The Depside Derivative Pericodepside Inhibits Cancer Cell Metastasis and Proliferation by Suppressing Epithelial-Mesenchymal Transition.

A depside derivative, named pericodepside (2), along with the known depside proatranorin III (1), was isolated from the solid cultivation of an Ascochyta rabiei strain that heterologously expresses atr1 and atr2 that are involved in the biosynthesis of atranorin in a fruticose lichen, Stereocaulon alpinum. The structure of 2 was determined by 1D and 2D NMR and MS spectroscopic data. The structure of 2 consisted of a depside-pericosine conjugate, with the depside moiety being identical to that found in 1, suggesting that 1 acted as an intermediate during the formation of 2 through the esterification process. Pericodepside (2) strongly suppressed cell invasion and proliferation by inhibiting epithelial-mesenchymal transition and the transcriptional activities of ß-catenin, STAT, and NF-κB in U87 (glioma cancer), MCF-7 (breast cancer), and PC3 (prostate cancer) cell lines.

Recent insights into autophagy and metals/nanoparticles exposure.

Some anthropogenic pollutants, such as heavy metals and nanoparticles (NPs), are widely distributed and a major threat to environmental safety and public health. In particular, lead (Pb), cadmium (Cd), chromium (Cr), arsenic (As), and mercury (Hg) have systemic toxicity even at extremely low concentrations, so they are listed as priority metals in relation to their significant public health burden. Aluminum (Al) is also toxic to multiple organs and is linked to Alzheimer's disease. As the utilization of many metal nanoparticles (MNPs) gradually gain traction in industrial and medical applications, they are increasingly being investigated to address potential toxicity by impairing certain biological barriers. The dominant toxic mechanism of these metals and MNPs is the induction of oxidative stress, which subsequently triggers lipid peroxidation, protein modification, and DNA damage. Notably, a growing body of research has revealed the linkage between dysregulated autophagy and some diseases, including neurodegenerative diseases and cancers. Among them, some metals or metal mixtures can act as environmental stimuli and disturb basal autophagic activity, which has an underlying adverse health effect. Some studies also revealed that specific autophagy inhibitors or activators could modify the abnormal autophagic flux attributed to continuous exposure to metals. In this review, we have gathered recent data about the contribution of the autophagy/mitophagy mediated toxic effects and focused on the involvement of some key regulatory factors of autophagic signaling during exposure to selected metals, metal mixtures, as well as MNPs in the real world. Besides this, we summarized the potential significance of interactions between autophagy and excessive reactive oxygen species (ROS)-mediated oxidative damage in the regulation of cell survival response to metals/NPs. A critical view is given on the application of autophagy activators/inhibitors to modulate the systematic toxicity of various metals/MNPs.

Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii infected mice.

BACKGROUND: The neurotrophic parasite Toxoplasma gondii (T. gondii) has been implicated as a risk factor for neurodegenerative diseases. However, there is only limited information concerning its underlying mechanism and therapeutic strategy. Here, we investigated the effects of T. gondii chronic infection on the goal-directed cognitive behavior in mice. Moreover, we evaluated the preventive and therapeutic effect of dimethyl itaconate on the behavior deficits induced by the parasite. METHODS: The infection model was established by orally infecting the cysts of T. gondii. Dimethyl itaconate was intraperitoneally administered before or after the infection. Y-maze and temporal order memory (TOM) tests were used to evaluate the prefrontal cortex-dependent behavior performance. Golgi staining, transmission electron microscopy, indirect immunofluorescence, western blot, and RNA sequencing were utilized to determine the pathological changes in the prefrontal cortex of mice. RESULTS: We showed that T. gondii infection impaired the prefrontal cortex-dependent goal-directed behavior. The infection significantly downregulated the expression of the genes associated with synaptic transmission, plasticity, and cognitive behavior in the prefrontal cortex of mice. On the contrary, the infection robustly upregulated the expression of activation makers of microglia and astrocytes. In addition, the metabolic phenotype of the prefrontal cortex post infection was characterized by the enhancement of glycolysis and fatty acid oxidation, the blockage of the Krebs cycle, and the disorder of aconitate decarboxylase 1 (ACOD1)-itaconate axis. Notably, the administration of dimethyl itaconate significantly prevented and treated the cognitive impairment induced by T. gondii, which was evidenced by the improvement of behavioral deficits, synaptic ultrastructure lesion and neuroinflammation. CONCLUSION: The present study demonstrates that T. gondii infection induces the deficits of the goal-directed behavior, which is associated with neuroinflammation, the impairment of synaptic ultrastructure, and the metabolic shifts in the prefrontal cortex of mice. Moreover, we report that dimethyl itaconate has the potential to prevent and treat the behavior deficits.

Age-related miRNAs dysregulation and abnormal BACE1 expression following Pb exposure in adolescent mice.

Numbers of emerging evidence suggest that lead (Pb) exposure contributes to cognitive decline and might also increase the risk of Alzheimer's disease (AD) dementia in the elderly by increasing the beta-amyloid burden. Here, we aimed to characterize the effects of Pb on the post-transcriptional regulators, microRNAs (miRNAs), which may participate in AD pathogenesis. At first, early chronic Pb exposure on neuronal miRNAs expression with increasing aging was profiled to elucidate the association of three selected miRNAs with ß-site APP-cleaving enzyme 1(BACE1), a rate-limiting enzyme for ß-amyloid (Aß) production. Next, we verified changes in BACE1 were observed by regulating miRNAs expression in vitro. While Pb promoted BACE1 levels, BACE1 levels were reduced in SH-SY5Y cells with miR-124-3p mimic, suggesting for the first time that miR-124-3p/BACE1 pathway modulation is critically involved in Pb-induced AD-like amyloidogenic processing. Findings from this study could provide new insight into the molecular mechanisms of Pb-associated neurodegenerative pathogenesis from an epigenetic perspective.

Highly Efficient Cleavage of Ether Bonds in Lignin Models by Transfer Hydrogenolysis over Dual-Functional Ruthenium/Montmorillonite.

Cleavage of ether bonds is a crucial but challenging step for lignin valorization. To efficiently realize this transformation, the development of robust catalysts or catalytic systems is required. In this study, montmorillonite (MMT)-supported Ru (denoted as Ru/MMT) is fabricated as a dual-functional heterogeneous catalyst to cleave various types of ether bonds through transfer hydrogenolysis without using any additional acids or bases. The prepared Ru/MMT material is found to efficiently catalyze the cleavage of various lignin models and lignin-derived phenols; cyclohexanes (fuels) and cyclohexanols (key intermediates) are the main products. The synergistic effect between electron-enriched Ru and the acidic sites on MMT contributes to the excellent performance of Ru/MMT. Systematic studies reveal that the reaction proceeds through two possible reaction pathways, including the direct cleavage of ether bonds and the formation of intermediates with one hydrogenated benzene ring, for all examined types of ether bonds, namely, 4-O-5, α-O-4, and ß-O-4.