RESUMO
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of ß-amyloid (Aß) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y2, P2Y6, P2Y12, and P2Y13. The adenosine P1 receptors expressed in microglia include A1R, A2AR, and A2BR. Among them, the activation of P2X4, P2X7, and adenosine A1, A2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y2, P2Y6, P2Y12, and P2Y13 receptors expressed by microglia can induce neuroprotective effects. However, A1R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aß production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.
RESUMO
BACKGROUND: The incidence of dyslipidemia increases after menopause. Electroacupuncture (EA) has been recommended for menopause-related disease. However, the positive effect on lipid metabolism disorders is still unclear. OBJECTIVES: To investigate the underlying mechanism of EA treatment on lipid metabolism disorders through ONT full-length transcriptome sequencing Methods: Adult female SD rats were randomly divided into Ctrl, sham operation+high-fat feed(Sham+HFD), Ovariectomized+high-fat feed (OVX+HFD), Ovariectomized+high-fat feed + Atorvastatin (OVX+HFD+ATO) and OVX+HFD+EA groups. Periovarian adipose tissue around the bilateral ovaries of rats in the Sham+HFD group was resected. Rats in the OVX+HFD, OVX+HFD+ATO and OVX+HFD+EA groups were subjected to bilateral oophorectomy to prepare the ovariectomized rat model. Treatment was applied to rats in the OVX+HFD+EA group. ST36, PC6, SP6, BL18 and ST40 were the selected acupoints. Daily food intake and body weights of rats were recorded. The samples were collected 30 days after treatment. The serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein (HDL-C) were detected to assess the improvement of lipid metabolism disorders. HE and oil red O staining were used to stain the liver tissues. Total RNA was extracted from liver tissues, and its transcriptional changes were determined by high-throughput sequencing. Additionally, RTÁqPCR and immunofluorescence staining were used to verify the crucial signal pathway screened by the ONT fullÁlength transcriptome sequencing. RESULTS: EA treatment resulted in a lowered weight of perirenal fat and liver and a significant improvement in the color of the liver. In addition, EA could improve the lipid profile and hepatic steatosis in OVX+HFD rats. According to fullÁlength transcriptome sequencing, 2292 genes showed differential expression in the OVX+HFD group; of these, 1121 were upregulated and 1171 down-regulated. 609 DEGs were found in the OVX+HFD+EA group compared to the OVX+HFD group; 235 up-regulated and 374 down-regulated. We also found that 77 genes are significantly upregulated after EA intervention through Venn map analysis (including Agtr1a, Pdia3, etc.), which may be the targeted genes for EA treatment of lipid metabolism disorders. Finally, we verified the expression of Pdia3, Perk and Qrich1 levels in liver tissues. HFD feeding could increase the expression of Pdia3 and its downstream signal pathways molecular Perk and Qrich1. But these effects were reversed by EA treatment, the results demonstrated that the expression of pdia3, Perk, as well as Qrich1 of OVX+HFD rats had a decreasing trend after EA treatment. CONCLUSIONS: EA could ameliorate lipid metabolic disorder in OVX+HFD rats. The Pdia3/Perk/Qrich1 signal pathway may play crucial roles in the improvement of lipid metabolism disorder of OVX+HFD rats after EA treatment.