Central inflammatory mechanism of celastrol in intervention of obesity-depression comorbidity in mice from amygdala-dorsal raphe nucleus
This study aims to further elucidate the efficacy targets of celastrol(CEL)intervention in central inflammation in mice with obesity-depression comorbiditiy,based on the differential mRNA expression in the amygdala(AMY)and dorsal raphe nucleus(DRN)after CEL intervention.C57BL/6J mice were randomly divided into a normal diet group(Chow),a obesity-depression comor-bidity(COM)group,and low-,medium-,and high-dose CEL groups(CEL-L,CEL-M,CEL-H,0.5,1.0,2.0 mg-kg-1).The Chow group received a normal diet,while the COM group and CEL-L,CEL-M,CEL-H groups received a high-fat diet combined with chronic stress from wet bedding.After 10 weeks of feeding,the mice were orally administered CEL for three weeks.Subsequently,the AMY and DRN of mice in the Chow,COM,and CEL-H groups were subjected to transcriptome analysis,and the intersection of target differentially expressed genes in both nuclei was visualized using a Venn diagram.The intersected genes were then imported into STRING for protein-protein interaction(PPI)analysis,and Gene Ontology(GO)analysis was performed using DAVID to identify the core targets regulated by CEL in the AMY and DRN.Independent samples were subjected to quantitative real-time PCR(qPCR)to validate the intersection genes.The results revealed that the common genes regulated by CEL in the AMY and DRN included chemo-kine family genes Ccl2,Ccl5,Ccl7,Cxcl1O,Cxcr6,and Hsp70 family genes Hspa1a,Hspa1b,as well as Myd88,Il2ra,Irf7,Slc17a8,Drd2,Parp9,and Nampt.GO analysis showed that the top 5 nodes Ccl2,Cxcl10,Myd88,Ccl5,and Irf7 were all involved in immune-inflammation regulation(P＜0.01).The qPCR results from independent samples showed that in the AMY,compared with the results in the Chow group,chemokine family genes,Hsp70,Myd88,Il2ra,Irf7,Slc17a8,Parp9,and Nampt were significantly up-regulated in the COM group,with Drd2 showing a decreasing trend;these pathological changes were significantly improved in the CEL-H group compared to the COM group.In the DRN,compared with the results in the Chow group,chemokine family genes,Hsp70,Myd88,I12ra,Irf7,Parp9,and Nampt were significantly down-regulated,while Slc17a8 was significantly up-regulated in the COM group;compared with those in the COM group,Cxcr6,Irf7,and Drd2 were significantly up-regulated,while Slc17a8 was signifi-cantly down-regulated in the CEL-H group.In both the AMY and DRN,the expression of Irf7 by CEL showed both inhibition and acti-vation in a dose-dependent manner(R2were 0.709 8 and 0.917 2,respectively).These findings suggest that CEL can effectively im-prove neuroinflammation by regulating bidirectional expression of the same target proteins,thereby intervening in the immune activation of the AMY and immune suppression of the DRN in COM mice.
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