Background In recent years, excellent results have suggested an association between the “brain-gut” axis and Alzheimer’s disease (AD) progression, yet the role of the “brain-gut” axis in AD pathogenesis still remains obscure. Herein, we provided a potential link between the central and peripheral neuroinflammatory disorders in AD progression. Methods The Morris water maze (MWM) test, immunohistochemistry, ELISA, ProcartaPlex Multiplex immunoassay, multiple LC-MS/MS methods, and the V3-V4 regions of 16S rRNA genes were applied to explore potential biomarkers. Results In Tg-APP/PS1 mice, gut dysbiosis and lipid metabolism were highly associated with AD-like neuroinflammation. The combination of inflammatory factors (IL-6 and INF-γ), phosphatidylcholines (PCs) and SCFA-producing bacteria were expected to be early diagnostic biomarkers for AD. Huanglian Jiedu decoction (HLJDD) suppressed gut dysbiosis and the associated Aβ accumulation, harnessed neuroinflammation and reversed cognitive impairment. Conclusion Together, our findings highlighted the roles of neuroinflammation induced by gut dysbiosis and lipid metabolism disorder in AD progression. This integrated metabolomics approach showed its potential to understand the complex mechanisms of HLJDD in the treatment of AD.

Circular RNAs (circRNAs) represent a class of widespread, diverse, and covalently closed circRNAs that function as microRNA (miRNA) sponges and crucial regulators of gene expression in mammals. However, the regulation and function of circRNAs in lower vertebrates are still unknown. Here, we first discover a highly conserved circRNA termed circRasGEF1B, which displays a high conservation from mammals to fish and serves as key regulator in eliciting antiviral immunity in teleost fish. Results indicate that circRasGEF1B was highly expressed in Siniperca chuatsi rhabdovirus-infected tissues and cells. Functionally, miR-21-3p could inhibit cellular antiviral responses significantly, whereas circRasGEF1B counteract the effects of miR-21-3p. In mechanism, the results demonstrate that circRasGEF1B acts as a competing endogenous RNA (ceRNA) of miR-21-3p to relieve the repressive effect of miR-21-3p on its target MITA, then enhance the innate antiviral responses. Our results not only provide a novel insight into the functions of circRNAs in lower vertebrates, but broaden our understanding of circRNAs in viral infection. IMPORTANCE Siniperca chuatsi rhabdovirus (SCRV) is a typical fish RNA rhabdovirus, which is one of the most significant viral pathogens in teleost fish and can cause severe hemorrhagic septicemia in freshwater and marine fishes. Here, we discovered a highly conserved circRNAs called circRasGEF1B, which acts as a key regulator for innate antiviral responses upon SCRV infection. circRasGEF1B acts as an endogenous sponge of miR-21-3p that downregulates miR-21-3p expression levels. circRasGEF1B is able to bind to miR-21-3p directly and regulates MITA expression. To our knowledge, this report is the first to characterize circRNA–miRNA regulatory networks that exist in lower vertebrates.

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Circular RNAs (circRNAs) are a class of widespread and diverse covalently closed circular endogenous RNAs that exert crucial functions in regulating gene expression in mammals. However, the function and regulation mechanism of circRNAs in lower vertebrates are still unknown. Here, we discovered a novel circRNA derived from PIKfyve, named circPIKfyve, that is related to the antiviral responses in teleost fish. The results showed that circPIKfyve plays essential roles in host antiviral immunity and inhibition of SCRV replication. Moreover, we also found that the antiviral effect inhibited by miR-21-3p could be reversed with the addition of circPIKfyve. In mechanism, our data revealed that circPIKfyve is a competitive endogenous RNA (ceRNA) of MAVS by sponging miR-21-3p, leading to activation of NF-κB/IRF3 pathway, which then enhance the innate antiviral responses. In addition, we firstly found that RNA binding protein QKI is involved in the formation and regulation of circPIKfyve. Our results provided a strong basis that circRNAs to play a regulatory role in antiviral immune responses in teleost fish. Importance: Here, we identified a novel circRNA, namely, circPIKfyve, that can act as a key regulator of the innate immune response in teleost fish. circPIKfyve acts as a molecular sponge by competitive adsorbing of miR-21-3p, thereby increasing the abundance of MAVS and activating the downstream NF-κB/IRF3 pathway to enhance the antiviral response. In addition, this study was the first to find that QKI protein is involved in regulating the formation of circPIKfyve in fish. The overall results of this study suggest that circPIKfyve plays an active regulatory role in the antiviral immune response of teleost fish.

Red clover consists of the overground parts and inflorescence of Trifolium pratense L., a leguminous plant belonging to the genus Trifolium. It is widely distributed worldwide and has long been used in traditional medicine. In this study, a combination approach using UPLC-MS and network pharmacology was applied to explore the quality control markers for the quality assessments of red clover. Firstly, UPLC-MS was used to identify the compounds in different parts of red clover. Twenty-eight compounds were totally identified. According to the traditional clinical efficacy of red clover, a compound-target-function network was constructed by network pharmacology to discover the main active compounds based on the identified compounds. Nine compounds of chlorogenic acid, daidzin, calycosin-7-O-β-d-glucoside, genistin, ononin, daidzein, genistein, formononetin, and biochanin A were filtrated and further confirmed in rat plasma in view of the blood-absorbed components taking effects. Finally, a novel method for simultaneously detecting the nine quality control markers was developed by UPLC-QQQ-MS in an effort to assess the quality of red clover. For all samples, the average contents of the nine compounds measured from high to low consist of formononetin, ononin, biochanin A, genistin, daidzin, calycosin-7-O-β-d-glucoside, genistein, daidzein, and chlorogenic acid. The samples from Gansu province showed the best quality in the three producing areas This study provides new strategies to explore the quality control markers and develops a novel method for the quality assessment of red clover.