Investigation of the Impact of CYP3A5 Polymorphism on Drug–Drug Interaction between Tacrolimus and Schisantherin A/Schisandrin A Based on Physiologically-Based Pharmacokinetic Modeling

Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus’s exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays with CYP3A5 genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with different CYP3A5 alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5; SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus’s exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated with CYP3A5 polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with different CYP3A5 genotypes.

Schisantherin-A Alleviates Lipopolysaccharide-Induced Inflammation and Apoptosis in WI-38 Cells

Schisantherin A, a dibenzocyclooctadiene lignan, isolated from the fruit of Schisandra sphenanthera has been widely used to exert anti-inflammatory or antioxidant activities in sepsis associated acute kidney injury and lipopolysaccharide associated acute respiratory distress syndrome. However, the protective effects of Schisantherin A against acute pneumonia in lipopolysaccharide-induced WI-38 remain to be explored. To this end, WI-38 cells were treated with lipopolysaccharide to establish an acute pneumonia model and evaluate the effect of Schisantherin A. The data show an increase in apoptosis and decrease in cell viability by lipopolysaccharide treatment that was reversed by Schisantherin A. Also, Schisantherin A dose dependently attenuated lipopolysaccharide-induced increase in proinflammatory cytokines. Lastly, expression of p65, p38 proteins, extracellular-signal-regulated kinase, and Jun N-terminal protein kinase phosphorylation were upregulated by lipopolysaccharide and decreased by Schisantherin A. In conclusion, Schisantherin A demonstrates anti-inflammatory and antiapoptotic roles in lipopolysaccharide induced WI-38 cells through inactivation of nuclear factor-kappa B/mitogen activated protein kinase pathway.

Schisandra henryi C. B. Clarke in vitro cultures: a promising tool for the production of lignans and phenolic compounds

We initiated and optimized in vitro culture conditions of the endemic Chinese plant species—Schisandra henryi C. B. Clarke. Different types of in vitro solid cultures (microshoot and callus), cultivation periods (10, 20, and 30 days), and selected concentrations of BA, IBA, GA3 (0 to 3 mg/l) in the Murashige and Skoog (MS) medium were tested. The presence of dibenzocyclooctadiene lignans (schisandrin, gomisin G, schisantherin A and B, deoxyschisandrin and schisandrin C), dibenzylbutane lignans (hernicine B), aryltetralin lignans (wulignan A1 and A2, epiwulignan A1, enshicine, epienshicine and dimethylwulignan A1), and triterpenoids: kadsuric acid and schisanhenric acid was confirmed by UHPLC–MS/MS analysis. Using HPLC–DAD, the qualitative and quantitative profiles of dibenzocyclooctadiene lignans, phenolic acids and flavonoids in methanolic extracts from biomass were estimated. The maximum total amounts of these groups of metabolites were 873.71, 840.89 and 421.98 mg/100 g DW, respectively. The main compounds were: schisantherin B (max. 622.59 mg/100 g DW), schisantherin A (max. 143.74 mg/100 g DW), neochlorogenic acid (max. 472.82 mg/100 g DW), caftaric acid (max. 370.81 mg/100 g DW), trifolin (max. 138.56 mg/100 g DW) and quercitrin (max. 122.54 mg/100 g DW). The highest total amounts of secondary metabolites estimated in the extracts from in vitro cultures were, respectively, 13.0, 7.0, and 1.4 times higher than in the leaf extracts analyzed for comparison. This is the first report on the biosynthetic potential of cells from Schisandra henryi in vitro cultures.

Schisantherin A Inhibits Pulmonary Fibrosis via Regulating ERK Signaling Pathway

There is no effective method for treating pulmonary fibrosis (PF) until now. This study investigated the anti-fibrotic effect of schisantherin A (SCA) extracted from Schisandra chinensis and its potential molecular mechanism in PF. A bleomycin-induced PF mouse model in vivo and transforming growth factor (TGF)-β1-induced A549 epithelial-mesenchymal transition (EMT) cell model in vitro were used for assessing the anti-fibrotic effect of SCA. Histopathological examination was conducted after hematoxylin and eosin and Masson staining. The level of TGF-β1 was tested by ELISA. The expression levels of α-smooth muscle actin, E-cadherin, and inflammatory cytokines (COX2, IL-1β, IL-6, and TNF-α) were determined by quantitative reverse transcription polymerase chain reaction and Western blot. The expression of extracellular signal-regulated kinase (ERK) was tested in lung tissues and cells by Western blot. The in vivo experiments revealed that SCA treatment markedly improved body weight and pulmonary index and reformed the destruction of the lung tissue structure. We observed that SCA inhibited the process of TGF-β1-induced EMT in the in vitro experiments. Inflammatory cytokines were reduced greatly in lung tissues and cells by SCA. Our study also indicated that SCA decreased phosphorylated ERK. It was concluded that SCA can attenuate PF by regulating the ERK signaling pathway, which suggests that SCA may be used as a potential therapeutic drug for PF.

Schisantherin A Improves the Learning and Memory by Reducing the Phosphorylation of Tau Protein of the Hippocampus in AD Mice

Memory disorders are the main symptoms of aging and Alzheimer’s disease and seriously affect the quality of life. Schisandra, as a famous traditional Chinese medicine, has been used for modulating “the internal organs” for a thousand years. The total lignans from Schisandra have been scientifically proved to improve learning and memory ability. Since it is unclear which monomer in Schisandra total lignans exerts such a function, we evaluated the potential effects of Schisantherin A (SCA), the main monomer from Schisandra, on improving learning ability and memory in amyloid β-protein (Aβ1-42)-induced Alzheimer’s disease (AD) model mice. We found that SCA (5 mg/kg) significantly prolonged the latency and reduced the number of errors in a step-through test. SCA significantly shortened the time of finding the platform and increased the number of crossing the platform and the residence time in a Morris water maze test. SCA increased superoxide dismutase activities and reduced the Malondialdehyde level of the hippocampal tissue, suggesting its role in reducing oxidative stress in the AD mice. Furthermore, we found that SCA significantly decreased the hyperphosphorylation of Tau by altering glycogen synthase kinase-3β (GSK-3β) phosphorylation on Tyr216 and Ser9. Our results revealed the mechanism underlying SCA-mediated learning and memory improvement by regulating GSK-3β activity and lowering the hyperphosphorylation of Tau protein in the hippocampus of AD mice.