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Tissue-specific enhancement of xenobiotic detoxification enzymes in mice by dietary rosemary extract

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Abstract

Plant foods contain nutritive and minor, nonnutritive components capable of inhibiting experimental carcinogenesis. Many of these cancer-protective extracts act by enhancing the activities of enzymes that can detoxify reactive substances. In the present study an extract of the spice plant rosemary was fed at concentrations of 0.3% and 0.6% (by weight) for 4 weeks to female A/J mice prior to determination of the activities of the detoxification enzymes glutathione-S-transferase (GST) and NAD(P)H: quinone reductase (QR) in lung, liver and stomach. Liver activities of GST and QR, and stomach GST activity were significantly increased in animals fed diets containing rosemary extract. However, diets supplemented with rosemary extract did not affect lung GST and QR activities. These results indicate that components of rosemary extract have the potential to protect mouse liver and stomach from carcinogenic or toxic agents.

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... Rosemary and its components were reported to modulate several pathways, such as those related to antioxidant response (e.g. glutathione metabolism [20] and Nfr2-dependent pathway [21]), AMPK and PPAR pathways [22], as well as apoptosisrelated genes [17], but the molecular mechanism responsible for its antitumor effects is not completely understood yet. In order to properly apply rosemary as a nutritional supplement for cancer therapy, additional information regarding the most effective composition, its antitumor effect in vivo and its main molecular mediators is still needed. ...
... Rosemary and their components were reported to modulate glutathione metabolism [20], Nfr2-dependent pathway [21], AMPK and PPAR pathways [22], among others, as well as apoptosis-related genes [17]. However, the antitumor mechanism of action is not completely understood. ...
... Tumor volumes were monitored twice a week during 32-35 days. Results are shown as mean 6 SEM (n =[16][17][18][19][20] and repeated measures ANOVA with Bonferroni's test was used to determine the statistically significant differences between treated and control groups (*p#0.05; **p#0.01; ...
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Colorectal and pancreatic cancers remain important contributors to cancer mortality burden and, therefore, new therapeutic approaches are urgently needed. Rosemary (Rosmarinus officinalis L.) extracts and its components have been reported as natural potent antiproliferative agents against cancer cells. However, to potentially apply rosemary as a complementary approach for cancer therapy, additional information regarding the most effective composition, its antitumor effect in vivo and its main molecular mediators is still needed. In this work, five carnosic acid-rich supercritical rosemary extracts with different chemical compositions have been assayed for their antitumor activity both in vivo (in nude mice) and in vitro against colon and pancreatic cancer cells. We found that the antitumor effect of carnosic acid together with carnosol was higher than the sum of their effects separately, which supports the use of the rosemary extract as a whole. In addition, gene and microRNA expression analyses have been performed to ascertain its antitumor mechanism, revealing that up-regulation of the metabolic-related gene GCNT3 and down-regulation of its potential epigenetic modulator miR-15b correlate with the antitumor effect of rosemary. Moreover, plasmatic miR-15b down-regulation was detected after in vivo treatment with rosemary. Our results support the use of carnosic acid-rich rosemary extract as a complementary approach in colon and pancreatic cancer and indicate that GCNT3 expression may be involved in its antitumor mechanism and that miR-15b might be used as a non-invasive biomarker to monitor rosemary anticancer effect.
... A mechanism that may be responsible for impairment of the initiation stage of carcinogenesis by rosemary extracts is the direction of the metabolism of chemical carcinogens towards the generation of inactive metabolites and/or detoxication of the reactive intermediates through conjugation. Indeed, feeding animals with a diet supplemented with rosemary extracts resulted in increases in hepatic glutathione S-transferase (GST) and NAD(P)H: quinone reductase (QR) activities (Singletary, 1996;Singletary and Rokusek, 1997). In most published studies, the chemical composition or the technology applied to the extracts of rosemary is not highlighted; therefore it is difficult to ascribe the inducing effects to specific components. ...
... previously described (Singletary, 1996;Singletary and Rokusek, 1997). No inhibition of CYP, as previously described by Offord et al. (1995Offord et al. ( , 1997 was found. ...
Article
The ability of rosemary to modulate cytochrome P450 (CYP) and detoxication enzymes in rat liver was evaluated by comparing the effects of dried leaves and leaf extracts with different chemical compositions: essential oil (EO) containing monoterpenes, a dichloromethane extract (DCME) containing phenolic diterpenes and a water-soluble extract (WSE) containing phenolic compounds such as rosmarinic acid and flavonoids. Chemical analyses were done in order to characterize the composition of extracts. Male Wistar rats received the leaves or extracts of rosemary in their diet at 0.5% (w/w) for 2 weeks. The effects of such treatments were evaluated for CYP (1A, 2B, 2E1), glutathione S-transferase (GST), NAD(P)H: quinone reductase (QR) and UDP-glucuronosyltransferase (UGT) activities and on protein levels (immunoblot analyses). Expression of specific UGT isoforms (mRNA semi-quantification by RT-PCR) was measured. Our study reports that EO selectively induced CYP, particularly CYP2B. WSE enhanced both CYP and detoxication enzymes. DCME acted as a monofunctional inducer, inducing GST, QR and UGT, in particular UGT1A6. Considering the specific pattern of induction obtained with DCME and WSE treatment, it should be relevant to evaluate the chemopreventive potency of these extracts on carcinogenesis in animal models.
... In particular, ursolic acid plays a key role in protecting against cancer, reducing intestinal tumor multiplicity, and effectively inhibiting CRC by reducing the occurrence of aberrant crypt foci, which are early precursors of colon adenoma (Ngo et al., 2011). Additionally, rosemary extract inhibits liver cancer by reduction of liver tumor virus, glutathione S-transferase (GST)-positive foci (Ngo et al., 2011;Singletary & Rokusek, 1997). Therefore, the antioxidant properties of rosemary by reducing oxidative stress may prevent DNA adducts before tumor development. ...
Article
Carcinogens such as heterocyclic amine (HCA), produced during meat cooking, pose a risk of digestive and reproductive cancers in humans. Nevertheless, the exact mechanisms for HCA formation in meat and the control of HCA formation are not known. In this review, we provide an overview of the main cause of HCA formation in cooked meat, fundamental data on natural materials to inhibit HCA carcinogenicity, and methods to analyze HCA in cooked meat. Related past studies has shown that natural substances contain various components that act as antioxidants, and these antioxidants can prevent HCA and mutagenic factors. Free radicals and DNA adducts produced by HCA metabolism have carcinogenic properties. Antioxidants have been found to inhibit oxidative stress caused by free radicals and DNA adducts. Therefore, we can be hypothesized that various natural materials can inhibit HCA carcinogens and mutagens.
... Ursolic acid was more effective, as it reduced approximately 50% of AZT-induced strand breaks. This can be explained by the fact that ursolic acid belongs among the phytochemicals which in addition to antioxidative effects acts also as detoxification agents for carcinogens by enhancing the activity of detoxification enzymes [50,51]. ...
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In this study we verified our assumption that the genotoxicity of the effective anti-HIV drug 3'-azido-3'-dideoxythymidine (AZT) on human cells could be reduced by non-toxic concentrations of two antioxidants that occur frequently in nature (ursolic acid and lignin biopolymer). Cytotoxicity of these natural compounds, well-known by their antimutagenic effects, was evaluated by the trypan blue exclusion technique. Genotoxic activity of AZT was measured on the basis of AZT-induced single and double strand breaks to DNA in two histopathologically different types of human cells, hepatoma cells HepG2 and colonic cells Caco-2. Induction of DNA strand breaks was measured by the comet assay processed in parallel at pH > or = 13.0 (standard alkaline technique which enables to recognize single strand DNA breaks of different origin) and at pH = 9.0 (neutral technique which enables to recognize double strand DNA breaks). As the level of AZT-induced double strand DNA breaks was rather low, protective effects of the antioxidants tested were evaluated only against AZT-induced single strand DNA breaks by the standard alkaline comet assay. Our findings showed that 1 h pre-incubation of cells with ursolic acid or lignin preceding to 3 h treatment of cells with AZT (3 mg/ml) significantly decreased in both cell types the level of AZT-induced single strand DNA breaks. Pre-incubation of HepG2 or Caco-2 cells with a mixture of both natural antioxidants did not increase the effects of individual treatments. This study confirms that AZT is genotoxic toward both used cell types of human origin and that ursolic acid and biopolymer lignin can protect the cells studied against genotoxic effect of AZT.
... Several biological activities of some of these compounds and rosemary extracts are probably linked to their ability to reduce the oxidative damage caused by free radicals over cellular elements like DNA, proteins or membrane phospholipids. It is generally assumed that these antioxidant molecules from R. officinalis may act as free radical scavengers but additionally might play a role by regulating the activity and/or expression of certain enzymatic systems implicated in relevant physiological processes like apoptosis, tumour promotion, intracellular signal transduction or xenobiotic-metabolizing enzymes in liver [8][9][10][11][12][13][14][15][16][17][18]. There are numerous studies about the biological activity of rosemary extracts and their isolated compounds, however there are hardly reports describing the effects of these molecules on the physical properties of biological membranes [19]. ...
Article
Rosemary (Rosmarinus officinalis) extracts are widely used in the food, nutraceutical and cosmetic areas. Their major bioactive components have shown antioxidant, antimicrobial, anti-inflammatory, antitumorigenic and chemopreventive activities. In this work, the bioactive compounds deriving from rosemary leaves (carnosol, CAR; carnosic acid, CA; rosmadial, RAL; genkwanin, GW; rosmarinic acid, RA) were isolated and their effects on the phase behaviour of model membranes were studied by several complementary biophysical techniques. All diterpenes studied, and specifically CAR, decreased the hydrophobic interactions between acyl chains, as well as broadened and shifted the phospholipid transition to lower temperatures into dimyristoylphosphatidylcholine (DMPC) membranes. In addition, all diterpenes and genkwanin increased the lipid order of fluid DMPC membranes, exhibiting CAR and RAL the strongest membrane-rigidifying effect. The diterpenoids, especially CA and RAL, promoted the formation of hexagonal-H(II) phases at low temperatures in dielaidoylphosphatidylethanolamine (DEPE) membranes which exhibited a smaller tube-to-tube distance compared to pure phospholipid. These diterpenes were also able of promoting isotropic structures in DEPE membranes which consisted of non-periodically ordered lipid structures as demonstrated by X-ray diffraction. In contrast, minor effects were observed by rosmarinic acid. In conclusion, diterpenes and genkwanin from rosemary show membrane-rigidifying effects which may contribute to their antioxidant capacity through hindering diffusion of free radicals.
... Moreover, expression of a second important phase II enzyme, NAD(P)H quinone reductase (QR), was induced by carnosol in parallel with GST. Tissuespecific enhancement of xenobiotic detoxification enzymes GST and QR in lung, liver and, stomach showed [7,8] that liver activities of GST and QR and stomach GST activity were significantly increased in mice fed diets containing rosemary extract. However, this diet did not affect lung GST and QR activities. ...
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In this study possible protective effects of rosemary against oxidative DNA damage induced by H2O2- and visible light-excited Methylene Blue in colon cancer cells CaCo-2 and hamster lung cells V79 were investigated. The level of DNA damage (DNA strand breaks) was measured using the classical and modified single cell gel electrophoresis, so-called comet assay. Our findings showed that an ethanol extract from rosemary reduced the genotoxic activity of both agents after a long-term (24 h; 0.3 microg/ml) or short-term (2 h; 30 microg/ml) pre-incubation of cells. We suggest that the extract of rosemary exhibits a protective effect against oxidative damage to DNA as a consequence of scavenging of both *OH radicals and singlet oxygen ((1)O2).
... Bu-Abbas et al. (41) indicated that three phase-II detoxicating enzymes (GST, glucuronosyl transferase, and epoxide hydrolase) were promoted in rats after four weeks of adding 2.5-7.5% (w/v) water extracts of green tea to their diets. Anticancer properties of extracts of rosemary were related to its promoting of GST activity (42). Thus, Prectera and Talalay (43) brought up that evaluating the ability to promote phase-II detoxification enzymes would be one of the indexes for detecting antimutagenicity and anticancer action of substances. ...
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The effects of water extracts from Cassia tora L. (WECT) treated with different degrees of roasting on benzo[a]pyrene (B[a]P)-induced DNA damage in human hepatoma cell line HepG2 were investigated via the comet assay without exogenous activation mixtures, such as S9 mix. WECT alone, at concentrations of 0.1-2 mg/mL, showed neither cytotoxic nor genotoxic effect toward HepG2 cells. B[a]P-induced DNA damage in HepG2 cells could be reduced by WECT in a dose-dependent manner (P < 0.05). At a concentration of 1 mg/mL, the inhibitory effects of WECT on DNA damage were in the order unroasted (72%) > roasted at 150 degrees C (60%) > roasted at 250 degrees C (23%). Ethoxyresorufin-O-dealkylase activity of HepG2 cells was effectively inhibited by WECT, and a similar trend of inhibition was observed in the order unroasted (64%) > roasted at 150 degrees C (42%) > roasted at 250 degrees C (18%). The activity of NADPH cytochrome P-450 reductase was also decreased by unroasted and 150 degrees C-roasted samples (50% and 38%, respectively). Furthermore, glutathione S-transferase activity was increased by treatment with unroasted (1.26-fold) and 150 degrees C-roasted (1.35-fold) samples at 1 mg/mL. In addition, the contents of anthraquinones (AQs) in WECT, including chrysophanol, emodin, and rhein, were decreased with increasing roasting temperature. Each of these AQs also demonstrated significant antigenotoxic activity in the comet assay. The inhibitory effects of chrysophanol, emodin, and rhein on B[a]P-mediated DNA damage in HepG2 cells were 78, 86, and 71%, respectively, at 100 microM. These findings suggested that the decreased antigenotoxicity of the roasted samples might be due to a reduction in their AQs content.
... according to Amrani et al. (2000); Porte et al. (2000) and Pintore et al. (2002). Biologically, rosemary extract improved feed conversion efficiency of broilers fed diet supplemented with such herb (Singletary and Rokusek, 1997). Rosemary has high amounts of a rosmaric acid (Nielsen et al., 1999), Flavonoids and phenolic acids (Ho et al., 2000) that have antioxidant capacities. ...
Article
This study was conducted to investigate the use of Rosemary leaves meal as a natural growth promoter in broiler diets on bird performance and immunity. RLM was added in either grower (7-28 day) or finisher (29-49day) diets at three concentrations (0.5, 1.0 and 2.0%). A total of 200 one-day old unsexed Arbor Acres chicks were assigned equally into four treatment groups, with five replicates of 10 chicks each. Chemical analysis of RLM showed a CF content of 19.4% of which 15.89% was present as cellulose. The essential oil of RLM ranged between 1.4-1.6% and the main active components were camphor (11-16%), alpha pinene (15-20%) and cineole (30-35%) which has a high degree of inhibition against many bacteria and fungi. Compared to control, chicks fed 0.5 % RLM exhibited higher body weights, greater weight gain, and better feed conversion during the experimental period as well as better physical properties of the chicken meat. Moreover, 0.5% dietary rosemary increased plasma total protein, albumin and globulin while decreasing glucose, total lipids and cholesterol content. RLM additions did not affect enzymatic activity related to liver and kidney functions. RLM stimulated thyroid function, as evidenced by increased plasma levels of T3, T4 compared to controls. Antibody production against sheep red blood cells was improved and the percentage of the lymphoid organs was increased compared to controls. Increasing the dietary level of RLM more than 0.5% lowered growth and the digestibility of most nutrients. Thus, low levels of dietary RLM could be safely used in broiler diets to promote growth and to impart healthful constituents to the consumer.
... Although, rosemary extracts have been widely used as a preserving agent in the food industry due to inherent high antioxidant activity, several studies indicate that rosemary extracts and their components inhibit both the initiation and tumor promotion stages of carcinogenesis in mice and rat models [3][4][5][6]. Singletary and Nelshoppen [6] showed that dietary supplementation with 0.5 % and 1.0 % rosemary extract inhibited total in vivo binding of 7,12-dimethylbenz [a]anthracene (DMBA) to mammary epithelial cell DNA by an average of 42 %. Huang et al. [5] evaluated the effects of a methanol extract of rosemary on tumor initiation and promotion in mouse skin, and showed that the application inhibited the covalent binding of benzo(a)pyrene (B(a)P) to epidermal DNA and inhibited tumor initiation by B(a)P and DMBA. ...
Article
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The leaves of Rosmarinus officinalis harvested from three different locations of Turkey were extracted by both methanolic and supercritical CO(2) extraction. Subsequently, six extracts and the active compounds, carnosic acid, and rosmarinic acid were applied to various human cancer cell lines including NCI-H82 (human, small cell lung, carcinoma), DU-145 (human, prostate, carcinoma), Hep-3B (human, black, liver, carcinoma, hepatocellular), K-562 (human chronic myeloid leukemia), MCF-7 (human, breast, adenocarcinoma), PC-3 (human, prostate, adenocarcinoma) and MDA-MB-231 (human, breast, adenocarcinoma) by MTT assay. Supercritical CO(2) extracts had superior antiproliferative effect compared to the soxhlet extracts. Although the extracts exhibited various cytotoxic effects against different cell lines, comparatively low IC(50) values ranging between 12.50 and 47.55 microg/ml were attained against K-562, being the most sensitive cell line. Moreover, carnosic acid caused the lowest cell viability with values ranging from 13 to 30 % at a concentration of 19 muM after 48 h of treatments, resulting in superior antiproliferative effect. Rosemary extract is a potential candidate to be included in the anti-cancer diet with pre-determined doses avoiding toxicity.
... At week 20 post DMBA treatment carnosol (100 and 200 mg/kg) administration resulted in a significant inhibition of tumor formation was observed with decreases of 33% (P < 0.001) and 30% (p < 0.005), respectively. The role of carnosol in preventing DMBA-induced mammary tumorigenesis may be partially explained by carnosol inducing detoxification enzymes including GST and quinone reductase which carnosol has been shown to modulate in other studies [34,45]. Another consideration is the microsomal metabolism of endogenous estrogens. ...
Article
The Mediterranean diet and more specifically certain meats, fruits, vegetables, and olive oil found in certain parts of the Mediterranean region have been associated with a decreased cardiovascular and diabetes risk. More recently, several population based studies have observed with these lifestyle choices have reported an overall reduced risk for several cancers. One study in particular observed an inverse relationship between consumption of Mediterranean herbs such as rosemary, sage, parsley, and oregano with lung cancer. In light of these findings there is a need to explore and identify the anti-cancer properties of these medicinal herbs and to identify the phytochemicals therein. One agent in particular, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals. This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent.
... The results of a study conducted by Steiner et al. (2001) indicate that carnosic acid is capable of antiproliferative action in leukemic cells and can cooperate with other natural anticancer compounds in growth-inhibitory and differentiating effects. Rosemary extracts have been shown to induce quinine reductase activity and glutathione-S-transferase in vitro and in animal study (Singletary & Rokusek, 1997;Tawfiq et al., 1994). Tumor development (secondary sources) may be reduced by decrease in the expression of the proinflammatory gene cyclooxygenase-2 (COX-2). ...
Article
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An evidence-based systematic review of rosemary (Rosmarinus officinalis), including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.
... Polyphenols are one such agent which can modulate cell growth and differentiation and interfere with cancer development and progression [6]. Several studies indicate that extracts of the plant rosemary (Rosemarinus officinalis), which is rich in polyphenols, inhibit both tumour initiation and progression in mice and rat models due to its inherent high anti-oxidant activity [7,8]. Carnosic acid (CA), the major polyphenolic diterpene of rosemary, has been shown to possess anti-inflammatory as well as antiproliferative activity in HL-60 and U937 myeloblastic cells [9,10]. ...
Article
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This study investigates the efficacy of carnosic acid (CA), a polyphenolic diterpene, isolated from the plant rosemary (Rosemarinus officinalis), on androgen-independent human prostate cancer PC-3 cells. CA induced anti-proliferative effects in PC-3 cells in a concentration- and time-dependent manner, which was due to apoptotic induction as evident from flow-cytometry, DNA laddering and TUNEL assay. Apoptosis was associated with the activation of caspase-8, -9, -3 and -7, increase in Bax:Bcl-2 ratio, release of cytochrome-c and decrease in expression of inhibitor of apoptosis (IAP) family of proteins. Apoptosis was attenuated upon pretreatment with specific inhibitors of caspase-8 (Z-IETD-fmk) and caspase-9 (Z-LEHD-fmk) suggesting the involvement of both intrinsic and extrinsic apoptotic cascades. Further, apoptosis resulted from the inhibition of IKK/NF-κB pathway as evident from decreased DNA binding activity, nuclear translocation of p50 and p65 and IκBα phosphorylation. The down-regulation of IKK/NF-κB was associated with inhibition of Akt phosphorylation and its kinase activity with a concomitant increase in the serine/threonine protein phosphatase 2A (PP2A) activity. Pharmacologic inhibition of PP2A by okadaic acid and calyculin A, significantly reversed CA-mediated apoptotic events in PC-3 cells indicating that CA induced apoptosis by activation of PP2A through modulation of Akt/IKK/NF-κB pathway. In addition, CA induced apoptosis in another androgen refractory prostate cancer DU145 cells via intrinsic pathway as evidenced from the activation of caspase 3, cleavage of PARP, increase in Bax:Bcl-2 ratio and cytochrome-c release. Carnosic acid, therefore, may have the potential for use in the prevention and/or treatment of prostate cancer.
... Bu-Abbas et al. (41) indicated that three phase-II detoxicating enzymes (GST, glucuronosyl transferase, and epoxide hydrolase) were promoted in rats after four weeks of adding 2.5-7.5% (w/v) water extracts of green tea to their diets. Anticancer properties of extracts of rosemary were related to its promoting of GST activity (42). Thus, Prectera and Talalay (43) brought up that evaluating the ability to promote phase-II detoxification enzymes would be one of the indexes for detecting antimutagenicity and anticancer action of substances. ...
Article
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Antrodia cinnamomea, a well-known tradition Chinese medicine, possesses anti-tumor, anti-oxidation activities and stimulates the immune system. The aim of this study was to investigate the protective effect of water-soluble polysaccharides from the fermented filtrate and mycelia of Antrodia cinnamomea in submerged culture (ACSC) on hydrogen peroxide-induced cytotoxicity and DNA damage in Chang liver cells. Oxidative DNA damage was evaluated by single cell gel electrophoresis (Comet assay) or by the formation of 8-hydroxy-deoxyguanosine (8-OHdG) adducts. The polysaccharides isolated by ion-exchange chromatography contained glucose, xylose, galactose, arabinose, and mannose. The results showed that incubation of Chang liver cells with isolated polysaccharides at 200 μg/mL for 5 h prior to H2O2 treatment (50 μM, 30 min) significantly reduced oxidative DNA damage as detected by the formation of comet tail DNA and 8-OHdG adducts by 89% and 69%, respectively. Pre-treatment Chang liver cells with polysaccharides also reduced the levels of thiobarbituric acid reactive substances (TBARS) (p < 0.01) and intracellular reactive species (ROS) (p < 0.01) induced by H2O2. Moreover, glutathione S-transferase (GST) and the GSH/GSSG ratio were significantly increased in Chang liver cells pre-incubated with the polysaccharides (p < 0.01). These results demonstrate that polysaccharides in ASCS have antioxidant properties which may involve up-regulation of GST activity, maintenance of normal GSH/GSSG ratio, and scavenging of ROS.
... The petitioner also reviewed the literature available regarding the potential beneficial effects of rosemary extracts. These studies are almost all dealing with the protection by rosemary extracts against CCl 4 liver toxicity (Debersac et al., 2001a, b; Singletary, 1996; Singletary and Rokusek, 1997; Sotelo-Felix et al., 2002a; Sotelo-Felix et al., 2002b; Fahim et al., 1999; Hoefler et al., 1987). Although these studies were not designed to investigate the safety of rosemary extracts no adverse effects of rosemary, carnosol or carnosic acid were reported. ...
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SUMMARY The Panel has been asked to reconsider the possible age-dependent toxicokinetics of BPA in animals and humans and their implication for hazard and risk assessment of BPA in food. The Panel concluded that the exposure of a human fetus to free BPA would be negligible due to the maternal capacity for conjugation whereas the fetal rat would be exposed to free BPA from the maternal circulation. Taking account of data in human neonates on compounds structurally related to BPA which undergo glucuronidation/sulphation, the Panel considers that there is sufficient capacity in the neonate to conjugate BPA at doses below 1 mg/kg bw (the Panel noted that exposures at the TDI of 0.05 mg/kg bw are 20 fold lower than this). Therefore, the Panel concluded that there is sufficient capacity for biotransformation of BPA to hormonally inactive conjugates in neonatal humans at exposures to BPA that were considered in the EFSA opinion of 2006 and the European Union Risk Assessment Report (EC, 2003, 2008). In addition, the Panel notes that because of the metabolic differences described, exposure to free BPA in adult, fetal and neonatal rats will be greater than in humans and that rats would therefore be more susceptible to BPA-induced toxic effects than humans on a equivalent dose basis. The Panel therefore considers that its previous risk assessment based on the overall NOAEL for effects in rats and using a default uncertainty factor of 100 can be considered as conservative for humans. The Panel concluded that the differences in age-dependent toxicokinetics of BPA in animals and humans would have no implication for the EFSA 2006 risk assessment of BPA.
... Rosemary crude extract showed a number of in vitro and in vivo [110] biological activities including strong antioxidant power, antimutagenic effects [27], anti-inflammatory activities and in vitro anti-metastatic properties in B16/F10 mouse melanoma cells [28]. Some of the protective effects of rosemary extracts were attributed to enhancement of xenobiotic detoxification [29]. Two main compounds of rosemary, carnosol and carnosic acid inhibited mRNA expression and activity of cytochrome P450 (CYP1A) and increased glutathione S-transferase (GST) and quinon reductase mRNA expression and activities in human liver and bronchial cells [30,31]. ...
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Cancer is one of the leading causes of death characterized by uncontrolled growth and spread of cancer cells. There are several hundred thousands of new cases of cancer worldwide. Clinical oncology is still challenged by toxicity and side effects of multimodal therapy strategies in which it is associated with poor prognosis for patients. There is an urgent necessity to develop novel therapy strategies and to utilize preventive potential of natural compounds. As the majority of anticancer drugs are of natural origin, natural products represent a valuable source for the identification and development of novel treatment options and chemopreventive mechanisms for cancer. This review is focused on the summary of published knowledges on the antioxidant and potential chemopreventive effects of biologically active substances present in the extracts of four plants of the family Lamiaceae (sage, thyme, rosemary and lavander) in different animal and in vitro systems. It is assumed that the chemopreventive and chemotherapeutic potential of natural compounds is the result of a combined action of several mechanisms. Keywords: sage, thyme, rosemary, lavender.
... While there is a lack in human clinical trial data, there are several animal studies which would indicate that certain herbs and roots, such as rosemary [144][145][146], turmeric/curcumin [147], milk thistle [148], and Gingko biloba [149], may influence glutathione levels. Rosemary extract in the diet of female rats at concentrations of 0.25% to 1.0% by weight resulted in a 3.5-to 4.5-fold increase in hepatic GST. ...
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Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status.
... Although, rosemary extracts have been widely used as a preserving agent in the food industry due to inherent high antioxidant activity, several studies indicate that rosemary extracts and their components inhibit both the initiation and tumor promotion stages of carcinogenesis in mice and rat models [3][4][5][6]. Singletary and Nelshoppen [6] showed that dietary supplementation with 0.5 % and 1.0 % rosemary extract inhibited total in vivo binding of 7,12-dimethylbenz [a]anthracene (DMBA) to mammary epithelial cell DNA by an average of 42 %. Huang et al. [5] evaluated the effects of a methanol extract of rosemary on tumor initiation and promotion in mouse skin, and showed that the application inhibited the covalent binding of benzo(a)pyrene (B(a)P) to epidermal DNA and inhibited tumor initiation by B(a)P and DMBA. ...
... Studies on the anticarcinogenic effect of spices such as turmeric, rosemary extract, sage extract, ginger, coriander seed, black pepper, cumin and garlic have been carried out by many research groups as shown in Table 1. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] Such spices have been known to be effective on large intestine cancer, liver cancer, stomach cancer, breast cancer, skin cancer, bladder cancer, and colon cancer. Some papers, however, reported the possible carcinogenicity of ethylene oxide which is used as a sterilizing agent of spices 31 and a epidemiologic study showed the high occurrence of esophageus cancer in immigrant Indian women in Israel where the use of spices is prevalent. ...
Article
To confirm the cytotoxic effect of instant curry containing combined spices on cancer cells in vivo, cancer was induced by transplanting cancer cells to mice, and the development of cancer upon feeding pure curry were examined. The concentration of lipid peroxide in the groups transplanted with cancer cells which were fed with normal feed was 19.6 nM, and it was increased as the amount of pure curry was increased. The concentration of cytochrome P-450 was decreased in the group transplanted with cancer cells which were fed with pure curry and the group without the transplant which were fed with pure curry when compared with the groups which were fed with normal feed. The activity of cytochrome P-450 was decreased as the concentration of cytochrome P-450 was decreased in the groups transplanted with cancer cells. However, it was increased in the groups without cancer cell transplant when over 2% of pure curry was fed. The amount of glutathione was increased in the groups transplanted with cancer cells when over 2% of pure curry was fed. The activities of glutathione peroxidase and glutathione S-transferase were decreased in the groups transplanted with cancer cells which were fed with over 1% of pure curry, and were restored to the level of the group without cancer cell transplant which were fed with normal feed. The superoxide dismutase activity in the groups transplanted with cancer cells was restored to the level of the group without cancer cell transplant which was fed with normal feed when over 1% of pure curry was fed.
... It is worth noting that the essential oils could improve the secretion of amylase, trypsin, and jejunal chime (Jang et al., 2004) and could decrease the attachment of pathogens such as C. perfringens and E. coli with the intestinal wall as authorized by Jamroz et al., 2006 andNikaido (2003). Previous reports of Singletary and Rokusek (1997) assured that rosemary extract improved the efficiency of feed conversion in broilers. Similar results were obtained by Abd El-Latif et al. (2013) who confirmed that enriching rosemary to the broilers' diets increased FCR compared with the control group and other experimental groups. ...
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This study was performed to study the impacts of rosemary cold-pressed oil (RCPO) for biostimulating health, growth performance, and intestinal bacterial populations of Japanese quail. The study included 300 growing 1-wk-old Japanese quails. Birds were divided into 3 groups in a complete randomized design experiment that involved 3 levels of RCPO (0, 1.00 and 2.00 mL/kg diet). Results revealed that the addition of rosemary oil numerically increased values of body weight and body weight gain when compared with the control group, particularly the highest level of RCPO (2.00 mL/kg diet). Birds fed diets supplemented with rosemary oil consumed more feed (P ≤ 0.01) compared with those fed the control diet. Feed conversion ratio tended to be improved in rosemary oil groups during the period 3 to 6 wk of age (P = 0.013). The highest level of rosemary oil (2.00 mL/kg diet) had the best impact on all carcass traits studied. RCPO supplementation showed an increase in serum total protein, metabolic hormones levels, while it reduced serum cholesterol and low-density lipoprotein cholesterol, 8-hydroxy-2′-deoxyguanosine, and protein carbonyl levels. Moreover, RCPO increased antioxidative enzymes, and reduced the lipid peroxidation in quail liver. The supplementation of 2 mL/RCPO kg diet showed significant reduction in populations of total cultural bacterial count, coliforms, Escherichia coli, and Salmonella spp. in the ileum when compared to the control. The current results showed that RCPO supplementation to Japanese quails diet could enhance the growth performance and reduce the intestinal pathogenic bacteria. Therefore, RCPO can be a beneficial antimicrobial and growth-promoting feed supplement for the Japanese quail.
... Rosmarinus officinalis L. has many medicinal uses such as, anti-inflammatory, antibacterial, antiviral (Bozin et al., 2007), antidiabetic (Bakırel et al., 2008). Also, rosemary extracts have been widely used as a preserving agent in the food industry due to inherent high antioxidant activity of crude extracts or of pure components (Singletary and Rokusek, 1997). The main polyphenols found in rosemary extract include the diterpenes carnosic acid and rosmarinic acid. ...
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Medicinal plants are of great importance in traditional medicine, in which in most part, the antioxidant activity of the plant-derived compounds is imagined responsible for treating various diseases. Rosmarinus officinalis L, contains several polyphenolic compounds with antioxidant activity; However, to elicit the anti-proliferative activity of R. officinalis, it is required to be improved via different strategies. Nowadays, green synthesis of metal nano- particles involving plant extract has attracted the attention of many researchers as this approach could help to derive the therapeutic benefits of the plant extracts. In this study, for the first time, the aqueous extract of rosemary was applied in green iron nanoparticle platform (Rosemary-FeNPs). Various methods, including dynamic light scattering(DLS), field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Transmission electron microscopy (TEM), and Raman spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR) were employed to characterize Rosemary-FeNPs. The mean size of the Rosemary-FeNPs were at about 100 nm with PDI of less than 0.12, which indicates a homogeneous size distribution of the nanoparticles. The cytotoxicity of Rosemary-FeNPs and total extract of rosemary was determined using MTT cytotoxic test on 4T1 and C26 cancer cell lines. The results showed that Rosemary-FeNPs could exert more cytotoxic effect than total extract on both cancer cell lines.
... The polyphenolic compounds found in rosemary have demonstrated antiproliferative effects in leukemia cells and may be used concomitantly with anticancer drugs (Steiner et al., 2001). These compounds also show hepatoprotective properties (Fahim et al., 1999), protective activity against carcinogens or agents toxic to the stomach (Singletary and Rokusek, 1997), and the potential to diminish the activation and increase the detoxification of the pro-carcinogen benzo[a]pyrene, indicating its chemopreventive activity (Offord et al., 1995). ...
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Polyphenolic compounds present in rosemary were found to have antioxidant properties, anticarcinogenic activity, and to increase the detoxification of pro-carcinogens. The aim of the study was to determine the effect the aqueous extract of rosemary (AER) on mutagenicity induced by methylmethane sulfonate in meristematic cells of Allium cepa, as well as to describe its mode of action. Anti-mutagenicity experiments were carried out with 3 different concentrations of AER, which alone showed no mutagenic effects. In antimutagenicity experiments, AER showed chemopreventive activity in cultured meristematic cells of A. cepa against exposure to methylmethane sulfonate. Additionally, post-treatment and simultaneous treatment using pre-incubation protocols were the most effective. Evaluation of different protocols and the percent reduction in DNA indicated bioantimutagenic as well desmutagenic modes of action for AER. AER may be chemopreventive and antimutagenic.
... Foods rich in antioxidants have also been proposed as a tool to prevent liver damage (Morisco et al., 2008). It is generally assumed that these antioxidant compounds may scavenge free radicals and regulate the activity and/or expression of certain enzymatic systems implicated in relevant physiological processes like the metabolism of xenobiotics in the liver (Singletary and Rokusek, 1997;Subbaramaiah et al., 2002). Synergistic interactions amongst the antioxidants present in the HE of R. officinalis leaves might reduce serum ALT, ALP, and AST levels. ...
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The hydroalcoholic extract of the leaves of Rosmarinus officinalis (HE), a species of medicinal value, and its constituent rosmarinic acid (RA) were evaluated for hepatoprotective in the acetaminophen-induced liver damage model. Groups of Wistar albino rats (n=6) were pre-administered with HE (100, 250 and 500 mg/kg, p.o.) and RA (10, 25 and 50 mg/kg, p.o.) prior to a single dose of acetaminophen (APAP, 600 mg/kg body weight; p.o). The hepatoprotective activity of HE extract was observed through histopathological analysis and reduction of the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). These observations were comparable to the normal group prior to APAP administration. Group that was treated with APAP alone exhibited high levels of transaminases and ALP. The obtained results from the present study suggested that HE may prevent APAP-induced hepatic injuries. RA did not displayed significant hepatoprotective activity against APAP-induced liver damage.
... Carnosol was able to reduce tumor molteplicity in a mouse model of colonic tumorigenesis [20]. In vitro and in vivo data indicated also that rosemary crude extracts or purified components exerted chemoprotective effects, by inhibiting early phases of tumor development, or contrasting the effect of chemical mutagenic compounds [21,22,23,24]. Mechanisms of chemoprotection probably involved inhibition of phase I enzymes of carcinogenesis, as well as increased expression of detoxifying enzymes [25]. ...
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Rosemary (Rosmarinus officinalis L.) has been used since ancient times in traditional medicine, while nowadays various rosemary formulations are increasingly exploited by alternative medicine to cure or prevent a wide range of health disorders. Rosemary's bioproperties have prompted scientific investigation, which allowed us to ascertain antioxidant, anti-inflammatory, cytostatic, and cytotoxic activities of crude extracts or of pure components. Although there is a growing body of experimental work, information about rosemary's anticancer properties, such as chemoprotective or anti-proliferative effects on cancer cells, is very poor, especially concerning the mechanism of action. Melanoma is a skin tumor whose diffusion is rapidly increasing in the world and whose malignancy is reinforced by its high resistance to cytotoxic agents; hence the availability of new cytotoxic drugs would be very helpful to improve melanoma prognosis. Here we report on the effect of a rosemary hydroalcoholic extract on the viability of the human melanoma A375 cell line. Main components of rosemary extract were identified by liquid chromatography coupled to tandem mass spectrometry (LC/ESI-MS/MS) and the effect of the crude extract or of pure components on the proliferation of cancer cells was tested by MTT and Trypan blue assays. The effect on cell cycle was investigated by using flow cytometry, and the alteration of the cellular redox state was evaluated by intracellular ROS levels and protein carbonylation analysis. Furthermore, in order to get information about the molecular mechanisms of cytotoxicity, a comparative proteomic investigation was performed.
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One mechanism through which bioactive food components may exert anticancer effects is by reducing the expression of the proinflammatory gene cyclooxygenase-2 (COX-2), which has been regarded as a risk factor in tumor development. Rosmarinic acid (RA) is a phenolic derivative of caffeic acid present in rosemary (Rosmarinus officinalis). Previous research documented that RA may exert antiinflammatory effects. However, the mechanisms of action of RA on COX-2 expression have not been investigated. Here, we report that in colon cancer HT-29 cells, RA (5, 10, and 20 micromol/L) reduced the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 promoter activity (P < 0.05) and protein levels (P < 0.05). In addition, the cotreatment with RA reduced (5 micromol/L, P < 0.05; 10 and 20 micromol/L, P < 0.01) TPA-induced transcription from a control activator protein-1 (AP-1) promoter-luciferase construct and repressed binding of the AP-1 factors c-Jun (10 micromol/L; P < 0.01) and c-Fos (10 micromol/L; P < 0.05) to COX-2 promoter oligonucleotides harboring a cAMP-response element (CRE). The anti-AP1 effects of RA were also examined in a nonmalignant breast epithelial cell line (MCF10A) in which RA antagonized the stimulatory effects of TPA on COX-2 protein expression (5 micromol/L, P < 0.05; 10 and 20 micromol/L, P < 0.01), the recruitment of c-Jun and c-Fos (10 micromol/L; P < 0.01) to the COX-2/CRE oligonucleotides, and activation of the extracellular signal-regulated protein kinase-1/2 (ERK1/2) (10 micromol/L; P < 0.01), a member of the mitogen-activated protein kinase pathway. Additionally, RA antagonized ERK1/2 activation in colon HT-29 and breast MCF-7 cancer cells (10 micromol/L; P < 0.01). Thus, we propose that RA may be an effective preventative agent against COX-2 activation by AP-1-inducing agents in both cancer and nonmalignant mammary epithelial cells.
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The protective effects of resveratrol and 4-hexylresorcinol against oxidative DNA damage in human lymphocytes induced by hydrogen peroxide were investigated. Resveratrol and 4-hexylresorcinol showed no cytotoxicity to human lymphocytes at the tested concentration (10-100 microM). In addition, DNA damage in human lymphocytes induced by H2O2 was inhibited by resveratrol and 4-hexylresorcinol. Resveratrol and 4-hexylresorcinol at concentrations of 10-100 microM induced an increase in glutathione (GSH) levels in a concentration-dependent manner. Moreover, these two compounds also induced activity of glutathione peroxidase (GPX) and glutathione reductase (GR). The activity of glutathione-S-transferase (GST) in human lymphocytes was induced by resveratrol. Resveratrol and 4-hexylresorcinol inhibited the activity of catalase (CAT). These data indicate that the inhibition of resveratrol and 4-hexylresorcinol on oxidative DNA damage in human lymphocytes induced by H2O2 might be attributed to increase levels of GSH and modulation of antioxidant enzymes (GPX, GR and GST).
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Background and purpose: Chemotherapy resistance is a major obstacle for the effective treatment of cancers. Although several studies have described the anticancer properties of rosemary extract and its components, the detailed mechanisms of action are poorly understood. Methods: Activity-guided fractionation and repeated chromatographic separation of the n-hexane fraction of the aqueous methanol extract over silica gel, RP C18, and Sephadex LH-20 led to the isolation of three compounds. The structures of the compounds were determined using (1)H, (13)C, and two-dimensional nuclear magnetic resonance spectroscopy, mass spectroscopy, and infrared spectroscopy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to evaluate the cytotoxicity of these compounds. Cell cycle, apoptotic cell populations, and mitochondrial membrane potential were analyzed by flow cytometry. Western blot analysis was conducted to detect apoptosis-related proteins. Results: An abietane diterpenoid, sageone (1), an icetexane diterpenoid, (-)-barbatusol (2), and a monoterpene, (+)-verbenone (3), were identified. Of these compounds, sageone (1) showed cytotoxicity against SNU-1 cells with an IC50 of 9.45 ± 1.33 µM. Sageone reduced the expression of Akt dramatically, as opposed to cisplatin, which increased phosphorylated Akt. Sageone combined with a subtoxic dose of cisplatin had synergistic effects on apoptosis induction in SNU-1 cells, as confirmed by calculating the combination index. Co-treatment was significantly more effective than monotherapy at reducing cell viability and inducing apoptosis, as determined by analyzing DNA fragmentation. The combined treatment of sageone and cisplatin markedly reduced Akt expression and phosphorylation, accompanied by increases in cleaved caspase-3, -9 and PARP. Conclusion: This is the first time compounds 1 and 2 have been isolated from R. officinalis. Sageone induced apoptosis in SNU-1 human gastric cancer cells and notably enhanced the cytotoxicity of cisplatin in SNU-1 cells, which are known to be resistant to cisplatin. These findings suggest that sageone represents a promising anticancer agent against gastric cancer that warrants further study.
Chapter
Cancer is largely an avoidable or preventable disease. It is estimated that more than two-thirds of cancer-related deaths can be prevented through lifestyle modification, particularly our daily diet. Frequent consumption of diets rich in fruits and vegetables has been consistently shown to reduce the risk of several forms of human cancer. A major prevention strategy has been the “Five a Day for Better Health” program sponsored by the U.S. National Cancer Institute (NCI), encouraging the public to include more fruit and vegetables in their diet.
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This chapter focuses on the health benefits of traditional culinary and medicinal plants of the Mediterranean region. The Mediterranean diet is mentioned to be rich in fruits and vegetables, monounsaturated fatty acids and olive oil and the diet has a negative association with incidence of metabolic syndrome that contributes to an increased risk for cardiovascular disease. Mediterranean plants are believed to prevent or cure a wide range of ailments based on their bioactive components that can exert anti-oxidant, anti-inflammatory, anti-carcinogenic or anti-diabetic activities. A table is presented that gives a list of Mediterranean plants and their health benefits as well as brief accounts of the medicinal use of the plants and includes rosemary, licorice, chamomile and olive oil among others. The consumption of olive oil has a strong correlation with reduced hypertension, cancers of the prostate, breast and colon. It highlights the mechanism of action of the bioactive components and the molecular targets derived from these plants.
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The effects of a water-soluble extract (WSE) of rosemary and its purified antioxidant rosmarinic acid (RA) on xenobiotic metabolizing enzymes (XME) were studied in rat liver after dietary administration. The modulation of phase I enzymes such as cytochrome P450 (CYP) 1A, 2B, 2E1, 3A, and phase II enzymes such as glutathione S-transferase (GST), quinone reductase (QR) and UDP-glucuronosyltransferase (UGT) was evaluated by measuring enzyme activities with specific substrates. Protein levels of CYPs and rGST A1/A2, A3/A5, M1, M2 and P1 were measured using antibodies in Western blots. Caffeic acid was also studied because it results from RA biotransformation in rat after oral administration. Male SPF Wistar rats received the different compounds at 0.5% (w/w) incorporated into their diet for 2 weeks. WSE, containing RA, flavones and monoterpenes enhanced CYP 1A1, 2B1/2, 2E1 and GST (especially rGST A3/A5, M1 and M2), QR and UGT. On the contrary, no modification of XME was observed in response to RA or CA (except for a slight increase of UGT activity after CA treatment). The induction of XME by WSE could be attributed to flavones, monoterpenes or an additive effect of all components.
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Oxidative stress is implicated in the etiology of cancer, hence compounds that alleviate oxidative stress by inducing enzymes that defend against free radical damage might be useful as cancer chemopreventives. Glutathione S-transferase (GST) has been suggested to be a candidate for a critical enzyme in protecting cells against free radical damage, in part, because its level of induction correlates with protection of the cell line IMR-32 against hydrogen peroxide-induced oxidative stress. The present study identified dietary ortho phenols that both induce GST and protect the cell line IMR-32 against hydrogen peroxide-caused oxidative stress. The ortho phenol (o-phenol) inducers were better protectors against oxidative stress than a number of GST inducers that did not bear phenolic groups, possibly because the phenol residues of the ortho phenols allowed their action as antioxidants as well as inducers of GST. GST has previously been thought to protect cells against cancer by detoxifying mutagenic xenobiotics. The present results suggest that ortho phenol inducers of GST might be useful as cancer chemopreventives that act by two independent mechanisms, the alleviation of oxidative stress and the detoxification of mutagenic xenobiotics.
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Food safety is of critical public concern, and has drawn great attention in society. Consequently, developments of rapid, robust and accurate methods and techniques for food safety evaluation and control are required. As a nondestructive and convenient tool, near-infrared spectroscopy (NIRS) has been widely shown to be a promising technique for food safety inspection and control due to its huge advantages of rapidity, noninvasive measurement, ease of use, and minimal sample preparation. This review presents the fundamentals of NIRS and focuses on recent advances on its applications, during the last ten years of food safety control, in meat, fish and fishery products, edible oils, milk and dairy products, grains and grain products, fruits and vegetables, and others. Based upon these applications, it can be demonstrated that NIRS combined with chemometric methods is a powerful tool for food safety surveillance and for the elimination of the occurrence of food safety problems. Some disadvantages that need to be solved or investigated regarding further development of NIRS are also discussed. Link to Journal: http://www.tandfonline.com/doi/full/10.1080/10408398.2012.732126#.U332OKRH5lY
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Oxidative stress occurs in biological systems due to an increase in oxidant generation, a decrease in antioxidant activity, and/or failure to repair oxidative damage. Reactive oxygen species and other free radicals present in the environment and that are derived from dietary sources are oxidative stress inducers. Dietary antioxidants play an important role in restoring the oxidant-antioxidant balance in biological systems when the existing cellular antioxidant defence mechanisms fail to combat increased levels of oxidizing agents. Antioxidants, camosol and camosic acid, derived from rosemary (Rosemarinus officinalis L.) leaf extracts, have shown to exert strong antioxidant activities against reactive oxygen species and free radical attacks in food as well as biological model systems.
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There is a general belief that herbal products, thus essential oils too, are safe because they are natural. Together with the increased appearance of common and selfinitiative usage of herbal preparations there is also an increased need of knowing and understanding possible interactions with concomitantly taken drugs. Since essential oils are mixtures of multiple active volatile compounds it is very likely for essential oils and especially their constituents also to interact with drugs. The presented treatise will reveal some of such interactions. Most of them are pharmacokinetic ones, while pharmacodynamic interactions seem to be less studied. While some of these interactions may have a negligible impact on the effect of drugs - and it was the aim of this paper to demonstrate the impact of volatile oils on the effect of drugs when applied together - other mutual effects may be rather harmful. Under certain circumstances it could be possible to use the effects of these interactions also for the benefit of the patients, but further clinical investigations are needed.
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Colorectal cancer is the second leading cause of cancer death in Australia. Nutrition, particularly intake of vegetables and certain plant components, has been reported to have a major role in cancer risk reduction. Recently, there has been a growing research interest in rosemary, a common household plant grown in many parts of the world. This study aims to review scientific evidence from all studies, published from 1996 to March 2010 that examined the protective effects of rosemary on colorectal cancer and other types of cancer. Literature evidence from animal and cell culture studies demonstrates the anticancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid. No evidence for other rosemary constituents was found. The reported anticancer properties were found to arise through the molecular changes in the multiple-stage process of cancer development, which are dose related and not tissue or species specific. This is evidenced by the ability of rosemary to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells. The results suggested that the different molecular targets modulated by rosemary and its active constituents are useful indicators of success in clinical cancer chemo-prevention trials.
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The cytotoxic effects of spices containing pure curry on animals with cancer cells was tested in vivo by inducing cancer experimentally by transplanting sarcoma—180 cancer cells into Isolated Barrier Room System (IBRS) #202 mice. The consumption of a normal diet supplemented with 5% pure curry prolonged the survival period of cancer-cell-transplanted mice by 20.97% (p < 0.01) relative to mice that consumed a normal diet without pure curry. The liver was significantly heavier in the curry groups with or without tumor cell transplantation than in the group consuming a normal diet; the kidney was significantly lighter in cancer-cell-transplanted mice than in nontreated mice (p < 0.01), regardless of the amount of pure curry in the diet; the heart weight did not differ significantly between the groups.
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In previous works, rosemary extracts (REs) obtained in our laboratory using supercritical fluid extraction exhibited inhibitory effect on proliferation of several cancer cell lines. However, the observed antiproliferative activity was not correlated to any compound present in the extract. In order to address this question, in this work the contribution of carnosic acid (CA) and carnosol (CS), two major compounds present in the RE, against colon cancer HT-29 cells proliferation is investigated using a comprehensive Foodomics approach. Although CA and CS exhibit additive antiproliferative effect when they are combined in solution at a molar ratio of 6.9:1, the results reveal that CA contributes more significantly than CS to the activity of RE against colon cancer cells proliferation. The Foodomics study reveals that CA induces transcriptional activation of genes that encode detoxifying enzymes and altered the expression of genes linked to other relevant functions such as transport and biosynthesis of terpenoids in the colon cancer cell line. Functional analysis highlighted the activation of the ROS metabolism and alteration of several genes involved in pathways describing oxidative degradation of relevant endogenous metabolites, providing new evidences about the transcriptional change induced by CA in HT-29 cells. Metabolomics analysis showed that the treatment with CA affected the intracellular levels of glutathione. Elevated levels of GSH provided additional evidences to transcriptomic results regarding chemopreventive response of cells to CA treatment. Moreover, the Foodomics approach was useful to establish the links between decreased levels of N-acetylputrescine and its degradation pathway at the gene level. The findings from this work and the predictions based on microarray data will help exploring novel metabolic processes and potential signaling pathways to further elucidate de effect of CA in colon cancer cells.
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Cancer remains an important cause of mortality nowadays and, therefore, new therapeutic approaches are still needed. Rosemary (Rosmarinus officinalis L.) has been reported to possess antitumor activities both in vitro and in animal studies. Some of these activities were attributed to its major components, such as carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Initially, the antitumor effects of rosemary were attributed to its antioxidant activity. However, in recent years, a lack of correlation between antioxidant and antitumor effects exerted by rosemary was reported, and different molecular mechanisms were related to its tumor inhibitory properties. Moreover, supported by the U.S. Food and Drug Administration and the European Food and Safety Authority, specific compositions of rosemary extract were demonstrated to be safe for human health and used as antioxidant additive in foods, suggesting the potential easy application of this agent as a complementary approach in cancer therapy. In this review, we aim to summarize the reported anticancer effects of rosemary, the demonstrated molecular mechanisms related to these effects and the interactions between rosemary and currently used anticancer agents. The possibility of using rosemary extract as a complementary agent in cancer therapy in comparison with its isolated components is discussed.
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The purification of homogeneous glutathione S-transferases B and C from rat liver is described. Kinetic and physical properties of these enzymes are compared with those of homogeneous transferases A and E. The letter designations for the transferases are based on the reverse order of elution from carboxymethylcellulose, the purification step in which the transferases are separated from each other. Transferase B was purified on the basis of its ability to conjugate iodomethane with glutathione, whereas transferase C was purified on the basis of conjugation with 1,2-dichloro-4-nitrobenzene. Although each of the four enzymes can be identified by its reactivity with specific substrates, all of the enzymes are active to differing degrees in the conjugation of glutathione with p-nitrobenzyl chloride. Assay conditions for a variety of substrates are included. All four glutathione transferases have a molecular weight of 45,000 and are dissociable into subunits of approximately 25,000 daltons. Despite the similar physical properties and overlapping substrate specificities of these enzymes, only transferases A and C are immunologically related.
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Approximately 200 studies that examined the relationship between fruit and vegetable intake and cancers of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary are reviewed. A statistically significant protective effect of fruit and vegetable consumption was found in 128 of 156 dietary studies in which results were expressed in terms of relative risk. For most cancer sites, persons with low fruit and vegetable intake (at least the lower one-fourth of the population) experience about twice the risk of cancer compared with those with high intake, even after control for potentially confounding factors. For lung cancer, significant protection was found in 24 of 25 studies after control for smoking in most instances. Fruits, in particular, were significantly protective in cancers of the esophagus, oral cavity, and larynx, for which 28 of 29 studies were significant. Strong evidence of a protective effect of fruit and vegetable consumption was seen in cancers of the pancreas and stomach (26 of 30 studies), as well as in colorectal and bladder cancers (23 of 38 studies). For cancers of the cervix, ovary, and endometrium, a significant protective effect was shown in 11 of 13 studies, and for breast cancer a protective effect was found to be strong and consistent in a meta analysis. It would appear that major public health benefits could be achieved by substantially increasing consumption of these foods.
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2(3)-tert-Butyl-4-hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarol-inhibited NAD(P)H:quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2] activity in mouse tissues in response to dietary administration of BHA. Cytosolic quinone reductase specific activity was increased significantly in 10 of 15 tissues examined from BHA-fed mice. The greatest proportionate increase, to 10 times control levels, was observed in liver. BHA also increased the quinone reductase activities of kidney, lung, and the mucosa of the upper small intestine severalfold. The increases of quinone reductase activities in liver and digestive tissues in response to BHA were comparable to the increases previously observed in glutathione S-transferase (EC 2.5.1.18) and epoxide hydratase (EC 3.3.2.3) activities. Quinones are among the toxic products of oxidative metabolism of aromatic hydrocarbons. NAD(P)H:quinone reductase exhibits broad specificity for structurally diverse hydrophobic quinones and may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protective effects of BHA appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the nonoxidative metabolism of a wide variety of xenobiotics.
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A methanol extract of the leaves of the plant Rosmarinus officinalis L. (rosemary) was evaluated for its effects on tumor initiation and promotion in mouse skin. Application of rosemary to mouse skin inhibited the covalent binding of benzo(a)pyrene [B(a)P] to epidermal DNA and inhibited tumor initiation by B(a)P and 7,12-dimethylbenz[a]anthracene (DMBA). Topical application of 20 nmol B(a)P to the backs of mice once weekly for 10 weeks, followed 1 week later by promotion with 15 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 21 weeks, resulted in the formation of 7.1 tumors per mouse. In a parallel group of animals that were treated topically with 1.2 or 3.6 mg of rosemary 5 min prior to each application of B(a)P, the number of tumors per mouse was decreased by 54 or 64%, respectively. Application of rosemary to mouse skin also inhibited TPA-induced ornithine decarboxylase activity, TPA-induced inflammation, arachidonic acid-induced inflammation, TPA-induced hyperplasia, and TPA-induced tumor promotion. Mice initiated with 200 nmol DMBA and promoted with 5 nmol TPA twice weekly for 19 weeks developed an average of 17.2 skin tumors per mouse. Treatment of the DMBA-initiated mice with 0.4, 1.2, or 3.6 mg of rosemary together with 5 nmol TPA twice weekly for 19 weeks inhibited the number of TPA-induced skin tumors per mouse by 40, 68, or 99%, respectively. Topical application of carnosol or ursolic acid isolated from rosemary inhibited TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. Topical application of 1, 3, or 10 mumol carnosol together with 5 nmol TPA twice weekly for 20 weeks to the backs of mice previously initiated with DMBA inhibited the number of skin tumors per mouse by 38, 63, or 78%, respectively. Topical application of 0.1, 0.3, 1, or 2 mumol ursolic acid together with 5 nmol TPA twice weekly for 20 weeks to DMBA-initiated mice inhibited the number of tumors per mouse by 45-61%.
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4. Print Bibliogr. na konci kapitol Na tit. listě vroč. 1989
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Following the oral feeding of a polyphenolic fraction isolated from green tea (GTP) in drinking water, an increase in the activities of antioxidant and phase II enzymes in skin, small bowel, liver, and lung of female SKH-1 hairless mice was observed. GTP feeding (0.2%, w/v) to mice for 30 days significantly increased the activities of glutathione peroxidase, catalase, and quinone reductase in small bowel, liver, and lungs, and glutathione S-transferase in small bowel and liver. GTP feeding to mice also resulted in considerable enhancement of glutathione reductase activity in liver. In general, the increase in antioxidant and phase II enzyme activities was more pronounced in lung and small bowel as compared to liver and skin. The significance of these results can be implicated in relation to the cancer chemopreventive effects of GTP against the induction of tumors in various target organs.
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The effect of dietary intake of an extract of the spice plant Rosmarinus officinalis L. on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis and on the in vivo formation of mammary DMBA-DNA adducts was evaluated. Supplementation of a semi-purified diet with 1.0% (by wt.) rosemary extract resulted in a significant (47%) decrease in mammary tumor incidence compared to controls. In subsequent studies, dietary supplementation with 0.5% and 1.0% rosemary extract inhibited total in vivo binding of DMBA to mammary epithelial cell DNA by an average of 42%. This decrease in total binding was not due to a uniform decrease in the formation of all mammary DMBA-DNA adducts. The formation of two major adducts derived from the anti-diastereomer of DMBA and bound to deoxyguanosine (anti-dGuo) was significantly decreased at both dietary rosemary concentrations. The formation of the syn-dGuo adduct also was inhibited, whereas formation of the syn-dAdo adduct was unaffected by consumption of the rosemary extract. These studies suggest that use of rosemary extract and its individual antioxidative constituents as chemopreventative agents for experimental mammary tumorigenesis warrant further investigation.
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In the present study, eight organosulfur compounds from garlic and onions were studied for their inhibitory effects on benzo[a]pyrene (BP)-induced neoplasia of forestomach and lung of female A/J mice when administered 96 and 48 h prior to carcinogen challenge. These compounds had one, two or three linearly connected sulfur atoms. They included the four allyl group-containing derivatives: allyl methyl trisulfide (AMT), allyl methyl disulfide (AMD), diallyl trisulfide (DAT), and diallyl sulfide (DAS), and also four corresponding saturated compounds in which propyl groups were substituted for the allyl groups. All four allylic compounds inhibited BP-induced neoplasia of the forestomach. The saturated analogs were almost without inhibitory activity, indicating the importance of the allyl groups. DAT, which contains two allyl groups, was more potent than AMT, which contains only one allyl group, thus providing further evidence for the role of allyl groups in the inhibitory effects observed. DAS and AMD, but not DAT or AMT, inhibited pulmonary adenoma formation. The fact that in the lung the monosulfide and disulfide inhibited, but the trisulfide did not inhibit, indicates that the number of sulfur atoms in the molecule can control the organ sites at which protection against carcinogenesis will occur. All four allylic compounds induced increased glutathione S-transferase (GST) activity in the forestomach, but varied in their capacity to induce GST in lung, liver and small bowel. Their saturated analogs produced little or no induction. In evaluating relationships between diet and cancer, it would be useful to consider the possible role of garlic and onion organosulfur compounds as protective agents. In addition, further studies of this class of chemicals might lead to the identification and development of useful new chemopreventive compounds.
Article
The commonly used spice and flavouring agent, rosemary, derived from the leaves of the plant Rosmarinus officinalis L., displays antioxidant properties in foods and in biological systems. Moreover, in animal models rosemary components were found to inhibit the initiation and tumour promotion phases of carcinogenesis. In this work, we studied the mechanisms by which rosemary components block initiation of carcinogenesis by the procarcinogen benzo[a]pyrene (B[a]P) in human bronchial epithelial cells (BEAS-2B). Whole rosemary extract (6 μg/ml) or an equivalent concentration of its most potent antioxidant constituents, carnosol or carnosic acid, inhibited DNA adduct formation by 80% after 6 h co-incubation with 1.5 μM B[a]P. Under similar conditions, cytochrome P450 (CYP) 1A1 mRNA expression was 50% lower in the presence of rosemary components, and CYP1A1 activity was inhibited 70–90%. The observed reduction of DNA adduct formation by rosemary components may mostly result from the inhibition of the activation of benzo[a]pyrene to its ultimate metabolites. Carnosol also affected expression of the phase II enzyme glutathione-S-transferase which is known to detoxify the proximate carcinogenic metabolite of B[a]P. Treatment of BEAS-2B cells with carnosol (1 μg/ml) for 24 h resulted in a 3- to 4-fold induction of GSTπ mRNA. Moreover, expression of a second important phase II enzyme, NAD(P)H: quinone reductase, was induced by carnosol in parallel with GSTπ. Therefore, rosemary components have the potential to decrease activation and increase detoxification of an important human carcinogen, identifying them as promising candidates for chemopreventive programs.
Article
Many potential strategies exist for chemical protection against carcinogenesis. Multiple stages of carcinogenesis, including initiation, promotion, and progression, can serve as targets for different types of interventions [see reviews by Wattenberg (32); De Flora and Ramel (10)]. However, in the majority of experimental systems, protection has been achieved by administering the chemoprotective agent prior to and/or concurrent with the exposure to carcinogen. Given this temporal relationship between administration of anticarcinogen and carcinogen, it seems likely that these agents act principally by affecting the metabolism and disposition of carcinogens, thereby altering events critical to the initiation of carcinogenesis. Using this experimental approach, it has been possible to document protection against a diverse array of chemical carcinogens acting at many different target organ sites. Important classes of chemoprotectors that modulate the metabolic processing of carcinogens include phenolic antioxidants, indoles, organic isothiocyanates, coumarins, flavones, allyl sulfides, dithiocarbamates, and dithiolethiones.
Chemorprotection by inducers of electrophile detoxication enzymes Antimutagenesis and anticarcinogenesis mechanisms, III
  • T Kensler
  • N Davidson
  • J Groopman
  • B Roebuck
  • H Prochaska
  • P Talalay
Inhibition of 1,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumorigenesis and of in vivo formation of mammary DMBA-DNA adducts by rosemary extract
  • K Singletary
  • J Nelshoppen
Singletary K, Nelshoppen J (1991) Inhibition of 1,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumorigenesis and of in vivo formation of mammary DMBA-DNA adducts by rosemary extract. Cancer Lett 60: 169-175.