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Antitumor activity of balsam fir oil: Production of reactive oxygen species induced by alpha-humulene as possible mechanism of action

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Abstract

The antitumor activity of the essential oil of Abies balsamea (balsam fir oil) was evaluated against several solid tumor cell lines including MCF-7, PC-3, A-549, DLD-1, M4BEU and CT-26. Balsam fir oil was found to be active against all the solid tumor cell lines tested, with GI 50 values ranging between 0.76 and 1.7 mg/mL. The oil was analyzed by GC-MS and the cytotoxicity of each oil constituent was determined. Balsam fir oil is essentially constituted of monoterpenes tau; 96 %) and some sesquiterpenes. All the compounds tested were inactive (tau; 250 microM) except for alpha-humulene (GI50 = 55 to 73 microM) which thus seems responsible for the cytotoxicity of the oil. We also tested the cytotoxicity of caryophyllene oxide, which proved inactive, and gamma-caryophyllene which was found to be active against all solid tumor cell lines tested. We evaluated the effects of balsam fir oil and alpha-humulene on the cellular glutathione (GSH) content and on the production of reactive oxygen species (ROS). Balsam fir oil and alpha-humulene induced a dose- and time-dependent decrease in cellular GSH content and an increase in ROS production. These results suggest that GSH depletion and ROS production may be implicated in the cytotoxicity of alpha-humulene and balsam fir oil.

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... β-Caryophyllene oxide was reported to possess antifungal, genoprotective, antioxidant, anti-inflammatory, chemosensitizing, and antiproliferative properties [124,[195][196][197][198][199][200][201][202][203][204], while antibacterial, antifungal, antiproliferative, and chemosensitizing effects were highlighted for α-humulene [205][206][207][208][209][210][211] ( Table 3). The antiproliferative activity of some α-humulene derivatives has been described, too [215,216]. ...
... Several preclinical studies focused on the antiproliferative properties of caryophyllane sesquiterpenes (Table 3). Legault et al. [209] found that α-humulene and isocaryophyllene were able to inhibit the growth of different tumor cells, with the highest potency in human M4BEU melanoma and in mouse CT-26 colon carcinoma and L-929 fibrosarcoma cells. Conversely, β-caryophyllene and β-caryophyllene oxide were ineffective in the experimental conditions [209]. ...
... Legault et al. [209] found that α-humulene and isocaryophyllene were able to inhibit the growth of different tumor cells, with the highest potency in human M4BEU melanoma and in mouse CT-26 colon carcinoma and L-929 fibrosarcoma cells. Conversely, β-caryophyllene and β-caryophyllene oxide were ineffective in the experimental conditions [209]. The cytotoxicity of α-humulene and isocaryophyllene was further confirmed in MCF-7, DLD-1, and L-929 [168]. ...
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Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess chemopreventive properties, although their clinical usefulness remains to be defined. Among them, caryophyllane sesquiterpenes are natural compounds widely occurring in nature kingdoms, especially in plants, fungi, and marine environments. Several structures, characterized by a common caryophyllane skeleton with further rearrangements, have been identified, but those isolated from plant essential oils, including β-caryophyllene, β-caryophyllene oxide, α-humulene, and isocaryophyllene, have attracted the greatest pharmacological attention. Emerging evidence has outlined a complex polypharmacological profile of caryophyllane sesquiterpenes characterized by blocking, suppressing, chemosensitizing, and cytoprotective properties, which suggests a possible usefulness of these natural substances in cancer chemoprevention for both preventive and adjuvant purposes. In the present review, the scientific knowledge about the chemopreventive properties of caryophyllane sesquiterpenes and the mechanisms involved have been collected and discussed; moreover, possible structure–activity relationships have been highlighted. Although further high-quality studies are required, the promising preclinical findings and the safe pharmacological profile encourage further studies to define a clinical usefulness of caryophyllane sesquiterpenes in primary, secondary, or tertiary chemoprevention.
... HML is a natural sesquiterpene isolated from Eupatorium odoratum L. (Supplementary Fig. 2A). Essential oils that possess antineoplastic properties contain HML as their active ingredient (Legault et al., 2003), but the effects of HML on HCC and its anti-tumor mechanisms are poorly understood. In this study, we examined the effects of HML on HCC cells and normal hepatocytes. ...
... In this study, HML, a natural 11-membered monocyclic terpene with three E-configured double bonds, was isolated from the plant species Eupatorium odoratum L. HML is widely distributed in the essential oils of various plants. Interestingly, these essential oils containing HML have known antineoplastic properties while the anti-cancer effects of HML appear to be tumor-selective (Costa et al., 2015;Da Silva et al., 2007;El Hadri et al., 2010;Legault et al., 2003;Loizzo et al., 2008). Recently, some antioxidant agents including Vitamin C, Vitamin E, Trolox and NAC (Piskounova et al., 2015;Sayin et al., 2014;Schafer et al., 2009;Subramani et al., 2014;Velauthapillai et al., 2017) and regulators of antioxidant pathway (Wang et al., 2016) were found to promote metastasis or survival by decreasing the inhibition from ROS in cancer. ...
... Our data revealed that HML has selective killing properties among HCC cell lines and hepatocytes, and exhibited concentration-and time-dependent antiproliferative effects on HepG2 and Hep3B cells. Similar result can observe in a preliminary literature, which suggested that HML treatment induced a decrease in cellular GSH content and an increase in ROS production, which may be implicated in its cytotoxicity (Legault et al., 2003). Furthermore, HepG2-bearing nude mouse models were used to confirm the in vivo 25 anti-HCC effects of HML. ...
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Hepatocellular carcinoma (HCC) is a prevalent malignancy and a leading cause of cancer-related mortality. α-Humulene (HML) is a natural 11-membered monocyclic terpene with three E-configured double bonds isolated from Eupatorium odoratum L. We recently showed that HML has significant anti-HCC activity in vitro and in vivo. We found that HML was cytotoxic to HCC cells and induced mitochondrial apoptosis of HCC cells, promoting caspase-3 activation and PARP cleavage. HCC cells show abnormal Akt signaling to resist apoptosis. Mechanistically, HML was found to inhibit Akt activation, subsequently decreasing GSK-3 and Bad phosphorylation, promoting apoptotic induction. HML also inhibited cell proliferation and enhanced apoptosis in HCC tumor xenografts further highlighting its activity in vivo. Although HML showed minimal cytotoxicity to normal hepatocytes, weight loss was observed in mice administered HML. Taken together, these data provide important and novel insights into the anti-HCC effects of HML through its ability to inhibit Akt, reduced HCC cell proliferation, and enhanced HCC cell apoptotic induction in vitro and in vivo.
... Some mechanisms associated with the anti-tumor activity of α-humulene and its isomers consisted of the accumulation of mitochondrial reactive oxygen species (ROS) (Ambrož, Boušová, Skarka, Hanušová, Králová, Matoušková et al., 2015;Legault et al., 2003), as well as a reduction in the mitochondrial membrane potential. When an increase in ROS levels occur within the mitochondria, a membrane potential imbalance can be triggered, causing the release of calcium into the cytosolic environment, which triggers cellular imbalance cascades resulting from high levels of oxidative stress and can lead to cell death Another mechanism concerns the potential some compounds may have to induce apoptotic activity by activating caspase 8 and 3 enzymes, and stimulation of the DR4/DR5 group of receptors, cell surface receptors that mediate apoptosis (Amiel et al., 2012;Chen et al., 2019;Lan et al., 2011aLan et al., , 2011b. ...
... When investigating the potential of these sesquiterpenes to potentiate the action of agents clinically used for the treatment of cancer, recent studies show that α-humulene, as well as β-caryophyllene, acted synergistically on the cytotoxic effect of doxorubicin (Ambrož et al., 2017;Sotto, Irannejad, Eufemi, Mancinelli, Abete, Mammola et al., 2020). It is also important to highlight that some studies have shown that the action of the compounds were significantly selective for tumor cells, with no cytotoxic activity over normal cells (Ambrož et al., 2015;Amiel et al., 2012;Chen et al., 2019;Legault et al., 2003), an interesting Description of studies carried out with α-humulene and/or its geometric isomer considering other pharmacological activities. • CAR showed antioxidant activity (probably due to its free radical scavenging activity, against hydroxyl radicals, superoxide anions and lipid peroxides). ...
... Some of the antitumor compounds investigated in the selected studies (Ambrož et al., 2019;Ambrož et al., 2015;Di Sotto et al., 2020;Costa et al., 2015;Su, Hsu, Wang, & Ho, 2015, elHadri et al., 2010Loizzo et al., 2008;Silva, Chaar, Figueiredo, & Yano, 2008;Cole et al., 2007;Legault & Pichette, 2007;Legault et al., 2003;Zheng et al., 1992) were also investigated addressing their antiinflammatory properties (Bento et al., 2011;Fernandes, Passos, Medeiros, Cunha, Ferreira, Campos et al., 2007;Gertsch et al., 2008;Horváth et al., 2012;Horváth et al., 2012Horváth et al., , 2012Medeiros et al., 2007;Passos et al., 2007;Rogerio et al., 2009;Santos, Souza, Araújo, Medeiros, Nunes, Carvalho et al., 2017;Varga et al., 2018). It is known, that the inflammatory process plays a significant role in the tumor microenvironment, since inflammatory mediators such as cytokines, extracellular matrix remodeling enzymes and growth factors, act similarly in both pathological processes (Figueiredo, 2019). ...
Article
Sesquiterpernes are natural compounds widely distributed in plants rich in essential oils; among these compounds, α-humulene and its isomers stand out for their multiple pharmacological properties and for their uses in the cosmetics, perfumery and food industries. The present study aimed to conduct a systematic review (SR) in order to identify the pharmacological and toxicological activities of α-humulene and its isomers. This SR was carried out in accordance with the PRISMA guidelines. The bibliographic search was performed using PubMed, Scopus and Web of Science databases. The inclusion criteria used were: original articles from preclinical and clinical studies that investigated the pharmacological activities and toxicological effects of α-humulene and its isomers, which were written in English, Portuguese and Spanish. The initial search resulted in 5165 articles, of which 46 were selected for final analysis. After grouping into categories by activity presented, 41% of the investigated articles reported that α-humulene and its isomers had antitumor activity, followed by anti-inflammatory and antimicrobial activities (20% for both), other pharmacological activities (15%) and potential toxic (2%). This SR is the first developed grouping studies on the pharmacological and toxicological activities of this group of compounds. In this perspective, it is concluded that α-humulene, as well as its isomers, have different pharmacological activities, listing them as an important precursor for new therapies. However, there is still a need for further toxicological investigation on these compounds, in order to ensure safety for their use.
... exocyclic double bond in its structure . It should act through blocking mitochondrial electron transport chain, thus leading to an increased intracellular oxidative stress (Legault et al., 2003). ...
... Similarly, α-humulene induced cancer cell death by promoting intracellular oxidative injury and apoptosis activation (Legault et al., 2003). ...
... Interestingly, both isocaryophyllene and α-humulene produced lower cytotoxic effects in noncancerous cells with respect to the cancer ones (Legault et al., 2003). Conversely, β-caryophyllene oxide was found cytotoxic at high concentrations, thus suggesting a potential chemosensitizing power instead of anticancer one (Di Giacomo et al., 2019;. ...
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Industrial hemp (Cannabis sativa L.) female inflorescences have long been considered as waste material in the hemp production chain. However, past studies focused on the valorization of female inflorescences as high-quality byproducts with promising health-promoting applications. In line with this evidence, the present research investigated the phytochemical and pharmacological properties with a comparative approach on two essential oils (EOs) obtained from the inflorescences of the industrial hemp varieties Kompolti and Tisza. The EOs composition in terpenes and terpenophenols was determined. The effects of the EOs in modulating the viability of different cancer cell lines was investigated. Whereas, in hypothalamic HypoE22 cells, the release of dopamine, norepinephrine, and serotonin was measured, as an index of neuromodulatory activity. Moreover, the EO mycostatic properties were explored towards different dermatophyte species. The prominent terpenes were iso-caryophyllene, α-humulene, and β-caryophyllene oxide in both Kompolti and Tisza EOs, whereas cannabidiol and cannabigerolic acid were the main terpenophenols, respectively. Both essential oils inhibited the viability of different cancer cells; particularly, the essential oil of Tisza variety displayed a marked cytotoxicity in chol-angiocarcinoma cells. A possible role of both terpenophenols and caryophyllane sesquiterpenes as bioactive anticancer compounds has been hypothesized. While cannabidiol could contribute to the stimulation of hypo-thalamic serotonin release by Kompolti EO. The essential oils also produced antimycotic effects, for which β-caryophyllene oxide could be partly responsible. Overall, the present findings highlight pharmacological properties of Kompolti and Tisza EOs, which deserve further investigations and strengthen the interest in industrial hemp inflorescences as valuable source of bioactive extracts and compounds.
... 44 Also, the incorporation of 5, 10, and 20% wt of alpha-humulene drastically reduced cell viability of L929 mouse fibroblast cells. Prior studies that assessed the cytotoxic effect of alpha-humulene suggested that it induced a decrease cellular glutathione and an increase in the production of reactive oxygen species, 45 and this cytotoxic effect is dose-dependent, as occurred in this study. An interesting finding was that Periobond ® promoted a severe cytotoxic effect. ...
... In previous studies, periodontal dressings containing eugenol delayed healing patterns, 46 increased allergenic reactions, and inhibited fibroblast proliferation. 45 Also, the release of zinc, rosin, or resin acids had a toxic effect on gingival fibroblasts. 48,49 On the other hand, the light-cured periodontal dressing Barricaid ® demonstrated high cell viability (Figure 3). ...
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The objective of this study was to formulate an experimental light-cured periodontal dressing containing alpha-humulene and to compare its physical, antimicrobial, and cytotoxicity properties with commercial gold standards (Barricaid® and Periobond®). Two periodontal dressing formulations were developed (a and b). The formulations were divided into 5 groups according to the alpha-humulene concentration as follows: Ea - control group, Ea1 - 1%, Ea5 - 5%, Ea10 - 10%, and Ea20 - 20%; Eb - control group, Eb1 - 1%, Eb5 - 5%, Eb10 - 10%, and Eb20 - 20%. Materials characterization was performed using the degree of conversion, cohesive strength, sorption, and solubility assays. Antimicrobial assay was performed using the modified direct contact test against E. faecalis and S. aureus. Cytotoxicity was assessed by the cell viability experiment using L929 fibroblasts. In general, the cohesive strength values of materials decreased as the alpha-humulene concentration increased. All the experimental dressings showed antimicrobial activity against both bacteria tested. Cell viability results for the Ea, Ea1, Eb, and Eb1 groups showed moderate cytotoxic effect. The formulations containing alpha-humulene showed similar behavior to the commercial references. Thus, formulations containing alpha-humulene have potential to be used as periodontal dressing.
... Antioxidant activity was evaluated using the DCFH-DA assay as described by Legault et al. (2003), with some modifications. Briefly, Human Skin Fibroblast cells were plated in 96 microwell plates at 10,000 cells per well and incubated for 48h at 37°C and 5% CO2. ...
... Since the ORAC assay follows a hydrogen atom transfer mechanism (the H of the polyphenols neutralizes the radicals formed), the results suggest that DCM and MeOH may contain potent antioxidants that have the ability to scavenge toxic peroxyl radical and thus possess radical chain breaking antioxidant activity by H-atom transfer (Ou et al., 2001). The antioxidant activity of T. microphylla fractions was also assessed ex-vivo using a cellular based-assay (Legault et al., 2003). DCF assay was performed with Human Skin Fibroblast cells (WS1). ...
Article
Thymelaea microphylla is an edible and medicinal species that exhibits high antioxidant activity and phenolic content. Moreover, four fractions (hexane, dichloromethane, methanol and water) were tested towards their ex-vivo antioxidant, anticancer, anti-inflammatory and antiviral effects. Dichloromethane fraction had marked protection against cell oxidative stress (IC50 = 1.5 µg/mL). Hexane, Dichloromethane and Methanol fractions exhibited prominent anti-proliferative activities against cancer cells especially A-549 cells, with very low IC50 values of 0.13, 0.018 and 0.5 µg/mL, respectively (50, 101 and 14 higher than Etoposide). Moreover, the three fractions showed no cytotoxicity on normal fibroblast WS-1. DCM exhibited high anti-inflammatory activity in RAW 264.7 cells. Theses fractions were also tested on herpes (HSV-1). MeOH fraction was the most active acting both directly on the virus and on its adsorption. Phenolics, terpenoids and saponins were the major classes. These findings demonstrate that T. microphylla is a very promising source of selective anticancer molecules.
... D, Enrichment diagram of 24 key differential metabolites; the hierarchical clustering of differential metabolites in WT and VeA OEV14 shows two different branches. By comparing the significant characteristics of specific metabolism of VeA OEV14 to those of WT, a clustering display diagram was constructed with respect to the average expression of differential metabolites in WT and VeA OEV14 candidate compounds screened have direct or indirect inhibitory effects on the growth of A549 cells, including lanosterol (Chung et al. 2010), humulene (Legault et al. 2003;Tian et al. 2019), geldanamycin (Mccollum et al. 2004;), cinnamaldehyde (Park et al. 2020;Song 2014), epicatechin gallate (Huang et al. 2016), astilbin (Thuan et al. 2017), alpha-mangostin (Shih et al. 2010;Ding et al. 2020), catechin (Sun et al. 2020), and l-arginine (Liu et al. 2017). Among the alkaloids, 2'-O-methyluridine was only found in VeA OEV14 , geldanamycin was upregulated 3.98-fold compared with WT, and 5-amino-4-imidazole carboxamide ribonucleoside (AICAR) was upregulated 5.31-fold compared to WT. ...
... Illudin M has anti-proliferative properties in various cancers, including prostate, kidney, pancreatic, breast, and lung cancers (Le et al. 2019;Sharma et al. 2021). Humulene, the main bioactive component of balsam fir oil, has inhibitory effects on various tumor cells including A549 cancer cells (Legault et al. 2003;Tian et al. 2019). Thus, terpene production may also contribute to augmentation of the antitumor activity of VeA OEV14 . ...
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A number of studies have demonstrated that endophytic fungi have the potential to produce antitumor active substances with novel structures and significant activities. In our previous studies, we isolated a Fusarium strain from the stem of the medicinal plant Nothapodytes pittosporoides (Oliv.). In this study, we identified this strain as Fusarium solani and found that its crude extract has significant antitumor activity against human alveolar adenocarcinoma cells (A549). We overexpressed the global regulatory factor VeA in F. solani (VeAOE), resulting in a significant increase in antitumor activity. The MTT assay results showed that the inhibition rate of the VeAOE mutant extract on A549 cancer cells was significantly higher than that of the WT extract, as the IC50 decreased from 369.22 to 285.89 μg/mL, and the apoptosis ratio was significantly increased by approximately 4.86-fold. In VeAOE, accumulation of alkaloids, terpenoids, carboxylic acid derivatives, phenols and flavonoid metabolites with potential antitumor activity was significantly increased compared with WT based on metabolomic analysis. Additionally, transcriptome analysis found that the expression patterns of 48 genes related to antitumor activity were significantly changed in VeAOE, mainly involving glycosyl hydrolases, the Zn(2)-Cys(6) class, cytochrome P450 monooxygenase, 3-isopropylmalate dehydratase, and polyketide synthases. These results suggested that VeA mediated the antitumor activity of the metabolites in F. solani HB1-J1 by regulating multiple metabolic pathways.
... Among the compounds identified in VBEO, eight are admittedly apoptosis inducers: β-caryophyllene, caryophyllene oxide, α-humulene, terpinen-4-ol, β-bourbonene, isoledene, β-ionone, and δ− cadinene. The apoptotic effect of these isolated substances, as well as their effects on ROS intracellular production and mitochondrial membrane potential, have already been described in the literature for several cell lines, as MG-63 [65,66], OVCAR3 [67,68], HCT116 [69][70][71], PC-3 [72][73][74], MCF-7 [72,75], L-929 fibroblasts [75], HL-60 cells [76], and others. There are also reports that caryophyllene oxide induces late apoptosis in Trypanosoma cruzi epimastigotes [77], a kinetoplastid as well as Leishmania infantum. ...
... Among the compounds identified in VBEO, eight are admittedly apoptosis inducers: β-caryophyllene, caryophyllene oxide, α-humulene, terpinen-4-ol, β-bourbonene, isoledene, β-ionone, and δ− cadinene. The apoptotic effect of these isolated substances, as well as their effects on ROS intracellular production and mitochondrial membrane potential, have already been described in the literature for several cell lines, as MG-63 [65,66], OVCAR3 [67,68], HCT116 [69][70][71], PC-3 [72][73][74], MCF-7 [72,75], L-929 fibroblasts [75], HL-60 cells [76], and others. There are also reports that caryophyllene oxide induces late apoptosis in Trypanosoma cruzi epimastigotes [77], a kinetoplastid as well as Leishmania infantum. ...
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The present study aimed to evaluate the antileishmanial effect, the mechanisms of action and the association with miltefosine of Vernonia brasiliana essential oil against Leishmania infantum promastigotes. This essential oil was obtained by hydrodistillation and its chemical composition was determined by gas chromatography-mass spectrometry (GC-MS). The antileishmanial activity against L. infantum promastigotes and cytotoxicity on DH82 cells were evaluated by MTT colorimetric assay. Ultrastructural alterations were evaluated by transmission electron microscopy. Changes in mitochondrial membrane potential, in the production of reactive oxygen species , and analysis of apoptotic events were determined by flow cytometry. The association between the essential oil and miltefosine was evaluated using the modified isobologram method. The most abundant component of the essential oil was β-caryophyllene (21.47 %). Anti-Leishmania assays indicated an IC 50 of 39.01 ± 1.080 μg/mL for promastigote forms after 72 h of treatment. The cytotoxic concentration for DH82 cells was 63.13 ± 1.211 μg/mL after 24 h of treatment. The effect against L. infantum was proven through the ultrastructural changes caused by the oil, such as kinetoplast and mitochondrial swelling, vesicles in the flagellar pocket, discontinuity of the nuclear membrane, nuclear fragmentation and condensation, and loss of organelles. It was observed that the oil leads to a decrease in the mitochondrial membrane potential (35.10 %, p = 0.0031), increased reactive oxygen species production, and cell death by late apoptosis (17.60 %, p = 0.020). The combination of the essential oil and miltefosine exhibited an antagonistic effect. This study evidences the antileishmanial action of V. brasiliana essential oil against L. infantum promastigotes.
... This observation could explain the fact that the P. guajava essential oil was less cytotoxic than that of M. indica. Indeed, a study of the anti-tumor activity of essential oils and several chemical compounds, including αhumulene and β-caryophyllene, indicated that α-humulene presented a significant activity compared to βcaryophyllene which was inactive (Legault et al., 2003). Moreover, application of a combination of these two compounds indicated that β-caryophyllene potentiated the cytotoxic activity of α-humulene (Legault and Pichette, 2007). ...
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This study aimed to evaluate the cytotoxic activity of aqueous, ethanol extracts and essential oils (EO) obtained from Psidium guajava leaf and Mangifera indica bark by the MTT assay. The cytotoxic effect of the samples against healthy skin human fibroblasts (CCD45-SK) and hepatocellular carcinoma cells (HepG2) was evaluated using the colorimetric MTT reduction assay, which analyses the number of viable cells, cultured in 96-cells microplates, by the cleavage of tetrazolium salt added to the culture medium (samples concentrations ranging from 0.005 to 0.2 mg/mL). An inhibition of CCD-45 SK cells proliferation generated by inhibitory concentrations of 0.1 and 0.063 mg/mL was observed with the EO obtained from P. guajava and M. indica respectively against 0.1 and 0.08 for HepG2 cells. HepG2 cells proliferation was decreased by inhibitory concentrations of P. guajava leaves extracts between 0.006 and 0.013 mg/mL while concentrations were between 0.065 to 0.1 mg/mL for M. indica bark extracts. Interesting, the two EO were cytotoxic on CCD-45 SK and HepG2 cells while aqueous and ethanol extracts were cytotoxic only on HepG2 cells. Finally, our results suggest that the aqueous and ethanol extracts from P. guajava and M. indica could be used as cytotoxic agent in human medicine.
... In addition to monoterpenes, sage oil contains about 10% of sesquiterpenes, 5% being a-humulene (Table 1). It has been reported that a-humu-lene is cytotoxic against several solid tumor cell lines (Dahl et al., 2003). ...
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Mutagenic and antimutagenic potential of essential oil (EO) of cultivated sage (S. officinalis L.) and its monoterpenes: thujone, 1,8-cineole, camphor and limonene against UVC-induced mutations was studied with Salmonella/microsome, E. coli WP2, E. coli K12 [Simić, D., Vuković-Gačić, B., Knežević-Vukčević, J., 1998. Detection of natural bioantimutagens and their mechanisms of action with bacterial assay-system. Mutat. Res. 402, 51–57] and S. cerevisiae D7 reversion assays. The toxicity of EO differed, depending on the strain used. The most sensitive were permeable strains TA100, TA102, E. coli K12 IB112 and non-permeable WP2. Mutagenic potential of EO and monoterpenes was not detected, with or without S9. EO reduced the number of UV-induced revertants in a concentration-dependent manner, reaching 50–70% of inhibition at the maximum non-toxic concentrations: 3 μl/plate (TA102), 5 μl/plate (WP2), 7.5 μl/plate (IB112), 30 μl/plate (E. coli K12 SY252) and 60 μl/plate (D7). The metabolic activation had no effect on antimutagenic potential of EO. Similar toxicity of monoterpenes was observed in TA100, E. coli SY252 and D7, with the exception of limonene (less toxic to D7). Reduction of UV-induced revertants by non-toxic concentrations of monoterpenes, tested with SY252 and D7, reached 40–50% at 15–20 μl/plate of thujone, 10 μl/plate of cineole and 1–10 μg/plate of camphor. Limonene showed antimutagenic effect only in D7. Our data recommend sage monoterpenes for further chemoprevention studies.
... Dentre esses constituintes muitos apresentam potencial farmacológico e/ou aplicações industriais. Como por exemplo, o a-humuleno que apresenta uma variedade de atividades biológicas como inseticida (Yang et al., 2003;Kim et al., 2003), antimicrobiana (Bougatsos et al., 2003), antioxidante (Weelet al., 1999), como também anticarcinogênica (Legault et al., 2003) além de ser o marcador analítico do Acheflan ® , um anti-inflamatório genuinamente brasileiro. O tujol é um monoterpeno presente em plantas, principalmente na família Asteraceae. ...
... Dentre esses constituintes muitos apresentam potencial farmacológico e/ou aplicações industriais. Como por exemplo, o a-humuleno que apresenta uma variedade de atividades biológicas como inseticida (Yang et al., 2003;Kim et al., 2003), antimicrobiana (Bougatsos et al., 2003), antioxidante (Weelet al., 1999), como também anticarcinogênica (Legault et al., 2003) além de ser o marcador analítico do Acheflan ® , um anti-inflamatório genuinamente brasileiro. O tujol é um monoterpeno presente em plantas, principalmente na família Asteraceae. ...
... Dentre esses constituintes muitos apresentam potencial farmacológico e/ou aplicações industriais. Como por exemplo, o a-humuleno que apresenta uma variedade de atividades biológicas como inseticida (Yang et al., 2003;Kim et al., 2003), antimicrobiana (Bougatsos et al., 2003), antioxidante (Weelet al., 1999), como também anticarcinogênica (Legault et al., 2003) além de ser o marcador analítico do Acheflan ® , um anti-inflamatório genuinamente brasileiro. O tujol é um monoterpeno presente em plantas, principalmente na família Asteraceae. ...
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Diurnal and crepuscular bees are efficient pollinators that play an important role in maintaining plant and animal communities. In the last decades the number of studies that aim to know the biology of these animals has been increasing, mainly due to the fact that research indicates that the populations of bees are in decline. To carry out these works, different methodologies are used, including trapping with odor baits. The present study aimed to test the efficiency of odor baits in the collection of diurnal and crepuscular bees, as well as to compare the attractiveness of different baits. Three collections were performed in Mucugê and two Itaitú-Jacobina in the Chapada Diamantina-Bahia region. We sampled 62 specimens of four genera, 2 genera of diurnal bees of the Euglossini tribe (67%) and 2 crepuscular genera (32%) of the individuals. The Jaccard similarity coefficient was 0.42, indicating that for bee species richness the two areas are 42% similar. Eugenol was the essence that attracted the largest abundance of diurnal bees, while for crepuscular bees the most attractive bait was methyl salicylate. The collection of crepuscular bees of the genus Ptiloglossa was first recorded in odor baits. We concluded that the odor baits, widely used for the sampling of Euglossini males, also proved to be an efficient tool for attracting crepuscular bees.
... Dentre esses constituintes muitos apresentam potencial farmacológico e/ou aplicações industriais. Como por exemplo, o a-humuleno que apresenta uma variedade de atividades biológicas como inseticida (Yang et al., 2003;Kim et al., 2003), antimicrobiana (Bougatsos et al., 2003), antioxidante (Weelet al., 1999), como também anticarcinogênica (Legault et al., 2003) além de ser o marcador analítico do Acheflan ® , um anti-inflamatório genuinamente brasileiro. O tujol é um monoterpeno presente em plantas, principalmente na família Asteraceae. ...
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Bee pollen can be used in medicine to improve human health. It will show how pollen grains contribute to the therapeutic treatments that use bee products (Apitherapy) due to their various nutritional functions and medicinal properties, as their biochemical components act beneficially on human health. The chapter will also show studies that corroborate that the biochemical components of pollen grains depend essentially on their botanical origin, specifically the plants that are attractive to bees in which they were produced. The pollen grains will be described briefly with respect to their morphological types and bee pollination processes. It also describes the collection methods of bee pollen in the apiaries and the laboratorial method of preparation. It will further describe the methods for identification of the botanical origin through pollen grains. At last medical evidence will be presented to corroborate the health benefits of the use of bee pollen through a synthesis of several results from bibliographic references in the scientific literature.
... Dentre esses constituintes muitos apresentam potencial farmacológico e/ou aplicações industriais. Como por exemplo, o a-humuleno que apresenta uma variedade de atividades biológicas como inseticida (Yang et al., 2003;Kim et al., 2003), antimicrobiana (Bougatsos et al., 2003), antioxidante (Weelet al., 1999), como também anticarcinogênica (Legault et al., 2003) além de ser o marcador analítico do Acheflan ® , um anti-inflamatório genuinamente brasileiro. O tujol é um monoterpeno presente em plantas, principalmente na família Asteraceae. ...
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Bee products have been consumed by mankind since ancient times. Nowadays, the search for these products has grown significantly due to their interesting biological properties and nutritional value, such as pollen and propolis. Performing their analysis is a way to guarantee the quality control and safety of these products and also to identifying the geographic region that they were produced. Propolis and bee pollen collected in the county of Bela Vista, Piauí, were analyzed by Gas Chromatography coupled with Mass Spectrometry (GC-MS) and by microscopy in pollen analysis. 17 volatile compounds were identified in the pollen sample (alpha-terpinolene was the major compound) and 27 compounds for propolis (n-octacosane was the major compound). The fixed compounds were identified in the two products after fractionation. The most frequent pollen type in the pollen samples belongs to the Leguminoseae family (Machaeriumsp). In the evaluation of the propolis samples, the families Leguminosae, Anacardiaceae, Combretaceae, Leguminosaetype 1 and Rubiaceae prevailed as the most predominant in terms of quantity. Thus, the composition of these products is quite diversified and the analysis of their characteristics has big value in order to assist producers in the process of obtaining these products with a much better market value.
... The monocyclic sesquiterpene, humulene, has cytotoxic activity on multiple cancer cell lines via increasing production of reactive oxygen species [244,245] and inhibition of AKT in hepatocellular carcinoma cells with activation of apoptosis [246]. In in vitro models, humulene enhanced 5-fluorouracil, oxaliplatin, and doxorubicin cytotoxic effects [239,242]. ...
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Citation: Cherkasova, V.; Wang, B.; Gerasymchuk, M.; Fiselier, A.; Kovalchuk, O.; Kovalchuk,
... Linalool (sedative, antipsychotic, anticonvulsant, anxiolytic, anesthetic, antidepressant, analgesic, antiepileptic, and antineoplastic) [64], terpineol (antioxidant, antibiotic, and relaxing effect) [65], or caryophyllene oxide (analgesic, anticancer, antifungal, and anti-inflammatory) [66]. Between others are also phellandrene (antifungal and digestive disorders) [67], ocimene (antifungal) [68], camphene (cardiovascular disease) [69], guaiol (antitumor) [70,71], α-humulene (antibacterial, anti-inflammatory, and antitumor) [72][73][74], γ-terpinene (analgesic, anti-inflammatory, antimicrobial, and anticancer) [75,76], β-elemene (antitumor, antineoplastic, and anticancer) [77][78][79][80], nerolidol (antiparasitic and antileishmanial) [81,82], or citral (antifungal, antimicrobial, antiproliferative, cytotoxic, anticancer, and antitumor) [83][84][85][86][87][88][89][90]. ...
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Cannabis sativa plant has not only cannabinoids as crucial compounds but also the other compounds that play important role as synergistic and/or entourage compound. Cannabis/hemp plant materials and essential oils were analyzed with the help of gas chromatography/mass spectrometry detector for the content of terpenes and terpenoids. The main terpenes/terpenoids and their abundance in the samples were evaluated. Results of this study will be helpful in the next evaluation of these compound in mixture with cannabinoids and their importance in medical treatment.
... In cannabis, it is found most often in sativa strains. A 2003 study [308] showed that in an extract of balsam fir oil, only alpha-humulene had active properties (GI50 = 55-73 μM). Balsam fir oil and alpha-humulene caused a dose-and time-dependent increase in ROS production and cytotoxic activity against cell lines including MCF-7, PC-3, A-549, DLD-1, M4BEU and CT-26. ...
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In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.
... Antioxidant and antiproliferative properties of cymene and γ-terpinene, two compound identified in the essential oils of five varieties of wax apple trees in this study, against a panel of human cancer cell lines were also investigated by Fitsiou et al. (2016). Anticancer effect of α-humulene, a compound identified in the essential oils of 'Sua' and 'Xanh Duong', toward a broad spectrum of cancer cell lines, such as MCF-7, PC3, A-549, DLD-1, M4BEU, and CT26 cells, has been reported (Legault et al., 2003). Bombarda et al. (2001) suggested that aromandendrene, a constituent of the essential oils of 'Hoa An' and 'Hong Dao', had a strong antioxidant activity. ...
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In the present study, essential oils from the leaves of five varieties of wax apple trees, ('An Phuoc', 'Hoa An', 'Hong Dao', 'Sua', and 'Xanh Duong') collected in Dong Thap Province, Vietnam were isolated using hydrodistillation, and their constituents were for the first time identified via gas chromatography - mass spectrometry. A total of 74 compounds from essential oils were identified. These compounds were classified into four clusters by hierarchical clustering analysis. The main constituents of the essential oils isolated from the leaves of five varieties of wax apple trees were o-cymene, α-cubebene, epizonarene, β-gurjunene, and α-selinene. The antibacterial activity of the essential oils isolated from the leaves of five varieties of wax apples were evaluated for the first time. The results showed that the essential oils could inhibit the growth of four tested microorganisms: Bacillus cereus, Escherichia coli, Salmonella enteritidis and Staphylococcus aureus.
... Antioxidant and antiproliferative properties of cymene and γ-terpinene, two compound identified in the essential oils of five varieties of wax apple trees in this study, against a panel of human cancer cell lines were also investigated by Fitsiou et al. (2016). Anticancer effect of α-humulene, a compound identified in the essential oils of 'Sua' and 'Xanh Duong', toward a broad spectrum of cancer cell lines, such as MCF-7, PC3, A-549, DLD-1, M4BEU, and CT26 cells, has been reported (Legault et al., 2003). Bombarda et al. (2001) suggested that aromandendrene, a constituent of the essential oils of 'Hoa An' and 'Hong Dao', had a strong antioxidant activity. ...
Article
Full-text available
In the present study, essential oils from the leaves of five varieties of wax apple trees, ('An Phuoc', 'Hoa An', 'Hong Dao', 'Sua', and 'Xanh Duong') collected in Dong Thap Province, Vietnam were isolated using hydrodistillation, and their constituents were for the first time identified via gas chromatography - mass spectrometry. A total of 74 compounds from essential oils were identified. These compounds were classified into four clusters by hierarchical clustering analysis. The main constituents of the essential oils isolated from the leaves of five varieties of wax apple trees were o-cymene, α-cubebene, epizonarene, β-gurjunene, and α-selinene. The antibacterial activity of the essential oils isolated from the leaves of five varieties of wax apples were evaluated for the first time. The results showed that the essential oils could inhibit the growth of four tested microorganisms: Bacillus cereus, Escherichia coli, Salmonella enteritidis and Staphylococcus aureus.
... The anti-mutagenic capacity, which could well be linked to an anti-carcinogenic activity of these natural oils, is well documented (11). Some studies have demonstrated that the pro-oxidant activity is also related to this anti-cancer biological activity, which is mainly related to the activity of some polyphenols present in EOs (21)(22)(23)(24)(25). Essential oils are very efficient in reducing local tumor volume or tumor cell proliferation by apoptotic and/or necrotic effects (26-28). ...
Article
Essential oils are products obtained from plants, by steam distillation, mechanical processes of citrus fruit epicarp, or dry distillation after separation of the aqueous phase by physical processes. They are usually composed of secondary metabolites of aromatic plants with oxygenated structures such as alcohols, ketones, aldehydes, and esters, presenting therapeutic properties such as antibacterial, antifungal and antioxidant activities. Essential oils are used in the pharmaceutical, food, and fragrance industries. The increasing use of plants by the pharmaceutical industry makes the study of essential oils crucial to design new bioactive delivery systems. This paper presents aliterature review that summarizes the best advanced data regarding the use of essential oils and their volatile constituents for biomedical applications with focuses on innovative pharmaceutical formulations. Nonetheless, it seems clear that more clinical evaluations are required until essential oils can be considered as possible applications in pharmacy or as adjuvants to current medications.
... μg/mL) cell lines in a concentration-dependent manner. The cytotoxic activities of the flowers, leaves and stems essential oils can be attributed to the high content of terpenoids, such as α-humulene, β-pinene, β-elemene and phytol, which have been reported to have cytotoxic activity [20][21][22][23]. In addition, β-caryophyllene, as a chemical component with less content in Z. striolatum essential oils, significantly potentiated the cytotoxic activity of α-humulene against human breast adenocarcinoma cell line (MCF-7) [24]. ...
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The purpose of this study was to investigate chemical composition and cytotoxic activities of essential oils from Zingiber striolatum Diels flowers, leaves and stems. 73, 68 and 66 compounds representing 97.0%, 94.8% and 93.7% of flowers, leaves and stems essential oils were identified using GC-FID and GC-MS, respectively. The main constituents of the flowers oil were β-phellandrene (28.5%), α-humulene (14.7%), β-pinene (8.2%), β-elemene (5.5%), humulene oxide II (3.5%), cryptone (3.3%) and tricosane (3.2%). The predominant components in the leaves oil were hexahydrofarnesyl acetone (24.7%), α-humulene (12.2%), phytol (11.9%), humulene oxide II (6.3%), β-pinene (4.3%), sandaracopimaradiene (3.1%) and β-elemene (3.0%). The stems oil contained mainly α-humulene (15.6%), humulene oxide II (7.9%), hexahydrofarnesyl acetone (7.4%), phytol (7.2%), humulene oxide I (4.1%), β-elemene (3.8%) and 4-terpineol (3.2%). The cytotoxic activity against human leukemic (K562), prostatic carcinoma (PC-3) and lung cancer (A549) cell lines of essential oils was assessed using MTT assay. The essential oils of flowers, leaves and stems exhibited significant cytotoxicity against K562 (IC50: 12.94–37.89 μg/mL), PC-3 (IC50: 69.06–82.56 μg/mL) and A549 (IC50: 45.73–66.12 μg/mL) cell lines. This is the first report on the chemical constituents and cytotoxic activities of Z. striolatum flowers, leaves and stems essential oils.
... Topical application of the essential oils from T. neriifolia used mortality of C. maculatus with the stem bark oil possessing the highest mortality effect (36.11%) at 12-18 hour post treatment (table 2), suggesting that the oils can adversely contribute to the survival of the beetles, this agrees with the findings of Ketol et al., 2005 [25] who reported 90% mortality of C. maculatus at 6.7μL/L due to treatment with C. schoenanthus essential oil for 24 hours resulted in 90% of adult mortality [25] . α-Humulene, the major constituents of the stem bark oil, in this study, is a sesquiterpene that is derived from farnesylpyrophosphate (FPP) whose formation is catalysed by sesquiterpene synthesis enzymes [26] and has been studied for potential anti-inflammatory effects [27] as well as anti-cancer effects [28,29] . Bioassay showed that the leaf oil from Commiphora leptophloeos whose major constituents are α-humulene, E-caryophyllene and βphellandrene exhibited strong oviposition deterrent effects against A. aegypti at concentrations between 25 and 100 ppm and possessed good larvicidal activity suggesting that it could be an alternative to synthetic insecticide [30] . ...
... Regarding the biological activity of α-humulene, Legault et al. reported cytotoxic effects on prostatic adenocarcinoma (PC-3), lung carcinoma (A-549), colon carcinoma (DLD-1) and human melanoma (M4BEU) cell lines through glutathione (GSH) depletion and reactive oxygen species (ROS) production [27]. Similarly, several papers demonstrated significant cytotoxic activity of α-humulene in human prostate carcinoma LNCaP [28], human lung carcinoma (A-549), human cervical carcinoma (HeLa) and human colon adenocarcinoma (HT-29) cells [29]. ...
Article
Aegle marmelos (L.) Corr. (Rutaceae), also known as Bael tree, is an herbal traditional remedy in the South East Asia. In the present work, the leaf essential oil distilled from a population collected in Nepal was analyzed for the chemical composition by GC-MS showing different phytochemical constituents compared with literature data. The obtained oil was rich in sesquiterpenes, mainly β-Caryophyllene (26%), whereas monoterpenes, known in literature as the major components, were present in little amounts. Due to richness in sesquiterpenes which are promising as anticancer drugs, the oil was tested against several human tumor cell lines namely pancreatic (PSN-1), colon (LoVo), lung (H157) and ovarian (2008) cells showing IC50 of 5.6 μg/mL, 6.5 μg/mL, 6.7 μg/mL and 2.3 μg/mL, respectively. In vivo distribution of oil was studied with a dose of 41.5 mg/kg in mice allowing the quantification of β-Caryophyllene, α-Humulene, γ-Muurulene and ar-Curcumene at 30 and 60 min after oral administration. Sesquiterpene were found in higer amount in, liver, kidney and heart whereas lung and blood contained lower levels. The tissue distribution study demonstrated that active sesquiterpenoids of the oil can efficiently reach different organs.
... Germacrene D, β-caryophyllene, α-humulene, and bicyclogermacrene are the main sesquiterpenes, representing 38.9% of HEOLv. Although the α-Humulene is an isomer of β-caryophyllene, and these two compounds are often present as a mixture in some plants [66,67]. α-Humulene has been reported to inhibit nuclear factor (NF)-κB and activating protein (AP)-1 activity, the expression of P-selectin, and the increased mucus secretion in the lung in experimental airway allergic inflammation [68]. ...
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Hypericum L. (Hypericaceae) extracts have been used for their therapeutic effects; however, not much is known about the immunomodulatory activity of essential oils extracted from this plant. We isolated essential oils from the flowers and leaves of H. perforatum and analyzed their chemical composition and innate immunomodulatory activity. Analysis of flower (HEOFl) versus leaf (HEOLv) essential oils using gas chromatography–mass spectrometry revealed that HEOFl was comprised mainly of monoterpenes (52.8%), with an abundance of oxygenated monoterpenes, including cis-p-menth-3-en-1,2-diol (9.1%), α-terpineol (6.1%), terpinen-4-ol (7.4%), and limonen-4-ol (3.2%), whereas the sesquiterpenes were found in trace amounts. In contrast, HEOLv was primarily composed of sesquiterpenes (63.2%), including germacrene D (25.7%) and β-caryophyllene (9.5%). HEOLv also contained oxygenated monoterpenes, including terpinen-4-ol (2.6%), while monoterpene hydrocarbons were found in trace amounts. Both HEOFl and HEOLv inhibited neutrophil Ca2+ mobilization, chemotaxis, and reactive oxygen species (ROS) production, with HEOLv being much more active than HEOFl. Furthermore, the pure sesquiterpenes germacrene D, β-caryophyllene, and α-humulene also inhibited these neutrophil responses, suggesting that these compounds represented the active components of HEOLv. Although reverse pharmacophore mapping suggested that potential protein targets of germacrene D, β-caryophyllene, bicyclogermacrene, and α-humulene could be PIM1 and mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAK2), a kinase binding affinity assay did not support this finding, implying that other biological targets are involved. Our results provide a cellular and molecular basis to explain at least part of the beneficial immunotherapeutic properties of the H. perforatum essential oils.
... [82,129] β-caryophyllene not only shows anticarcinogenic properties, but it also potentiates the anti-cancer activity of α-humulene, [143] which was identified as an anti-cancer agent towards human breast, prostatic, lung, and colon cancer cells. [144] Limonene also has an ability to induce apoptosis in cancer cells and has antiproliferative and chemopreventive effects that classify it as an anti-cancer agent. [127,128] Limonene is successful in growth inhibition of lung, breast, liver, kidney, and skin cancer cells. ...
Article
Hop cones (Humulus lupulus L.), or more specifically the lupulin glands, hold the reason for the specific, pleasant aroma of hops – its essential oil. The hops themselves, or the extracted oil, are used almost exclusively in beer production. The essential oil is an indispensable part of beer and is responsible for its characteristic aroma. However, hop essential oil (HEO) also has a broad range of positive effects on human health and is a potential natural pesticide that has no harmful impacts on humans. This review summarizes basic information about HEO, including its chemical composition and methods for extraction and analysis, while also providing a comprehensive overview of the contribution to beer aroma, health, and insecticide applications for this versatile essential oil.
... Эфирное масло пихты обладает массой полезных свойств. Установлено, что пихтовое масло и его компоненты (α-карриофилен и гумулен) проявляют противоопухолевую активность [8]. Антибактериальная активность эфирного масла пихты сибирской в большей степени проявляется на грамположительные микроорганизмы [9]. ...
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The component composition and antihypoxic activity of Siberian fir (Abies sibirica) essential oil fractions were researched. The foliage of Siberian fir, collected on the territory of the Ilyinsky district of the Perm region in a dark coniferous forest was the raw material for obtaining the essential oil. Samples for the research were collected in December 2018 from trees 40–50 years old. The essential oil was obtained with the Clevenger apparatus. Determination of the component composition of Siberian fir essential oil fractions was made by using chromatography-mass-spectrometry. Experiments for determination of antihypoxic activity of Siberian fir essential oil fractions were made on a hypoxic hypoxia model with hypercapnia. According to the results of the research, it was found that the first fraction is more saturated with monoterpene compounds, but the proportion of sesquiterpenoids increases in following fractions. The main components of all fir oil fractions are: bornylacetate, limonene, ∆3-carene, karyophyllene. It was found that the fractions 1 and 2 have the highest antihypoxic activity in comparison with the reference sample. For further research, we offer fraction 1, because it contains the high level of bornylacetate, and the lowest content of ∆3-carene, which inhibits the ubiquinol cytochrome-C reductase complex, interrupting mitochondrial and cell respiration.
... Studies have demonstrated that the essential oil in its leaves is responsible for the anticancer effect of B. lacera. Specifically, α-humulene acts by reactive oxygen species-induced cytotoxicity and β-caryophyllene potentiates the anticancer activity of α-humulene [43,44]. ...
... The monocyclic sesquiterpene, humulene, has cytotoxic activity on multiple cancer cell lines via increasing production of reactive oxygen species [244,245] and inhibition of AKT in hepatocellular carcinoma cells with activation of apoptosis [246]. In in vitro models, humulene enhanced 5-fluorouracil, oxaliplatin, and doxorubicin cytotoxic effects [239,242]. ...
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The endocannabinoid system (ECS) is an ancient homeostasis mechanism operating from embryonic stages to adulthood. It controls the growth and development of many cells and cell lineages. Dysregulation of the components of the ECS may result in uncontrolled proliferation, adhesion, invasion, inhibition of apoptosis and increased vascularization, leading to the development of various malignancies. Cancer is the disease of uncontrolled cell division. In this review, we will discuss whether the changes to the ECS are a cause or a consequence of malignization and whether different tissues react differently to changes in the ECS. We will discuss the potential use of cannabinoids for treatment of cancer, focusing on primary outcome/care—tumor shrinkage and eradication, as well as secondary outcome/palliative care—improvement of life quality, including pain, appetite, sleep, and many more factors. Finally, we will complete this review with the chapter on sex- and gender-specific differences in ECS and response to cannabinoids, and equality of the access to treatments with cannabinoids.
... It has been demonstrated that upregulation of p21, which occurs from the deactivation of mdm2 as a result of the dephosphorylation of the Akt protein, causes the cell cycle to be interrupted in lung carcinoma cells. The G1-S phase transition was suppressed by increasing the binding of p21 to cyclins (Legault et al. 2003). A transcription factor (TF) called Nuclear factor, often known as NF-κB, is triggered in cancer cells. ...
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Awareness about pollution worldwide through the excessive use of chemicals that affect every part of our environment makes the urgent need to use natural alternatives eco-friendly materials to reduce the losses come from synthetic chemicals. In recent decades, a great leap has been made to control weed by synthetic herbicides which are considered the most effective weed control method in comparison with the other methods. Although synthetic herbicides are considered less toxic between other pesticides such as insecticides and fungicides, the usual use, even if it is used at the recommended rates harmed the environment and human health. Previous works indicated that Essential oils have been demonstrated to have good phytotoxic activity on various plant species by suppressing germination and reducing growth parameters. Phytotoxic activity of essential oils can act directly as bioherbicide by effects on one or more than one of the biological processes inside plants which cause the death of plant completely or partially. This chapter highlights the desirable phytotoxic activity of essential oils and their possible uses as natural weed killers.KeywordsAllelopathyEssential oilsPhytotoxic activitySynthetic herbicidesNatural weed killer
... It has been demonstrated that upregulation of p21, which occurs from the deactivation of mdm2 as a result of the dephosphorylation of the Akt protein, causes the cell cycle to be interrupted in lung carcinoma cells. The G1-S phase transition was suppressed by increasing the binding of p21 to cyclins (Legault et al. 2003). A transcription factor (TF) called Nuclear factor, often known as NF-κB, is triggered in cancer cells. ...
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Fungi are organisms that feed from organic matter and act as parasites in living organisms. They are found in different environments and their growth in food products has become a global concern, as well as the resistance to commercial fungicides, due to the economic damage generated by food deterioration and the harmful effects on human health. Thus, the search for new natural fungicides has increased, such as essential oils from plants that have been promising in combating fungi, improving the quantity and quality of foods with low toxicity. This chapter aimed to carry out a bibliographical review on promising essential oils in combating fungal species of the genera Aspergillus, Penicillium, Fusarium, Alternaria, Candida and Cladosporium, the main food spoilage, and their constituents.KeywordsFungiFoodDeteriorationEssential oil Aspergillus Penicillium Fusarium Alternaria Candida Cladosporium
... It has been demonstrated that upregulation of p21, which occurs from the deactivation of mdm2 as a result of the dephosphorylation of the Akt protein, causes the cell cycle to be interrupted in lung carcinoma cells. The G1-S phase transition was suppressed by increasing the binding of p21 to cyclins (Legault et al. 2003). A transcription factor (TF) called Nuclear factor, often known as NF-κB, is triggered in cancer cells. ...
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Essential oils are chemical substances composed mainly of terpenes and terpenoids. These compounds are widely investigated due to their lipophilic characteristics and biological and pharmacological properties. Therefore, the objective of this review was to investigate the potential of essential oils against species of the genus Leishmania, parasites causing the infectious disease leishmaniasis. Using the descriptors “Essential oil AND Leishmania” information available in the Scopus© database was collected. 114 articles met the inclusion criteria and were selected for analysis in this study. Among the tests performed, most were of the in vitro type (97.4%) and L. amazonensis (47.4%) and L. infantum (28.9%) were the species most used in these studies. Among the studies that investigated the mechanism of action, the essential oil of the species Tetradenia riparia showed the best result of IC50 (0.03μg/mL) against L. amazonensis isolates. Several works attribute the anti-Leishmania activities of essential oils with different bioactivities, such as: morphological and immunological alterations, antioxidant capacity and enzymatic action. Finally, it is concluded that essential oils have great potential for the development of new drugs against leishmaniasis, however further research is needed through in vivo tests to elucidate the mechanisms of action of such compounds.KeywordsLeishamaniasisTerpenesTerpernoidsMedicinal plantAnthropozoonosisMonoterpenesSesquiterpenes Lutzomyia Phlebotomus Mechanisms of action
... Moreover the essential oil of balsam fir which contains alpha-humulene depicting high anticancer property in several cell lines and low toxicity to healthy cells [29]. In addition to this limonene an active component of citrus essential oil has been reported to show anticancer activity at the level of stomach cancer and liver cancer [30]. Chamomile essential oil containing an active component alpha-bisabolol sesquiterpene alcohol has been reported to show antigliomale activity [31]. ...
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It is a common perspective that medicinal plants have played and continue to perform an undeniably major role in the lives of people worldwide. Essential oils are the key constituents of medicinal herbs and their biological activities have been discovered since ancient times and are enormously utilised in multiple industries. The essential oils possess important biological properties like antibacterial, antioxidant, antiviral, insecticidal, etc. Because of these unique features they are more acceptable and are utilised in various fields throughout the world. In the cosmetics industry they play an important role in the development of perfumes while in the food industry they have been used as food preservatives. Essential oil components are interestingly utilised for pharmaceutical applications. The most investigated properties are antioxidant, anti-inflammatory, antimicrobial, wound-healing, anxiolytic activities etc. The current thrust area is evaluation for aromatherapy and anti-cancer, as it is noted that essential oils reported in plants may prevent, inhibit, or even reverse formation of cancerous cells. The aim of this chapter is to provide a concise and comprehensive overview on the therapeutic and pharmaceutical potential of essential oils in the current scenario.
... With respect to the minor compounds of S. officinalis EO, Almeida et al. (2012) through a comet assays reported the absence of genotoxicity and mutagenicity risk of trans-β-caryophyllene to mice. The same happens for the effect of low toxicity of α-humulene were significantly less toxic against normal cells than against tumor cells (Legault et al., 2003). In this sense, the minor compounds of S. officinalis EO they seem have low toxicity in other targets different to insects. ...
... The methanolic extract of S. fruticosa had the highest activity when compared to a medicinal plant (Juglans regia) and conventional antioxidants like Trolox (2.17 0.22 and 2.52 0.35 lmol TE/mg, respectively) [29]. Ex vivo, the antioxidant activity of these extracts was determined using a cellular-based test [30]. An earlier study done by Saleh et al reported that S. fruticosa hexane extract can be considered as potent anti-cancer agent [31]. ...
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In traditional medicine, Suaeda fruticosa has importance due their usage for therapeutic purposes. They have antibacterial, antioxidant, and anticancer properties reported by few studies. In Pakistan, Suaeda fruticosa is commonly found but their biological potential has not been determined. Therefore this study was carried out with the aim to determine the antimicrobial, antioxidant and antidiabetic potential of Suaeda fruticosa L. The S. fruticosa whole plants were collected in Latamber areas of district Karak in August 2019. The collection process was carried out in flowering season which helped in identification process. Different plants extract were prepared and then antibacterial, antidiabetic and antioxidant potential of different extracts were determined. The antibacterial activity was determined using the well diffusion technique. The antioxidant activity was determined by ferric reducing antioxidant power assay while antidiabetic activity was determined by α-Glucosidase Inhibition Assay. All the fractions of S. fruticosa have shown activity against all the bacteria. The study showed that the extracts of Suedea fruticosa have concentration dependent antimicrobial activities against E. coli, S. aureus, P. aureginosa and K. Pneumoniae. In S. fruticosa, all extracts showed a significant level of antioxidant activity, ranging from 11.98 mmol to 27.52 mmol Fe(II)/g in dry plant. In the α-glucosidase assay, the methanol extract showed a significant impact, dependent on concentration. Our study concludes that S. fruticosa have excellent antibacterial, antidiabetic and antioxidant activities. Further study to determine the toxicity is recommended.
... Viridiflorol, a common compound among the species studied, is registered as having anti-inflammatory, antioxidant and antimycobacterial properties (Trevizan et al., 2016). The compound α-humulene, has biological properties registered as antitumor (Legault et al., 2003), anti-inflammatory (Fernandes et al., 2007) and antimicrobial against Bacteroides fragilis (Jang, Rhee & Eom, 2020). We can relate the biological activities of these compounds with those mentioned by popular use and preliminary pharmacological studies of extracts, oils and fractions of the species S. cumini, S. malaccense and S. jambos, which justifies some medicinal properties of the studied species. ...
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The species Syzygium cumini, Syzygium malaccense and Syzygium jambos, belong to the family Myrtaceae and are popularly known, respectively, by jambolan, red jambo and yellow jambo. These species are used in traditional medicine to treat diabetes mellitus, asthma, bronchitis, diuresis, gastrointestinal and respiratory infections, properties antipyretic, anti-inflammatory, antirheumatic and several other uses. The objective of this work is to identify and quantify the volatile compounds in the leaves of S. cumini, S. malaccense and S. jambos. The volatile oils were obtained by hydrodistillation using Clevenger apparatus and analyzed by Gas Chromatography Coupled to Mass Spectrometry (GC-MS). It was possible to identify 44 compounds present in the volatile oils of the leaves, being 20 compounds of S. cumini, 9 compounds of S. malaccense and 15 compounds of S. jambos. The major compounds present in the species S. cumini were α-terpineol, β-caryophyllene and α-humulene; for the species S. malaccense were aristolochene, γ-himachalene and δ-amorphene; and for S. jambos species were β-cariophyllene, (E,E)-α-farnesene and cariophyllene alcohol. The species S. cumini, S. malaccense and S. jambos showed considerable differences in terms of volatile compounds, it is important to know their constituents in order to promote further studies focused on their medicinal potential.
... Caryophyllene and caryophyllene oxide are natural bicyclic sesquiterpenes, which have been experimentally proven to have anticancer properties in vitro [47]. Humulene which showed an affinity of −8.3 kcal/mol has also been proven to exhibit anticancer properties in vitro [48,49]. The anticancer properties of muurola-4,10(14)-dien-8beta-ol, copaborneol, and copaene against breast cancer has been less studied in vitro. ...
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Abstract: Several drugs now employed in cancer therapy were discovered as a result of anticancer drug research based on natural products. Here, we reported the in vitro antioxidant and anticancer activity followed by in silico anticancer and estrogen-like activity of Psidium guajava L. essential oil against ER-α receptors which lead to potential inhibitory action against breast cancer pathways. Methods: The bioactive compounds in guava essential oil were screened using gas chromatography– mass spectrometry (GC-MS). Similarly, the antioxidant properties of the extracted oil were evaluated using 2,2-Diphenyl-1-picrylhydrazyl scavenging assay. Furthermore, the in vitro anticancer activity of guava oil was observed through the MTT assay and an in silico molecular docking experiment was also carried out to ensure that they fit into the estrogen receptors (ERs) and possess anticancer potential. Results: The GC–MS profile of the essential oil revealed the presence of 17 chemicals, with limonene (51.3%), eucalyptol (21.3%), caryophyllene oxide (6.2%), caryophyllene (5.6%), and nerolidol (4.5%) occupying more than one-third of the chromatographic spectrum zone. Guava leaves’ essential oil (EO) inhibited DPPH (2,2-diphenyl-1-picrylhydrazyl) radicals and exhibited concentration dependent free radical scavenging activity, acting as a potent antioxidant with an IC50 value of 29.3 ± 0.67 ug/mL. The outcome of the MTT assay showed that the extracted guava oil had nearly the same efficacy against breast and liver cancer cells at a low concentration (1μg/mL), giving 98.3 ± 0.3% and 98.5 ± 0.4% cell viability against HepG2 at 1 μg/mL, respectively. When the concentration of essential oil was increased, it showed a small reduction in the percentage of viable cells. While conducting an in silico study of all the screened compounds, the potential for hydroxycaryophyllene, caryophyllene, caryophyllene oxide, humulene, terpineol, and calamenene to inhibit tumor growth was bolstered due to a resemblance to 4 hydroxytamoxifen, thereby implying that these compounds may act as selective estrogen receptor modulators (SERMs). The ADME analysis of the compounds indicated above revealed that they exhibit excellent drug likeness properties and follow the Lipinski rule of five. Conclusions: Consequently, they have a substantial anticancer therapeutic potential and can be used for novel drug discovery in the effort to minimize the global burden of breast cancer.
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The tree fir Abies guatemalensis grows in Guatemala and neighboring countries, is an endangered species due to ecosystem loss, depredation for its aroma and seeding difficulties. Its phytochemical composition was studied throughly, as seeds, roots, bark, wood, and branches were individually extracted with a gradient polarity solvent system (hexane, diethyl ether, ethanol and water). Terpenoids were the dominant secondary family across the study. Other metabolites detected were fatty acids, carotenoids, flavonoids, glycosides, anthocyanins, and saponins. All non-polar extracts showed a DL50 below 100 ppm against Artemia salina. Further research of its components will lead to a better understading of the species and probably to find bioactive compounds.
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Chapter
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“Molecular modeling” can also be alternatively expressed as “CADD” (Computer-aided drug design) or “CAMD” (computer assisted molecular design), etc. (Yu and Mackerell, Methods Mol Biol 1520:85–106. 2017). This technique can simply be defined as a range of computerized methods useful to analyze molecules or molecular systems or to predict biological activity based on theoretical chemistry principles and experimental data. Therefore, in this chapter, we will cover various molecular modeling methods used to investigate, among other things, naturally occurring compounds that are capable of interacting with molecular targets of pharmacological importance. Here we will address methodologies such as: SAR, QSAR, molecular docking, molecular dynamics simulations and methods used to calculate the affinity energy in protein-ligand complexes. In addition, we will also devote a portion of the chapter to demonstrate how these methods can be used to investigate the interaction of fixed and volatile compounds with molecular targets.KeywordsMolecular modelingDrug designMethods Natural compoundsEssential oil
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Copaiba oils are oleoresins naturally produced and exuded from the tree trunk of several species of the Copaifera genus, a Leguminosae. Like all natural oleoresins, it has a volatile and a resinous portion. In the case of copaiba oils, these portions are comprised of sesquiterpenes and diterpenes, respectively. Among the main sesquiterpenes present in copaiba oils of some Copaifera species are caryophyllene, humulene, and their derivatives. These molecules have potent anti-inflammatory properties and are present in commercial herbal medicines, for example, from Cordia verbenacea. Caryophyllene is currently one of the most important substances in copaiba oils, as it has shown activity in several pharmacological models, including cannabinoid receptors of the CB2 type. The ancestral uses of copaiba oils by people from Latin America for different applications have been confirmed in pharmacological and biotechnological studies. Its importance as a natural bioactive product has grown exponentially, especially with the recent discoveries of the properties of caryophyllene.
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Scots pine is a widespread plant on the territory of the Russian Federation. Scots pine cones are thought of as an advanced raw material for the research of the chemical composition and pharmacological activity. The object of this paper was the research of the essential oil component composition and antioxidative activity of young Scots pine cones collected in the Perm region. The samples of Scots pine cones were collected in the Yurlinsky, Ilyinsky, Permsky and Bardymsky districts of the Perm Region for the essential oil component composition research. The essential oil component composition was determined by the gas chromatograph with a mass selective detector Agilent 7890A. The antioxidative activity of raw materials infusions was determined by their ability to bind the free radical 2,2-diphenyl-1-picrylhydrazyl. As a result of the research, 10 components related to monoterpenes and sesquiterpenes were identified in the essential oil of Scots pine cones of all regions. The monoterpene fraction predominates in the essential oil of Scots pine cones in all districts of the research. The content of sesquiterpenes slightly increases in the essential oil of the more southern districts of the region, such as Permsky and Bardymsky. The content of sesquiterpenes in the essential oil of more southern districts grows mainly due to an increase of caryophyllene and humulene. The main component of Scots pine cones essential oil is the dicyclic monoterpene α-pinene. Basing on the results of the antioxidative activity determination, it was found that the infusions prepared from young pine cones collected in the Ilyinsky, Bardymsky and Permsky districts have the maximal ability to bind free radicals. The infusion of the pine cones from the Yurlinsky district has showed the least antioxidative activity, which can be ascribed to a high content of the monoterpene fraction in the essential oil.
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The Ritter reaction of humulene with acetonitrile occurs as the biomimetic process to afford the amide having the skeleton of a natural alcohol. The structures of the amides obtained from humulene and caryophyllene were confirmed by XRD data. The activity of some cage compounds against influenza virus allowed one to suggest the mechanism of antiviral action based on interfering with membrane fusion activity of viral hemagglutinin.
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BACKGROUND Recent studies have demonstrated that various tumors express enhanced levels of the radical scavenger glutathione (GSH). Moreover, there are grounds for claiming that GSH plays a crucial role in cell proliferation and tumor resistance. In the current study, we investigated the relation between cell growth and GSH levels in the pancreatic adenocarcinoma cell line, AsPC-1, and the significance of GSH in tumor resistance to chemotherapy.METHODS Cell growth in AsPC-1 was initiated through transforming growth factor-alpha (TGF-α) or fetal calf serum (FCS). Then, cell cycle, cell proliferation, and cellular GSH content were analyzed at different times in the presence or absence of buthionine sulfoximine (BSO). The impact of GSH on chemotherapy-induced apoptosis was studied using 5-fluorouracil or melphalan in the presence or absence of BSO. Finally, we compared the GSH content of 15 pancreatic tumor specimens with 10 normal pancreatic tissue specimens.RESULTSAnalysis of GSH in pancreatic tissues demonstrated increased GSH levels in cancerous compared with normal tissue (17.5 ± 2.3 vs. 8.8 ± 1.4 nmol/mg protein; P < 0.004). Incubation of AsPC-1 with TGF-α or FCS resulted in cell proliferation and cell cycle activity, whereas GSH content was not altered. Incubation of GSH-depleted cells with TGF-α did not stimulate cell growth. In addition, GSH-depletion resulted in an increased rate of apoptosis after melphalan (6.3 ± 0.3 % vs. 11.2 ± 0.3 %; P < 0.001), but not after 5-fluorouracil treatment.CONCLUSIONS Taken together, our results show enhanced GSH levels in pancreatic carcinoma and an essential role of GSH in cell proliferation and in resistance of AsPC-1 cells. Therefore, GSH-depletion may improve the effectivity of adjuvant therapy in pancreatic carcinoma. Cancer 2000;89:1440–7. © 2000 American Cancer Society.
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This study was undertaken to investigate the intracellular induction of reactive oxygen species (ROS) by cis-dichlorodiammineplatinum (CDDP) and the augmentation of their cytotoxicity in bladder cancer cells (KU7) by enhancement of ROS generation by the glutathione (GSH) depletors buthionine sulphoximine (BSO) and diethylmaleate (DEM). CDDP-induced cytotoxicity in KU7 cells and its modulation by GSH depletors were determined using spectrophotometric measurement with crystal violet staining. The effects of GSH depletors on intracellular GSH levels were confirmed using the GSH reductase-DTNB recycling method. Intracellular ROS generation induced by CDDP with or without GSH depletors was estimated from the amount of intracellular dichlorofluorescein (DCF), an oxidized product of dichlorofluorescein (DCFH), which was measured with an anchored cell analysis and sorting system. The cytotoxic effects of CDDP (IC50 15.0 +/- 2.5 microM) were significantly enhanced by BSO (IC50 9.3 +/- 2.6 microM, P < 0.01) and DEM (IC50 10.3 +/- 0.3 microM, P <0.01). BSO and DEM produced a significant depletion in intracellular GSH levels (9.6 +/- 0.4 nmol 10(-6) cells, 17.9 +/- 1.0 nmol 10(-6) cells) compared with the controls (30.5 +/- 0.6 nmol 10(-6) cells). Intracellular DCF production in KU7 cells treated with CDDP (1.35 +/- 0.33 microM) was significantly enhanced by the addition of BSO (4.43 +/- 0.33 microM) or DEM (3.12 +/- 0.22 microM) at 150 min. These results suggest that ROS may play a substantial role in CDDP-induced cytotoxicity and that GSH depletors augment its cytotoxicity through an enhancement of ROS generation in bladder cancer cells.
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The mechanism of tumor necrosis factor α (TNFα)-induced cytotoxicity in metabolically inhibited cells is unclear, although some studies have suggested that mitochondrial dysfunction and generation of reactive oxygen species may be involved. Here we studied the effect of TNFα on the redox state of mitochondrial cytochromes and its involvement in the generation of reactive oxygen species in metabolically inhibited L929 cells. Treatment with TNFα and cycloheximide (TNFα/CHX) induced mitochondrial cytochrome c release, increased the steady-state reduction of cytochrome b, and decreased the steady-state reduction of cytochromes cc 1 andaa 3. TNFα/CHX treatment also induced lipid peroxidation, intracellular generation of reactive oxygen species, and cell death. Furthermore, as the cells died mitochondrial morphology changed from an orthodox to a hyperdense and condensed and finally to a swollen conformation. Antimycin A, a mitochondrial respiratory chain complex III inhibitor that binds to cytochrome b, blocked the formation of reactive oxygen species, suggesting that the free radicals are generated at the level of cytochrome b.Moreover, antimycin A, when added after 3 h of TNFα/CHX treatment, arrested the further release of cytochrome c and the cytotoxic response. We propose that the reduced cytochromeb promotes the formation of reactive oxygen species, lipid peroxidation of the cell membrane, and cell death.
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Very little variation was found in mature leaves and twigs throughout the year or in buds during winter. Major changes were recorded in the percentages of the main terpenes of the buds 4-6 wk before bud burst, newly-formed buds in midsummer, and somewhat smaller ones in those of the new leaves from first measurements to midsummer. Except in newly formed twigs, twig oil composition varied little through the year.-from Authors
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We show here the identity of Alamar Blue as resazurin. The ‘resazurin reduction test’ has been used for about 50 years to monitor bacterial and yeast contamination of milk, and also for assessing semen quality. Resazurin (blue and nonfluorescent) is reduced to resorufin (pink and highly fluorescent) which is further reduced to hydroresorufin (uncoloured and nonfluorescent). It is still not known how this reduction occurs, intracellularly via enzyme activity or in the medium as a chemical reaction, although the reduced fluorescent form of Alamar Blue was found in the cytoplasm and of living cells nucleus of dead cells. Recently, the dye has gained popularity as a very simple and versatile way of measuring cell proliferation and cytotoxicity. This dye presents numerous advantages over other cytotoxicity or proliferation tests but we observed several drawbacks to the routine use of Alamar Blue. Tests with several toxicants in different cell lines and rat primary hepatocytes have shown accumulation of the fluorescent product of Alamar Blue in the medium which could lead to an overestimation of cell population. Also, the extensive reduction of Alamar Blue by metabolically active cells led to a final nonfluorescent product, and hence an underestimation of cellular activity.
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Bioassay-directed fractionation of clove terpenes from the plant Eugenia caryophyllata has led to the isolation of the following five active known compounds: beta-caryophyllene [1], beta-caryophyllene oxide [2], alpha-humulene [3], alpha-humulene epoxide I [4], and eugenol [5]. Their structures were determined on the basis of spectral analysis (hreims, 1H and 13C nmr). These compounds showed significant activity as inducers of the detoxifying enzyme glutathione S-transferase in the mouse liver and small intestine. The ability of natural anticarcinogens to induce detoxifying enzymes has been found to correlate with their activity in the inhibition of chemical carcinogenesis. Thus, these sesquiterpenes show promise as potential anticarcinogenic agents.
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A new ring-A secotriterpene, koetjapic acid [1], and five known compounds, 3-oxo-olean-12-en-29-oic acid [2] (a novel natural product), katonic acid [3], (-)-alloaromadendrene, (-)-caryophyllene oxide, and (+)-spathulenol, have been isolated and characterized from a cytotoxic Et2O-soluble extract of Sandoricum koetjape stems. Of these compounds, 2 and 3 demonstrated significant cytotoxic activity against cultured P-388 cells (ED50 values of 0.61 and 0.11 microgram/ml, respectively). Significant, albeit less intense, cytotoxicity was also observed with a variety of cultured human cancer cells. The 13C-nmr chemical shifts of these triterpenes were assigned unambiguously using selective INEPT nmr experiments. Aside from compounds 2 and 3, these substances were not toxic with cultured cells.
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The currently available flow cytometric stains for cellular glutathione were evaluated, examining the labelling of both human and rodent cell lines under various conditions of concentration, time, and temperature. Procedures were used that depleted glutathione (GSH) while having a minimal effect on other cellular sulphydryls in order to estimate linearity and the extent of background staining. As previously reported, monochlorobimane was highly specific for GSH in rodent cells but failed to label human cells adequately because of its low affinity for human glutathione S-transferases. Higher concentrations of monochlorobimane achieved more complete labelling of the human cellular GSH pool but gave increased background fluorescence due to non-GSH binding. The analogue monobromobimane, which binds nonenzymatically to sulphydryls, reacted more readily with GSH than with protein sulphydryls and, provided that stain concentration and incubation time were controlled, gave reproducible staining of human cells with approximately 20% of total fluorescence due to background staining. Of the currently available stains for measuring GSH in human cells, monobromobimane is the agent of choice. Mercury orange also binds more readily to GSH than to protein, giving a degree of specificity, and it has the additional advantage of being excited at 488 nm. However, the reproducibility of staining with mercury orange was less consistent than that using monobromobimane, and a higher background fluorescence was seen. Two additional stains, o-phthaldialdehyde and chloromethyl fluorescein, could also be used to label cellular GSH, but both gave an unacceptably high level of background staining. It is recommended that flow cytometric GSH assays should routinely include a sample of cells that have been depleted of GSH in order to determine the extent of background labeling.
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Glutathione (GSH) and glutathione-related enzyme systems in astrocytes play an important role in cellular defense against oxidative stress in the nervous system. The present study was designed to characterize the cellular responses of cultured astrocytes to chemically-induced perturbations of mitochondrial and cytosolic GSH homeostasis. Treatment of astrocytes in culture with ethacrynic acid (EA), a mitochondrion-penetrating thiol reagent, induced rapid and extensive depletion of both cytosolic and mitochondrial pools of GSH. Concomitant with the effects of EA on cellular GSH were significant and concentration-dependent increases in intracellular generation of reactive oxygen species (ROS) as indicated by the oxidation of preloaded 2',7'-dichlorofluorescein diacetate. Significant elevation of intracellular ROS occurred by 15 min following exposure to 100 microM EA and reached peak levels by 30 min which were approximately 7-fold higher than corresponding control levels. Ethacrynic acid-induced GSH depletion and intracellular ROS elevation was followed by marked decreases in glutathione reductase (GR) activity in mitochondria, and to a lesser extent, in cytosolic fractions of cultured astrocytes. This inhibitory effect was time- and concentration-dependent, and other GSH-related enzymes, glutathione peroxidase and glutathione S-transferase, were not or only slightly affected. Kinetic studies showed that EA markedly diminished V(max) values of both mitochondrial and cytosolic GR without affecting K(m), suggesting noncompetitive inhibition of this thiol-dependent enzyme. Another thiol-dependent enzyme glyceraldehyde-3-phosphate dehydrogenase was also markedly inhibited by EA in a time-dependent fashion. Subsequent decline of mitochondrial transmembrane potential (rhodamine 123 uptake) and cellular ATP production following EA treatment occurred prior to the onset of loss of cell viability as indicated by lactate dehydrogenase leakage. These results suggest that the loss of mitochondrial GSH may render the astrocytes unable to combat the pathological sequelae of endogenous oxidative stress, leading to perturbations of thiol-dependent enzyme activities, mitochondrial function and energy metabolism.
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Four sesquiterpenoids, beta-caryophyllene, beta-caryophyllene 4,5 alpha-oxide, 7-hydroxy-3,4-dihydrocadalin, and 7-hydroxycadalin, isolated from the dried flower of Heterotheca inuloides Cass. (Asteraceae), have been found to exhibit cytotoxic activity against several solid tumor cell lines. Among them, 7-hydroxy-3,4-dihydrocadalin and 7-hydroxycadalin have also been found to inhibit autoxidative and microsomal lipid peroxidation.
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The gastric cytoprotective effect of beta-caryophyllene, an anti-inflammatory sesquiterpene, was investigated in rats. The oral administration of beta-caryophyllene to rats significantly inhibited gastric mucosal injuries induced by necrotizing agents such as absolute ethanol and 0.6 N HCl, although it failed to prevent water immersion stress- and indomethacin-induced gastric lesions. In addition, this compound hardly affected the secretion of gastric acid and pepsin. Thus, beta-caryophyllene elicited anti-inflammatory effects without any indication of gastric mucosal damage typical of non-steroidal anti-inflammatory agents. Furthermore, this compound manifested cytoprotective effects, rendering the two-dimensional efficacious beta-caryophyllene to be a clinically safe and potentially useful agent.
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In this study, we show that 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a putative metabolite of benzene, induces apoptosis in human promyelocytic leukemia (HL-60) cells. Prior to the onset of apoptosis, TGHQ depletes intracellular glutathione (GSH) in a reactive oxygen species (ROS)-independent manner. Neutral, Mg(2+)-dependent sphingomyelinases, which are normally inhibited by GSH, are subsequently activated, as evidenced by increases in intracellular ceramide and depletion of sphingomyelin. As ceramide levels rise, effector caspase (DEVDase) activity steadily increases. Interestingly, while catalase has no effect on TGHQ-mediated depletion of GSH, this hydrogen peroxide (H(2)O(2)) scavenger does inhibit DEVDase activity and apoptosis, provided the enzyme is added to HL-60 cells before an increase in ceramide can be observed. Since ceramide analogues inhibit the mitochondrial respiratory chain, these data imply that ceramide-mediated generation of H(2)O(2) is necessary for the activation of effector caspases-3 and/or -7, and apoptosis. In summary, these studies indicate that TGHQ, and perhaps many quinol-based toxicants and chemotherapeutics, may induce apoptosis in hematopoietic cells by depleting GSH and inducing the proapoptotic ceramide-signaling pathway.
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Ebselen, a selenoorganic compound, has recently been shown to display a novel property of inducing apoptosis through rapid depletion of intracellular thiols in human hepatoma cells, HepG(2). The present study was thus designed to explore the mechanism of how ebselen triggers apoptosis upon depletion of intracellular thiols. The results demonstrated that ebselen treatment triggered mitochondrial permeability transition rather rapidly as revealed by redistribution of calcein green fluorescence from cytosol into mitochondria. Ebselen treatment also caused a dose- and time-dependent loss of mitochondrial membrane potential (MMP) and release of cytochrome c. Pretreatment with N-acetylcysteine, a precursor of intracellular reduced glutathione (GSH) synthesis, significantly attenuated the ebselen-induced MMP disruption and subsequently inhibited the apoptosis. In contrast, pretreatment with buthionine sulfoximine, a specific inhibitor of intracellular GSH synthesis, significantly augmented the ebselen-induced MMP alteration, and enhanced the apoptosis. Although ebselen treatment significantly increased the intracellular superoxide radical and calcium concentrations, superoxide dismutase, and BAPTA (a calcium chelator), however, failed to prevent ebselen-induced MMP loss and apoptosis. Neither caspase-9 nor caspase-3 activation was detected in ebselen-treated cells. Z-VAD-FMK, a general caspase inhibitor, also had no effect on ebselen-induced MMP decrease and apoptosis. The overall findings thus suggest that mitochondrial permeability transition resulted from intracellular thiol depletion is a critical event in ebselen-induced apoptosis.
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Diethyl maleate (DEM) (5 mM) and ethyl methanesulfonate (EMS) (35 mM) treatments rapidly depleted cellular reduced glutathione (GSH) below detectable levels (1 nmol/10(6) cells), and induced lipid peroxidation and necrotic cell death in freshly isolated rat hepatocytes. In hepatocytes incubated with 2.5 mM DEM and 10 mM EMS, however, the complete depletion of cellular GSH observed was not sufficient to induce lipid peroxidation or cell death. Instead, DEM- and EMS-induced lipid peroxidation and cell death were dependent on increased reactive oxygen species (ROS) production as measured by increases in dichlorofluorescein fluorescence. The addition of antioxidants (vitamin E succinate and deferoxamine) prevented lipid peroxidation and cell death, suggesting that lipid peroxidation is involved in the sequence of events leading to necrotic cell death induced by DEM and EMS. To investigate the subcellular site of ROS generation, the cytochrome P450 inhibitor, SKF525A, was found to reduce EMS-induced lipid peroxidation but did not protect against the loss of cell viability, suggesting a mitochondrial origin for the toxic lipid peroxidation event. In agreement with this conclusion, mitochondrial electron transport inhibitors (rotenone, thenoyltrifluoroacetone and antimycin A) increased EMS-induced lipid peroxidation and cell death, while the mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone, blocked EMS- and DEM-mediated ROS production and lipid peroxidation. Furthermore, EMS treatment resulted in the significant loss of mitochondrial alpha-tocopherol shortly after its addition, and this loss preceded losses in cellular alpha-tocopherol levels. Treatment of hepatocytes with cyclosporin A, a mitochondrial permeability transition inhibitor, oxypurinol, a xanthine oxidase inhibitor, or BAPTA-AM, a calcium chelator, provided no protection against EMS-induced cell death or lipid peroxidation. Our results indicate that DEM and EMS induce cell death by a similar mechanism, which is dependent on the induction of ROS production and lipid peroxidation, and mitochondria are the major source for this toxic ROS generation. Cellular GSH depletion in itself does not appear to be responsible for the large increases in ROS production and lipid peroxidation observed.
Article
The bioactive fractions obtained from the extract of Asteriscus vogelii afforded a new humulene derivative, the 8-oxo-6,7,9,10-tetrahydrohumulen-1,12-olide (1), in addition to the known asteriscunolides A (2), C (3) and D (4), and the acids 8-oxo-alpha-humula-6Z,9Z-dien-12-oic acid (5), 8-oxo-alpha-humula-6E,9Z-dien- 12-oic acid (6) and 8-oxo-alpha-humula-6E,9E-dien-12-oic acid (7), characterized as their methyl esters. Evaluation of their phytotoxic and cytotoxic activities was accomplished. Compounds 3 and 4 gave the highest inhibition of plant cell cultures and of the plant Lemna paucicostata. Compound 4 was also the most active against P-338 lymphoma in mice, A-549 carcinoma of human lung, HT-29 carcinoma of human colon and MEL-28 human melanoma.