Study on the antidepressive effects and mechanism of raw and fried Ziziphi Spinosae Semen via metabolomics and gut microbiota analysis.

Ziziphi Spinosae Semen (ZSS) and fried ZSS (FZSS) have been used for treating insomnia and depression in China. However, the potential influence of chemical variations on their efficacy remains unclear. This study demonstrated that compared with ZSS, FZSS exhibited an increase in the content of seven compounds, while the fatty oil content decreased. Both ZSS and FZSS exhibited antidepressive effects in a chronic unpredictable mild stress rat model, indicating a synergistic regulation of deficiencies in 5-hydroxytryptamine in the brain and the hyperactivation of severe peripheral inflammation. ZSS demonstrated a superior modulatory effect compared with FZSS, as indicated by integrated pharmacodynamic index, metabolic profile, and relative distance value. The potential mechanism underlying their antidepressive effects involved the modulation of gut microbiota structure to alleviate excessive inflammatory responses and imbalanced tryptophan metabolism. Correlation analysis indicated that the higher fatty oil contents should be comprehensively considered as the main reason for ZSS's superior antidepressive effects, achieved through the regulation of pyroglutamic acid levels.

[Processing of Ziziphi Spinosae Semen: evolution and research progress].

Ziziphi Spinosae Semen(ZSS), a precious bulk Chinese medicinal, has long been used for nourishing heart and tonifying liver, calming the heart and tranquilizing the mind. Based on materia medica records, medical classics, and relevant literature, this study summarized the evolution and development of the processing methods of ZSS, verified the purposes of ancient processing and efficacy of ZSS, checked whether the decoction pieces of ZSS had been included in national and provincial standards, and concluded the research progress on processing mechanism of ZSS. A total of 9 processing methods have been recorded, such as plain stir-frying and stir-frying with adjuvants. It was a common view that ZSS was endowed with a different purpose after being processed in ancient times. However, in modern times, different views, such as ZSS and processed ZSS for the same purpose, and processing enhancing the efficacy of ZSS, emerge. At the moment, processed ZSS are included in 10 editions of Chinese Pharmacopoeia and the processing methods of ZSS can be retrieved in 22 provincial specifications on processing. Plain stir-frying is currently the mainstream processing method. The chemical components, such as flavonoids, saponins, and fatty acids, in the medicinal, change after processing, but ZSS and the stir-fried ZSS show no significant difference in tranquilizing mind, improving learning and memory, and alleviating anxiety. The problems in the research on ZSS processing were analyzed in this study. In addition, the author also discussed the inheritance of ancient methods, the scientific connotation of processing, and the improvement of decoction pieces standards, hoping to provide new ideas for the clinical rational use and the decoction pieces standard improvement of ZSS.

[Study on mechanism of enhancing antioxidant activity in fermented Ziziphi Spinosae Semen with Poria cocos].

In this study, the antioxidant property changes in fermented Ziziphi Spinosae Semen(FZSS) with Poria cocos were analyzed by DPPH, ABTS and FRAP methods. Then the content determination of active ingredients and ~1H nuclear magnetic resonance(~1H-NMR) spectroscopy were also used to investigate the mechanism of FZSS with P. cocos in enhancing the antioxidant activity. The results showed that the content of active ingredients such as total phenols, total saponins and total polysaccharides were significantly increased during the fermentation time. The results of ~1H-NMR metabonomics showed that the contents of amino acids such as leucine, lysine, valine and alanine, nitrogen compounds such as creatine, creatinine, and betaine, and secondary metabolites, for instance, jujuboside A and spinosin were higher after fermentation, and above components showed positive correlation with antioxidant capacity in Pearson correlation analysis. Therefore, it was inferred that the enhancement of antioxidant activity of FZSS may be the result of the joint action of various chemical components. This study preliminarily clarified the mechanism of FZSS in enhancing the antioxidant activity, and provided new research ideas for the product development and utilization of FZSS.

Comparative pharmacokinetics of six major compounds in normal and insomnia rats after oral administration of Ziziphi Spinosae Semen aqueous extract.

Ziziphi Spinosae Semen (ZSS), a traditional Chinese medicine, is used in clinics for the treatment of insomnia in China and other Asian countries. Herein, we described for the first time a comparative pharmacokinetics study of the six major compounds of ZSS in normal control (NC) and para-chlorophenylalanine (PCPA)-induced insomnia model (IM) rats that were orally administered the aqueous extract of ZSS. An ultra-high-performance liquid chromatography coupled with quadrupole orbitrap mass (UHPLC-Q-Orbitrap-MS) method was developed and validated for the simultaneous determination of coclaurine, magnoflorine, spinosin, 6‴-feruloylspinosin, jujuboside A (JuA), and jujuboside B (JuB) in ZSS in rat plasma. The established approach was successfully applied to a comparative pharmacokinetic study. The systemic exposures of spinosin and 6‴-feruloylspinosin were decreased in the IM group compared to the NC group, while plasma clearance (CL) was significantly increased. The Tmax values of JuA and JuB in IM rats were significantly lower than those in NC rats. The T1/2 of JuA in the IM group was significantly accelerated. The pharmacokinetic parameters of coclaurine and magnoflorine were not evidently affected between the two groups. These results indicate that the pathological state of insomnia altered the plasma pharmacokinetics of spinosin, 6‴-feruloylspinosin, JuA, and JuB in the ZSS aqueous extract, providing an experimental basis for the role of ZSS in insomnia treatment. The comparative pharmacokinetics-based UHPLC-Q-Orbitrap-MS using full-scan mode can therefore provide a reliable and suitable means for the screening of potentially effective substances applied as quality markers of ZSS.

Metabolic profile and underlying antioxidant improvement of Ziziphi Spinosae Folium by human intestinal bacteria.

Ziziphi Spinosae Folium, the leaf of Ziziphus jujuba Mill. Var. spinosa (Bunge) Hu ex H. F. Chou (LZJS), is currently used as a healthy tea in China. This study evaluated the chemical components and antioxidant activities of LZJS flavonoid (LZJSF) and fermented LZJSF (FLZJSF) using human intestinal bacteria (HIB) through dynamic fermentation. Eighteen flavonoids were simultaneously identified in LZJSF using UHPLC-Q-Orbitrap-MS method, nine of which were targeted for a HIB metabolism study. Seven small phenolic acids were identified in FLZJSF. Not only at chemical level but also at PC12 cell level, FLZJSF samples fermented for 4 and 6 h showed significant positive correlation between their activities and flavonoid aglycones, which were transformed from LZJSF. However, FLZJSF samples (8 h and longer time) mainly contained phenolic acids and indicated weak activities. Thus, LZJSF was found to result in increased antioxidant activity and could be commercially utilized as a novel functional food.

Determination of five neurotransmitters in the rat brain for the study of the hypnotic effects of Ziziphi Spinosae Semen aqueous extract on insomnia rat model by UPLC-MS/MS.

Ziziphi Spinosae Semen (ZSS) has been used for treatment of insomnia in China for centuries. To reveal the influence of insomnia on the levels of the neurotransmitters including serotonin (5-HT), glutamic acid (Glu), γ-aminobutyric acid (GABA), noradrenaline (NE) and dopamine (DA), and to study the role of ZSS aqueous extract in the treatment of insomnia, an UPLC-ESI- MS/MS method was developed and validated for simultaneous determination of five neurotransmitters in the rat brain. The brain samples were pretreated by one-step direct protein precipitation with acetonitrile. The analytes were detected in positive mode with multiple reaction monitoring (MRM) and the procedure was completed in less than 10 min. The method showed a good linearity (R2 > 0.9967) with the other validation parameters were within acceptance range. The results indicated that the concentration of 5-HT, GABA and DA is significantly lower (P < 0.01) in para-chlorophenylalanine (PCPA)-induced insomnia rat model group, while Glu and NE significantly higher than those in control group (P < 0.01). Treatment with ZSS aqueous extract (4 or 8 g·kg-1·d-1 for seven days) could ameliorate the symptoms of insomnia by significantly changing the levels of the neurotransmitter parameters mentioned above. The data obtained in this study demonstrate that ZSS aqueous extract could ameliorate the symptoms of insomnia by modulating the levels of monoamines and amino acid neurotransmitters in the brain.

[Compatibility chemistry of acid-alkaline pair medicine of Dahuang and Huangbai in Dahuang Xiaoshi decoction].

OBJECTIVE: To determine the change pattern of alkaline and acid components of Dahuang and Huangbai amoung different combinations in Dahuang Xiaoshi decotion. METHOD: The contents of anthraquinones and berberine were determined by HPLC in samples of Dahuang extracts, Huangbai extracts, Dahuang and Huangbai pair medicine extracts, and extracts of whole recipe. RESULT: The contents of anthraquinones and berberine were decreased with the changes of combinations: from component medicinal material alone to pair medicines, and to whole recipe. the change pattern was more apparent in water decoctions than in ethanol extracts. CONCLUSION: The contents of alkaline and acid components are changed with different extract methods and different combinations.

[Compatability chemistry of acid-alkaline pair medicine of dahuang and Fuzi in Dahuang Fuzi decoction].

OBJECTIVE: To determine the change pattern of alkaline and acid components of Dahuang and Fuzi in different combinations. METHOD: The contents of anthraquinones and aconite alkaloids were determined by HPLC in samples of Dahuang extracts, Fuzi extracts, Dahuang and Fuzi pair medicines extracts, and extracts of whole recipe. RESULT: As for Dahuang, the contents of anthraquinones were decreased with changes of combination: higher contents were in decoctions of Dahuang alone, lower contents were in decoctions of pair medicines, and the lowest contents were in decoctions of whole recipe. As for Fuzi, monoester aconite alkaloids could be detected in water extracts, and both biester and monoester aconite alkaloids could be detected in ethanol extracts. The contents of aconite alkaloids were decreased with changes of combinations: from Fuzi alone to pair medicines, and to whole recipe. The change pattern was more apparent when extracted in water decoction. CONCLUSION: The contents of alkaline and acid components are changed with different extract methods and different combinations.

[Compatability chemistry of acid-alkaline pair medicine of Fuzi and Gancao in Sini decoction].

OBJECTIVE: To determine the change pattern of alkaline and acid components of Fuzi and gancao amoung different combinations in Sini Decotion. METHOD: The contents of aconite alkaloids and glycyrrhizic acid were determined by HPLC in samples of Fuzi extracts, gancao extracts, Fuzi and gancao pair medicines extracts, and extracts of whole recipe. RESULT: As for Fuzi, monoester aconite alkaloids could be detected in water extracts, and both biester and monoester aconite alkaloids could be detected in ethanol extracts. The contents of aconite alkaloids were decreased with changes of combinations: from Fuzi alone to pair medicines, and to whole recipe. The change pattern was more apparent when extracted in water decoction. As for Gancao, the glycyrrhizic acid was lowered from single medicine to pair medicines, and to whole recipe. CONCLUSION: The contents of alkaline and acid components were changed with different extract methods and different combinations of Fuzi and Gancao.

[Research on compatibility chemistry of acid-alkaline pair medicines in formulas of traditional Chinese medicine].

Compatibility chemistry of acid-alkaline pair medicines in formulas of traditional Chinese medicine (TCM) is an important research field which should merit to pay attention. The ideas and methods in prescription compatibility research on formulas containing alkaline-acid pair medicines were summarized from the aspect of chemical groups of alkaline and acid ingredients; the research results were introduced and analyzed; the research meaning was elaborated; and the expectation of the field was viewed.

[Compatability chemistry of acid-alkaline pair medicine of Ephedra sinica and Glycyrrhiza uralencis in Maxing Shigan decoction].

OBJECTIVE: To investigate the change regularity of ephedrine and glyrihhzine acid in Ephedra sinila and Glycyrrhiza uralencis pair medicines and in Maxing Shigan decoction. METHOD: The contents of ephedrine and glycyrrhizic acid were determined by HPLC in samples of E. sinica extracts, G. uralencis extracts, pair medicines extracts of Maxing Shigao decoction sinica and G. uralencis, and extracts of E. sinica. RESULT: There were no significant difference in ephedrine contents amoung different samples; the contents of glycyrrhizic acid were lower in decoctions of Maxing Shigan decoction than in G. uralencis decoction and pair medicines extracts. CONCLUSION: Macromolecular complex was NOT formed by ephedrine and Glycyrrhizic acid in decoctions containing pair medicines of E. sinica and G. uralencis.

[Studies on chemical structure of complexes compounds formed by acid and alkaline components of pair medicines in decoction].

OBJECTIVE: To study the chemical structures of macromolecular complexes formed by aconitine and glycyrrhizic acid, aconitine and rhein, berberine and rhein, ephedrine and glycyrrhizic acid in decoctions. METHOD: The binding energy of reactants and products was determined by X-ray spectrography, the ground level charge distribution of products was caculated by density function theory of quantum chemistry. RESULT: The binding energy of aconitine and glycyrrhizic acid, aconitine and rhein, berberine and rhein were changed after reaction. The characteristic atoms in the molecular structures of acid components have higher positive electric charge, while the ones in alkaline components have higher negative charge. CONCLUSION: Aconitine and glycyrrhizic acid, aconitine and rhein, berberine and rhein can form macromolecular complexes, ephedrine and glycyrrhizic acid can not.