Previous studies have shown that long-term exposure to fine particulate matter (PM_2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM_2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM_2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2^−/− (KO) mice were exposed to the real-ambient system for six weeks. After PM_2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2^−/− mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM_2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM_2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM_2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM_2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM_2.5 exposure. Nrf2 facilitates lung injury during PM_2.5 exposure and CYP2E1 metabolism is involved in this process.

Folate and vitamin B₁₂ involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B₁₂ in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients’ clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B₁₂ levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15–0.60), 0.33 (0.17–0.65), and 0.19 (0.09–0.38). Compared to the subjects in the lowest quartile of plasma vitamin B₁₂, only the subjects in the highest quartile of vitamin B₁₂ exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02–3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B₁₂ levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B₁₂ than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B₁₂ levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results.

Exposure to fine particulate matter (PM_2.5) could damage multiple organs and systems. Recent epidemiological studies have shown that PM_2.5 can disrupt dynamic balance of thyroid hormone (TH). However, the underlying mechanism by which PM_2.5 interferes with TH remains unclear. This study evaluated the role of Gli-similar3 (GLIS3) in the effect of PM_2.5 on TH synthesis in mice using a real-ambient exposure system, in Shijiazhuang City, Hebei Province. The PM_2.5exposure group (PM) and filtered air group (FA) were placed in the exposure device for four and eight weeks. The results showed that the PM_2.5 exposure altered the structure of the thyroid gland. Moreover, after PM_2.5 exposure for eight weeks, the exposure level of free thyroxine (FT4) increased and the expression level of thyroid stimulating hormone (TSH) decreased in serum of mice. In addition, PM_2.5 exposure significantly increased the expression of proteins related to thyroid hormone synthesis, such as sodium iodide transporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG). Next, we found that GLIS3 and thyroid transcription factor Paired box 8 (PAX8) also increased after PM_2.5 exposure. In order to further explore the potential molecular mechanism, we carried out transcriptome sequencing. KEGG analysis of the top 10 pathways revealed that the Ras-associated protein 1 (Rap1) signaling pathway could activate transcription factors and is related to thyroid cell survival. Additionally, PM_2.5 exposure significantly increased the protein levels of Rap1 and its active form (Rap1 +GTP). We speculate that the active state of Rap1 is believed to be involved in activating the expression of transcription factor GLIS3. In conclusion, PM_2.5 exposure induces histological changes in the thyroid gland and thyroid dysfunction in mice. The exposure activates GLIS3 through the Rap1/PI3K/AKT pathway to promote the expression of proteins related to thyroid hormone synthesis, leading to increased dysregulating TH homeostasis.

Epidemiological studies show conflicting results regarding the link between serum triglyceride and the risk of prostate cancer and breast cancer. Therefore, we performed a meta-analysis of prospective studies to clarify this association. We searched PubMed, EMBASE, the Chinese Biomedical Database (CBM), and the China National Knowledge Infrastructure (CNKI) database to identify relevant prospective studies of the relationship between serum triglyceride and prostate cancer and breast cancer risk. Study-specific estimates adjusting for potential confounders were combined to evaluate a summary relative risks (RRs) and 95% confidence intervals (95% CIs) using a fixed- or random-effects model. A total of 11 prospective studies (619,410 subjects and 15,691 incident prostate cancer patients) and 8 prospective studies (590,878 subjects and 12,177 incident breast cancer patients) were respectively included in our meta-analysis to assess the associations of serum triglyceride with prostate cancer and breast cancer risk. The pooled adjusted RR estimates for prostate cancer and breast cancer for the highest versus the lowest exposure levels of serum triglycerides were 0.95 (95% CI: 0.87-1.04) and 0.94 (95% CI: 0.87-1.00), respectively. Additionally, a dose-response analysis revealed that serum levels of triglycerides were not associated with the risk of prostate cancer and breast cancer. We found that serum triglyceride was not related to the risk of prostate cancer and breast cancer.

Cytochrome P450 (CYP450) can mediate fine particulate matter (PM_2.5) exposure leading to lung injury. Nuclear factor E2-related factor 2 (Nrf2) can regulate CYP450 expression; however, the mechanism by which Nrf2^−/− (KO) regulates CYP450 expression via methylation of its promoter after PM_2.5 exposure remains unclear. Here, Nrf2^−/− (KO) mice and wild-type (WT) were placed in a PM_2.5 exposure chamber (PM) or a filtered air chamber (FA) for 12 weeks using the real-ambient exposure system. The CYP2E1 expression trends were opposite between the WT and KO mice following PM_2.5 exposure. After exposure to PM_2.5,CYP2E1 mRNA and protein levels were increased in WT mice but decreased in KO mice, and CYP1A1 expression was increased after exposure to PM_2.5 in both WT and KO mice. CYP2S1 expression decreased after exposure to PM_2.5 in both the WT and KO groups. We studied the effect of PM_2.5 exposure on CYP450 promoter methylation and global methylation levels in WT and KO mice. In WT and KO mice in the PM_2.5 exposure chamber, among the methylation sites examined in the CYP2E1 promoter, the CpG2 methylation level showed an opposite trend with CYP2E1 mRNA expression. The same relationship was evident between CpG3 unit methylation in the CYP1A1 promoter and CYP1A1 mRNA expression, and between CpG1 unit methylation in the CYP2S1 promoter and CYP2S1 mRNA expression. This data suggests that methylation of these CpG units regulates the expression of the corresponding gene. After exposure to PM_2.5, the expression of the DNA methylation markers ten-eleven translocation 3 (TET3) and 5-hydroxymethylcytosine (5hmC) was decreased in the WT group but significantly increased in the KO group. In summary, the changes in CYP2E1, CYP1A1, and CYP2S1 expression in the PM_2.5 exposure chamber of WT and Nrf2^−/− mice might be related to the specific methylation patterns in their promoter CpG units. After exposure to PM_2.5, Nrf2 might regulate CYP2E1 expression by affecting CpG2 unit methylation and induce DNA demethylation via TET3 expression. Our study revealed the underlying mechanism for Nrf2 to regulate epigenetics after lung exposure to PM_2.5.

Mesenchymal stromal cells (MSCs) widely exist in many tissues and have multiple differentiation potential and immunomodulatory capacities. Recently, MSCs have become promising tools for the treatment of various degenerative disorders and autoimmune diseases. The properties of MSCs could be modified in different microenvironments. Thus, it is important to explore the factors controlling MSC function. The presence of Toll-like receptors (TLRs) in MSCs was demonstrated according to previous studies. Consistently, we also illustrated the expression of TLRs in both murine and human MSCs, and displayed that the expression patterns of TLRs in MSCs from different sources. Furthermore, we explored the role of TLR and TLR signaling pathway in MSCs. Interestingly, activation of TLR4-induced expression of cytokines and some specific genes in MSCs. However, MSCs retained much lower mRNA level compared with macrophages. We explored the expression of CD14 in MSCs from different sources, which played a vital role in TLR4 signaling pathway, and found that MSCs are almost negative for CD14. Moreover, only partial activation of TLR4 signaling pathway was observed in MSCs, with no activation of AKT, NF-κB and P38. Here, in the study we defined TLR expression, function and activation in MSCs, which is critical for designing MSC-based therapies.