Pituitary adenoma (PA) includes invasive pituitary adenoma (IPA) and noninvasive pituitary adenoma (NIPA), which are associated with the endocrine system. The gut microbiome plays an important role in human metabolism, but the association between the gut microbiome and pituitary adenoma remains unclear. A total of 44 subjects were enrolled in this study. Of these, 29 PA patients were further divided into IPA patients (n = 13) and NIPA patients (n = 16), while 15 healthy age-matched subjects were defined as control subjects. We collected faecal samples and characterized the gut microbial profiles by metagenomic sequencing using the Illumina X-ten platform. PLS-DA showed different microbial clusters among the three groups, and slightly different microbial ecological networks were observed. LEfSe analysis revealed significant alterations in the microbial community among PA patients. In particular, the enrichment of Clostridium innocuum, along with the reduced abundance of Oscillibacter sp. 57_20 and Fusobacterium mortiferum, were observed both in the IPA and NIPA groups compared to the control group. Moreover, PA patients could be effectively classified based on these bacteria using a support vector machine algorithm. In summary, this study demonstrated significant differences in the gut microbiome between PA patients and healthy controls. Future mechanistic experiments are needed to determine whether such alterations are a cause or consequence of pituitary adenoma.

PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer’s disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aβ40 and Aβ42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aβ plaques in APP/PS1 mice and decreased the levels of Aβ40 and Aβ42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain ¹⁸F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

BACKGROUND: MFN2 (mitofusin-2), a transmembrane dynamin-like protein located on the outer mitochondrial membrane, plays a key role in regulating mitochondrial fusion and autophagy. In vitro studies suggested that MFN2 may exert neuroprotective effects postischemia. In gain-of-function and loss-of-function experiments, we investigated MFN2’·s roles in regulating neuronal ischemia/reperfusion injury in vivo and in vitro. METHODS: MFN2 was knocked down by neuron-specific conditional knockout or siRNA-mediated knockdown and overexpressed by adeno-associated viral vectors or plasmid vectors in C57BL/6 mice of both sexes (10–12 weeks) exposed to middle cerebral artery occlusion and SY5Y cells exposed to oxygen-glucose deprivation/reoxygenation. Neurological deficits were examined using a 48-point score and rotarod tests. Infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining. A RealTime Apoptosis and Necrosis Assay was used to measure apoptotic and necrotic cell death. Reactive oxygen species (ROS) formation and autophagic flux were analyzed by functional assays. Protein expression and interaction were evaluated using Western blots, immunoaffinity chromatography, mass spectrometry, and immunoprecipitation analysis. To assess the role of MFN2’s interaction partner BAG6, BAG6 was overexpressed in middle cerebral artery occlusion mice and overexpressed or knocked down in SY5Y cells. RESULTS: Neuron-specific MFN2 deletion exacerbated cerebral ischemia/reperfusion injury, while MFN2 overexpression reduced it. MFN2 deficiency elevated mitochondrial ROS levels and inhibited autophagy, whereas MFN2 overexpression decreased ROS levels. In immunoprecipitation studies, we found a direct interaction between MFN2 and BAG6. Of note, BAG6 overexpression mimicked the effect of MFN2 overexpression on cerebral ischemia/reperfusion injury. Combined MFN2 and BAG6 overexpression synergistically reduced ischemia/reperfusion injury by drastically decreasing cerebral ROS levels, stabilizing mitochondrial function, and modulating autophagy. CONCLUSIONS: Our study suggests that MFN2 enhances stroke outcome through 2 pathways: by decreasing ROS levels and modulating autophagy via interaction with BAG6. BAG6 potentiates the ROS-lowering, cytoprotective MFN2 actions. The MFN2-BAG6 axis represents a promising target for stroke therapy.