Nuciferine

Br J Pharmacol. 2014 Nov 19.

Nuciferine relaxes rat mesenteric arteries through endothelium-dependent and -independent mechanisms.[Pubmed: 25409881]

Nuciferine, a constituent of lotus leaf, is an aromatic ring-containing alkaloid, with antioxidative properties. We hypothesize Nuciferine might affect vascular reactivity. This study aimed at determining the effects of Nuciferine on vasomotor tone and the underlying mechanism.
METHODS AND RESULTS:
Nuciferine-induced relaxations in rings of rat main mesenteric arteries were measured by wire myographs. Endothelial NOS (eNOS) was determined by immunoblotting. Intracellular NO production in HUVECs and Ca2+ level in both HUVECs and vascular smooth muscle cells (VSMCs) from rat mesenteric arteries were assessed by fluorescence imaging. Nuciferine induced relaxations in arterial segments pre-contracted by KCl or phenylephrine. Nuciferine-elicited arterial relaxations were reduced by removal of endothelium or by pretreatment with the eNOS inhibitor L-NAME or the NO-sensitive guanylyl cyclase inhibitor ODQ. In HUVECs, the phosphorylation of eNOS at Ser1177 and increase in cytosolic NO level induced by Nuciferine were mediated by extracellular Ca2+ influx. Under endothelium-free conditions, Nuciferine attenuated CaCl2 -induced contraction in Ca2+ -free depolarizing medium. In the absence of extracellular calcium, Nuciferine relieved the vasoconstriction induced by phenylephrine and the addition of CaCl2 . Nuciferine also suppressed Ca2+ influx in Ca2+ -free K+ -containing solution in VSMCs.
CONCLUSIONS:
Nuciferine has a vasorelaxant effect via both endothelium-dependent and -independent mechanisms. These results suggest that Nuciferine may have a therapeutic effect on vascular diseases associated with aberrant vasoconstriction.

PLoS One . 2016 Mar 10;11(3):e0150602.

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine[Pubmed: 26963248]

Abstract Rationale: The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes Nuciferine using in vitro and in vivo pharmacological assays. Methods: Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Results: Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, Nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. Conclusions: The molecular profile of Nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that Nuciferine has atypical antipsychotic-like actions.

Int J Parasitol Drugs Drug Resist . 2016 Dec;6(3):364-370.

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist[Pubmed: 27397763]

Abstract 5-hydroxytryptamine (5-HT) is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL), prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products - Nuciferine, D-glaucine, boldine and bulbocapnine - were demonstrated to block Sm.5HTRL evoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRL antagonists as hypomotility-evoking drugs across different parasite life cycle stages. Keywords: 5-HT; Methoxyisoquinoline; Natural products; Schistosomiasis.

PLoS One. 2013 May 15;8(5):e63770.

Nuciferine prevents hepatic steatosis and injury induced by a high-fat diet in hamsters.[Pubmed: 23691094]

Nuciferine is a major active aporphine alkaloid from the leaves of N. nucifera Gaertn that possesses anti-hyperlipidemia, anti-hypotensive, anti-arrhythmic, and insulin secretagogue activities. However, it is currently unknown whether Nuciferine can benefit hepatic lipid metabolism.
METHODS AND RESULTS:
In the current study, male golden hamsters were randomly divided into four groups fed a normal diet, a high-fat diet (HFD), or a HFD supplemented with Nuciferine (10 and 15 mg/kg·BW/day). After 8 weeks of intervention, HFD-induced increases in liver and visceral adipose tissue weight, dyslipidemia, liver steatosis, and mild necroinflammation in hamsters were analyzed. Nuciferine supplementation protected against HFD-induced changes, alleviated necroinflammation, and reversed serum markers of metabolic syndrome in hamsters fed a HFD. RT-PCR and western blot analyses revealed that hamsters fed a HFD had up-regulated levels of genes related to lipogenesis, increased free fatty acid infiltration, and down-regulated genes involved in lipolysis and very low density lipoprotein secretion. In addition, gene expression of cytochrome P4502E1 and tumor necrosis factor-α were also increased in the HFD group. Nuciferine supplementation clearly suppressed HFD-induced alterations in the expression of genes involved in lipid metabolism.
CONCLUSIONS:
Nuciferine supplementation ameliorated HFD-induced dyslipidemia as well as liver steatosis and injury. The beneficial effects of Nuciferine were associated with altered expression of hepatic genes involved in lipid metabolism.

J Ethnopharmacol. 2012 Jul 13;142(2):488-95.

Nuciferine stimulates insulin secretion from beta cells-an in vitro comparison with glibenclamide.[Pubmed: 22633982 ]

Several Asian plants are known for their anti-diabetic properties and produce alkaloids and flavonoids that may stimulate insulin secretion.
METHODS AND RESULTS:
Using Vietnamese plants (Nelumbo nucifera, Gynostemma pentaphyllum, Smilax glabra, and Stemona tuberosa), we extracted two alkaloids (neotuberostemonine, Nuciferine) and four flavonoids (astilbin, engeletin, smitilbin, and 3,5,3'-trihydroxy-7,4'-dimethoxyflavone), and studied their insulin stimulatory effects. Nuciferine, extracted from Nelumbo nucifera, stimulated both phases of insulin secretion in isolated islets, whereas the other compounds had no effect. The effect of Nuciferine was totally abolished by diazoxide and nimodipine, and diminished by protein kinase A and protein kinase C inhibition. Nuciferine and potassium had additive effects on insulin secretion. Nuciferine also stimulated insulin secretion in INS-1E cells at both 3.3 and 16.7 mM glucose concentrations. Compared with glibenclamide, Nuciferine had a stronger effect on insulin secretion and less beta-cell toxicity. However, Nuciferine did not compete with glibenclamide for binding to the sulfonylurea receptor.
CONCLUSIONS:
Among several compounds extracted from anti-diabetic plants, Nuciferine was found to stimulate insulin secretion by closing potassium-adenosine triphosphate channels, explaining anti-diabetic effects of Nelumbo nucifera.

J Ethnopharmacol. 2015 May 13;165:83-93.

Nuciferine, extracted from Nelumbo nucifera Gaertn, inhibits tumor-promoting effect of nicotine involving Wnt/β-catenin signaling in non-small cell lung cancer.[Pubmed: 25698245 ]

The leaves of Nelumbo nucifera Gaertn are recorded in the earliest written documentation of traditional Chinese medicinal as "Ben Cao Gang Mu", a medicinal herb for blood clotting, dysentery and dizziness. Recently, Nuciferine (NF), one of N. nucifera Gaertn leaf extracts has been shown to possess several pharmacological properties, including anti-viral and anti-cancer. The aim of this study is to investigate the underlying molecular mechanism of the anti-cancer activity of NF in NSCLC progression induced by nicotine.
METHODS AND RESULTS:
NF significantly inhibited the proliferation of NSCLC cells in the presence of nicotine, suppressed the activity of Wnt/β-catenin signaling, enhanced the stabilization of Axin, and induced apoptosis. NF down-regulated the expression levels of β-catenin and its downstream targets including c-myc, cyclin D and VEGF-A. NF also decreased the ratio of Bcl-2/Bax, which may explain the pro-apoptosis effect of NF. In tumor xenograft nude mice, NF not only inhibited the growth of non-small cell lung cancer (NSCLC) cells, but also remarkably alleviated the injury induced by nicotine in liver function.
CONCLUSIONS:
NF has the remarkable effect to inhibit nicotine-induced NSCLC progression, which was due to its ability to reduce the activity of Wnt/β-catenin signaling. Thus, the work stated here emphasizes the importance of this traditional medicine and presents a potential novel alternative to NSCLC prevention and therapy.

Eur J Pharmacol. 2015 Jan 15;747:59-70.

Nuciferine restores potassium oxonate-induced hyperuricemia and kidney inflammation in mice.[Pubmed: 25499818]

METHODS AND RESULTS:
Nuciferine, a major aporphine alkaloid of the leaves of Nelumbo nucifera, was found to decrease serum urate levels and improved kidney function, as well as inhibited system and renal interleukin-1β (IL-1β) secretion in potassium oxonate-induced hyperuricemic mice. Furthermore, Nuciferine reversed expression alteration of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette, subfamily G, membrane 2 (ABCG2), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1), and organic cation/carnitine transporters 1/2 (OCTN1/2) in hyperuricemic mice. More importantly, Nuciferine suppressed renal activation of Toll-like receptor 4/myeloid differentiation factor 88/NF-kappaB (TLR4/MyD88/NF-κB) signaling and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome to reduce serum and renal IL-1β levels in hyperuricemic mice with renal inflammation reduction. The anti-inflammatroy effect of Nuciferine was also confirmed in human proximal renal tubular epithelial cells (HK-2 cells) incubated with 4mg/dl uric acid for 24h.
CONCLUSIONS:
This study firstly reported the anti-hyperuricemic and anti-inflammatory effects of Nuciferine by regulating renal organic ion transporters and inflammatory signaling in hyperuricemia. These results suggest that a dietary supplement of Nuciferine rich in lotus leaf may be potential for the prevention and treatment of hyperuricemia with kidney inflammation.

J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jun 15;961:20-8.

A sensitive liquid chromatography-tandem mass spectrometry method for pharmacokinetics and tissue distribution of nuciferine in rats.[Pubmed: 24854711]

Nuciferine is an important drug candidate for the treatment of obesity-related diseases. However, few investigations have been conducted about the pharmacokinetics and tissue distribution of Nuciferine to better understand its behavior and action mechanism in vivo.
METHODS AND RESULTS:
Thus, a sensitive and reliable liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method was established and validated for the quantification of Nuciferine in rat plasma and tissue samples. The validated method was successfully applied to the pharmacokinetic and tissue distribution study of Nuciferine in rats. One-compartmental pharmacokinetic parameters indicated that Nuciferine had rapid distribution, extensive tissue uptake, and poor absorption into systemic circulation. The values of absolute bioavailability were (3.8±1.4)%, (4.2±1.3)% and (3.9±1.0)% after oral administration of 2.0, 5.0 and 10.0mg/kg Nuciferine and intravenous administration of 0.2mg/kg Nuciferine in rats. The results of the tissue distribution study suggested that Nuciferine was distributed into the brain, liver and adipose tissue after intravenous administration.
CONCLUSIONS:
In conclusion, the present study may provide a material basis for study of the pharmacological action of Nuciferine in the treatment of obesity, and meaningful insights into further study on dosage modification.