Nuciferine,an aromatic ring-containing alkaloid,delivers sedative-hypnotic effects through serotoner-gic system / 中国药理学与毒理学杂志

OBJECTIVE Insomnia is the most fre-quent sleep disorder worldwide and the clinical applica-tion of therapeutic drugs has various adverse effects.In recent years,drugs developed from natural herbs have become potential alternative therapies for insomnia.Nuciferine,one of the main bioactive components obtained from the lotus leaves,has been reported to possess extensive pharmacological activities.However,its hypnotic and sleep regulatory effects have rarely been reported.Hence,this study was intended to investigate the pharma-cological effects of nuciferine and its mechanisms of action in insomnia.METHODS The hypnotic and seda-tive effects of nuciferine were investigated using the eval-uation of locomotor activity test and pentobarbital-induced sleep test in normal and serotonin(5-HT)depletion-induced insomniac mice.Furthermore,the sleep regulatory effects,including sleep time,sleep architecture,and δ-wave power spectral density,were explored using elec-troencephalography/electromyogram(EEG/EMG)-based sleep profiling in normal rats.Finally,the mechanisms of the hypnotic and sedative effects of nuciferine were explored usingin vivoand in silico experiments.RESULTS Nuciferine reduced locomotor activity and prolonged pen-tobarbital-induced sleep time in a dose-dependent man-ner in normal and insomniac model mice.Nuciferine sig-nificantly increased the total sleep time and non-rapid eye movement(NREM)sleep time,inhibited NREM sleep fragmentation,and improved delta power between 0.5 Hz and 1 Hz in normal rats.The results of molecular experiments showed that nuciferine could increase the 5-HT content and 5-HT1A receptor level in the hypothala-mus of insomnia model mice.CONCLUSION This study combined network pharmacological prediction and experi-mental pharmacological techniques to discover the seda-tive-hypnotic effect of nuciferine for the first time Nucif-erine can ameliorate sleep disorder in mice with insom-nia,possibly via serotonergic system.Nuciferine may rep-resent a novel treatment that alleviate the insomnia-like symptoms by modulating 5-HT system.

Effect of nuciferine on gut microbiota and inflammatory response in obese model mice / 中国中药杂志

The aim of this study was to elucidate the mechanism of nuciferine on alleviating obesity based on modulating gut microbiota, ameliorating chronic inflammation, and improving gut permeability. In this study, the obese model mice were induced by high-fat diet and then randomly divided into model group, and nuciferine group; some other mice of the same week age were fed with normal diet as normal group. In the modeling process, the mice were administered intragastrically(ig) for 12 weeks. In the course of both modeling and treatment, the body weight and food intake of mice in each group were measured weekly. After modeling and treatment, the Lee's index, weight percentage of inguinal subcutaneous fat, and the level of blood lipid in each group were measured. The pathological changes of adipocytes were observed by HE staining to evaluate the efficacy of nuciferine treatment in obese model mice. 16 S rRNA sequencing analysis was conducted to study the changes in diversity and abundance of gut microbiota after nuciferine treatment. Enzyme-linked immunosorbent assay(ELISA) and quantitative Real-time polymerase chain reaction(qPCR) were used to detect the levels of inflammatory factors interleukin-6(IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α) and the expression of related genes in adipose tissue of mice in each group, so as to evaluate the effect of nuciferine on chronic inflammation of mice in obese model group. qPCR was used to detect the expression of occludin and tight junction protein 1(ZO-1)gene in colon tissure, so as to evaluate the effect of nuciferine on intestinal permeability of mice in obese group. Nuciferine decreased the body weight of obese mice, Lee's index, weight percentage of inguinal subcutaneous fat(P<0.05), and reduced the volume of adipocytes, decreased the level of total cholesterol(TC), triglyceride(TG), and low density lipoprotein cholesterol(LDL-C)(P<0.05) in serum, improved dysbacteriosis, increased the relative abundance of Alloprevotella, Turicibacter, and Lactobacillus, lowered the relative abundance of Helicobac-ter, decreased the expression of inflammatory cytokines IL-6, IL-1β, and TNF-α genes in adipose tissue(P<0.01), decreased the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in serum(P<0.05), and increased the expression of occludin and ZO-1 genes related to tight junction in colon tissue(P<0.01). Nuciferine could treat obesity through modulating gut microbiota, decreasing gut permeability and ameliorating inflammation.

Research progress on chemical constituents and lipid-lowering mechanism of alkaloids in Nelumbinis Folium / 中草药

Nelumbinis Folium is a Chinese herbal medicine with the effect of regulating lipid and losing weight recorded in “Compendium of Materia Medica”. The alkaloids extracted from lotus leaves have bacteriostatic, lipid-lowering, antispasmodic and other biological activities. In recent years, much attention has been paid to the health problems caused by obesity, so the effect of alkaloids in Nelumbinis Folium on lowering fat and losing weight has become a research hotspot. The chemical constituents, lipid-lowering mechanisms and application in medicine of alkaloids in Nelumbinis Folium were reviewed, which provides a theoretical reference for the development of slimming products and lipid-lowering mechanism of alkaloids in Nelumbinis Folium.

Biopharmaceuticals classification system(BCS) of nuciferin in Nelumbinis Folium / 中国中药杂志

Nuciferin is the main active ingredients in Nelumbinis Folium， which was proved to have good hypolipidemic， antioxidative and anti-inflammatory bioactivities. Currently， pharmacokinetic studies of nuciferin showed different results based on different animal models. evaluation experiments were low-cost， stable and controllable. Biopharmaceutical classification system(BCS) was an effective and reliable simulation method to evaluate the bioavailability of oral drugs. It was a scientific framework for classifying drugs or active pharmaceutical ingredients(API) according to their solubility and impermeability . In the study， BCS was applied in an active ingredient in traditional Chinese medicine(TCM)， which was consisted of numerous chemical components. To study the equilibrium solubility of nuciferine， ideal solution model， Ape blat model and polynomial model were adopted. The permeability was measured based on partition coefficient(logP) and distribution coefficient(logD). Besides， apparent permeabilities of Caco-2 cells and murine intestine tissues were evaluated. Nuciferine was classified as BCSⅠ， since it had a good solubility and permeability in all methods under acidic conditions. However， in neutral and alkaline environments， nuciferine was classified as BCSⅣ by using everted intestinal sac. It indicated that the species of experimental animals has a significant influence on the absorption of nuciferine. This experiment can provide data support to the prediction in a complex environment(medicinal materials and absorbed parts). The application of BCS on TCM ingredients provided a new method to evaluate and screen out the druggability of TCM ingredients.

Research Advances in Pharmacological Effects of Nuciferine / 中国药师

Nuciferine is a major aporphine alkaloid in the leaves of Nelumbo nueifera. It has great effects such as lipid-lowering,anti-oxidation,antimicrobial activitity and anti-cancer. The review focused on its pharmacological effects and pharmacokinetic characters reported in recent years,which can be helpful to the further researches on nuciferine.

Simultaneous Determination of Three Active Compounds in Heye Granule by RP-HPLC / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of rutin,quercetin and nuciferine in Heye gran-ule. METHODS:HPLC was performed on the column of Hypersil ODS2 with mobile phase of acetonitrile-water(containing 0.3%phosphoric acid and 0.4% triethylamine)(gradient elution)at a flow rate of 1.0 ml/min,the detection wavelength was 256 nm,the column temperature was 25 ℃,and the injection volume was 10 μl. RESULTS:The linear range was 0.012-0.240 μg for rutin(r=0.999 9),0.010 4-0.208 μg for quercetin(r=0.999 9)and 0.015-0.300 μg for nuciferine(r=0.999 9);RSDs of precision,stability and reproducibility tests were lower than 2.0%;recoveries were 98.5%-101.3%(RSD=1.1%,n=6),99.1%-101.6%(RSD=1.0%, n=6)and 98.9%-101.7%(RSD=1.2%,n=6). CONCLUSIONS:The method is simple,accurate and reliable,and can provide ref-erence for quality control of Heye granule.

Effects of Nuciferine on Mice with Hyperlipidemia and Its Mechanisms / 医药导报

Objective To investigate the effects of nuciferine on hyperlipidemia in mice and to clarify the molecular mechanism. Methods Mice were divided into three groups according to the diet: normal control group ( n=10 ) , model control group (n=10), and the intervention group (n=10). The normal control group was treated with common diet (ANI-76A feed:12. 4% fat, 68. 8% carbohydrate, 18. 8% protein). The model control group was induced with high fat diet (37. 1% fat, 42. 4% carbohydrate, 20. 5% protein). The intervention group was supplemented with 0. 5% nuciferine based on high fat diet. The mice were allowed free access to food and water for a total of 10 weeks. Several indices were analyzed in the 3 groups, including the body weight, serum lipid, lipid metabolism key enzyme, oxidative stress and metabolic pathway. Results Our results suggested that the high-fat diet-induced animal models developed obesity and dyslipidemia (P0.05).Theactivityofhepaticlipidmetabolismkeyenzymes[(4.15±1.26) U·mL-1vs.(9.01±1.34) U·mL-1] andthe activity of hepatic lipase and lipoprotein lipase[(8.12±3.07) U·mL-1 vs.(13.48±3.75) U·mL-1] were elevated.Oxidative stress was also affected by nuciferine (P<0. 05). Mechanism study suggested that lipid synthesis genes (like SREBP-1c, FAS, SCD-1 and PPAR gamma mRNA) were up-regulated by high fat diet (P<0. 05), and the lipid oxidation metabolism genes, PPARαand CPT-1a mRNA, were down-regulated (P<0. 05), while the intervention group treatment reversed these changes (P<0. 05). Conclusion Nuciferine can improve hyperlipidemia, which might be related to the regulation of enzyme activity, oxidative stress and the changes of lipid synthesis and oxidative metabolism.

Simultaneous determination of eight components in Hedan Tablets by UPLC / 中草药

Objective: To develop a UPLC method for the simultaneous determination of nuciferine, psoralen, isopsoralen, tanshinone IIA, danshensu, sennoside A, sennoside B, and ursolic acid in Hedan Tablets. Methods: The chromatographic separation was achieved on an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 μm) with methanol-acetonitrile (40:60, A)-0.1% formic acid (B) as mobile phases at the flow rate of 0.6 mL/min for gradient elution: 0-4.0 min, 90% B; 4.0-6.0 min, 90%-80% B; 6.0-9.0 min, 80%-70% B; 9.0-10.5 min, 70%-60% B; 10.5-12.0 min, 60%-50% B, 12.0-16.0 min, 50%-10% B; Detection with variable wavelength: 0-4.0 min was 215 nm, 4.0-12.0 min was 270 nm, 12.0-16.0 min was 340 nm, and the column temperature was 40°C. Its linear relationship, precision, repeatability, stability, and recoveries were investigated. Results: The results showed that the eight active components were well separated and showed good linearity. The precision was good and RSD was less than 3.0%. The repeatability was good and RSD was less than 3.0%. The stability was good in 24 h. The average recoveries were between 99.21%-101.91% and RSD was less than 3.0%. Conclusion: The method is accurate, sensitive, credible, and repeatable. It could be applied to the quality control of Hedan Tablets.

Separation and preparation of alkaloids in Nelumbinis Folium by pH-zone-refining counter-current chromatography / 中草药

Objective: A novel method for the separation of alkaloids from Nelumbinis Folium by pH-zone-refining counter-current chromatography (pH-ZRCCC). Methods: The two-phase solvent system composed of MtBE-methanol-water (4:1:5), 10 mmol/L triethylamine (TEA) in organic stationary phase and 5 mmol/L HCl in aqueous mobile phase. The upper phase was used as the stationary phase, while the lower phase was used as the mobile phase. In one-step elution under the conditions of a flow rate of 1.5 mL/min, 800 r/min and the effluent was detected at 254 nm. Results: From 2.18 g of the crude extract, 110 mg N-nornuciferin, 420 mg O-nornuciferin, 310 mg nuciferine, and 190 mg roemerine were obtained and each with a purity of over 98% as determined by HPLC. The structures of the isolated compounds were identified by HPLC, MS, and 1H-NMR. Conclusion: The present pH-ZRCCC method may be applied to the purification of other various alkaloids from natural products.

Effect of processing on the contents of nuciferine and quercetin in Nelumbo nucifera Gaertn / 中成药

AIM: To study the effect of the processing on the contents of nuciferine and quercetin existed in lotus leaf(Nelumbo nucifera Gaertn).METHODS: Nuciferine and quercetin were allowed for the markers and its contents were assayed by HPLC.Marker constituents were compared among raw herb,carbonizing by stir-frying and carbonizing by calcining.RESULTS: By means of carbonizing processing,nucifering content of lotus leaf reduced to 99.25% and 99.23% compared with the unprocessed lotus leaf,quercetin content of lotus leaf increased to 608.56% and 643.85% compared with the unprocessed lotus leaf.CONCLUSION: The heating processing has remarkable effect on the contents of nuciferine and quercetin in Nelumbo nucifera Gaertn.