Nootkatone

J Ethnopharmacol. 2011 Apr 26;135(1):48-54.

Antiplatelet effects of Cyperus rotundus and its component (+)-nootkatone.[Pubmed: 21354294 ]

Cyperus rotundus, a well-known oriental traditional medicine, has been reported to exhibit wide spectrum activity in biological systems including the circulatory system, however, little information is available on its antiplatelet activity. This study was undertaken to investigate the antiplatelet effects of Cyperus rotundus EtOH extract (CRE) and its constituent compounds.
METHODS AND RESULTS:
The antiplatelet activities of CRE and its eight constituent compounds were evaluated by examining their effects on rat platelet aggregations in vitro and ex vivo, and on mice tail bleeding times. During the in vitro platelet aggregation study, CRE showed significant and concentration-dependent inhibitory effects on collagen-, thrombin-, and/or AA-induced platelet aggregation. Of its eight components, (+)-Nootkatone was found to have the most potent inhibitory effect on collagen-, thrombin-, and AA-induced platelet aggregation. In addition, CRE- and (+)-Nootkatone-treated mice exhibited significantly prolonged bleeding times. Furthermore, (+)-Nootkatone had a significant inhibitory effect on rat platelet aggregation ex vivo.
CONCLUSIONS:
This study demonstrates the antiplatelet effects of CRE and its active component (+)-Nootkatone, and suggests that these agents might be of therapeutic benefit for the prevention of platelet-associated cardiovascular diseases.

J Econ Entomol. 2009 Dec;102(6):2316-24.

Ability of two natural products, nootkatone and carvacrol, to suppress Ixodes scapularis and Amblyomma americanum (Acari: Ixodidae) in a Lyme disease endemic area of New Jersey.[Pubmed: 20069863]

We evaluated the ability of the natural, plant-derived acaricides Nootkatone and carvacrol to suppress Ixodes scapularis Say and Amblyomma americanum (L.) (Acari: Ixodidae).
METHODS AND RESULTS:
Aqueous formulations of 1 and 5% Nootkatone applied by backpack sprayer to the forest litter layer completely suppressed I. scapularis nymphs through 2 d. Thereafter, the level of reduction gradually declined to < or =50% at 28 d postapplication. Against A. americanum nymphs, 1% Nootkatone was less effective, but at a 5% concentration, the level of control was similar or greater to that observed with I. scapularis through 21 d postapplication. Initial applications of 0.05% carvacrol were ineffective, but a 5% carvacrol formulation completely suppressed nymphs of both species through 2 d and resulted in significant reduction in I. scapularis and A. americanum nymphs through 28 and 14 d postapplication, respectively. Backpack sprayer applications of 5% Nootkatone to the shrub and litter layers resulted in 100% control of I. scapularis adults through 6 d, but the level of reduction declined to 71.5% at 28 d postapplication. By contrast, high-pressure applications of 2% Nootkatone to the litter layer resulted in 96.2-100% suppression of both I. scapularis and A. americanum nymphs through 42 d, whereas much lower control was obtained from the same formulation applied by backpack sprayer. Backpack sprayer application of a 3.1% Nootkatone nanoemulsion resulted in 97.5-98.9 and 99.3-100% reduction in I. scapularis and A. americanum nymphs, respectively, at 1 d postapplication. Between 7 d and 35 d postapplication, the level of control varied between 57.1% and 92.5% for I. scapularis and between 78.5 and 97.1% for A. americanum nymphs.
CONCLUSIONS:
The ability of natural products to quickly suppress and maintain significant control of populations of these medically important ticks at relatively low concentrations may represent a future alternative to the use of conventional synthetic acaricides.

J Chem Ecol. 2001 Mar;27(3):523-31.

Nootkatone is a repellent for Formosan subterranean termite (Coptotermes formosanus).[Pubmed: 11441443]

We examined the behavior of Formosan subterranean termites toward one of the components of vetiver grass oil, the roots of which manufacture insect repellents.
METHODS AND RESULTS:
We found Nootkatone, a sesquiterpene ketone, isolated from vetiver oil is a strong repellent and toxicant to Formosan subterranean termites. The lowest effective concentration tested was 10 micrograms/g substrate.
CONCLUSIONS:
This is the first report of Nootkatone being a repellent to insects.

Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E266-75.

Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.[Pubmed: 20501876 ]

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome.
METHODS AND RESULTS:
Here, we identified and characterized Nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(12) cells and C57BL/6J mouse muscle. In addition, administration of Nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by Nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) Nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% Nootkatone than in control mice.
CONCLUSIONS:
These findings indicate that long-term intake of Nootkatone is beneficial toward preventing obesity and improving physical performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver.

Biochem Biophys Res Commun. 2014 May 2;447(2):278-84.

(+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells.[Pubmed: 24704449]

Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-Nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells.
METHODS AND RESULTS:
We found that (+)-Nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells.
CONCLUSIONS:
Taken together, these results suggest that (+)-Nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-Nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.

Bioorg Med Chem. 2011 Apr 1;19(7):2464-9.

Microbial transformation of (+)-nootkatone and the antiproliferative activity of its metabolites.[Pubmed: 21377882 ]

METHODS AND RESULTS:
Six metabolites were obtained as a result of microbial transformation of (+)-Nootkatone (1) by the fungal strains: Botrytis, Didymosphaeria, Aspergillus, Chaetomium and Fusarium. Their structure were established as (+)-(4R,5S,7R,9R)-9α-hydroxyNootkatone (2), (+)-(4R,5S,7R)-13-hydroxyNootkatone (3) and (+)-(4R,5S,7R,9R,11S)-11,12-epoxy-9α-hydroxyNootkatone (4), (+)-(4R,5S,7R,11S)-11,12-epoksyNootkatone (5), (+)-(4R,5S,7R)-11,12-dihydroxyNootkatone (6) and (+)-(4R,5S,7R)-7,11,12-trihydroxyNootkatone (7) on the basis of their spectral data. Two products: (4) and (7) were not previously reported in the literature.
CONCLUSIONS:
The antiproliferative activity of (+)-Nootkatone (1) and isolated metabolites (2-7) of its biotransformation has been evaluated.