The methanol extract from the aerial parts of Roldana barba-johannis (Asteraceae) afforded sargachromenol, sargahydroquinoic acid, and sargaquinoic acid. These natural products and their corresponding acetylated and methylated derivatives showed insecticidal and insect growth regulatory activities against the Fall Armyworm [Spodoptera frugiperda J.E. Smith, (Lepidoptera: Noctuidae)], an important insect pest of corn. The most active compounds were sargachromenol and its acetylated derivative; sargahydroquinoic acid and its acetylated derivative; and a mixture of sargachromenol, sargahydroquinoic acid, and sargaquinoic acid (6:3:1) and the acetylated form of this mixture. All these compounds and mixtures had significant inhibitory effects between 5.0 and 20.0 ppm in diets. Most compounds were insecticidal to larvae, with lethal doses between 20 and 35 ppm. In addition, these substances also demonstrated scavenging properties toward 2,2-diphenyl-1-picrylhydrazyl radical in TLC autographic and spectrophotometric assays. These compounds appear to have selective effects on the pre-emergence metabolism of the insect. The results from these compounds were fully comparable in activity to those known natural insect growth inhibitors such as gedunin and methanol extracts of Cedrela salvadorensis and Yucca periculosa. These substances may be useful as natural insecticidal agents.
Blog Archives
Tocols represent a family of tocopherols, tocotrienols, and their derivatives, and are fundamentally derived from the simplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman, which is referred to as “tocol”. The most common tocol is D-alpha-tocopherol, also known as vitamin E. Tocols can be excellent solvents for water insoluble drugs and are compatible with other cosolvents, oils and surfactants. This review highlights the major developments in the use of tocols in parenteral emulsions for drug delivery, with a focus on drug solubilization, physicochemical properties, and biopharmaceutical applications. Tocol emulsions offer an appealing alternative for the parenteral administration of poorly soluble drugs, including major chemotherapeutics such as paclitaxel. Data will be presented on solubilization of paclitaxel, a key chemotherapeutic agent, and its corresponding formulation development, toxicity, efficacy and pharmacokinetic studies in animal models and humans. The breadth of the utility of tocol-based emulsions will be discussed and examples of specific therapeutic drugs and applications will be provided. As these formulations progress further in the clinic, the therapeutic utility of tocol emulsions is anticipated to expand.
Tocotrienol-rich fraction from palm oil affects gene expression in tumors resulting from MCF-7 cell inoculation in athymic mice
Nesaretnam K, Ambra R, Selvaduray KR, Radhakrishnan A, Reimann K, Razak G, Virgili F.
Lipids. 2004 May;39(5):459-67.
It has recently been shown that tocotrienols are the components of vitamin E responsible for inhibiting the growth of human breast cancer cells in vitro, through an estrogen-independent mechanism. Although tocotrienols act on cell proliferation in a dose-dependent manner and can induce programmed cell death, no specific gene regulation has yet been identified. To investigate the molecular basis of the effect of tocotrienols, we injected MCF-7 breast cancer cells into athymic nude mice. Mice were fed orally with 1 mg/d of tocotrienol-rich fraction (TRF) for 20 wk. At end of the 20 wk, there was a significant delay in the onset, incidence, and size of the tumors in nude mice supplemented with TRF compared with the controls. At autopsy, the tumor tissue was excised and analyzed for gene expression by means of a cDNA array technique. Thirty out of 1176 genes were significantly affected. Ten genes were downregulated and 20 genes up-regulated with respect to untreated animals, and some genes in particular were involved in regulating the immune system and its function. The expression of the interferon-inducible transmembrane protein-1 gene was significantly up-regulated in tumors excised from TRF-treated animals compared with control mice. Within the group of genes related to the immune system, we also found that the CD59 glycoprotein precursor gene was up-regulated. Among the functional class of intracellular transducers/effectors/modulators, the c-myc gene was significantly down-regulated in tumors by TRF treatment. Our observations indicate that TRF supplementation significantly and specifically affects MCF-7 cell response after tumor formation in vivo and therefore the host immune function. The observed effect on gene expression is possibly exerted independently from the antioxidant activity typical of this family of molecules.
With increasing evidence suggesting the involvement of oxidative stress in various disorders and diseases, the role of antioxidants in vivo has received much attention. Chemically, tocopherols and tocotrienols are closely related; however, it has been observed that they have widely varying degrees of biological effectiveness. The present study has been carried out in an attempt to deepen our understanding of whether there is a significant difference in distribution between tocopherol and tocotrienol homologs to rat eye tissues. Rats were administered 5 microL of pure tocopherol or tocotrienol to each eye once a day for 4 d. Various tissues of the eyes were separated and analyzed for tocopherol and tocotrienol concentrations. The concentration of alpha-to-cotrienol increased markedly in every tissue to which it was administered; however, no significant increase was observed in the case of alpha-tocopherol. The intraocular penetration of gamma-tocopherol and gamma-tocotrienol did not differ significantly. Additionally, a significant increase in total vitamin E concentration was observed in ocular tissues, including crystalline lens, neural retina, and eye cup, with topical administration using a relatively small amount (5 microL) of vitamin E, whereas no significant increase was observed when the same amount of vitamin E was administered orally. Topical administration of tocotrienols is thus an effective way to increase ocular tissue vitamin E concentration.
Induction of apoptosis by tocotrienol in rat hepatoma dRLh-84 cells
Sakai M, Okabe M, Yamasaki M, Tachibana H, Yamada K
Anticancer Res. 2004 May-Jun;24(3a):1683-8.
Our aim was to evaluate the antitumor activities of tocopherol (Toc) and tocotrienol (T3) derivatives. At first, we examined the effect of these vitamin E homologues on the proliferation of rat normal hepatocyte RLN-10 and hepatoma dRLh-84 cells and found that especially T3 inhibited cell proliferation in dRLh-84 cells. Then, we examined the effect of vitamin E homologues on apoptosis induction and found that T3 induced DNA fragmentation and stimulated a rise of caspase-3 activity. In addition, T3 stimulated a rise in caspase-8 activity, while a caspase-8 inhibitor suppressed apoptosis induction by T3. We also examined the incorporation of vitamin E homologues into dRLh-84 cells. T3 was incorporated more quickly compared to Toc. These results indicated that T3 induces apoptosis in dRLh-84 cells and that caspase-8 is involved in this apoptosis induction. The difference in terms of apoptosis induction by vitamin E homologues seems to be related to their different rates of cellular incorporation.
Background & aims: Carboxyethyl-hydroxychromans (CEHC) are hydrosoluble vitamin E metabolites excreted through the renal filter. In this study we investigated the effect of the kidney damage on the blood levels of CEHC.
Methods: Plasma levels of a-CEHC, g-CEHC and their precursors (namely, α-tocopherol and γ-tocopherol) were measured by HPLC with electrochemical detection in chronic (CRF) and end-stage renal failure patients on regular hemodialysis (HD) before and after dialysis. CRF patients (n=26) were divided into three subgroups with different extent of kidney damage as measured by the intervals of creatinine clearance (CrCl, in ml/min): (a) 2–10, (b) 10–20, and (c) 20–45. HD patients (n=8) did not show residual renal function. In all the subjects the intake of vitamin E
(as α-tocopherol) was assessed using a food frequency questionnaire. In the HD group, the plasma concentrations of ascorbic and uric acid (AA and UA, respectively), total thiols, the total antioxidant status (TAS) and reactive carbonyls were also measured.
Results: The progressive deterioration of the kidney function in the different groups of patients produced an exponential increase of both α-CEHC and γ-CEHC in plasma. Compared with healthy controls (α-CEHC¼20.1713.4 and γ-CEHC=230.6±83.0 nmol/l) the levels of CEHC approximately doubled in patients with CrCl<20 ml/min (42.4±20.2 and 424.5.5±174.4; P<0:05 or higher in both) and reached a 3-fold maximum increase in HD patients (77.3±45.7 and 636.6±219.3). The hemodialysis provided a significant, but only a transient, correction of CEHC accumulation (44.8±23.5, 364.2±189.9). The HD patients showed lower intake and levels of vitamin E (α-tocopherol=5.17=±1.0 and γ-tocopherol=0.32±0.11 mmol/mmol cholesterol; P<0:05) compared to healthy controls (5.8±0.8 and 0.43±0.14), but in the CRF patients tocopherol levels were normal or only slightly decreased even though approximately half of the subject had lowered vitamin E intake. When the entire patient population was considered, the blood concentrations of parental tocopherols and CEHC did not correlate. The HD patients before dialysis showed a marked decrease of TAS/UA, AA and thiols levels, while UA and free carbonyls significantly increased. After dialysis, the depletion of AA and thiols further worsened and also UA and TAS/UA decreased, but free carbonyls slightly increased.
Plasma C-reactive protein concentrations in active and passive smokers: Influence of antioxidant supplementation
Gladys Block, PhD, Christopher Jensen, PhD, Marion Dietrich, PhD, Edward P. Norkus, PhD, Mark Hudes, PhD, and Lester Packer, PhD
J Am Coll Nutr. 2004 Apr;23(2):141-7.
Objective: C-reactive protein (CRP) may directly affect the progression of atherosclerosis, and therefore, may be a target for reducing disease risk. The objective was to determine whether antioxidant supplementation reduces plasma CRP in active and passive smokers.
Design: Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to study supplements.
Setting: Berkeley and Oakland, California.
Subjects: Healthy adult men and women, consuming <4 daily servings of fruits and vegetables, and who were actively or passively exposed to cigarette smoke. Analysis was limited to participants with detectable baseline CRP concentrations and no evidence of inflammation associated with acute illness at baseline or follow-up as reflected in CRP elevations (≥10.0 mg/L). A total of 1393 individuals were screened, 216 randomized, 203 completed the study, and 160 were included in the analysis.
Interventions: Participants were randomized to receive a placebo or vitamin C (515 mg/day) or antioxidant mixture (per day: 515 mg vitamin C, 371 mg α-tocopherol, 171 mg γ-tocopherol, 252 mg mixed tocotrienols, and 95 mg α-lipoic acid).
Measures of Outcome: Change in plasma CRP concentration.
Results: Vitamin C supplementation yielded a 24.0% reduction (95% confidence interval, -38.9% to-5.5%, p =0.036 compared to control) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction (-23.9% to 19.3%) and 4.3% increase (-15.1% to 28.2%), respectively. Results were adjusted for baseline body mass index and CRP concentrations.
Conclusions: Plasma CRP itself may serve as a potential target for reducing the risk of atherosclerosis, and antioxidants, including vitamin C, should be investigated further to confirm their CRP-lowering and anti-inflammatory effects.
Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association
Agarwal MK, Agarwal ML, Athar M, Gupta S.
Cell Cycle. 2004 Feb;3(2):205-11.
Anti-cancer properties of palm oil have been attributed to the presence of tocotrienols and carotenoids. Studies from various laboratories have shown that tocotrienol-rich fraction (TRF) of palm oil inhibits cell growth and induces apoptosis in both preneoplastic and neoplastic cells. However, the mechanism by which TRF induces apoptosis remains largely unknown. Since several chemopreventive agents have been shown to utilize p53 pathway in negative regulation of cell growth, using human colon carcinoma RKO cells which express wild type p53, we investigated the effect of TRF on components of p53 signaling network. Treatment of cells with TRF resulted in a dose- and time- dependent inhibition of growth and colony formation. Further, TRF treatment of RKO cells resulted in the induction of WAF1/p21 which appears to be independent of cell cycle regulation and is transcriptionally upregulated in p53 dependent fashion. These results were further confirmed by using cells that express luciferase from a p53 responsive promoter where TRF treatment leads to activation of p53 reporter activity. TRF treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1. This altered expression of Bcl2 family members triggered the activation of initiator caspase-9 followed by activation of effector caspase-3. These signaling cascades lead to condensed chromatin, DNA fragmentation and shrinkage of cell membrane resulting into apoptosis. Our data suggest that TRF-induced apoptosis in colon carcinoma cells is mediated by p53 signaling network which appears to be independent of cell cycle association.
Dietary antioxidant intake and risk of type 2 diabetes
Montonen J, Knekt P, Järvinen R, Reunanen A.
Diabetes Care. 2004 Feb;27(2):362-6.
Objective: The intake of antioxidants was studied for its ability to predict type 2 diabetes.
Research Design & Methods: A cohort of 2,285 men and 2,019 women 40-69 years of age and free of diabetes at baseline (1967-1972) was studied. Food consumption during the previous year was estimated using a dietary history interview. The intake of vitamin C, four tocopherols, four tocotrienols, and six carotenoids was calculated. During a 23-year follow-up, a total of 164 male and 219 female incident cases occurred.
Results: Vitamin E intake was significantly associated with a reduced risk of type 2 diabetes. The relative risk (RR) of type 2 diabetes between the extreme quartiles of the intake was 0.69 (95% CI 0.51-0.94, P for trend = 0.003). Intakes of alpha-tocopherol, gamma-tocopherol, delta-tocopherol, and beta-tocotrienol were inversely related to a risk of type 2 diabetes. Among single carotenoids, beta-cryptoxanthin intake was significantly associated with a reduced risk of type 2 diabetes (RR 0.58, 95% CI 0.44-0.78, P < 0.001). No association was evident between intake of vitamin C and type 2 diabetes risk.
Conclusion: This study supports the hypothesis that development of type 2 diabetes may be reduced by the intake of antioxidants in the diet.
A simple and reliable method for the simultaneous determination of all eight homologs of Vitamin E in chicken meat is described. All analytes, including the internal standard (alpha-tocopherol acetate), were eluted within 35 min and detected using their native fluorescence (295 nm excitation and 330 nm emission). Chromatography using hexane based eluent on a normal phase silica column included an initial column conditioning step to prevent irreversible adsorption of tocopherols and tocotrienols on silica. Lowest detectable levels of alpha-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol and delta-tocotrienol were 0.73, 0.86, 1.0, 1.2, 1.7 and 1.3 ng, respectively.