The Molecular Mechanisms of Ferroptosis and Its Role in Blood-Brain Barrier Dysfunction.

The blood-brain barrier (BBB) is a selective, semi-permeable layer of endothelial cells that protects the central nervous system from harmful substances circulating in blood. It is one of the important barriers of the nervous system. BBB dysfunction is an early pathophysiological change observed in nervous system diseases. There are few treatments for BBB dysfunction, so this motivates the review. Ferroptosis is a novel cell death mode caused by iron-mediated lipid peroxidation accumulation, which has recently attracted more attention due to its possible role in nervous system disorders. Studies have shown that lipid peroxidation and iron accumulation are related to the barrier dysfunction, especially the expression of tight junction proteins. Therefore, examination of the relationship between ferroptosis and BBB dysfunction may reveal new targets for the treatment of brain diseases.

Functional characterization of a diuretic hormone receptor associated with desiccation, starvation and temperature tolerance in gypsy moth, Lymantria dispar.

Variety of diuretic hormone neuropeptides is known to regulate water and ion balance in invertebrates. By activating their specific neuropeptide, diuretic hormone receptor (DHR) transmits extracellular signals into the cell, and then produces functional cell activity, which plays an important role in regulating physiology and behavior. However, little is known about the function of DHR gene in Lymantria dispar. DHR gene was firstly identified in L. dispar and its physiological functions were investigated using RNA interference (RNAi) technology. The results showed that except for the 6th instar larvae, the expression levels of DHR gene in the larval stages are higher than that in the egg, pupal and adult stages. The DHR gene is highly expressed in hindgut and midgut tissues. The L. dispar larvae significantly increased their water content and high temperature tolerance after the DHR was silenced, while decreasing excretion and feeding behavior. The physiological function of DHR is associated with desiccation, high temperature and starvation resistance. DHR could contribute to future development of novel insecticide to manage this global forest pest population.

miRNA-34c-5p targets Fra-1 to inhibit pulmonary fibrosis induced by silica through p53 and PTEN/PI3K/Akt signaling pathway.

Silica dust particles are representative of air pollution and long-term inhalation of silicon-containing dust through the respiratory tract can cause pulmonary fibrosis. Epithelial-mesenchymal transformation (EMT) plays an important role in the development of fibrosis. This process can relax cell-cell adhesion complexes and enhance cell migration and invasion properties of these cells. Dysregulation of microRNA-34c (miR-34c) is highly correlated with organ fibrosis including pulmonary fibrosis. In this study, we found that miR-34c-5p could alleviate the occurrence and development of silica-mediated EMT. Fos-related antigen 1 was identified as a functional target of miR-34c-5p by bioinformatics analysis and the dual luciferase gene reporting assay. Importantly, chemically induced up-regulation of hsa-miR-34c-5p correlated inversely with the expression of Fra-1 and further exploration found that the miR-34c-5p/Fra-1 axis inhibits the activation of the phosphatase and tensin homolog deleted on chromosome 10/phosphatidylinositol-4,5-bisphosphate3-kinase/protein kinase B (PTEN/PI3K/AKT) signaling pathway. In addition, through interaction with PTEN/p53 it inhibits the proliferation and migration of human bronchial epithelial cells stimulated by silica, and promotes cell apoptosis, thereby preventing EMT. This finding provides a promising biomarker for the diagnosis and prognosis of pulmonary fibrosis. Furthermore, overexpression of miR-34c-5p represents a potential therapeutic approach.

Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway.

Long-term exposure to crystalline silica particles leads to silicosis characterized by persistent inflammation and progressive fibrosis in the lung. So far, there is no specific treatment to cure the disease other than supportive care. In this study, we examined the effects of metformin, a prescribed drug for type || diabetes on silicosis and explored the possible mechanisms in an established rat silicosis model in vivo, and an in vitro co-cultured model containing human macrophages cells (THP-1) and human bronchial epithelial cells (HBEC). Our results showed that metformin significantly alleviated the inflammation and fibrosis of lung tissues of rats exposed to silica particles. Metformin significantly reduced silica particle-induced inflammatory cytokines including transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in rat lung tissue and HBEC culture supernatant. The protein levels of Vimentin and α-smooth muscle actin (α-SMA) were significantly decreased by metfomin while expression level of E-cadherin (E-Cad) increased. Besides, metformin increased the expression levels of phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK), microtubule-associated protein (MAP) light chain 3B (LC3B) and Beclin1 proteins, and reduced levels of phosphorylated mammalian target of rapamycin (p-mTOR) and p62 proteins in vivo and in vitro. These results suggest that metformin could inhibit silica-induced pulmonary fibrosis by activating autophagy through the AMPK-mTOR pathway.

Emodin attenuates silica-induced lung injury by inhibition of inflammation, apoptosis and epithelial-mesenchymal transition.

Silicosis is a fatal pulmonary disease caused by the inhalation of silica dust, and characterized by inflammation and fibrosis of the lung, with no effective treatment to date. Here we investigate the effect of emodin, an anthraquinone derivative isolated from rhubarb using a mouse silicosis model and in vitro cultured human macrophages and alveolar epithelial cells. Results from histological examination indicated that emodin reduced the degree of alveolitis and fibrosis in the lungs of mice exposed to silica particles. We also demonstrated that emodin effectively inhibited the phosphorylation of Smad3 and NF-κB and reduced the levels of inflammatory factors in the lung tissue of mice treated with silica particles. In addition, we found that emodin inhibited apoptosis and demonstrated an anti-fibrotic effect by down-regulating the pro-apoptotic protein Bax and up-regulating the anti-apoptotic protein Bcl-2. Furthermore, emodin increased E-cadherin levels, reduced the expression of Vimentin, α-SMA and Col-I, as well as pro-inflammatory factors TGF-ß1, TNF-α and IL-1ß in vivo and in vitro. These results suggested that emodin can regulate epithelial-mesenchymal transition (EMT) through the inhibition of the TGF-ß1/Smad3 signaling pathway and the NF-κB signaling pathway to prevent alveolar inflammation and apoptotic process. Overall, this study showed that emodin can alleviate pulmonary fibrosis in silicosis through regulating the inflammatory response and fibrotic process at multiple levels.