The Role of HSP90 Molecular Chaperones in Depression: Potential Mechanisms.

Major depressive disorder (MDD) is characterized by high rates of disability and death and has become a public health problem that threatens human life and health worldwide. HPA axis disorder and neuroinflammation are two common biological abnormalities in MDD patients. Hsp90 is an important molecular chaperone that is widely distributed in the organism. Hsp90 binds to the co-chaperone and goes through a molecular chaperone cycle to complete its regulation of the client protein. Numerous studies have demonstrated that Hsp90 regulates how the HPA axis reacts to stress and how GR, the HPA axis' responsive substrate, matures. In addition, Hsp90 exhibits pro-inflammatory effects that are closely related to neuroinflammation in MDD. Currently, Hsp90 inhibitors have made some progress in the treatment of a variety of human diseases, but they still need to be improved. Further insight into the role of Hsp90 in MDD provides new ideas for the development of new antidepressant drugs targeting Hsp90.

Quercetin Ameliorates Cognitive Impairment in Depression by Targeting HSP90 to Inhibit NLRP3 Inflammasome Activation.

Cognitive dysfunction was a common symptom of major depressive disorder (MDD). In previous studies, psychological stress leads to activation and proliferation of microglial cells in different brain regions. Quercetin, a bioflavonoid derived from vegetables and fruits, exerts anti-inflammatory effects in various diseases. To demonstrate the role of quercetin in the hippocampal inflammatory response in depress mice. The chronic unpredictable stress (CUS) depressive mice model built is used to explore the protective effects of quercetin on depression. Neurobehavioral test, protein expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and heat shock protein 90 (HSP90), and cytokines (IL-6, IL-1ß, MCP-1, and TNF-α) were assessed. Quercetin ameliorated depressive-like behavior and cognitive impairment, and quercetin attenuates neuroinflammation and by targeting HSP90 to inhibit NLRP3 inflammasome activation. Quercetin inhibited the increase of HSP90 levels in the hippocampus and reverses inflammation-induced cognitive impairment. Besides, quercetin inhibited the increased level of cytokines (IL-6, IL-1ß, MCP-1, and TNF-α) in the hippocampus of the depressive model mouse and the increased level of cytokines (IL-6, IL-1ß, and MCP-1) in microglia. The current study indicated that quercetin mitigated depressive-like behavior and by targeting HSP90 to inhibit NLRP3 inflammasome activation in microglia and depressive mice model, meanwhile ameliorated cognitive impairment in depression. Quercetin has huge potential for the novel pharmacological efficacy of antidepressant therapy.

Transcriptome analysis reveals key transcription factors and pathways of polian vesicle associated with cell proliferation in Vibrio splendidus-challenged Apostichopus japonicus.

Polian vesicle is thought to produce coelomocytes and contribute to the sea cucumber's immune system. Our previous work has indicated that polian vesicle was responsible for cell proliferation at 72 h post pathogenic challenge. However, the transcription factors related to the activation of effector factors and the molecular process behind this remained unknown. In this study, to reveal the early functions of polian vesicle in response to the microbe, a comparative transcriptome sequencing of polian vesicle in V. splendidus-challenged Apostichopus japonicus, including normal group (PV 0 h), pathogen challenging for 6 h (PV 6 h) and 12 h (PV 12 h) was performed. Compared PV 0 h to PV 6 h, PV 0 h to PV 12 h, and PV 6 h to PV 12 h, we found 69, 211, and 175 differentially expressed genes (DEGs), respectively. KEGG enrichment analysis revealed the DEGs, including several transcription factors such as fos, FOS-FOX, ATF2, egr1, KLF2, and Notch3 between PV 6 h and PV 12 h were consistently enriched in MAPK, Apelin and Notch3 signaling pathways related to cell proliferation compared with that in PV 0 h. Important DEGs involved in cell growth were chosen, and their expression patterns were almost the same as the transcriptome profile analysis by qPCR. Protein interaction network analysis indicated that two DEGs of fos and egr1 were probably significant as key candidate genes controlling cell proliferation and differentiation in polian vesicle after pathogenic infection in A. japonicus. Overall, our analysis demonstrates that polian vesicles may play an essential role in regulating proliferation via transcription factors-mediated signaling pathway in A. japonicus and provide new insights into hematopoietic modulation of polian vesicles in response to pathogen infection.

Comparative analysis for immune response of coelomic fluid from coelom and polian vesicle in Apostichopus japonicus to Vibrio splendidus infection.

The polian vesicle and coelom of sea cucumber Apostichopus japonicus were full of coelomic fluid in which many types of coelomocytes with different functions were suspended. Our previous work has indicated the differences of coelomocytes between two sites mainly in subtype proportion, non-specific immune enzymes activities and several immune-related genes expression levels in healthy A. japonicus. However, the functional similarities and differences of coelomic fluid in two sites including the coelom and polian vesicle after pathogenic infection still remain unclear. Here, we investigated the changes of the total coelomocyte density (TCD) and differential coelomocyte density (DCD) after pathogen infection by Vibrio splendidus in coelom and polian vesicle. After infected by V. splendidus, the TCD in the coelom and polian vesicle rapidly declined at 12 h, and then the TCD in the coelom showed a stably ascending trend, while the TCD in the polian vesicle reached a peak at 24 h post infection (hpi), and then showed a continuously decline trend from 24 hpi to 72 hpi followed by a slow elevation until recovering the normal level from 72 hpi to 96 hpi. Then the activities of acidic phosphatase (ACP), alkaline phosphatase (AKP), catalase (CAT) and superoxide dismutase (SOD) were determined to evaluate the response of cell-free coelomic fluid to V. splendidus infection. The activities of ACP, AKP and CAT showed similar trends in the coelom and polian vesicle. The SOD activity significantly increased in the polian vesicle, whereas it exhibited a decreasing trend in the coelom. Finally, the expression profiles of nine immune-related genes including Aj-MyD88, Aj-IRAK4, Aj-i-Lys, Aj-Rel, Aj-p50, Aj-DMBT1, Aj-CDC, Aj-Rrp15 and Aj-Fibrinogen C were detected after V. splendidus challenge. The results suggested all the detected genes were significantly up-regulated both in the coelom and polian vesicle, and the expression levels of these genes in two sites shared similar trends except Aj-MyD88 and Aj-DMBT1. This research provides a new insight into the differentially immune roles of coelomic fluid and coelomocytes in polian vesicle and coelom response to bacterial infections and supplements comprehensive resources for better understanding the innate immune response of A. japonicus.