Buqi Huoxue Tongnao prescription protects against chronic cerebral hypoperfusion via regulating PI3K/AKT and LXRα/CYP7A1 signaling pathways.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been confirmed as one of the pathogenesis underlying vascular cognitive impairment. A series of pathological changes, including inflammation, oxidative stress, and apoptosis, are involved in this pathophysiology and contribute to cognitive impairment and neuropathological alterations. The traditional Chinese medicine (TCM) of Buqi Huoxue Tongnao (BQHXTN) prescription possesses a remarkable clinical efficacy for treating patients with CCH, but still lacks a scientific foundation for its pharmacological mechanisms. PURPOSE: To investigate the role and underlying mechanism of the effects of BQHXTN on CCH both in vitro and in vivo. METHODS: In this study, we established a two-vessel occlusion (2-VO) induced CCH model in Sprague-Dawley rats, an oxygen-glucose deprivation model in BV2 cells, and a steatosis cell model in L02 cells to reveal the underlying mechanisms of BQHXTN by behavioral test, histopathological analysis and the detection of pro-inflammatory cytokine, apoptotic factors and reactive oxide species. Donepezil hydrochloride and Buyang Huanwu decoction were used as positive drugs. RESULTS: Compared with the 2-VO group, BQHXTN treatment at three doses significantly enhanced the memory and learning abilities in the Y-maze and novel object recognition tests. The hematoxylin-eosin staining indicated that BQHXTN protected against hippocampal injury induced by CCH. Of note, in both in vivo and in vitro experiments, BQHXTN prominently inhibited the production of IL-1ß, TNF-α, cleaved-caspase 3, and iNOS by regulating the PI3K/AKT pathway, consequently exerting anti-inflammatory, anti-apoptotic, and antioxidant effects. Moreover, it provided the first initial evidence that BQHXTN treatment mitigated dyslipidemia by increasing the LXRα/CYP7A1 expression, thereby delaying the neuropathological process. CONCLUSION: In summary, these findings firstly revealed the pharmacodynamics and mechanism of BQHXTN, that is, BQHXTN could alleviate cognitive impairment, neuropathological alterations and dyslipidemia in CCH rats by activating PI3K/AKT and LXRα/CYP7A1 signaling pathways, as well as providing a TCM treatment strategy for CCH.

Pharmacokinetics and pharmacodynamics of bioactive compounds in Penyanqing preparation in THP-1 inflammatory cells induced by Lipopolysaccharide.

BACKGROUND: Penyanqing (PYQ), a traditional Chinese medicine (TCM), has a good clinical efficacy for the treatment of pelvic inflammatory disease (PID). Previously, researches on its anti-inflammatory effect and mechanism in vitro, in silico, and in vivo have been reported by our team. However, the interrelationship between the anti-inflammatory activity and the active compounds in PYQ are not clear. Here, the pharmacokinetics-pharmacodynamics (PK-PD) study was carried out for more proper clinical use. METHODS: The plasma concentrations of salvianolic acid B (SAB), protocatechualdehyde (PRO), paeoniflorin (PE), astilbin (AST), ferulic acid (FE), and chlorogenic acid (CH) in SD rats after PYQ administration were determined by a selective and rapid HPLC-MS/MS method. In addition, the PK-PD on cell model was used to explore the relationship between the plasma concentration and inflammatory biomarkers (TNF-α, IL-1ß). RESULTS: The results of this study showed that the six components could reach the peak blood concentration within 0.29 h, indicating the rapid absorption of it. The eliminations of AST, CH, FE, PE, and PRO were relatively fast due to their mean residence times (MRTs) within 3 h, while the elimination of SAB was slower (MRT 5.67 ± 0.66 h). Combined with a THP-1 cell model, there was a significant correlation between inflammatory factors and component plasma concentrations with correlation coefficients in the range of -0.9--0.746. Correspondingly, the drug-containing plasma obtained at 0.25 h point exhibited the best inhibition effect on production of IL-1ß and TNF-α in LPS-induced THP-1 cells. CONCLUSION: The six main components in PYQ could be quickly absorbed, and there was a potential good correlation between their pharmacokinetics and the pharmacodynamics of PYQ.

Comparison of the chronic unpredictable mild stress and the maternal separation in mice postpartum depression modeling.

Postpartum depression (PPD) is a serious mental health concern of new mothers worldwide. In view of the particularity of puerpera, the research on pathogenesis and drug development of PPD are highly dependent on animal models. Although both maternal separation (MS) and chronic unpredictable mild stress (CUMS) modeling approaches have been used in PPD studies, the characteristics of the two rodent models have not been compared to explain which is more advantageous in PPD research. In this study, we applied 21-day MS and CUMS paradigms to induce mouse model of PPD and compared their differences in behavior, physiology and gut microbiota. As a result, the two models exhibited significant increases of immobility time in forced swim test (FST) and tail suspension test (TST), whereas sucrose preference index and pup weight were significantly decreased. Both displayed depression-like behaviors, and CUMS was more obvious, which demonstrated by the lower levels of 5-hydroxytryptamine (5-HT) and higher hypothalamic-pituitary-adrenal (HPA) axis related mRNA expression (corticotropin releasing hormone, corticotropin releasing hormone receptor 1) in CMUS group than that in MS group. The gut microbiota in MS and CUMS groups were significantly different in terms of the relative abundances of Bacteroidetes, Firmicutes, Proteobacteria. In conclusion, MS model and CUMS model have different performance in behavior and physiology. The CUMS model showed more obvious parameter changes, which may be more suitable for PPD induced by various social environmental factors.