Banxia Xiexin decoction alleviates AS co-depression disease by regulating the gut microbiome-lipid metabolic axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin decoction (BXD) is a classic Chinese herbal formulation consisting of 7 herbs including Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix, Glycyrrhizae Radix, Coptidis Rhizoma, and Jujubae Fructus, which can exert effects on lowering lipids and alleviating depressive mood disorders via affecting gastrointestinal tract. AIM OF THE STUDY: The pathogenesis of atherosclerosis (AS) co-depression disease has not been well studied, and the current clinical treatment strategies are not satisfactory. As a result, it is critical to find novel methods of treatment. Based on the hypothesis that the gut microbiome may promote the development of AS co-depression disease by regulating host lipid metabolism, this study sought to evaluate the effectiveness and action mechanism of BXD in regulation of the gut microbiome via an intervention in AS co-depression mice. MATERIALS AND METHODS: To determine the primary constituents of BXD, UPLC-Q/TOF-MS analysis was carried out. Sixteen C56BL/6 mice were fed normal chow as a control group; 64 ApoE-/- mice were randomized into four groups (model group and three treatment groups) and fed high-fat chow combined with daily bind stimulation for sixteen weeks to develop the AS co-depression mouse model and were administered saline or low, medium or high concentrations of BXD during the experimental modeling period. The antidepressant efficacy of BXD was examined by weighing, a sucrose preference test, an open field test, and a tail suspension experiment. The effectiveness of BXD as an anti-AS treatment was evaluated by means of biochemical indices, the HE staining method, and the Oil red O staining method. The impacts of BXD on the gut microbiome structure and brain (hippocampus and prefrontal cortex tissue) lipids in mice with the AS co-depression model were examined by 16S rDNA sequencing combined with lipidomics analysis. RESULTS: The main components of BXD include baicalin, berberine, ginsenoside Rb1, and 18 other substances. BXD could improve depression-like behavioral characteristics and AS-related indices in AS co-depression mice; BXD could regulate the abundance of some flora (phylum level: reduced abundance of Proteobacteria and Deferribacteres; genus level: reduced abundance of Clostridium_IV, Helicobacter, and Pseudoflavonifractor, Acetatifactor, Oscillibacter, which were significantly different). The lipidomics analysis showed that the differential lipids between the model and gavaged high-dose BXD (BXH) groups were enriched in glycerophospholipid metabolism, and lysophosphatidylcholine (LPC(20:3)(rep)(rep)) in the hippocampus and LPC(20:4)(rep) in the prefrontal cortex both showed downregulation in BXH. The correlation analysis illustrated that the screened differential lipids were mainly linked to Deferribacteres and Actinobacteria. CONCLUSION: BXD may exert an anti-AS co-depression therapeutic effect by modulating the abundance of some flora and thus intervening in peripheral lipid and brain lipid metabolism (via downregulation of LPC levels).

Icetexane diterpenoids as Cav3.2 T-type calcium channel inhibitors from Salvia prattii and analgesic effect of their Semi-synthesized derivatives.

Ten new icetexane diterpenoids, salpratins E-N (1-10) and a known analogue (11) were characterized from Salvia prattii Hemsl. Structurally, 1 is the first 19(4 â†’ 3)-abeo-icetexane diterpenoid featuring with a 6/7/6 ring system. The structures of isolated compounds were determined by comprehensive analyses of spectroscopic data, ECD calculation, and single-crystal X-ray diffraction. Biological studies initially revealed that 1, 7, 10, and 11 are notable Cav3.2 T-type Ca2+ channel (TTCC) inhibitors with IC50 values of 2.9, 5.1, 2.3, and 3.2 µM, respectively. Five icetexane related derivatives (13-17) were synthesized from an abietane type precursor, (+)-carnosic acid (12), for the purpose of overcoming the poor water solubility of aforementioned active compounds and further investigating diverse diterpenes with valuable activity. Among them, 13 and 14 showed potent inhibitions on Cav3.2, having IC50 values of 6.7 and 2.4 µM, respectively. Significantly, they exhibited dose-dependent (1, 3, and 10 mg/kg) and comparable analgesic effects as that of Z944, a TTCCs inhibitor under clinical trial for pain management, in the mouse acetic acid writhing test. These findings further enrich structural diversity and bioactivity of Salvia diterpenoids, as well as provide promising structural templates for the development of Cav3.2 analgesics.