Alcohol Exposure Induces Depressive and Anxiety-like Behaviors via Activating Ferroptosis in Mice

Alcohol use disorder (AUD) is a global public health problem and is frequently comorbid with mental disorders, including anxiety and depression. Ferroptosis is an iron-dependent cell death, which is involved in the pathological process of various diseases such as neurodegenerative diseases, but the role of ferroptosis in the mediation of AUD and its induced mental disorders is unclear. In this study, we aimed to investigate whether ferroptosis was involved in alcohol-induced depressive and anxiety-like behaviors in mice. Following an 8-week period of intermittent alcohol exposure, the alcohol group showed noticeable depressive and anxiety-like behaviors. In addition, nissl staining revealed that alcohol exposure induced neuron damage in the hippocampus (Hip) and prefrontal cortex (PFC) of mice. The levels of synapse-related proteins were significantly reduced in the alcohol group. Iron staining demonstrated that alcohol increased the number of iron-positive staining cells. The protein expression of the transferrin receptor (TFRC) was increased, and the expression of glutathione peroxidase 4 (GPX4) was decreased, respectively, in the alcohol group. Furthermore, the ferroptosis inhibitor ferrostatin-1 significantly prevented alcohol-induced neuron damage and enhanced the expression of N-methyl-d-aspartic acid (NMDA) receptor 2B (NR2B), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor 1 (GluA1) and GPX4 in vitro. These results indicated that alcohol exposure could induce depressive and anxiety-like behaviors, and that this effect may occur via activating ferroptosis

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Giardia duodenalis, formerly known as Giardia lamblia, is an important zoonotic protozoan parasite. It mainly infects the intestines of humans, dogs, cats and domestic animals, causing diarrhea, abdominal pain, indigestion and weight loss. At present, all the clinical drugs for the treatment of Giardia have problems such as side effects and drug resistance to varying degrees, and the development of new drugs for the treatment of Giardia is still a hot issue. There is growing interest in using probiotics as an anti-intestinal parasite strategy. The present study aimed to assess the effect of supernatants of Bifidobacterium Animalis Subsp. lactis BB-12 on giardia the growth of giardia trophozoites. In this study, the Bifidobacterium animalis subsp. lactis BB-12 were cultured in BBL liquid medium, and the effects of the supernatants on the growth and adhesion of trophozoites of Giardia were observed. The results showed that the growth of Giardia flagellate was significantly inhibited by the supernatant. The influence of the supernatant on the morphology of the trophozoites was observed by microscope, and it was found that the surface of the trophozoites was uneven, the shape was atrophied, the surface cell membrane was broken to some extent, and the contents were spilt. In summary, the results of this study suggest that the fresh-cultured supernatants of the probiotic Bifidobacterium Animalis subsp. lactis BB-12 have anti-Giardia effects

SET SUMOylation promotes its cytoplasmic retention and induces tau pathology and cognitive impairments

Abstract PP2A is a major regulator of tau phosphorylation, which is principally regulated by an endogenous nuclear protein inhibitor 2 of PP2A (I2 PP2A), also named SET. However, how SET is post-translationally regulated and translocates from the nucleus to the cytoplasm remain incompletely understood. Here we show SET is SUMOylated at K68 residue that induces its cytoplasmic retention, resulting in Alzheimer disease (AD) like tau pathology and cognitive defects. SET is predominantly SUMOylated at K68 that leads to its translocation from the nucleus to the cytoplasm and subsequently induces inhibition of PP2A and hyperphosphorylation of tau in HEK-293 cells. Moreover, overexpression of wild type SET significantly inhibits PP2A activity, leading to tau hyperphosphorylation, less synapse loss and cognitive deficits. Conversely, blocking SET SUMOylation via mutating Lys 68 to Arg rescues tau pathology and cognitive impairments in C57/BL6 mice infected with adeno-associated virus encoding SET. Further, β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of SET. Our findings suggest that SET SUMOylation stimulates its cytoplasmic retention and inhibits PP2A activity, consequently leading to tau hyperphosphorylation and cognitive impairments, which provides a new insight into the AD-like tau pathology

Bacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice

Abstract Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors’ fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice