Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown with a neuroprotective function against inflammation and neuronal injury in Alzheimer’s disease (AD). However, the TREM2 induced anti-inflammatory mechanism is still not well known. In this study it has been demonstrated that the expression of TREM2 was upregulated in hippocampus of 5xFAD mice, whereas TREM2 knock-out mediated by AAV significantly increased the levels of pro-inflammatory cytokines and aggravated cognitive defect. Additionally, FoxO3a, a downstream member of the PI3K/AKT pathway, could be activated by TREM2 defect via the PI3K/AKT signaling in 5xFAD mice. That suggests TREM2-induced protection is associated with the PI3K-FoxO3a axis. On the contrary, overexpression of TREM2 alleviated the LPS-induced inflammatory response and induced M2 phenotype microglia in vitro. This phenomenon can be abolished by applying the PI3K inhibitor LY294002, suggesting FoxO3a not only participates in TREM2-induced anti-inflammation response, but is also involved in regulating the phenotype of microglia. Taken together, our results show that the protective functions of TREM2, both in inflammatory response and cognitive impairment as well as in the decrease of M1 phenotype microglia, are related to PI3K/AKT/FoxO3a signaling pathway in AD mice.
Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. Results The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.
The long noncoding RNA cancer susceptibility candidate 9 (CASC9) has been revealed to be an oncogenic gene in several types of cancer, and high CASC9 expression is related to tumorigenesis and cancer progression. However, the role of CASC9 in bladder cancer (BC), particularly during epithelial-mesenchymal transition (EMT), has not been characterized. RT-qPCR, EdU, CCK-8, wound scratch, Transwell and flow cytometric assays were performed to detect CASC9 expression, miR-758-3p expression and their functions in BC. RNA FISH was used to detect CASC9 subcellular localization. Luciferase reporter assay, RT-qPCR assay and western blotting were used to explore the relationship of CASC9, miR-758-3p and TGF-β2. In the present study, it was revealed that CASC9 regulated EMT in BC. CASC9 expression was significantly upregulated in BC cell lines and specimens compared to that in adjacent normal bladder tissues. Upregulated CASC9 was associated with increased invasion ability and poor prognosis of BC. CASC9 knockdown inhibited BC cell proliferation, migration and invasion. Furthermore, a bioinformatics study and luciferase reporter assays revealed that CASC9 functioned as a ceRNA for miR-758-3p. CASC9 inhibited microRNA (miR)-758-3p activity and resulted in the de-suppression of its target transforming growth factor (TGF)-β2. TGF-β signaling driven by TGF-β2 was crucial for CASC9 to promote EMT in BC. Collectively, these results indicated that CASC9 sponged miR-758-3p to regulate the expression of TGF-β2, which activated the TGF-β signaling pathway and promoted proliferation and EMT in BC.
Objective: Many pieces of research have focused on pain within individuals, but little attention has been paid to whether pain can change an individual's empathic ability and affect social relationships. The purpose of this study is to explore how chronic low back pain changes empathy. Methods: Twenty-four chronic low back pain patients and 22 healthy controls were recruited. We set up an experimental pain-exposed model for each healthy subject. All subjects received a painful-empathic magnetic resonance scan. After the scan, all subjects rated the pain intensity and multiple empathy-related indicators. The clinical assessment scale was the 20-item Basic Empathy Scale in Adults. Result: The chronic low back pain patients reported lower scores on the total scores of BES-A, the subscale scores of emotional disconnection and cognitive empathy, and the discomfort rating. The fMRI results in the chronic low back pain patients showed that there were multiple abnormal brain pathways centered on the anterior insula. The DTI results in the chronic low back pain patients showed that there were reduced fractional anisotropy values in the corpus callosum, bilateral anterior thalamic radiation (ATR), right posterior thalamic radiation (PTR), right superior longitudinal fasciculus (SLF), and left anterior corona radiate (ACR). Conclusion: Our study found that patients with chronic low back pain have impaired empathy ability. The abnormal functional connectivity of multiple brain networks, multiple damaged white matter tracts, and the lower behavioral scores in chronic low back pain patients supported our findings.
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