Schisandra chinensis fruit is a widely edible and medicinal resource, whose extract had a good inhibitory effect on airway inflammation in asthmatic mice. However, the main active components remain unknown. In this work, we found that PET2, a subfraction of its ethanolic extract petroleum ether, displayed significant anti-inflammatory effects in interleukin (IL)-4/tumor necrosis factor (TNF)-α-stimulated BEAS-2B cells. Meanwhile, in the ovalbumin (OVA)-induced allergic asthma mice model, PET2 (200 and 400 mg/kg) had significant effects on attenuating airway inflammatory cell infiltration and reducing serum Th2-related cytokines. Further studies led to the isolation and identification of 14 compounds, guided by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based rapid characterization of chemical constituents. Combining network pharmacology analysis and in vitro experiments, we found that six compounds from PET2 had good anti-inflammatory properties. The potential mechanism may be involved in Fc epsilon RI, T cell receptor, and Jak-STAT signaling pathways. This study clarified the anti-inflammatory properties of the main active fraction and active compounds of S. chinensis fruit and provided a theoretical basis for its anti-asthma scientific utilization.
The present quality control method of Chinese medicinal materials (CMM) has obvious deficiency, which cannot be compatible with the multi-target and multi-component characteristics and production process of CMM. Plant metabolomics with a huge impetus to comprehensively characterize the metabolites and clarify the complexity and integrity of CMM, has been widely used in the research of CMM. This article comprehensively reviewed the application of plant metabolomics in the quality control of CMM. It introduced the concept, technique, and application examples, discussed the prospects, limitations, improvements of plant metabolomics. MS and NMR, as important techniques for plant metabolomics, are mainly highlighted in the case references. The purpose of this article is to clarify the advantage of plants metabolomics for promoting the optimization of the CMM quality control system and proposing a system approach to realize the overall quality control of CMM based on plant metabolomics combined with multidisciplinary method.
Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is a common metabolic liver disease worldwide. Currently, satisfactory drugs for NAFLD treatment remain lacking. Obesity and diabetes are the leading causes of NAFLD, and compounds with anti-obesity and anti-diabetic activities are considered suitable candidates for treating NAFLD. In this study, biochemical and histological assays revealed that a natural lignan schisanhenol (SAL) effectively decreased lipid accumulation and improved hepatic steatosis in free fatty acid (FFA)-treated HepG2 cells and high-fat diet (HFD)-induced NAFLD mice. Further, molecular analyses, microRNA (miRNA)-seq, and bioinformatics analyses revealed that SAL may improve NAFLD by targeting the miR-802/adenosine monophosphate-activated protein kinase (AMPK) pathway. Liver-specific overexpression of miR-802 in NAFLD mice significantly impaired SAL-mediated liver protection and decreased the protein levels of phosphorylated (p)-AMPK and PRKAB1. Dual-luciferase assay analysis further confirmed that miR-802 inhibits hepatic AMPK expression by binding to the 3ʹ untranslated region of mouse Prkab1 or human PRKAA1. Additionally, genetic silencing of PRKAA1 blocked SAL-induced AMPK pathway activation in FFA-treated HepG2 cells. The results demonstrate that SAL is an effective drug candidate for treating NAFLD through regulating miR-802/AMPK-mediated lipid metabolism.
Dirigent(DIR) proteins are involved in the biosynthesis of lignin, lignans, and gossypol in plants and respond to biotic and abiotic stresses. Based on the full-length transcriptome of Schisandra chinensis, bioinformatics methods were used to preliminarily identify the DIR gene family and analyze the physico-chemical properties, subcellular localization, conserved motifs, phylogeny, and expression patterns of the proteins. The results showed that a total of 34 DIR genes were screened and the encoded proteins were 156-387 aa. The physico-chemical properties of the proteins were different and the secondary structure was mainly random coil. Half of the DIR proteins were located in chloroplast, while the others in extracellular region, endoplasmic reticulum, cytoplasm, etc. Phylogenetic analysis of DIR proteins from S. chinensis and the other 8 species such as Arabidopsis thaliana, Oryza sativa, and Glycine max demonstrated that all DIR proteins were clustered into 5 subfamilies and that DIR proteins from S. chinensis were in 4 subfamilies. DIR-a subfamily has the unique structure of 8 β-sheets, as verified by multiple sequence alignment. Finally, through the analysis of the transcriptome of S. chinensis fruit at different development stages, the expression pattern of DIR was clarified. Combined with the accumulation of lignans in fruits at different stages, DIR might be related to the synthesis of lignans in S. chinensis. This study lays a theoretical basis for exploring the biological functions of DIR genes and elucidating the biosynthesis pathway of lignans in S. chinensis.
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a global pandemic, and there remains an urgent demand for specific/targeted drugs for the disease. The 3C-like protease (3CLpro) is a promising target for developing anti-coronavirus drugs. Schisandra sphenanthera fruit is a well-known traditional Chinese medicine (TCM) with good antiviral activity. This study found that the ethanolic extract displayed a significant inhibitory effect against SARS-CoV-2 3CLpro. Forty-four compounds were identified in this extract using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Combining molecular docking and in vitro experiments, we found that two epimeric 7,8-secolignans, rel-(1S,2R)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (2) and rel-(1S,2S)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (4), potently inhibited 3CLpro with IC50 values of 4.88 ± 0.60 μM and 4.75 ± 0.34 μM, respectively. Moreover, in vivo and in vitro experiments indicated that compounds 2 and 4 were potent in regulating the inflammatory response and preventing lung injury. Our findings indicate that compounds 2 and 4 may emerge as promising SARS-CoV-2 inhibitors via 3CLpro inhibition and anti-inflammatory mechanisms.
Phenylpropenes such as isoeugenol and eugenol are produced as defend compounds, floral attractants, and flavor constituents by phenylpropene synthases belonging to the PIP reductase family. Moreover, isoeugenol is suggested to participate in the biosynthesis of dibenzocyclooctadiene lignans, the principal active compounds of Schisandra chinensis (Turcz.) Baill. fruits (SCF). S. chinensis is a woody vine plant widely utilized for its medicinal, horticultural, edible, and economic values. Here, a total of nine ScPIP genes were identified and characterized from the transcriptome datasets of SCF. The expression profiles revealed that ScPIP genes were differentially expressed at different developmental stages of SCF. According to phylogenetic analysis, three ScPIPs were selected as candidate genes encoding phenylpropene synthases and cloned. In vivo functional characterization in Escherichia coli showed that only ScPIP1 functioned as isoeugenol synthase (IGS) and was designated as ScIGS1. Subcellular localization analysis demonstrated that ScIGS1 was localized in the cytoplasm and nucleus. The three-dimensional (3D) model of ScIGS1 was obtained using homology modeling. Additionally, site-directed mutagenesis experiments revealed that the substitution of residues at positions 110 and 113 impacted the product specificity of ScIGS1, with the change of Lys157 to Ala abolishing the catalytic function. The results of kcat prediction showed that the kcat values of mutants were lower than that of ScIGS1. In conclusion, this study provides a foundation for further research on PIP reductases and the biosynthetic pathway of dibenzocyclooctadiene lignans.
The fruits of Schisandra chinensis (SCF) and Schisandra sphenanthera (SSF) are traditional Chinese herbal medicines classified as medicinal and food homologous materials, known for their significant neuroprotective efficacy. However, the differences in their therapeutic effects and active components for the treatment of vascular cognitive impairment (VCI) remain unclear. This study aimed to elucidate the neuroprotective activities of SCF and SSF on VCI and investigate the compositional disparities between the two. The lipopolysaccharide-induced and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced BV2 cell models were used to evaluate the protective effects of SCF and SSF against neuroinflammation and mitochondrial damage, respectively. The therapeutic effects were further validated using a bilateral common carotid artery stenosis mouse model. Compositional differences were analyzed using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), and drug-like properties of their constituents were assessed. In vitro experiments showed that SCF and SSF at concentrations of 6.4, 16, and 40 μg/mL reduced nitric oxide, tumor necrosis factor-alpha, and interleukin-6 levels in a dose-dependent manner. Notably, at the same concentrations, SCF significantly mitigated OGD/R-induced mitochondrial damage, whereas SSF showed no significant effect. Compared with SSF, SCF exhibited stronger anti-neuroinflammatory and antioxidant properties. In vivo experiments further demonstrated that SCF, administered at 400 mg/kg, was more effective in improving learning ability, spatial learning and memory, cerebral blood flow, and nerve fiber repair than SSF. Moreover, 71 and 64 compounds were identified in SCF and SSF, respectively, using UPLC-Q-TOF/MS. Drug-like property analysis of these compounds revealed that the superior therapeutic effects of SCF may be attributed to differences in biphenylcyclooctene-type lignans. Our data support the conclusion that SCF possesses significantly superior neuroprotective activity compared to SSF, providing a theoretical basis for its clinical application in VCI.
Codonopsis radix is an important edible and medicinal plant resource for immunomodulation in China and Southeast Asia. However, the chemical quality evaluation of C. radix in Chinese Pharmacopoeia (2020 Version) is still lacking; therefore, it is necessary to develop an effective method to evaluate its quality accurately and systematically. Herein, a reliable method for a comprehensive chemical analysis of bioactive compounds in C. radix by ultra-performance liquid chromatography-diode array detector was developed based on the quality marker (Q-marker) concept, which can efficiently reflect its immune activity. Our previous research explored the seven potential bioactive compounds reflecting the immune regulation activities of C. radix by spectrum-effect relationship analysis. Therefore, in this study, we researched on establishing a quality control method and selected the modern pharmacodynamic experiment of immune regulation to verify the potential bioactive compounds as quality markers. A real quality control method that reflected the traditional efficacy of C. radix in strengthening the spleen and tonifying lungs was developed. Furthermore, the C. radix extract and the seven bioactive compounds could promote the proliferation of immune-related cells and regulate the secretion of inflammatory factors, thus playing a role in immune regulation.
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