Silica nanoparticles (SiNPs) have been reported to induce pulmonary fibrosis (PF) with an unknown mechanism. Recently, the activation of autophagy, a lysosome-dependent cell degradation pathway, by SiNPs has been identified in alveolar epithelial cells (AECs). However, the underlying mechanism and the relevance of SiNPs-induced autophagy to the development of PF remain elusive. Here, we report that autophagy dysfunction and subsequent apoptosis in AECs are involved in SiNPs-induced PF. SiNPs engulfed by AECs enhance autophagosome accumulation and apoptosis both in vivo and in vitro. Mechanically, SiNPs block autophagy flux through impairing lysosomal degradation via acidification inhibition. Lysosomal reacidification by cyclic-3′,5′-adenosine monophosphate (cAMP) significantly enhances autophagic degradation and attenuate apoptosis. Importantly, enhancement of autophagic degradation by rapamycin protects AECs from apoptosis and attenuates SiNPs-induced PF in the mouse model. Altogether, our data demonstrate a repressive effect of SiNPs on lysosomal acidification, contributing to the decreased autophagic degradation in AECs, thus leading to apoptosis and subsequent PF. These findings may provide an improved understanding of SiNPs-induced PF and molecular targets to antagonize it.

Few epidemiological studies have investigated associations of exposure to multiple metals with thyroid hormone homeostasis, especially for the pregnant women. Among all the 1644 participants enrolled in Hangzhou Birth Cohort Study (HBCS) at baseline, a total of 915 pregnant women with complete data of interest were analyzed. Eleven metals were measured in blood samples collected around 25 weeks gestation. Serum levels of thyroid hormones including free triiodothyronine (FT3), total triiodothyronine (TT3), free thyroxine (FT4), total thyroxine (TT4) and thyroid-stimulating hormone (TSH) were abstracted from the medical records. Relationships between tertiles of metal levels (setting the lowest tertile as the reference) and percent changes in thyroid hormones were estimated by multivariable adjusted linear regression models. Five metals [arsenic (As), selenium (Se), manganese (Mn), nickel (Ni), antimony (Sb)] were significantly linked to decreased levels of one or more thyroid hormones based on trend tests in the single-metal models. Percent changes [95% confidence intervals (CIs)] in thyroid hormones for the third tertiles of metals remained significant between FT3 and As [-3.53% (-5.48%, -1.54%)]; and between TT3 and As [-4.19% (-7.00%, -1.31%)]; and between FT4 and Mn [-2.05% (-3.49%, -0.58%)], Sb [-1.99% (-3.44%, -0.52%)] in the multiple-metal models. Thyroid hormone concentrations were reversely related to the levels of blood metals of As, Mn and Sb among Chinese pregnant women. Additional prospective studies are warranted to confirm the causality. Paper capsule: Exposure to multiple metals was reversely associated with one or more thyroid hormones in the Chinese pregnant women.

Colorectal cancer (CRC) is one of the most common cancers worldwide and its metastasis accounts for the majority of deaths. However, the molecular mechanisms underlying CRC progression are not well characterized. In this study, we identified miR‐409‐3p as a tumor suppressor of CRC. MiR‐409‐3p expression was significantly downregulated in CRC tissue compared to adjacent non‐tumor tissue, and reduced miR‐409‐3p expression was correlated with CRC metastasis. In vitro and in vivo studies revealed that miR‐409‐3p negatively regulated CRC metastatic capacities, including suppressing cancer cell migration, invasion and metastasis. To explore the mechanism of action of miR‐409‐3p, we adopted a pathway and pathophysiological event‐based target screening and validation approach, and found nine known metastasis‐related genes as potential targets. The 3′‐UTR binding assays between the candidates and miR‐409‐3p suggested that only GAB1, NR4A2 and LMO4 were directly regulated by the miRNA. However, endogenous expression analysis revealed that only GAB1 was modulated by miR‐409‐3p in CRC cells at both the mRNA and protein levels. Furthermore, we provided evidence to conclude that GAB1 was partially responsible for miR‐409‐3p‐mediated metastasis. Taken together, our data demonstrate that miR‐409‐3p is a metastatic suppressor, and post‐transcriptional inhibition of the oncoprotein GAB1 is one of the mechanisms of action of this miRNA. Our finding suggests miR‐409‐3p might be a novel target for CRC metastasis treatment.