites. The results showed that treatment with Lactobacillus plantarum WSJ-06 alleviated memory dysfunction and reduced the levels of inflammatory cytokines in the serum and hippocampus induced by lead exposure. In addition, Lactobacillus plantarum WSJ-06 partially restored the lead-induced gut microbiota dysbiosis. It also increased the proportion of some beneficial metabolites in the serum, such as arachidonic acid, tryptophan hydroxylase, serotonin, vitamin B12, trehalose, and kynurenic acid, and decreased some metabolites in the serum, such as LPS 20:5 and L-kynurenine. A correlation analysis further indicated that lead-induced neurobehavioral disorders were related to intestinal microbiota (the [Eubacterium]_siraeum_group, Roseburia, Lactobacillus, etc) and serum metabolites (LPS 20:5, serotonin, vitamin B12, etc). In conclusion, Lactobacillus plantarum WSJ-06 alleviated neuroinflammation and memory impairment caused by lead exposure by modulating the gut microbiota and metabolites in the serum.

DNA adduct formation and reduced EIF4A3expression contributes to benzo[a]pyrene-induced DNA damage in human bronchial epithelial BEAS-2B cells.

Benzo[a]pyrene(B[a]P) is a known human carcinogen. The ability of B[a]P to form stable DNA adducts has been repeatedly demonstrated. However, the relationship between DNA adduct formation and cell damage and its underlying molecular mechanisms are less well understood. In this study, we determined the cytotoxicity of benzo[a]pyrenediolepoxide, a metabolite of B[a]P, in human bronchial epithelial cells (BEAS-2B). The formation of BPDE-DNA adducts was quantified using a dot blot. DNA damage resulting from the formation of BPDE-DNA adducts was detected by chromatin immuneprecipitation sequencing (ChIP-Seq), with minor modifications, using specific antibodies against BPDE. In total, 1846 differentially expressed gene loci were detected between the treatment and control groups. The distribution of the BPDE-bound regions indicated that BPDE could covalently bind with both coding and non-coding regions to cause DNA damage. However, the majority of binding occurred at protein-coding genes. Furthermore, among the BPDE-bound genes, we found 16 protein-coding genes related to DNA damage repair. We explored the response to BPDE exposure at the transcriptional level using qRT-PCR and observed a strong inhibition of EIF4A3. We then established an EIF4A3 overexpression cell model and performed comet assays, which revealed that the levels of DNA damage in EIF4A3-overexpressing cells were lower than those in normal cells following BPDE exposure. This suggests that the BPDE-DNA adduct-induced reduction in EIF4A3 expression contributed to the DNA damage induced by BPDE exposure in BEAS-2B cells. These novel findings indicate that ChIP-Seq combined with BPDE specific antibody may be used for exploring the underlying mechanism of DNA adduct-induced genomic damage.

The linc00152 Controls Cell Cycle Progression by Regulating CCND1 in 16HBE Cells Malignantly Transformed by Cigarette Smoke Extract.

Smoking is one of the major environmental risk factors for lung cancer. In recent years, the role of long-chain noncoding RNAs (lncRNAs) in chemical carcinogenesis has attracted extensive research attention. In this study, we treated human bronchial epithelial cells with cigarette smoke extract (CSE) at a dose of 2 µg/ml to establish a malignantly transformed cellular model (16HBE-M). Screening of lncRNAs highly expressed in transformed cells via differential analysis revealed a crucial role of linc00152 in CSE-induced malignant transformation. The linc00152 serum level in CSE-exposed individuals was increased in a dose-dependent manner and its high expression associated with metastasis and proliferation of lung cancer tissue. In malignantly transformed 16HBE-M cells, linc00152 was involved in regulation of cell adhesion, epithelial transition and other malignant phenotypes, which in turn, affected in vivo metastasis. Interference with linc00152 expression led to G1/S arrest and inhibition of proliferation of 16HBE-M and H1299 cells. Furthermore, linc00152 promoted cyclin D1 expression and G1/S transition by functioning as an endogenous competitive RNA targeting miR-193b. Our collective findings supported a critical regulatory role of linc00152 in cell cycle alterations and abnormal proliferation in CSE-induced malignant transformation of human bronchial epithelial cells.

Silencing of lncRNA AFAP1-AS1 suppressed lung cancer development by regulatory mechanism in cis and trans.

Although the long noncoding RNA AFAP1-AS1 has been shown to be involved in various types of cancer, its involvement in lung cancer remains poorly understood. In the current study, we found that AFAP1-AS1 was substantially over expressed in lung cancer tissues and cell lines. In addition, AFAP1-AS1 expression level was proven to be associated with the malignant features of lung cancer. Knockdown of AFAP1-AS1 significantly suppressed cell proliferation by increasing cell apoptosis and G0/G1 phase retardation of cell cycle in lung cancer cells. Furthermore, AFAP1-AS1 knockdown could suppress tumor growth of lung cancer in BALB/c nude mice. We also identified that AFAP1-AS1 silencing could influence the expression of AFAP1 and KRT1 on mRNA and protein level by cis and trans regulatory mechanism. Moreover, the oncogenic activities of AFAP1-AS1 on cell proliferation are partially mediated by KRT1. In summary, these findings demonstrate that AFAP1-AS1 plays an essential role in promoting lung cancer development in vitro and vivo. It indicated that AFAP1-AS1 is a promising prognostic predictor for patients with lung cancer.

Noncoding RNAs in Growth and Death of Cancer Cells.

The mammalian genomes are mostly comprised of noncoding genes. And mammalian genomes are characterized by pervasive expression of different types of noncoding RNAs (ncRNAs). In sharp contrast to previous collections, these ncRNAs show strong purifying selection evolutionary conservation. Previous studies indicated that only a small fraction of the mammalian genome codes for messenger RNAs destined to be translated into peptides or proteins, and it is generally assumed that a large portion of transcribed sequences-including pseudogenes and several classes of ncRNAs-do not give rise to peptides or proteins. However, ribosome profiling suggests that ribosomes occupy many regions of the transcriptome thought to be noncoding. Moreover, these observations highlight a potentially large and complex set of biologically regulated translational events from transcripts formerly thought to lack coding potential. Furthermore, accumulating evidence from previous studies has suggested that the novel translation products exhibit temporal regulation similar to that of proteins known to be involved in many biological activity processes. In this review, we focus on the coding potential of noncoding genes and ncRNAs. We also sketched the possible mechanisms for their coding activities. Overall, our review provides new insights into the word of central dogma and is an expansive resource of functional annotations for biomedical research. At last, the outcome of the majority of the translation events and their potential biological purpose remain an intriguing topic for future investigation.

Pluripotency transcription factors and cancer stem cells: small genes make a big difference.

Cancer stem cells (CSCs) are thought to drive uncontrolled tumor growth, and the existence of CSCs has recently been proven by direct experimental evidence, including tracing cell lineages within a growing tumor. However, CSCs must be analyzed in additional cancer types. Cancer stem cell-like cells (CSCLCs) are a good alternative system for the study of CSCs, which hold great promise for clinical applications. OCT4, NANOG, and SOX2 are three basic transcription factors that are expressed in both CSCLCs and embryonic stem cells (ESCs). These transcription factors play critical roles in maintaining the pluripotence and self-renewal characteristics of CSCLCs and ESCs. In this review, we discuss the aberrant expression, isoforms, and pseudogenes of OCT4, NANOG, and SOX2 in the CSCLC niche, which contribute to the major differences between CSCLCs and ESCs. We also highlight an anticancer therapy that involves killing specific cancer cells directly by repressing the expression of OCT4, NANOG, or SOX2. Importantly, OCT4, NANOG, and SOX2 provide great promise for clinical applications because reducing their expression or blocking the pathways in which they function may inhibit tumor growth and turn-off the cancer "switch." In the future, a clear understanding of transcription factor regulation will be essential for elucidating the roles of OCT4, NANOG, and SOX2 in tumorigenesis, as well as exploring their use for diagnostic and therapeutic purposes.