RESUMO
BACKGROUND: The oral bioavailability and blood-brain barrier permeability of many herbal products are too low to explain the significant efficacy fully. Gut microbiota and liver can metabolize herbal ingredients to more absorbable forms. The current study aims to evaluate the ability of a novel biotransformation-integrated network pharmacology strategy to discover the therapeutic mechanisms of low-bioavailability herbal products in neurological diseases. METHODS: A study on the mechanisms of Astragaloside IV (ASIV) in treating intracerebral hemorrhage (ICH) was selected as an example. Firstly, the absorbed ASIV metabolites were collected by a literature search. Next, the ADMET properties and the ICH-associated targets of ASIV and its metabolites were compared. Finally, the biotransformation-increased targets and biological processes were screened out and verified by molecular docking, molecular dynamics simulation, and cell and animal experiments. RESULTS: The metabolites (3-epi-cycloastragenol and cycloastragenol) showed higher bioavailability and blood-brain barrier permeability than ASIV. Biotransformation added the targets ASIV in ICH, including PTK2, CDC42, CSF1R, and TNF. The increased targets were primarily enriched in microglia and involved in cell migration, proliferation, and inflammation. The computer simulations revealed that 3-epi-cycloastragenol bound CSF1R and cycloastragenol bound PTK2 and CDC42 stably. The In vivo and in vitro studies confirmed that the ASIV-derived metabolites suppressed CDC42 and CSF1R expression and inhibited microglia migration, proliferation, and TNF-α secretion. CONCLUSION: ASIV inhibits post-ICH microglia/macrophage proliferation and migration, probably through its transformed products to bind CDC42, PTK2, and CSF1R. The integrated strategy can be used to discover novel mechanisms of herbal products or traditional Chinses medicine in treating diseases.
RESUMO
BACKGROUND: Cognitive frailty describes cognitive impairment associated with physical decline. Few studies have explored whether short cognitive screens identify frailty. We examined the diagnostic accuracy of the Chinese versions of the Quick Mild Cognitive Impairment (Qmci-CN) screen and Montreal Cognitive Assessment (MoCA-CN) in identifying cognitive frailty. METHODS: Ninety-five participants with cognitive symptoms [47 with mild cognitive impairment (MCI), 34 with subjective cognitive disorder, and 14 with dementia] were included from two outpatient rehabilitation clinics. Energy (work intensity) and physical activity levels were recorded. Cognitive frailty was diagnosed by an interdisciplinary team using the IANA/IAGG consensus criteria, stratified on the Clinical Frailty Scale (CFS). Instruments were administered sequentially and randomly by trained assessors, blind to the diagnosis. RESULTS: The mean age of the sample was 62.6 ± 10.2 years; median CFS score was 4 ± 1 and 36 (38%) were cognitively frail. The Qmci-CN had similar accuracy in differentiating the non-frail from cognitively frail compared to the MoCA-CN, AUC 0.82 versus 0.74, respectively (p = 0.19). At its optimal cut-off (≤55/100), the Qmci-CN provided a sensitivity of 83% and specificity of 67% versus 91% and 51%, respectively, for the MoCA-CN (≤23/30). Neither was accurate in separating MCI from cognitive frailty but both accurately separated cognitive frailty from dementia. CONCLUSION: Established short cognitive screens may be useful in identifying cognitive frailty in Chinese adults with cognitive complaints but not in separating MCI from cognitive frailty. The Qmci-CN had similar accuracy to the MoCA-CN and a shorter administration time in this small and under-powered study, necessitating the need for adequately powered studies in different healthcare settings.