Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC.

Background: Stress is an important risk factor to induce psychiatric disorders such as depression. Phloretin (PHL), a natural dihydrochalcone compound, has been shown to exhibit anti-inflammatory and anti-oxidative effects. However, the impact of PHL on the depression and the underlying mechanism remain unclear. Methods: The animal behavior tests were used to determine the protective of PHL on the chronic mild stress (CMS)-induced depression-like behaviors. The Magnetic Resonance Imaging (MRI), electron microscopy analysis, fiber photometry, electrophysiology, and Structure Illumination Microscopy (SIM) were used to investigate the protective of PHL on the structural and functional impairments induced by CMS exposure in the mPFC. The RNA sequencing, western blot, reporter gene assay, and chromatin immunoprecipitation were adopted to investigate the mechanisms. Results: We showed that PHL efficiently prevented the CMS-induced depressive-like behaviors. Moreover, PHL not only attenuated the decrease of synapse losses but also improved the dendritic spine density and neuronal activity in the mPFC after CMS exposure. Furthermore, PHL remarkably inhibited the CMS-induced microglial activation and phagocytic activity in the mPFC. In addition, we demonstrated that PHL decreased the CMS-induced synapse losses by inhibiting the deposition of complement C3 deposition onto synapses and subsequent microglia-mediated synaptic engulfment. Finally, we revealed that PHL inhibited the NF-κB-C3 axis to display neuroprotective effects. Conclusions: Our results indicate that PHL represses the NF-κB-C3 axis and subsequent microglia-mediated synaptic engulfment to protect against CMS-induced depression in the mPFC.

Calcitonin gene-related peptide and its receptor plays important role in nociceptive regulation in the arcuate nucleus of hypothalamus of rats with inflammatory pain.

The present study has explored the role of calcitonin gene-related peptide (CGRP) and its receptor in inflammatory pain modulation in arcuate nucleus of hypothalamus (ARC). Our study demonstrated that intra-ARC injection of CGRP induced antinociceptive effects to naïve rats and rats with inflammatory pain, the effect could be inhibited by the selective CGRP receptor antagonist CGRP8-37. Interestingly, the CGRP-induced antinociception effect was decreased in rats with inflammatory pain compared to naïve rats. Similarly, we found that calcitonin receptor like receptor (CLR), a main component of CGRP receptor, had a low decreased expression levels in the ARC regions of rats with inflammatory pain. The CGRP-induced antinociceptive effect was significantly impaired after reducing CLR expression by intra-ARC administration of CLR targeted siRNA. These findings demonstrated that CGRP might play a crucial role in nociceptive modulation in the ARC during inflammatory pain, which was mediated by CGRP receptor in the ARC. This study shed light upon CGRP and its receptor interaction might be valuable strategies for the alleviation of inflammatory pain.

[The study of autophagy in alveolar macrophages of patients with coal workers' pneumoconiosis].

OBJECTIVE: To evaluate the differences in the autophagy activity of alveolar macrophages between patients with different stages of coal workers' pneumoconiosis (CWP). METHODS: A total of 116 coal workers were investigated in the field. Their lung lavage fluid was collected and purified to obtain alveolar macrophages. The morphological characteristics of autophagy were observed by transmission electron microscopy. The expression of autophagy marker (LC3) and autophagy regulators (Beclin1, mTOR, and p-mTOR) was measured by Western blot. The autophagy activity of alveolar macrophages was compared between dust-exposed subjects and patients with stage I, II, and III CWP. RESULTS: The autophagy activity of alveolar macrophages differed between patients with different stages of CWP, according to transmission electron microscopy. Patients with stage II CWP had significantly higher protein expression of LC3 II/I and Beclin1 in pulmonary macrophages than those with stage ICWP (P < 0.05); patients with stage III CWP had significantly lower protein expression of LC3 II/I and Beclin1 in pulmonary macrophages than those with stage II CWP (P < 0.05), but had significantly higher protein expression of LC3 II/I and Beclin1 than those with stage I CWP (P < 0.05); patients with stage II CWP had a significantly higher protein expression of Beclin1 than the dust-exposed subjects (P < 0.05). Patients with stage II CWP had significantly lower expression of mTOR and p-mTOR in pulmonary macrophages than the dust-exposed subjects and those with stage I CWP (P < 0.05), while patients with stage III CWP had significantly higher expression of mTOR and p-mTOR than those with stage II CWP (P < 0.05). CONCLUSION: The autophagy activity of alveolar macrophages varies between patients with different stages of CWP.