Association between per- and polyfluoroalkyl substances and semen quality.

Some studies have suggested that perfluoroalkyl and polyfluoroalkyl substance (PFAS) exposure may be associated with semen quality in the general population, but with inconsistent results. To identify a more precise relationship between them, a meta-analysis was performed. We searched Embase, the PubMed, The Cochrane Library, Ovid databases, and Web of Science databases (before March 2022) for appropriate studies on the correlations of PFAS exposure with semen parameters. We extracted ß value and 95% confidence intervals (CIs) to conduct meta-analysis. Subgroup analyses was performed by sample size, geographic location, and sample type. A total of seven articles involving 2190 participants were included in this study. The concentrations of perfluorooctanoic acid (PFOA) (ß value = - 1.38; 95% CI: - 2.44, - 0.32) and perfluorononanoic acid (PFNA) (ß value = - 1.31, 95% CI: - 2.35, - 0.26) were negatively associated with sperm progressive motility. Subgroup analysis revealed that PFNA exposure was related to sperm morphology in studies with the sample size exceeding 200 people (ß value = - 0.14; 95% CI: - 0.26, - 0.01). Our study supports that exposure to some PFASs (e.g., PFNA, PFOA) may be associated with semen quality, such as lower sperm progressive motility. Therefore, it is of great significance for the prevention of male infertility by control the use of PFASs.

DNA methylation was involved in total glucosides of paeony regulating ERα for the treatment of female systemic lupus erythematosus mice.

Total glucosides of paeony (TGP) is a bioactive compound extracted from paeony roots and has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the therapy of autoimmune diseases remains unclear. ERα has a pro-inflammatory role in SLE disease. In this study, we found that TGP treatment significantly decreased the expression of ERα by up-regulating ERα promoter methylation levels. Further investigation revealed that treatment with TGP increased the expression of DNMT in lupus mice. We also used DNA methyltransferase inhibitors to verify whether DNA methylation was involved in these process. HE staining results showed that TGP can reduce renal injury in SLE mice. Moreover, cytokines including IFN-γ, IL6 and IL12 expression and dsDNA levels in serum were inhibited by TGP treatment. These findings indicate that TGP inhibits autoimmunity in SLE mice possibly by downregulate ERα expression, which may in turn be due to its ability to regulate the methylation status of the ERα promoter.

Central IKK2 Inhibition Ameliorates Air Pollution-Mediated Hepatic Glucose and Lipid Metabolism Dysfunction in Mice With Type II Diabetes.

Previous studies supported a role of hypothalamic inflammation in fine ambient particulate matter (PM2.5) exposure-mediated diabetes development. We therefore investigated the effects of PM2.5 exposure on insulin resistance and the disorders of hepatic glucose and lipid metabolism via hypothalamic inflammation. KKAy mice, a genetically susceptible model of type II diabetes mellitus, were administered intra-cerebroventricularly with IKK2 inhibitor (IMD-0354) and were exposed to either concentrated PM2.5 or filtered air (FA) for 4 weeks simultaneously via a versatile aerosol concentration exposure system. At the end of the exposure, fasting blood glucose and serum insulin were evaluated before epididymal adipose tissue and liver were collected, flow cytometry, quantitative PCR and Western blot were performed at euthanasia. We observed that intracerebroventricular administration of IMD-0354 attenuated insulin resistance, inhibited macrophage polarization to M1 phenotype in epididymal adipose tissue in response to PM2.5 exposure. Although the treatment did not affect hepatic inflammation or endoplasmic reticulum stress, it inhibited the expression of the enzymes for gluconeogenesis and lipogenesis in the liver. Therefore, our current finding indicates an important role of hypothalamic inflammation in PM2.5 exposure-mediated hepatic glucose and lipid metabolism disorder.

Curcumin Reactivates Silenced Tumor Suppressor Gene RARß by Reducing DNA Methylation.

Reactivation of tumor suppressor genes by nontoxic bioactive food component represents a promising strategy for cancer chemoprevention. Retinoic acid receptor ß (RARß), one member of the RAR receptor family, is considered as a tumor suppressor. Reduced expression of RARß has been reported in lung cancer and other solid tumors. DNA hypermethylation of the promoter region of RARß is a major mechanism for its silencing in tumors. Recently, curcumin has been considered as a potential DNA methyltransferase inhibitor. Herein, we demonstrated that curcumin significantly elevate RARß expression at the mRNA and protein levels in tested cancer cells. Additionally, curcumin decreased RARß promoter methylation in lung cancer A549 and H460 cells. Mechanistic study demonstrated that curcumin was able to downregulate the mRNA levels of DNMT3b. In a lung cancer xenograft node mice model, curcumin exhibited protective effect against weight loss because of tumor burden. Tumor growth was strongly repressed by curcumin treatment. As the results from in vitro, RARß mRNA were increased and DNMT3b mRNA were decreased by curcumin treatment compared with the mice in control group. Altogether, this study reveals a novel molecular mechanism of curcumin as a chemo-preventive agent for lung cancer through reactivation of RARß.

Mechanism of Dose-Dependent Regulation of UBE1L by Polyphenols in Human Bronchial Epithelial Cells.

Ubiquitin activating enzyme E1-like (UBE1L) is the activating enzyme for ISG15ylation (ISG15, interferon stimulated gene 15). UBE1L is thought to be a candidate tumor suppressor gene and has positive activity against stress responses such as viral infections. Both type I interferon and retinoic acid are known to induce UBE1L expression. However, the molecular mechanism of UBE1L regulation is unclear. Here, the effect of several chemopreventive polyphenols on UBE1L expression in human bronchial epithelial cells (Beas-2B) was investigated. Lower concentrations of curcumin, (-)-epigallocatechin-3-gallate (EGCG) and resveratrol upregulated UBE1L, while high concentrations of curcumin, EGCG and resveratrol downregulated UBE1L levels. Interestingly, curcumin, EGCG and resveratrol diminished intracellular reactive oxygen species (ROS) at lower concentrations but generated ROS at higher concentrations. The antioxidant N-acetylcysteine (NAC) increased UBE1L protein levels, while pro-oxidants such as hydrogen peroxide and tert-butyl hydroperoxide (tBHP) decreased UBE1L protein levels, indicating that the intracellular redox status is associated with UBE1L expression. Kinase inhibitors were used to examine the contribution of mitogen-activated protein kinase (MAPK) activity to the polyphenol-regulated UBE1L. Only the inhibition of c-Jun N-terminal kinase (JNK) significantly reduced UBE1L expression. Knockdown of nuclear factor erythroid-2 related factor-2 (Nrf2) caused a concomitant decrease in UBE1L protein levels. It is concluded from the above mentioned results that JNK/Nrf2 signal pathway is involved in the regulation of UBE1L via intracellular ROS status when cells came in contact with polyphenols.

Down-regulation of epidermal growth factor receptor by curcumin-induced UBE1L in human bronchial epithelial cells.

UBE1L, ubiquitin-activating enzyme E1-like, is the activating enzyme of ISG15ylation (ISG15, interferon stimulated gene 15). Loss of UBE1L and activation of epidermal growth factor receptor (EGFR) signaling are common events in lung carcinogenesis. Curcumin, a well-studied chemopreventive agent, is known to down-regulate EGFR. The present study demonstrated that curcumin decreased EGFR expression in human bronchial epithelial (HBE) Beas-2B cells and lung cancer A549 cells. For the first time, UBE1L was found to be induced by curcumin in HBE cells. Interestingly, overexpression of UBE1L reduced EGFR at posttranslational level in HBE cells. UBE1L triggered EGFR membrane internalization and promoted complex formation between ISG15 and EGFR. Curcumin decreased EGFR downstream signaling pAKT and nuclear factor κB (NF-κB). Overexpression or knockdown of UBE1L also resulted in down-regulation or up-regulation of phosphoinositide 3-kinase/AKT/NF-κB correspondently. In human samples, there was an inverse relationship between UBE1L and EGFR/AKT/NF-κB in non-small cell lung cancer tissues and adjacent tissues. These results uncover a novel chemopreventive mechanism of curcumin in inducing UBE1L and down-regulating EGFR signaling in HBE cells.