(+)-Nootkatone and (+)-valencene from rhizomes of Cyperus rotundus increase survival rates in septic mice due to heme oxygenase-1 induction

Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-290, Republic of Korea.
Journal of ethnopharmacology (Impact Factor: 3). 08/2011; 137(3):1311-7. DOI: 10.1016/j.jep.2011.07.062
Source: PubMed


The rhizomes of Cyperus rotundus have been used as traditional folk medicine for the treatment of inflammatory diseases. However, the mechanism by which extract of rhizomes of Cyperus rotundus (ECR) elicits anti-inflammation has not been extensively investigated so far. The aim of the present study was to test whether heme oxygenase (HO)-1 induction is involved in the anti-inflammatory action of ECR.
Induction of HO-1 and inhibition of inducible nitric oxide synthase (iNOS)/NO production by ECR and its 12 constituents (3 monoterpenes, 5 sesquiterpenes, and 4 aromatic compounds) were investigated using RAW264.7 cells in vitro. In addition, anti-inflammatory action of ECR and its two active ingredients (nookkatone, valencene) were confirmed in sepsis animal model in vivo.
ECR increased HO-1 expression in a concentration-dependent manner, which was correlated with significant inhibition of iNOS/NO production in LPS-activated RAW264.7 cells. Among 12 compounds isolated from ECR, mostly sesquiterpenes induced stronger HO-1 expression than monoterpenes in macrophage cells. Nootkatone and valencene (sesquiterpenes) significantly inhibited iNOS expression and NO production in LPS-simulated RAW264.7 cells. Inhibition of iNOS expression by nootkatone, valencene, and ECR were significantly reduced in siHO-1 RNA transfected cells. Furthermore, all three showed marked inhibition of high mobility group box-1 (HMGB1) in LPS-activated macrophages and increased survival rates in cecal ligation and puncture (CLP)-induced sepsis in mice.
Taken together, we concluded that possible anti-inflammatory mechanism of ECR is, at least, due to HO-1 induction, in which sesquiterpenes such as nootkatone and valencene play a crucial role.

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    • "Among these compounds, nootkatone was relatively abundant in WEAO (Figure 1E). Nootkatone has been shown to have multiple pharmacological properties including anti-inflammatory [27], anti-allergic [28], antiplatelet [29], and anti-obesity [30] activities. We found that nootkatone (10–40 μM) dose-dependently inhibits RANKL-induced osteoclast differentiation without affecting cell viability (Figure 1F and G). "
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    ABSTRACT: Background Excessive bone resorption by osteoclasts causes pathological bone destruction, seen in various bone diseases. There is accumulating evidence that certain herbal extracts have beneficial effects on bone metabolism. The fruits of Alpinia oxyphylla has been traditionally used for the treatment of diarrhea and enuresis. In this study, we investigated the effects of water extract of the fruits of Alpinia oxyphylla (WEAO) on osteoclast differentiation and osteoclast-mediated bone destruction. Methods For osteoclast differentiation assay, mouse bone marrow-derived macrophages (BMMs) were cultured in the presence of RANKL and M-CSF. RANKL signaling pathways and gene expression of transcription factors regulating osteoclast differentiation were investigated by real-time PCR and Western blotting. A constitutively active form of NFATc1 was retrovirally transduced into BMMs. Bone resorbing activity of mature osteoclast was examined on a plate coated with an inorganic crystalline calcium phosphate. The in vivo effect against bone destruction was assessed in a murine model of RANKL-induced osteoporosis by micro-computed tomography and bone metabolism marker analyses. Results WEAO dose-dependently inhibited RANKL-induced osteoclast differentiation from BMMs by targeting the early stages of osteoclast differentiation. WEAO inhibited RANKL-induced expression of NFATc1, the master regulator of osteoclast differentiation. Overexpression of a constitutively active form of NFATc1 blunted the inhibitory effect of WEAO on osteoclast differentiation, suggesting that NFATc1 is a critical target of the inhibitory action of WEAO. WEAO inhibited RANKL-induced expression of c-Fos, an upstream activator of NFATc1, by suppressing the classical NF-κB signaling pathway. WEAO also inhibited RANKL-induced down-regulation of Id2 and MafB, negative regulators of NFATc1. WEAO does not directly affect bone resorbing activity of mature osteoclasts. In accordance with the in vitro results, WEAO attenuated RANKL-induced bone destruction in mice by inhibiting osteoclast differentiation. Conclusions This study demonstrates that WEAO exhibits a protective effect against bone loss by inhibiting RANKL-induced osteoclast differentiation. These findings suggest that WEAO might be useful for the prevention and treatment of bone diseases associated with excessive bone resorption.
    BMC Complementary and Alternative Medicine 09/2014; 14(1):352. DOI:10.1186/1472-6882-14-352 · 2.02 Impact Factor
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    • "Many studies have shown that a number of plant-based extracts (phytopharmaceuticals) induce HO-1, leading to ameliorated oxidative stress and inflammation. The sources of these compounds are several different plant species and plant organs, ranging from seeds to fruits to leaves to roots [238] [245] [247] [280] [281] [282] [283] [284] [285] [286] [287] [288] [289] [290] [291] [292] [293]. Some of these compounds can be Fig. "
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    ABSTRACT: Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that sub-serves cytoprotective responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, brain HO-1 expression is increased, presumably reflecting an endogenous neuroprotective response against ongoing cellular injury. In contrast,we have found in human immunodeficiency virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress, and neurodegeneration, HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways activated by HIV infection. We have also shown that HO-1 expression is markedly suppressed by HIV replication in cultured macrophages, which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this glutamate mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages.Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in macrophages, which could promote neuronal survival through HO-1-modulation ofendogenous antioxidant and immune modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV infection is also discussed.
    Current HIV Research 05/2014; 12(3). DOI:10.2174/1570162X12666140526122709 · 1.76 Impact Factor
    • "Jung et al. (2013) reported that -cyperone, inhibits LPS-induced inflammation in RAW 264.7 cells by regulation of COX- 2 expression, PGE2 production and NFB signalling. The rhizome of this plant has been reported to have analgesic, nootropic, sedative , antimalarial, anti-inflammatory and antispasmodic properties and also used to relieve diarrhoea and bowel disorders (Zhu et al., 1998; Uddin et al., 2006; Kilani et al., 2005; Tsoyi et al., 2011). The starch extracted from tuberous part of this plant found to have various applications in food and confectionary industries (Umerie and Ezeuzo, 2000). "
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    ABSTRACT: Cyperus rotundus is a traditional medicinal herb used in the treatment of various ailments. In the present study, we have evaluated in vitro anti-oxidant and free radical scavenging activities of 70% ethanolic, methanolic and water extracts of C. rotundus root. Among the extracts, the 70% ethanolic extract was found to be most potent with the IC50 values of 64.64 ± 5.3 μg/mL, 85.89 ± 6.3 μg/mL and 8.42 ± 0.45 mg/mL against DPPH, metal chelating and nitric oxide scavenging activities and the observed activity could be correlated with metabolites such as polyphenols, flavonoids and sesquiterpenes identified by LC–ESI-MS/MS. Further C. rotundus was evaluated for its protective properties against macromolecules such as DNA, protein and lipid damage. The extract showed 48% protection against H2O2 induced DNA damage and inhibited the AAPH and SIN-1 induced oxidation and nitration of BSA. Moreover, C. rotundus pretreatment restored the antioxidant status in white blood cells treated with H2O2. C. rotundus showed acetylcholine esterase inhibitory activity and the extract was found to be non-toxic up to 100 μg/mL in SH-SY5Y human neuroblastoma cell line. The ethanolic extract (200 mg/kg) also proved to be a potent anxiolyte as assessed by behavioural tests. Overall, the results suggest that this plant extract may be useful in combating oxidative stress related diseases through its antioxidant activity.
    Industrial Crops and Products 01/2014; 52:815–826. DOI:10.1016/j.indcrop.2013.11.040 · 2.84 Impact Factor
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