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Zexieyin formula (ZXYF) has been identified to have therapeutic actions of atherosclerosis (AS). It's unknown that whether ZXYF has therapeutic potential of atherosclerosis (AS) with cognitive impairment (CI) and its underlying mechanisms. To elucidate therapeutic effect of ZXYF for AS with CI as well as its underlying mechanisms in AS with CI mice model. To establish AS with CI model, we fed ApoE−/− mice with high-fat diet (HFD) for 8 weeks. Oil red O staining (ORO) and Hematoxylin-eosin staining (HE) were used to detect aortic plaque area. Morris water maze (MWM) and Y-maze were used to measure cognitive function and cognitive improvement after administration of ZXYF and atorvastatin (ATO). Network pharmacology was used to screen for potential mechanisms for improving cognitive function. Western blot was used to detect expressions of MAPK, Aβ and synaptic proteins in hippocampus. HFD caused and accelerated the AS in ApoE−/− mice, while it was easier able to produce CI than normal mice. Administration of ZXYF or ATO for 8 weeks significantly reduced aortic plaque area in ORO and HE tests, and improved cognitive abilities in MWM and Y-maze tests. Network pharmacology results showed that MAPK or synaptic proteins were highly associated with CI. HFD contributed to abnormal expressions of MAPK (pERK, pP38, pJNK), NF-kB, synaptic proteins (PSD95, synapsin1) and β-amyloid (Aβ) in hippocampus, which were all reversed by ZXYF. However, ERK and PSD95 expressions were not reversed by ATO in hippocampus. ZXYF mitigated AS, further alleviating CI by modulating MAPK signaling, relating to synaptic proteins enhancing and Aβ protein decreasing in the hippocampus. This study firstly lit up the new clinical application of ZXYF, which might promote the use of ZXYF in AS and CI patients. [Display omitted] • Long-term HFD caused atherosclerosis with cognitive impairment only in ApoE−/− mice but not in WT mice. • Zexieyin formula mitigated atherosclerosis to relieve cognitive impairment by modulating MAPK signaling, synaptic proteins and β-amyloid in hippocampus. • This study firstly shed light on clinical application of Zexieyin formula for the treatment of comorbidities such as atherosclerosis with cognitive impairment in patients. [ABSTRACT FROM AUTHOR]

Pyrolae herba (PH), a kind of Chinese herb, has been identified to have an anti-inflammatory effect, while the potential for treating cognitive impairment (CI), as well as the underlying mechanisms, is unclear. Currently, the interaction between neuroinflammation and neural function play a critical role in pathophysiology of CI. To elucidate therapeutic effect of PH for CI as well as its underlying mechanisms with LPS-treated mice model. In this study, male C57BL6/J mice received lipopolysaccharide (LPS) injection for 10 days to establish CI model and were administrated with PH for 14 days. We used piracetam as a positive control. Memory and spatial function was tested by Morris water maze (MWM). The level of inflammation-related cytokines (TNF-α, IL-1β, IL-10, IL-6) were determined by enzyme-linked immunosorbent assay (ELISA) in serum and western blot in hippocampus. Immunofluorescence (IF) was used to measure the levels of ionized calcium binding linker molecule 1 (IBA-1), glial fibrillary acidic protein (GFAP), BrdU, Ki67 and doublecortin (DCX) in hippocampus. The mRNA sequencing was used to screen the potential target of PH with therapeutic CI. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene alteration of triggering receptor expressed on myeloid cells 2 (TREM2) in hippocampus. We used western blot to determine protein expressions of TREM2 and its related signaling, as well as synaptic proteins in hippocampus. The results revealed that LPS contributed to CI, and PH or piracetam treatment significantly ameliorated CI in MWM test. LPS contributed to increasing expressions of TNF-α and IL-1β in serum and hippocampus, which both reversed by PH or piracetam. PH or piracetam could inhibit the activation of glial cells including microglia and astrocyte in the hippocampus in LPS-induced CI model. The mRNA sequencing and RT-PCR results showed that LPS significantly increased the gene expression of TREM2, which was reversed by PH. The alteration of TREM2 expression was the most significant among the 10 genes (TREM2, Slc24a2, Ptch2, Gck, Il1rapl1, Cadps2, Btbd11, Secisbp2l, Tenm3 and Prepl) in hippocampus. Protein results showed that LPS upregulated the expressions of TREM2 and its related proteins including DAP12, spleen tyrosine kinase (SYK) phosphorylation and ADAM 10, which were all reversed by PH or piracetam in hippocampus. Furthermore, LPS was capable of reducing the expression of BrdU and DCX co-labeled positive cells in hippocampal dentate gyrus (DG), which was reversed only by PH. Moreover, PH or piracetam treatment significantly increased the expression of Ki67 and DCX co-labeled positive cells in hippocampal DG. The expression of synapsin1 was obviously decreased by LPS and was significantly reversed by PH or piracetam. PH could alleviate CI by suppressing the secretion of pro-inflammatory cytokines and mitigating astrocyte activity by restraining microglia's activation in hippocampus, further facilitating neurogenesis and proliferation, thereby enhancing pre-synaptic protein. This study highlighted on the clinical application of PH, which might promote the use of phytomedicine in CI patients. [Display omitted] • Pyrolae herba has capable of improving the cognitive impairment in LPS-treated mice. • The effects of Pyrolae herba on improving cognitive impairment by reversing Trem2-related signaling in the hippocampus of LPS-treated mice. • Pyrolae herba enhances neurogenesis, proliferation, and pre-synaptic protein in the hippocampus of LPS-treated mice. • This study shed light on the clinical application of Pyrolae herba, which would promote the use of medicinal herbs in cognitive impairment patients. [ABSTRACT FROM AUTHOR]

Jiawei-Xiaoyao pill (JWX), a traditional Chinese medicine, was recorded in ancient Chinese medicine pharmacopoeia using for treatment of various diseases, including mood disorders. Current mainstream antidepressants have a disadvantage in delayed onset of action. The rapid antidepressant potential of JWX and the underlying mechanisms remain unclear. We aimed to assess the rapid antidepressant potential of JWX, within the prescription dose range, and the distinct underlying neuroplasticity signaling mechanism. The rapid antidepressant response of JWX were determined using various behavioral paradigms, and in a corticosterone (CORT)-induced depression model in mice. The molecular neuroplasticity signaling and the expression of BDNF in the hippocampus was evaluated using immunoblotting and immunostaining. The contribution of specific signaling was investigated using pharmacological interventions. A single dose of JWX induced rapid and persistent antidepressant effects in both the normal and chronic CORT-exposed mice. The phosphorylation of CaMKII, mTOR, ERK and the expressions of BDNF, synapsin1 and PSD95 increased at 30 min post JWX. JWX restored the expression of BDNF in the hippocampal dentate gyrus reduced by CORT-exposure. The rapid antidepressant effect and upregulation of BDNF expression by JWX was blunted by a mTOR antagonist, rapamycin, or a CaMKII antagonist, KN-93. CaMKII signaling blockade blunted mTOR signaling activated by JWX, but not vice versa. JWX elicits a rapid antidepressant effect, via quickly stimulating CaMKII signaling, subsequently activating mTOR-BDNF signaling pathway, and thus enhancing hippocampal neuroplasticity. [Display omitted] • Jiawei-Xiaoyao pill (JWX) elicits rapid anxiolytic and antidepressant effects. • JWX-activated hippocampal mTOR-BDNF signaling regulates rapid antidepressant effects. • JWX-activated mTOR-BDNF signaling relied on stimulation of CaMKII signaling. [ABSTRACT FROM AUTHOR]