Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation.

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in the progressive age-related neurodegenerative disorders such as Alzheimer's disease (AD) and vascular dementia. In the present study, we for the first time found that nobiletin, a novel leading compound for AD therapy, improved cerebral ischemia-induced memory deficits in vivo. Treatment with 50 mg/kg of nobiletin (i.

Identification of nobiletin, a polymethoxyflavonoid, as an enhancer of adiponectin secretion.

Adiponectin, an adipocyte-derived protein with insulin-sensitizing, anti-diabetic and anti-atherogenic activities, is known to be induced during adipocyte differentiation. Nobiletin, a citrus polymethoxy flavonoid, was found to induce the differentiation of ST-13 preadipocytes into mature adipocytes and enhance the production of adiponectin protein at a concentration of 10 microM.

Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease.

Increasing evidence suggests that the elevation of beta-amyloid (Abeta) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signal-regulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates Abeta-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice].

Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus.

Nobiletin isolated from citrus peels prevents bulbectomy- and amyloid-beta protein-induced memory impairment in rodents. In the present study, using combined methods of biochemistry and electrophysiology, we examined the effects of nobiletin on phosphorylation of GluR1 receptor, the subunit of alpha-amino-3-hydroxy-5-methyl-D-aspartate (AMPA) receptors, and the receptor-mediated synaptic transmission in the hippocampus, a region implicated in memory formation, in culture and/or in slices. Western blot analysis showed that nobiletin-stimulated phosphorylation of multiple protein kinase A (PKA) substrates at 10 min following the treatment in cultured hippocampal neurons.

Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice.

We have recently reported that nobiletin, a citrus flavonoid, improves impaired memory in olfactory-bulbectomized (OBX) mice, which have been widely utilized as a useful paradigm that shares some major clinical features of Alzheimer's disease. Here, we examined the effects of nobiletin on OBX-induced cholinergic neurodegeneration in mice. OBX mice showed reduced acetylcholinesterase (AChE) staining and choline acetyltransferase (ChAT) expression in the hippocampus.

Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling.

Recent studies have indicated that learning-induced activation of extracellular signal-regulated kinase (ERK) signaling via N-methyl-D-aspartate (NMDA) receptors is required for consolidation of the resultant learning. These findings raise an idea that control of ERK signaling may be a potential target for treatment of cognitive dysfunction. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from Citrus depressa, enhances cAMP/protein kinase A/ERK signaling in cultured rat hippocampal neurons and PC12D cells.

Neocimicigenosides A and B, cycloartane glycosides from the rhizomes of Cimicifuga racemosa and their effects on CRF-stimulated ACTH secretion from AtT-20 cells.

Two new cycloartane glycosides, named neocimicigenosides A (1) and B (2), were isolated from the rhizomes of Cimicifuga racemosa. The structures of 1 and 2 were determined on the basis of extensive spectroscopic analysis and enzymatic hydrolysis followed by chromatographic and spectroscopic analyses to be (16S,23R,24S)-24-acetoxy-16,23:16,25-diepoxy-15alpha-hydroxycycloartan-3beta-yl alpha-L-arabinopyranoside (1) and (16S,23R,24S)-24-acetoxy-16,23:16,25-diepoxy-15alpha-hydroxycycloartan-3beta-yl beta-D-xylopyranoside (2), respectively. Neocimicigenosides A and B enhanced CRF-stimulated ACTH secretion from AtT-20 cells.

Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and memory deterioration. Production and accumulation of beta-amyloid peptide (Abeta) is central to the pathogenesis of AD. Recent studies have demonstrated that PKA/CREB-dependent signaling pathway and long-term potentiation are inhibited by sublethal concentrations of Abeta(1-42) in cultured hippocampus neurons.

Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities.

cAMP response element (CRE) transcription is dysregulated in neurodegenerative disorders in the central nervous system (CNS), including polyglutamine diseases. As the first step to find natural compounds with protective action against neurodegeneration in the CNS, we here examined whether six citrus flavonoids, namely nobiletin, 5-demethylnobiletin, tangeretin, sinensetin, 6-demethoxytangeretin, and 6-demethoxynobiletin, stimulated CRE-dependent transcription and induced neurite outgrowth in PC12D cells. Among the compounds, nobiletin most potently enhanced CRE-dependent transcription and neurite outgrowth by activating ERK/MAP kinase-dependent signalling to increase CREB phosphorylation.

Mechanism of neurotrophic action of nobiletin in PC12D cells.

Nobiletin is a nonpeptide compound with a low molecular weight from a citrus fruit and has the activity to rescue bulbectomy-induced memory impairment. Here we describe that nobiletin itself induces neurite outgrowth in PC12D cells, a rat pheochromocytoma cell line, like NGF, and the molecular mechanism of its neurotrophic action. As cultured in the presence of nobiletin or NGF for 48 h and then assayed using a scanning electron microscope, PC12D cells treated with nobiletin showed morphology with flatter and larger cell bodies than the cells cultured with NGF.

New glycosides of the campesterol derivative from the rhizomes of Tacca chantrieri.

Seven new glycosides of the campesterol derivative (24R,25S)-ergost-5-ene-3beta,26-diol (1-7) were isolated from the rhizomes of Tacca chantrieri (Taccaceae). Their structures were determined by extensive spectroscopic analysis, including 2D NMR data, and a few chemical transformations.

Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice.

Turmeric, the rhizome of Curcuma longa L., has a wide range of effects on human health. The chemistry includes curcuminoids and sesquiterpenoids as components, which are known to have antioxidative, anticarcinogenic, and antiinflammatory activities.

Effects of inhaling the vapor of Lavandula burnatii super-derived essential oil and linalool on plasma adrenocorticotropic hormone (ACTH), catecholamine and gonadotropin levels in experimental menopausal female rats.

The effects of inhaling the vapor of Lavandula burnatii super-derived essential oil and one of the main components of lavender oil, linalool on plasma adrenocorticotropic hormone (ACTH), catecholamine and gonadotropin levels in menopausal model rats under ether-inhalation were studied. The increased plasma ACTH levels induced by ether-inhalation tended to decrease by pre-inhalation of Lavandula burnetii super and linalool vapor was induced the decrease of ACTH level. The decrease in adrenaline, noradrenaline and dopamine levels induced by ether-inhalation tended to recover, especially, the dopamine level significantly recovered to the normal level by the inhalation of Lavandula burnetii super and linalool vapor.

27-norlanostane glycosides from the bulbs of Muscari paradoxum.

Eight 27-norlanostane glycosides (1-8), including five new compounds (3 and 5-8), were isolated from the MeOH extract of the bulbs of Muscari paradoxum. The structures of the new compounds were determined on the basis of extensive spectroscopic analysis, including 2D NMR data, and the results of hydrolytic cleavage. The cytotoxic activity of 1-8 against HSC-2 human oral squamous cell carcinoma cells is also reported.

Taccasterosides A-C, novel C28-sterol oligoglucosides from the rhizomes of Tacca chantrieri.

Three novel C(28)-sterol oligoglucosides, named taccasterosides A-C (1-3), were isolated from the rhizomes of Tacca chantrieri (Taccaceae). Their structures were determined by detailed spectroscopic analysis, including 2D NMR data, and a few chemical transformations.

Steroidal glycosides from the bulbs of Ornithogalum thyrsoides.

Phytochemical analyses have been carried out on the fresh bulbs of Ornithogalum thyrsoides with particular attention to the steroidal glycoside constituents, resulting in the isolation of four new spirostanol saponins and seven new cholestane glycosides, together with three known steroidal compounds. The structures of the new glycosides were determined on the basis of their spectroscopic data, including 2D NMR spectroscopy, and the results of hydrolytic cleavage. The isolated compounds were evaluated for their cytotoxic activities against HL-60 human promyelocytic leukemia cells and HSC-2 human oral squamous cell carcinoma cells.

Ultraviolet derivatization of steroidal saponin in garlic and commercial garlic products as p-nitrobenzoate for liquid chromatographic determination.

A method is described for determination of the steroidal saponin, eruboside B, originating in garlic and garlic products as the p-nitrobenzoyl chloride (PNBC) derivative by reversed-phase liquid chromatography (with ultraviolet detection at 260 nm. Proto-eruboside B was extracted from garlic (Allium sativum L.); subjected to solid-phase extraction (SPE) with a C18 cartridge, Florisil column chromatography, and silica gel column chromatography; and then enzymatically converted to eruboside B, which was applied as an external standard.

Triterpene saponins from the roots of Clematis chinensis.

A saponin-enriched fraction prepared from the MeOH extract of the roots of Clematis chinensis showed cytotoxic activity against HL-60 promyelocytic leukemia cells, from which five new triterpene saponins based on oleanolic acid, along with three known saponins, were isolated. The structures of the new saponins were determined on the basis of spectroscopic analysis, including extensive 1D and 2D NMR data and hydrolysis followed by chromatographic and spectroscopic analysis. Among the isolated saponins, monodesmosidic saponins exhibited cytotoxic activities against cultured tumor cells.

The structure of a new crystalline cevane alkaloid: its identity with persicanidine B and harepermine.

The structure of a new crystalline base (melting point (mp) 167-169 degrees C) obtained from Fritillaria imperialis was elucidated as (20R, 25R)-5alpha,17beta-cevanine-3beta,6beta-diol, X-ray diffraction analysis of the mono-hydrate. The base was found to be identical with persicanidine B and also with harepermine.

Anti-AIDS agents. Part 57: Actein, an anti-HIV principle from the rhizome of Cimicifuga racemosa (black cohosh), and the anti-HIV activity of related saponins.

Actein (1), a tetracyclic triterpenoid from the rhizome of Cimicifuga racemosa (black cohosh), and 82 related triterpenoid and steroidal saponins isolated from higher plants were evaluated for anti-HIV activity as a continuing study to discover potential anti-AIDS agents from natural products. Actein showed potent activity and another twelve saponins showed moderate activity. The active compounds included two steroidal, seven tetracyclic triterpenoid, and four pentacyclic triterpenoid compounds.

Urinary metabolites of nobiletin orally administered to rats.

During the course of our systematic investigation of the metabolism of flavonoids, the polymethoxyflavone nobiletin, occurring in the fruits of Citrus depressa, was orally administered to rats. The urinary metabolites were separated and identified by three-dimensional HPLC equipped with a photodiode array detector and the structure was determined by spectroscopic methods to be 4'-hydroxy-3',5,6,7,8-pentamethoxyflavone (1).

Phenolics with PPAR-gamma ligand-binding activity obtained from licorice (Glycyrrhiza uralensis roots) and ameliorative effects of glycyrin on genetically diabetic KK-A(y) mice.

The EtOAc extract of licorice (Glycyrrhiza uralensis roots) exhibited considerable PPAR-gamma ligand-binding activity. Bioassay-guided fractionation of the extract using a GAL-4-PPAR-gamma chimera assay method resulted in the isolation of two isoflavenes, one of which is a new compound named dehydroglyasperin D, an isoflavan, two 3-arylcoumarins, and an isoflavanone as the PPAR-gamma ligand-binding active ingredients of licorice. The isoprenyl group at C-6 and the C-2' hydroxyl group in the aromatic ring-C part in the isoflavan, isoflavene, or arylcoumarin skeleton were found to be the structural requirements for PPAR-gamma ligand-binding activity.

Lanosterol and tetranorlanosterol glycosides from the bulbs of Muscari paradoxum.

Three tetranorlanostane glycosides, named lucilianosides C-E, and three lanostane glycosides, named scillasaponins E-G, together with a known lanostane glycoside, were isolated from the MeOH extract of Muscari paradoxum (Liliaceae) bulbs, as confirmed by detailed analysis of their 1H, 13C, and two-dimensional NMR spectroscopic data, and by the results of hydrolytic cleavage. The isolated compounds were evaluated for their cytotoxic activity against HSC-2 human oral squamous cell carcinoma cells.

A licorice ethanolic extract with peroxisome proliferator-activated receptor-gamma ligand-binding activity affects diabetes in KK-Ay mice, abdominal obesity in diet-induced obese C57BL mice and hypertension in spontaneously hypertensive rats.

The metabolic syndrome, including type 2 diabetes, insulin resistance, obesity/abdominal obesity, hypertension and dyslipidemia, is a major public health problem. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands such as thiazolidinediones are effective against this syndrome. In this study, we showed that nonaqueous fractions of licorice (Glycyrrhiza uralensis Fisher) extracted with ethanol, ethyl acetate and acetone, but not an aqueous extract, had PPAR-gamma ligand-binding activity with a GAL4-PPAR-gamma chimera assay.